WorldWideScience

Sample records for pretargeted cytokine therapy

  1. Cancer Imaging and Therapy with Bispecific Antibody Pretargeting.

    Science.gov (United States)

    Goldenberg, David M; Chatal, Jean-Francois; Barbet, Jacques; Boerman, Otto; Sharkey, Robert M

    2007-03-01

    This article reviews recent preclinical and clinical advances in the use of pretargeting methods for the radioimmunodetection and radioimmunotherapy of cancer. Whereas directly-labeled antibodies, fragments, and subfragments (minibodies and other constructs) have shown promise in both imaging and therapy applications over the past 25 years, their clinical adoption has not fulfilled the original expectations due to either poor image resolution and contrast in scanning or insufficient radiation doses delivered selectively to tumors for therapy. Pretargeting involves the separation of the localization of tumor with an anticancer antibody from the subsequent delivery of the imaging or therapeutic radionuclide. This has shown improvements in both imaging and therapy by overcoming the limitations of conventional, or 1-step, radioimmunodetection or radioimmunotherapy. We focus herein on the use of bispecific antibodies followed by radiolabeled peptide haptens as a new modality of selective delivery of radionuclides for the imaging and therapy of cancer. Our particular emphasis in pretargeting is the use of bispecific trimeric (3 Fab's) recombinant constructs made by a modular method of antibody and protein engineering of fusion molecules called Dock and Lock (DNL).

  2. Cancer Imaging and Therapy with Bispecific Antibody Pretargeting

    OpenAIRE

    Goldenberg, David M.; Chatal, Jean-Francois; Barbet, Jacques; Boerman, Otto; Sharkey, Robert M.

    2007-01-01

    This article reviews recent preclinical and clinical advances in the use of pretargeting methods for the radioimmunodetection and radioimmunotherapy of cancer. Whereas directly-labeled antibodies, fragments, and subfragments (minibodies and other constructs) have shown promise in both imaging and therapy applications over the past 25 years, their clinical adoption has not fulfilled the original expectations due to either poor image resolution and contrast in scanning or insufficient radiation...

  3. Bispecific Antibody Pretargeting for Improving Cancer Imaging and Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Sharkey, Robert M.

    2005-02-04

    The main objective of this project was to evaluate pretargeting systems that use a bispecific antibody (bsMAb) to improve the detection and treatment of cancer. A bsMAb has specificity to a tumor antigen, which is used to bind the tumor, while the other specificity is to a peptide that can be radiolabeled. Pretargeting is the process by which the unlabeled bsMAb is given first, and after a sufficient time (1-2 days) is given for it to localize in the tumor and clear from the blood, a small molecular weight radiolabeled peptide is given. According to a dynamic imaging study using a 99mTc-labeled peptide, the radiolabeled peptide localizes in the tumor in less than 1 hour, with > 80% of it clearing from the blood and body within this same time. Tumor/nontumor targeting ratios that are nearly 50 times better than that with a directly radiolabeled Fab fragment have been observed (Sharkey et al., ''Signal amplification in molecular imaging by a multivalent bispecific nanobody'' submitted). The bsMAbs used in this project have been composed of 3 antibodies that will target antigens found in colorectal and pancreatic cancers (CEA, CSAp, and MUC1). For the ''peptide binding moiety'' of the bsMAb, we initially examined an antibody directed to DOTA, but subsequently focused on another antibody directed against a novel compound, HSG (histamine-succinyl-glycine).

  4. Bispecific antibody complex pre-targeting and targeted delivery of polymer drug conjugates for imaging and therapy in dual human mammary cancer xenografts. Targeted polymer drug conjugates for cancer diagnosis and therapy

    Energy Technology Data Exchange (ETDEWEB)

    Khaw, Ban-An; Gada, Keyur S.; Patil, Vishwesh; Panwar, Rajiv; Mandapati, Savitri [Northeastern University, Department of Pharmaceutical Sciences, Bouve College of Health Sciences, School of Pharmacy, Boston, MA (United States); Hatefi, Arash [Rutgers University, Department of Pharmaceutics, New Brunswick, NJ (United States); Majewski, Stan [West Virginia University, Department of Radiology, Morgantown, WV (United States); Weisenberger, Andrew [Thomas Jefferson National Accelerator Facility, Jefferson Lab, Newport News, VA (United States)

    2014-08-15

    Doxorubicin, a frontline chemotherapeutic agent, limited by its cardiotoxicity and other tissue toxicities, was conjugated to N-terminal DTPA-modified polyglutamic acid (D-Dox-PGA) to produce polymer pro-drug conjugates. D-Dox-PGA or Tc-99 m labeled DTPA-succinyl-polylysine polymers (DSPL) were targeted to HER2-positive human mammary carcinoma (BT-474) in a double xenografted SCID mouse model also hosting HER2-negative human mammary carcinoma (BT-20). After pretargeting with bispecific anti-HER2-affibody-anti-DTPA-Fab complexes (BAAC), anti-DTPA-Fab or only phosphate buffered saline, D-Dox-PGA or Tc-99 m DSPL were administered. Positive therapeutic control mice were injected with Dox alone at maximum tolerated dose (MTD). Only BT-474 lesions were visualized by gamma imaging with Tc-99 m-DSPL; BT-20 lesions were not. Therapeutic efficacy was equivalent in mice pretargeted with BAAC/targeted with D-Dox-PGA to mice treated only with doxorubicin. There was no total body weight (TBW) loss at three times the doxorubicin equivalent MTD with D-Dox-PGA, whereas mice treated with doxorubicin lost 10 % of TBW at 2 weeks and 16 % after the second MTD injection leading to death of all mice. Our cancer imaging and pretargeted therapeutic approaches are highly target specific, delivering very high specific activity reagents that may result in the development of a novel theranostic application. HER/2 neu specific affibody-anti-DTPA-Fab bispecific antibody pretargeting of HER2 positive human mammary xenografts enabled exquisite targeting of polymers loaded with radioisotopes for molecular imaging and doxorubicin for effective therapy without the associating non-tumor normal tissue toxicities. (orig.)

  5. Improvement of radioimmunotherapy using pretargeting

    Directory of Open Access Journals (Sweden)

    Eric eFrampas

    2013-06-01

    Full Text Available During the past two decades, considerable research has been devoted to radionuclide therapy using radiolabelled monoclonal antibodies and receptor binding agents. Conventional Radioimmunotherapy (RIT is now an established and important tool in the treatment of hematologic malignancies such as Non-Hodgkin lymphoma. For solid malignancies, the efficacy of RIT has not been as successful due to lower radiosensitivity, difficult penetration of the antibody into the tumor and potential excessive radiation to normal tissues. Innovative approaches have been developed in order to enhance tumor absorbed dose while limiting toxicity to overcome the different limitations due to the tumor and host characteristics.Pretargeting techniques (pRIT are a promising approach that consists of decoupling the delivery of a tumor monoclonal antibody (mAb from the delivery of the radionuclide. This results in a much higher tumor-to-normal tissue ratio and is favorable for therapy as well and imaging. This includes various strategies based on avidin/streptavidin-biotin, DNA-complementary DNA and bispecific antibody-hapten bindings. PRIT continuously evolves with the investigation of new molecular constructs and the development of radiochemistry. Pharmacokinetics improve dosimetry depending on the radionuclides used (alpha, beta and Auger emitters with prediction of tumor response and host toxicities. New constructs such as the Dock and Lock technology allow production of a variety of mABs directed against tumor-associated antigens. Survival benefit has already been shown in medullary thyroid carcinoma. Improvement in delivery of radioactivity to tumors with these pretargeting procedures associated with reduced hematologic toxicity will become the next generation of RIT. The following review addresses actual technical and clinical considerations and future development of pRIT.

  6. Improvement of radioimmunotherapy using pretargeting.

    Science.gov (United States)

    Frampas, Eric; Rousseau, Caroline; Bodet-Milin, Caroline; Barbet, Jacques; Chatal, Jean-Francois; Kraeber-Bodéré, Françoise

    2013-01-01

    During the past two decades, considerable research has been devoted to radionuclide therapy using radiolabeled monoclonal antibodies and receptor binding agents. Conventional radioimmunotherapy (RIT) is now an established and important tool in the treatment of hematologic malignancies such as Non-Hodgkin lymphoma. For solid malignancies, the efficacy of RIT has not been as successful due to lower radiosensitivity, difficult penetration of the antibody into the tumor, and potential excessive radiation to normal tissues. Innovative approaches have been developed in order to enhance tumor absorbed dose while limiting toxicity to overcome the different limitations due to the tumor and host characteristics. Pretargeting techniques (pRIT) are a promising approach that consists of decoupling the delivery of a tumor monoclonal antibody (mAb) from the delivery of the radionuclide. This results in a much higher tumor-to-normal tissue ratio and is favorable for therapy as well and imaging. This includes various strategies based on avidin/streptavidin-biotin, DNA-complementary DNA, and bispecific antibody-hapten bindings. pRIT continuously evolves with the investigation of new molecular constructs and the development of radiochemistry. Pharmacokinetics improve dosimetry depending on the radionuclides used (alpha, beta, and Auger emitters) with prediction of tumor response and host toxicities. New constructs such as the Dock and Lock technology allow production of a variety of mABs directed against tumor-associated antigens. Survival benefit has already been shown in medullary thyroid carcinoma. Improvement in delivery of radioactivity to tumors with these pretargeting procedures associated with reduced hematologic toxicity will become the next generation of RIT. The following review addresses actual technical and clinical considerations and future development of pRIT.

  7. Molecular advances in pretargeting radioimunotherapy with bispecific antibodies.

    Science.gov (United States)

    Chang, Chien-Hsing; Sharkey, Robert M; Rossi, Edmund A; Karacay, Habibe; McBride, William; Hansen, Hans J; Chatal, Jean-François; Barbet, Jacques; Goldenberg, David M

    2002-05-01

    The use of antibodies against tumor-associated cell surface antigens for the targeted delivery of radionuclides was introduced >20 years ago. Although encouraging results have been achieved with radiolabeled antibodies in the management of hematopoietic malignancies, there remains a need for successfully treating solid tumors with this modality. One promising approach involving pretargeted delivery of radionuclides has been shown to be capable of significantly increasing the radioactive uptake in tumor relative to normal organs, thereby potentially improving the efficacy of both detection and therapy of cancer. Uncoupling of the radionuclide from the tumor-targeting antibody allows the relatively slow process of antibody localization and clearance to occur before a very rapid and highly specific delivery of the radioactive payload carried on a small molecule, such as a peptide. This minireview discusses the various strategies and advancements made since the concept of pretargeting was proposed in the mid-1980s, with emphasis on those comprising bispecific antibodies for cancer therapy. Critical aspects of these pretargeting systems for achieving higher tumor:nontumor ratios are considered. In addition, both preclinical and clinical results obtained from a pretargeting method known as the Affinity Enhancement System are presented. Future directions of pretargeting technology are also suggested.

  8. Antibody pretargeting advances cancer radioimmunodetection and radioimmunotherapy.

    Science.gov (United States)

    Goldenberg, David M; Sharkey, Robert M; Paganelli, Giovanni; Barbet, Jacques; Chatal, Jean-François

    2006-02-10

    This article reviews the methods of pretargeting, which involve separating the targeting antibody from the subsequent delivery of an imaging or therapeutic agent that binds to the tumor-localized antibody. This provides enhanced tumor:background ratios and the delivery of a higher therapeutic dose than when antibodies are directly conjugated with radionuclides, as currently practiced in cancer radioimmunotherapy. We describe initial promising clinical results using streptavidin-antibody constructs with biotin-radionuclide conjugates in the treatment of patients with malignant gliomas, and of bispecific antibodies with hapten-radionuclides in the therapy of tumors expressing carcinoembryonic antigen, such as medullary thyroid and small-cell lung cancers.

  9. A pretargeting system for tumor PET imaging and radioimmunotherapy.

    Science.gov (United States)

    Kraeber-Bodéré, Françoise; Rousseau, Caroline; Bodet-Milin, Caroline; Frampas, Eric; Faivre-Chauvet, Alain; Rauscher, Aurore; Sharkey, Robert M; Goldenberg, David M; Chatal, Jean-François; Barbet, Jacques

    2015-01-01

    Labeled antibodies, as well as their fragments and antibody-derived recombinant constructs, have long been proposed as general vectors to target radionuclides to tumor lesions for imaging and therapy. They have indeed shown promise in both imaging and therapeutic applications, but they have not fulfilled the original expectations of achieving sufficient image contrast for tumor detection or sufficient radiation dose delivered to tumors for therapy. Pretargeting was originally developed for tumor immunoscintigraphy. It was assumed that directly-radiolabled antibodies could be replaced by an unlabeled immunoconjugate capable of binding both a tumor-specific antigen and a small molecular weight molecule. The small molecular weight molecule would carry the radioactive payload and would be injected after the bispecific immunoconjugate. It has been demonstrated that this approach does allow for both antibody-specific recognition and fast clearance of the radioactive molecule, thus resulting in improved tumor-to-normal tissue contrast ratios. It was subsequently shown that pretargeting also held promise for tumor therapy, translating improved tumor-to-normal tissue contrast ratios into more specific delivery of absorbed radiation doses. Many technical approaches have been proposed to implement pretargeting, and two have been extensively documented. One is based on the avidin-biotin system, and the other on bispecific antibodies binding a tumor-specific antigen and a hapten. Both have been studied in preclinical models, as well as in several clinical studies, and have shown improved targeting efficiency. This article reviews the historical and recent preclinical and clinical advances in the use of bispecific-antibody-based pretargeting for radioimmunodetection and radioimmunotherapy of cancer. The results of recent evaluation of pretargeting in PET imaging also are discussed.

  10. A pretargeting system for tumor PET imaging and radioimmunotherapy

    Directory of Open Access Journals (Sweden)

    Françoise eKraeber-Bodéré

    2015-03-01

    Full Text Available Labeled antibodies, as well as their fragments and antibody-derived recombinant constructs, have long been proposed as general vectors to target radionuclides to tumor lesions for imaging and therapy. They have indeed shown promise in both imaging and therapeutic applications, but they have not fulfilled the original expectations of achieving sufficient image contrast for tumor detection or sufficient radiation dose delivered to tumors for therapy. Pretargeting was originally developed for tumor immunoscintigraphy. It was assumed that directly-radiolabled antibodies could be replaced by an unlabeled immunoconjugate capable of binding both a tumor-specific antigen and a small molecular weight molecule. The small molecular weight molecule would carry the radioactive payload and would be injected after the bispecific immunoconjugate. It has been demonstrated that this approach does allow for both antibody-specific recognition and fast clearance of the radioactive molecule, thus resulting in improved tumor-to-normal tissue contrast ratios. It was subsequently shown that pretargeting also held promise for tumor therapy, translating improved tumor-to-normal tissue contrast ratios into more specific delivery of absorbed radiation doses. Many technical approaches have been proposed to implement pretargeting, and two have been extensively documented. One is based on the avidin-biotin system, and the other on bispecific antibodies binding a tumor-specific antigen and a hapten. Both have been studied in preclinical models, as well as in several clinical studies, and have shown improved targeting efficiency. This article reviews the historical and recent preclinical and clinical advances in the use of bispecific-antibody-based pretargeting for radioimmunodetection and radioimmunotherapy of cancer. The results of recent evaluation of pretargeting in PET imaging also are discussed.

  11. Inflammation, cytokines and anti-inflammatory therapies in heart failure.

    Science.gov (United States)

    Tabet, J Y; Lopes, M E; Champagne, S; Su, J B; Merlet, P; Hittinger, L

    2002-03-01

    Both experimental and clinical studies have shown a role for inflammation in the pathogenesis of heart failure. This seems related to an imbalance between pro-inflammatory and anti-inflammatory cytokines. Certain categories in patients with dilated cardiomyopathy have shown the presence of humoral and cellular immunity activation suggesting a possible relation between myocarditis and dilated cardiomyopathy. Recent studies suggest a link between the circulating levels of cytokines (TNF alpha IL-1 et IL-6), the clinical status and prognostic. However, the mechanisms connecting heart failure and cytokine activation are unclear and the sites of cytokines production remain controversial. In the clinical setting, specific measurements of cytokines are not available. As tests of inflammation, erythrocyte sedimentation rate and C-reactive protein concentration appear to have interesting pronostic values. Current conventional therapy i.e. ACE inhibitors, type I angiotensin II antagonist and beta-blockers have shown some anti-cytokine properties. Recently, immunosuppressive therapies have shown their ability to improve symptoms and LV ejection in selected patients with dilated cardiomyopathy and clear sign of myocardium inflammation. Specific anti-cytokine therapy have been developed and showed interesting results in preliminary clinical studies. However large clinical trials testing this new therapy have been stoppel prematurely because of deterious effects.

  12. [Prospects of the anti-cytokine therapy in rheumatoid arthritis].

    Science.gov (United States)

    Lukina, G V

    2003-01-01

    The development and introduction of the anti-cytokine therapy applicable to rheumatoid arthritis (RA) is a most significant achievement in RA therapy. A high degree of purpose-orientation and selectivity of the mentioned method ensuring a high therapeutic effect and providing, simultaneously, for defining a number of important chains in RA pathogenesis is an essential advantage of the discussed approach. The clinical use of neutralization of key cytokines TNF-alpha, IL-1 and IF-gamma is a serious progress within this trend. Possibilities of developing new directions of the cytokines therapy are preconditioned, to a great extent, by the role of new, including little-studied cytokines, in the evolution of immune inflammation. A search for more simple low-molecular inhibitors of cytokines, which do not cause any tolerance-related problems, is another important trend. Hopefully, a further study of anti-cytokines and of their application in combination with other antirheumatic drugs will improve the general treatment results and outline new opportunities in antirheumatic therapy.

  13. Feasibility of Affibody-Based Bioorthogonal Chemistry-Mediated Radionuclide Pretargeting.

    Science.gov (United States)

    Altai, Mohamed; Perols, Anna; Tsourma, Maria; Mitran, Bogdan; Honarvar, Hadis; Robillard, Marc; Rossin, Raffaella; ten Hoeve, Wolter; Lubberink, Mark; Orlova, Anna; Karlström, Amelie Eriksson; Tolmachev, Vladimir

    2016-03-01

    Affibody molecules constitute a new class of probes for radionuclide tumor targeting. The small size of Affibody molecules is favorable for rapid localization in tumors and clearance from circulation. However, high renal reabsorption of Affibody molecules prevents the use of residualizing radiometals, including several promising low-energy β- and α-emitters, for radionuclide therapy. We tested a hypothesis that Affibody-based pretargeting mediated by a bioorthogonal interaction between trans-cyclooctene (TCO) and tetrazine would provide higher accumulation of radiometals in tumor xenografts than in the kidneys. TCO was conjugated to the anti-human epidermal growth factor receptor 2 (HER2) Affibody molecule Z2395. DOTA-tetrazine was labeled with (111)In and (177)Lu. In vitro pretargeting was studied in HER2-expressing SKOV-3 and BT474 cell lines. In vivo studies were performed on BALB/C nu/nu mice bearing SKOV-3 xenografts. (125)I-Z2395-TCO bound specifically to HER2-expressing cells in vitro with an affinity of 45 ± 16 pM. (111)In-tetrazine bound specifically and selectively to Z2395-TCO pretreated cells. In vivo studies demonstrated HER2-specific (125)I-Z2395-TCO accumulation in xenografts. TCO-mediated (111)In-tetrazine localization was shown in tumors, when the radiolabeled tracer was injected 4 h after an injection of Z2395-TCO. At 1 h after injection, the tumor uptake of (111)In-tetrazine and (177)Lu-tetrazine was approximately 2-fold higher than the renal uptake. Pretargeting provided more than a 56-fold reduction of renal uptake of (111)In in comparison with direct targeting. The feasibility of Affibody-based bioorthogonal chemistry-mediated pretargeting was demonstrated. The use of pretargeting provides a substantial reduction of radiometal accumulation in kidneys, creating preconditions for palliative radionuclide therapy. © 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

  14. Pretargeted radioimmunotherapy (pRAIT) in medullary thyroid cancer (MTC).

    Science.gov (United States)

    Kraeber-Bodéré, Françoise; Salaun, Pierre-Yves; Ansquer, Catherine; Drui, Delphine; Mirallié, Eric; Faivre-Chauvet, Alain; Barbet, Jacques; Goldenberg, David M; Chatal, Jean-François

    2012-06-01

    Prognosis of medullary thyroid carcinoma (MTC) varies from long- to short-term survival, based on prognostic factors, such as serum calcitonin doubling time (Ct DT). Pretargeted radioimmunotherapy (pRAIT) is a novel targeted radionuclide therapy, using a bispecific monoclonal antibody (BsMAb) and a radiolabeled bivalent hapten, designed to improve the therapeutic index and to deliver increased tumor-absorbed doses to relatively radioresistant solid tumors. Pretargeting has demonstrated a more favorable therapeutic index and clinical efficacy than directly labeled anti-carcinoembryonic antigen (CEA) MAb in preclinical MTC models. Moreover, two phase I/II clinical trials assessing anti-CEA × anti-DTPA-indium BsMAb (murine F6x734 and chimeric hMN14x734) with (131)I-di-DTPA-indium showed encouraging therapeutic results in progressive, metastatic, MTC patients, with an improved survival in intermediate- and high-risk (pre-pRAIT Ct DT, <2 years) patients, as compared to contemporaneous untreated patients (median overall survival, 110 months vs 61 months; P < 0.030). pRAIT efficacy has been recently confirmed in a prospective multicenter phase II study assessing hMN14x734 and (131)I-di-DTPA-indium in rapidly progressive MTC patients. New pRAIT compounds are now available with fully humanized, recombinant, trivalent BsMAb (anti-CEA TF2) and histamine-succinyl-glutamine (HSG) peptides. The HSG peptide allows easy and stable labeling with different radiometals, such as (177)Lu or (90)Y beta-emitters having favorable physical features for pRAIT or (68)Ga and (18)F positron-emitters, allowing the development of a highly sensitive and specific immuno-positron emission tomography method in MTC or other CEA-positive tumors.

  15. Inflammatory cytokine levels in chronic venous insufficiency ulcer tissue before and after compression therapy

    Science.gov (United States)

    Beidler, Stephanie K.; Douillet, Christelle D.; Berndt, Daniel F.; Keagy, Blair A.; Rich, Preston B.; Marston, William A.

    2015-01-01

    Objective Elevated inflammatory cytokine levels have been implicated in the pathogenesis of non3 healing chronic venous insufficiency (CVI) ulcers. The goal of this study was to determine the protein levels of a wide range of inflammatory cytokines in untreated CVI ulcer tissue before and after 4 weeks of high strength compression therapy. These levels were compared to cytokines present in healthy tissue. Methods Thirty limbs with untreated CVI and leg ulceration received therapy for 4 weeks with sustained high compression bandaging at an ambulatory wound center. Biopsies were obtained from healthy and ulcerated tissue before and after therapy. A multiplexed protein assay was used to measure multiple cytokines in a single sample. Patients were designated as rapid or delayed healers based on ulcer surface area change. Results The majority of pro-inflammatory cytokine protein levels were elevated in ulcer tissue compared to healthy tissue, and compression therapy significantly reduced these cytokines. TGF-β1 was up-regulated in ulcer tissue following compression therapy. Rapid healing ulcers had significantly higher levels of IL-1α, IL-1β, IFN-γ, IL-12p40 and GM-CSF before compression therapy, and IL-1 Ra after therapy. IFN-γ levels significantly decreased following therapy in the rapidly healing patients. Conclusion CVI ulcer healing is associated with a pro-inflammatory environment prior to treatment that reflects metabolically active peri-wound tissue that has the potential to heal. Treatment with compression therapy results in healing that is coupled with reduced pro-inflammatory cytokine levels and higher levels of the anti-inflammatory cytokine IL-1 Ra. Clinical Relevance This data suggests that cytokines may provide targets in which topical therapeutic inhibition or promotion at appropriate time points in the healing process may provide novel therapeutic approaches to the healing of CVI ulcers. PMID:19341889

  16. Anti-cytokine therapies in T1D

    DEFF Research Database (Denmark)

    Nepom, Gerald T; Ehlers, Mario; Mandrup-Poulsen, Thomas

    2013-01-01

    Therapeutic targeting of proinflammatory cytokines is clinically beneficial in several autoimmune disorders. Several of these cytokines are directly implicated in the pathogenesis of type 1 diabetes, suggesting opportunities for design of clinical trials in type 1 diabetes that incorporate select...... suitable for modulating the immune response in T1D....

  17. Improvement of Radioimmunotherapy Using Pretargeting

    OpenAIRE

    Frampas, Eric; Rousseau, Caroline; Bodet-Milin, Caroline; Barbet, Jacques; Chatal, Jean-Francois; Kraeber-Bod?r?, Fran?oise

    2013-01-01

    During the past two decades, considerable research has been devoted to radionuclide therapy using radiolabeled monoclonal antibodies and receptor binding agents. Conventional radioimmunotherapy (RIT) is now an established and important tool in the treatment of hematologic malignancies such as Non-Hodgkin lymphoma. For solid malignancies, the efficacy of RIT has not been as successful due to lower radiosensitivity, difficult penetration of the antibody into the tumor, and potential excessive r...

  18. Cytokine and anti-cytokine therapy for the treatment of asthma and allergic disease

    Directory of Open Access Journals (Sweden)

    Stephen T Holgate

    2004-01-01

    Full Text Available Asthma is a chronic inflammatory disorder of the airways superimposed upon structural changes that include an increase in smooth muscle and airway wall remodeling. In addition to a background of chronic mediator release, asthma is characterized by considerable variations in airway function brought about by important interactions with the environment, including allergen, pollutant and virus exposure. At least in mild-moderate disease, cytokines released from Th2 cells appear important in orchestrating the inflammation. The situation in more severe disease is complicated by the superimposition of a Th1 on top of a Th2 response. Until recently, the only controller treatment for chronic asthma has been corticosteroids. However, identification of specific effector molecules in asthma has led to targeting of specific pathways by using cytokines and cytokine inhibitors. Administration of a monoclonal blocking antibody against IgE has been shown to be highly efficacious in severe allergic asthma, but enhancement of Th1 responses or attempts to reduce eosinophils using anti-interleukin-5 monoclonal antibodies have no clinical benefit. In more severe asthma, blockade of tumor necrosis factor-a using the decoy etanercept has revealed efficacy in a small open study supporting the view that Th1, in addition to Th2, pathways are important as the disease adopts a more severe phenotype. Thus, like atopic dermatitis, it is likely that asthma is not a single disease, but a group of disorders that differ in

  19. Resolution of orbitocerebral aspergillosis during combination treatment with voriconazole and amphotericin plus adjunctive cytokine therapy.

    Science.gov (United States)

    Bethell, Delia; Hall, Georgina; Goodman, T Robin; Klein, Nigel; Pollard, Andrew J

    2004-05-01

    Orbitocerebral aspergillosis has a very high fatality rate and cure is unusual. We describe the successful management of a child with cereberal aspergillosis who had a dramatic response to therapy with a combination of liposomal amphotericin and voriconazole with adjunctive cytokine therapy during immunosuppresive chemotherapy for acute lymphoblastic leukaemia.

  20. Regulating cytokine function enhances safety and activity of genetic cancer therapies.

    Science.gov (United States)

    Chen, Hannah; Sampath, Padma; Hou, Weizhou; Thorne, Stephen H

    2013-01-01

    Genetic therapies, including transfected immune cells and viral vectors, continue to show clinical responses as systemically deliverable and targeted therapeutics, with the first such approaches having been approved for cancer treatment. The majority of these employ cytokine transgenes. However, expression of cytokines early after systemic delivery can result in increased toxicity and nonspecific induction of the immune response. In addition, premature immune-mediated clearance of the therapy may result, especially for viral-based approaches. Here, it was initially verified that cytokine (interleukin (IL)2) or chemokine (CCL5) expression from a systemically delivered oncolytic virus resulted in reduced oncolytic activity and suboptimal immune activation, while IL2 also resulted in increased toxicity. However, all these limitations could be overcome through incorporation of exogenous regulation of cytokine or chemokine transgene function through fusion of a small and externally controllable destabilizing domain to the protein of interest. Regulation allowed an initial phase without cytokine function, permitting enhanced delivery and oncolytic activity before activation of cytokine function and a subsequent phase of enhanced and tumor-targeted immunotherapeutic activity. As a result of this exogenous regulation of cytokine function, both oncolytic and immune-mediated mechanisms of action were optimized, greatly enhancing therapeutic activity, while toxicity was significantly reduced.

  1. Dual functionality of interleukin-1 family cytokines: implications for anti-interleukin-1 therapy.

    Science.gov (United States)

    Luheshi, N M; Rothwell, N J; Brough, D

    2009-08-01

    Dysregulated inflammation contributes to disease pathogenesis in both the periphery and the brain. Cytokines are coordinators of inflammation and were originally defined as secreted mediators, released from expressing cells to activate plasma membrane receptors on responsive cells. However, a group of cytokines is now recognized as having dual functionality. In addition to their extracellular effects, these cytokines act inside the nuclei of cytokine-expressing or cytokine-responsive cells. Interleukin-1 (IL-1) family cytokines are key pro-inflammatory mediators, and blockade of the IL-1 system in inflammatory diseases is an attractive therapeutic goal. All current therapies target IL-1 extracellular actions. Here we review evidence that suggests IL-1 family members have dual functionality. Several IL-1 family members have been detected inside the nuclei of IL-1-expressing or IL-1-responsive cells, and intranuclear IL-1 is reported to regulate gene transcription and mRNA splicing. However, further work is required to determine the impact of IL-1 intranuclear actions on disease pathogenesis. The intranuclear actions of IL-1 family members represent a new and potentially important area of IL-1 biology and may have implications for the future development of anti-IL-1 therapies.

  2. Engineering an antibody with picomolar affinity to DOTA chelates of multiple radionuclides for pretargeted radioimmunotherapy and imaging

    Energy Technology Data Exchange (ETDEWEB)

    Orcutt, Kelly Davis; Slusarczyk, Adrian L. [Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139 (United States); Cieslewicz, Maryelise [Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139 (United States); Ruiz-Yi, Benjamin [Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139 (United States); Bhushan, Kumar R. [Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Boston, MA 02215 (United States); Frangioni, John V. [Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Boston, MA 02215 (United States); Department of Radiology, Beth Israel Deaconess Medical Center, Boston, MA 02215 (United States); Wittrup, K. Dane, E-mail: wittrup@mit.ed [Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139 (United States); Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139 (United States); Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139 (United States)

    2011-02-15

    Introduction: In pretargeted radioimmunotherapy (PRIT), a bifunctional antibody is administered and allowed to pre-localize to tumor cells. Subsequently, a chelated radionuclide is administered and captured by cell-bound antibody while unbound hapten clears rapidly from the body. We aim to engineer high-affinity binders to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelates for use in PRIT applications. Methods: We mathematically modeled antibody and hapten pharmacokinetics to analyze hapten tumor retention as a function of hapten binding affinity. Motivated by model predictions, we used directed evolution and yeast surface display to affinity mature the 2D12.5 antibody to DOTA, reformatted as a single chain variable fragment (scFv). Results: Modeling predicts that for high antigen density and saturating bsAb dose, a hapten-binding affinity of 100 pM is needed for near-maximal hapten retention. We affinity matured 2D12.5 with an initial binding constant of about 10 nM to DOTA-yttrium chelates. Affinity maturation resulted in a 1000-fold affinity improvement to biotinylated DOTA-yttrium, yielding an 8.2{+-}1.9 picomolar binder. The high-affinity scFv binds DOTA complexes of lutetium and gadolinium with similar picomolar affinity and indium chelates with low nanomolar affinity. When engineered into a bispecific antibody construct targeting carcinoembryonic antigen, pretargeted high-affinity scFv results in significantly higher tumor retention of a {sup 111}In-DOTA hapten compared to pretargeted wild-type scFv in a xenograft mouse model. Conclusions: We have engineered a versatile, high-affinity, DOTA-chelate-binding scFv. We anticipate it will prove useful in developing pretargeted imaging and therapy protocols to exploit the potential of a variety of radiometals.

  3. Metformin as a new therapy for endometriosis, its effects on both clinical picture and cytokines profile

    Directory of Open Access Journals (Sweden)

    Ashraf Ahmed Foda

    2012-12-01

    Conclusion: Metformin therapy in patients with endometriosis resulted in a significant reduction in the symptomatic cases, increased chance of pregnancy, and a decrease in the levels of serum cytokines, suggesting that it may have a therapeutic potential as an anti-endometriotic drug.

  4. ANTI-CYTOKINE THERAPY FOR CHILDREN WITH INFLAMMATORY BOWEL DISEASES

    Directory of Open Access Journals (Sweden)

    A.S. Potapov

    2009-01-01

    Full Text Available The article describes the findings of a pilot research devoted to the estimation of the efficiency of a therapy with TNF α inhibitors for children with inflammatory bowel diseases. Methods: we carried out the retrospective analysis for a therapy with Infliximab in 15 children with a nonspecific ulcerative colitis and Сrohn's disease. Results: 66% of the children with inflammatory bowel diseases react to the first injection of Infliximab, whereas 13% of the children demonstrate a clinical remission of their diseases. After the third injection, a positive response to the used therapy is shown by 60% of the children with inflammatory bowel diseases, and 33% of the children are diagnosed with a clinical remission. Conclusion: The use of Infliximab allowed the children with a refractory course of nonspecific ulcerative colitis and Сrohn's disease to make their inflammation significantly less active and improve the quality of their life.Key words: nonspecific ulcerative colitis, Сrohn's disease, treatment, TNF α inhibitors, children

  5. Antimonial Therapy Induces Circulating Proinflammatory Cytokines in Patients with Cutaneous Leishmaniasis

    Science.gov (United States)

    Kocyigit, Abdurrahim; Gur, Selahaddin; Gurel, Mehmet S.; Bulut, Vedat; Ulukanligil, Mustafa

    2002-01-01

    The objective of this study was to evaluate the association between antimonial therapy and circulating levels of proinflammatory cytokines in patients with cutaneous leishmaniasis (CL). Patients were treated with conventional chemotherapy by using pentavalent antimonium salts (Glucantime) for 3 weeks. Circulating plasma levels of the proinflammatory cytokines interleukin-1β (IL-1β), IL-6, IL-8, and tumor necrosis factor alpha (TNF-α) were determined for CL patients and healthy subjects before and 3 weeks after the treatment was started. Plasma IL-1β, IL-6, IL-8, and TNF-α levels were significantly higher for pretreatment CL patients than for healthy subjects. Proinflammatory cytokines significantly increased after 21 days postinfection compared to levels for the pretreatment patients. These increments were approximately 3-fold for IL-1β and TNF-α levels, 10-fold for IL-6 levels, and 20-fold for IL-8 levels in patients with CL. Taken together these results indicate that circulating proinflammatory cytokine levels were increased in patients with CL as a consequence of host defense strategies, and antimonial therapy may induce these cytokines by affecting the macrophage or other components of the host defense system. PMID:12438329

  6. Cytokine-induced killer (CIK cell therapy for patients with hepatocellular carcinoma: efficacy and safety

    Directory of Open Access Journals (Sweden)

    Ma Yue

    2012-04-01

    Full Text Available Abstract Purpose To evaluate the efficacy of cytokine-induced killer (CIK cell therapy in the treatment of hepatocellular carcinoma. Materials and methods Randomized phase II and III trials on CIK cell-based therapy were identified by electronic searches using a combination of "hepatocellular carcinoma" and "cytokine-induced killer cells". Results The analysis showed significant survival benefit (one-year survival, p p p p p p +, CD4+, CD4+CD8+ and CD3+CD4+ T cells significantly increased in the CIK group, compared with the non-CIK group (p Conclusions CIK cell therapy demonstrated a significant superiority in prolonging the median overall survival, PFS, DCR, ORR and QoL of HCC patients. These results support further larger scale randomized controlled trials for HCC patients with or without the combination of other therapeutic methods.

  7. THE INFLUENCE OF PATHOGENETIC THERAPY ON THE LEVER OF CYTOKINES IN PATIENTS WITH ACUTE BRUCELLOSIS

    Directory of Open Access Journals (Sweden)

    N. I. Kovalevich

    2016-01-01

    Full Text Available The purpose of the study was to determine the level of proinflammatory cytokines: IL-12, IL-8 and IFNγ, neopterin and lipopolysaccharide-binding protein in the serum of patients with acute brucellosis before and after antibiotic therapy. The clinical data from 32 patients with laboratory-confirmed diagnosis — “acute brucellosis” admitted to the diagnosis, treatment and examination of occupational diseases brucellosis GBUZ SC “City Clinical Hospital No. 2”, the city of Stavropol were used in the study. The concentrations IL-12, IL-8, IFNγ cytokines and acute-phase proteins in serum was determined by ELISA. In the acute phase of brucellosis infection (before treatment had high levels of pro-inflammatory cytokines IL-8 and IFNγ, but despite holding a course of antibiotic treatment in the serum of patients with preserved high levels of IL-8, indicative of active inflammation in the absence of clinical manifestations. IL-12 level, a key cytokine in the initiation of lymphocyte-dependent immune response was lower than in the control group. Evaluation of the cytokine status (IL-8, IL-12, IL-18 and proteins of acute inflammation phase (neopterin and lipopolysaccharide-binding protein will provide valuable information for monitoring the effect of pharmacotherapy of acute brucellosis. Indicators of lipopolysaccharide-binding protein and neopterin in the serum of patients with brucellosis should be considered as a marker of inflammatory activity and as a predictor of outcome of acute brucellosis.

  8. Predicting the biodistribution of radiolabeled cMORF effector in MORF-pretargeted mice

    International Nuclear Information System (INIS)

    Liu, Guozheng; Dou, Shuping; He, Jiang; Liu, Xinrong; Rusckowski, Mary; Hnatowich, Donald J.

    2007-01-01

    Pretargeting with phosphorodiamidate morpholino oligomers (MORFs) involves administration of a MORF-conjugated anti-tumor antibody such as MN14 as a pretargeting agent before that of the radiolabeled complementary MORF (cMORF) as the effector. The dosages of the pretargeting agent and effector, the pretargeting interval, and the detection time are the four pretargeting variables. The goal of this study was to develop a semiempirical description capable of predicting the biodistribution of the radiolabeled effector in pretargeted mice and then to compare predictions with experimental results from pretargeting studies in tumored animals in which the pretargeting interval and the detection time were both fixed but the dosages of both the effector and the pretargeting agent were separately varied. Pretargeting studies in LS174T tumored mice were performed using the anti-CEA antibody MN14 conjugated with MORF and the cMORF radiolabeled with 99m Tc. A description was developed based on our previous observations in the same mouse model of the blood and tumor levels of MORF-MN14, accessibility of MORF-MN14 to labeled cMORF, the tumor accumulation of labeled cMORF relative to MORF-MN14 levels therein, and the kidney accumulation of labeled cMORF. The predicted values were then compared with the experimental values. The predicted biodistribution of the radiolabeled effector and the experimental data were in gratifying agreement in normal organs, suggesting that the description of the pretargeting process was reliable. The tumor accumulations occasionally fell outside two standard deviations of that predicted, but after tumor size correction, good agreement between predicted and experimental values was observed here as well. A semiempirical description of the biodistribution of labeled cMORF was capable of predicting the biodistribution of the radiolabeled effector in the pretargeted tumored mouse model, demonstrating that the underlying pretargeting concepts are correct. We

  9. Anthelmintic Therapy Modifies the Systemic and Mycobacterial Antigen-Stimulated Cytokine Profile in Helminth-Latent Mycobacterium tuberculosis Coinfection.

    Science.gov (United States)

    Anuradha, Rajamanickam; Munisankar, Saravanan; Bhootra, Yukthi; Dolla, Chandrakumar; Kumaran, Paul; Nutman, Thomas B; Babu, Subash

    2017-04-01

    Helminth infections are known to modulate cytokine responses in latent tuberculosis (LTB). However, very few studies have examined whether this modulation is reversible upon anthelmintic therapy. We measured the systemic and mycobacterial (TB) antigen-stimulated levels of type 1, type 2, type 17, and regulatory cytokines in individuals with LTB and with or without coexistent Strongyloides stercoralis infection before and after anthelmintic therapy. Our data reveal that individuals with LTB and coexistent S. stercoralis infection have significantly lower levels of systemic and TB antigen-stimulated type 1 (gamma interferon [IFN-γ], tumor necrosis factor alpha [TNF-α], and interleukin-2 [IL-2]) and type 17 (IL-17A and/or IL-17F) cytokines and significantly higher levels of systemic but not TB antigen-stimulated type 2 (IL-4 and IL-5) and regulatory (transforming growth factor beta [TGF-β]) cytokines. Anthelmintic therapy resulted in significantly increased systemic levels of type 1 and/or type 17 cytokines and in significantly decreased systemic levels of type 2 and regulatory (IL-10 and TGF-β) cytokines. In addition, anthelmintic therapy resulted in significantly increased TB antigen-stimulated levels of type 1 cytokines only. Our data therefore confirm that the modulation of systemic and TB antigen-stimulated cytokine responses in S. stercoralis -LTB coinfection is reversible (for the most part) by anthelmintic treatment. Copyright © 2017 American Society for Microbiology.

  10. Pretargeting with the affinity enhancement system for radioimmunotherapy.

    Science.gov (United States)

    Barbet, J; Kraeber-Bodéré, F; Vuillez, J P; Gautherot, E; Rouvier, E; Chatal, J F

    1999-06-01

    The pretargeting technique referred to as the Affinity Enhancement System (AES) uses bispecific antibodies and radiolabeled bivalent haptens that bind cooperatively to target cells in vivo. Experimental and clinical data demonstrate that AES can deliver large radiation doses to tumor cells with high tumor to normal tissue contrast ratios and long activity residence time in tumors. Preliminary clinical results of radioimmunotherapy of medullary thyroid carcinomas and lung cancers look promising.

  11. The effect of conventional immunosuppressive therapy on cytokine serum levels in pemphigus vulgaris patients.

    Science.gov (United States)

    Mortazavi, Hossein; Esmaili, Nafiseh; Khezri, Somayeh; Khamesipour, Ali; Vasheghani Farahani, Iman; Daneshpazhooh, Maryam; Rezaei, Nima

    2014-06-01

    Pemphigus vulgaris is an autoimmune disease, in which the role of Th17 cytokines needs to be further explored. This study was performed to assess serum levels of three interleukins (IL) required for Th17 differentiation (IL-1β, IL-6 and IL-23) and two specific Th17 cytokines (IL-17 and IL-22) in a group of patients with pemphigus vulgaris, at baseline, 3 weeks and 6 months after treatment. Correlations between anti-desmogleins and cytokines with disease severity as well as the influence of therapy on the above factors were assessed. Forty-three first-admitted pemphigus vulgaris patients with the active disease entered the study, but only 31 completed the study. Forty-five healthy volunteers were recruited as a control group. The patients were treated with conventional immunosuppressive therapy (oral prednisolone and azathioprine). Cytokines and anti-desmogleins were measured, using enzyme-linked immunosorbent assay. General linear model was used to evaluate the changes over time. In patients at baseline, mean serum level of IL-6 was higher, while mean levels of IL-1β and IL-22 were lower than the controls. After 3 weeks of therapy, IL-1β and IL-6 levels showed a decreasing trend, whereas IL-22 showed an increasing trend. Mean anti-desmogleins 1 and 3 values decreased significantly during the time. Anti-desmoglein values were significantly correlated with disease severity. In conclusion, IL-1β and IL-6 could be involved in the pathogenesis of pemphigus vulgaris. The positive trend of IL-22 is a new finding and should be confirmed by further studies.

  12. Grading of cytokine release syndrome associated with the CAR T cell therapy tisagenlecleucel.

    Science.gov (United States)

    Porter, David; Frey, Noelle; Wood, Patricia A; Weng, Yanqiu; Grupp, Stephan A

    2018-03-02

    Anti-CD19 CAR T cell therapy has demonstrated high response rates in patients with relapsed or refractory (r/r) B cell malignancies but is associated with significant toxicity. Cytokine release syndrome (CRS) is the most significant complication associated with CAR T cell therapy, and it is critical to have a reproducible and easy method to grade CRS after CAR T cell infusions. The Common Terminology Criteria for Adverse Events scale is inadequate for grading CRS associated with cellular therapy. Clinical experience with the anti-CD19 CAR T cell therapy tisagenlecleucel at the University of Pennsylvania (Penn) was used to develop the Penn grading scale for CRS. The Penn grading scale depends on easily accessible clinical features; does not rely on location of care or quantitation of supportive care; assigns grades to guide CRS management; distinguishes between mild, moderate, severe, and life-threatening CRS; and applies to both early-onset and delayed-onset CRS associated with T cell therapies. Clinical data from 55 pediatric patients with r/r B cell acute lymphoblastic leukemia and 42 patients with r/r chronic lymphocytic lymphoma treated with tisagenlecleucel were used to demonstrate the current application of the Penn grading scale. We show that the Penn grading scale provides reproducible CRS grading that can be useful to guide therapy and that can be applied across clinical trials and treatment platforms.

  13. Pharmacokinetics and Dosimetry Studies for Optimization of Pretargeted Radioimmunotherapy in CEA-Expressing Advanced Lung Cancer Patients

    Directory of Open Access Journals (Sweden)

    Caroline eBodet-Milin

    2015-11-01

    Full Text Available Objectives. A phase I pretargeted radioimmunotherapy trial (EudractCT 200800603096 was designed in patients with metastatic lung cancer expressing carcinoembryonic antigen (CEA to optimize bispecific antibody and labelled peptide doses, as well as the delay between their injections.Methods. Three cohorts of 3 patients received the anti-CEA x anti-histamine-succinyl-glycine (HSG humanized trivalent bispecific antibody (TF2 and the IMP288 bivalent HSG-peptide. Patients underwent a pre-therapeutic imaging session S1 (44 or 88 nmol/m2 of TF2 followed by 4.4 nmol/m2, 185 MBq, of 111In-labelled IMP288, and, 1-2 weeks later, a therapy session S2 (240 or 480 nmol/m2 of TF2 followed by 24 nmol/m2, 1.1 GBq/m2, 177Lu-labeled IMP288. The pretargeting delay was 24 or 48 hours. The dose schedule was defined based on pre-clinical TF2 pharmacokinetic studies, on our previous clinical data using the previous anti-CEA pretargeting system and on clinical results observed in the first patients injected using the same system in the Netherlands.Results. TF2 pharmacokinetics (PK was represented by a two-compartment model in which the central compartment volume was linearly dependent on the patient's surface area. PK were remarkably similar, with a clearance of 0.33 +/- 0.03 L/h per m2. 111In- and 177Lu-IMP288 PK were also well represented by a two-compartment model. IMP288 PK were faster (clearance 1.4 to 3.3 l/h. The central compartment volume was proportional to body surface area and IMP288clearance depended on the molar ratio of injected IMP288 to circulating TF2 at the time of IMP288 injection. Modelling of image quantification confirmed the dependence of IMP288 kinetics on circulating TF2, but tumour activity PK were variable. Organ absorbed doses were not significantly different in the 3 cohorts, but the tumour dose was significantly higher with the higher molar doses of TF2 (p < 0.002. S1 imaging predicted absorbed doses calculated in S2. Conclusion. The best

  14. Cytokines as remedies for early pathogenetic therapy of radiation injuries. Efficiency and mechanism

    International Nuclear Information System (INIS)

    Legeza, V.I.; Chigireva, N.G.; Abdul', Yu.A.; Galeev, I.Sh.

    2000-01-01

    The efficiency of applying interleukins in the case of early pathogenetic therapy of the acute radiation disease is studied in experiments with mice, rats and dogs. The animal were subjected to the gamma-radiation with the dose rate of 1.5 Gy/min. It is shown that administration of human recombinant interleukins 1α and 1β separately (to mice and rats) or in combination with antibiotic therapy (dogs) during the first hours after irradiation essentially increases the survival rate, facilitates more rapid regeneration of the cellular content of the bone marrow and peripheral blood, intensifies the processes of endogenic colony formation and DNA synthesis in the bone marrow and liver and decreases the expressivity of radiation-induced endotoxemia. The importance of using cytokines in the system of remedial measures by radiation pathology is discussed [ru

  15. CYTOKINE RESPONSE ASSOCIATED WITH HEPATITIS C VIRUS CLEARANCE IN HIV COINFECTED PATIENTS INITIATING PEG INTERFERON- BASED THERAPY.

    OpenAIRE

    Truong Tam Nguyen; Reihani Niloofar; Pierre-Alain Rubbo; Kuster Nils; Karine Bollore; Jacques Ducos; Georges-Philippe Pageaux; Jacques Reynes; Philippe Van de Perre; Edouard Tuaillon

    2016-01-01

    Background: Treatment against hepatitis C virus (HCV) infection based on peginterferon-a (pegIFNa) and ribavirin induces important changes on cytokine release and T cell activation. Objective: Immune response to pegIFNa-ribavirin therapy was explored in patients coinfected by HCV and HIV. Methods: Concentrations of 25 cytokines and CD8+ T cell activation were monitored in HCV/HIV coinfected patients classified as sustained virological responders (SVR, n=19) and non-responders (NR, n=1...

  16. Biomarkers of cytokine release syndrome and neurotoxicity related to CAR-T cell therapy.

    Science.gov (United States)

    Wang, Zhenguang; Han, Weidong

    2018-01-01

    Severe cytokine release syndrome (CRS) and neurotoxicity following chimeric antigen receptor T cell (CAR-T) therapy can be life-threatening in some cases, and management of those toxicities is still a great challenge for physicians. Researchers hope to understand the pathophysiology of CRS and neurotoxicity, and identify predictive biomarkers that can forecast those toxicities in advance. Some risk factors for severe CRS and/or neurotoxicity including patient and treatment characteristics have been identified in multiple clinical trials of CAR-T cell therapy. Moreover, several groups have identified some predictive biomarkers that are able to determine beforehand which patients may suffer severe CRS and/or neurotoxicity during CAR-T cell therapy, facilitating testing of early intervention strategies for those toxicities. However, further studies are needed to better understand the biology and related risk factors for CRS and/or neurotoxicity, and determine if those identified predictors can be extrapolated to other series. Herein, we review the pathophysiology of CRS and neurotoxicity, and summarize the progress of predictive biomarkers to improve CAR-T cell therapy in cancer.

  17. Photodynamic therapy induced production of cytokines by latent Epstein Barr virus infected epithelial tumor cells

    Science.gov (United States)

    Koon, H. K.; Lo, K. W.; Lung, M. L.; Chang, C. K. C.; Wong, R. N. S.; Mak, N. K.

    2007-02-01

    Photodynamic therapy (PDT) is a method to treat cancer or non-cancer diseases by activation of the light-sensitive photosensitizers. Epstein Barr virus (EBV) has been implicated in the development of certain cancers such as nasopharyngeal carcinoma and B cell lymphoma. This study aims to examine the effects of EBV infection on the production of pro-inflammatory cytokines and chemokines in cells after the photosensitizer Zn-BC-AM PDT treatment. Epithelial tumor cell lines HONE-1 and latent EBV-infected HONE-1 (EBV-HONE-1) cells were used in this study. Cells were treated with the photosensitizer Zn-BC-AM for 24 hours before light irradiation. RT-PCR and quantitative ELISA methods were used for the evaluation of mRNA expression and production of cytokines, respectively. Results show that Zn-BC-AM PDT increases the production of IL-1a and IL-1b in EBV-HONE-1. Over a 10-fold increase in the production of IL-6 was observed in the culture supernatant of Zn-BC-AM PDT-treated HONE-1 cells. PDT-induced IL-6 production was observed in HONE-1 cells. EBV-HONE-1 has a higher background level of IL-8 production than the HONE-1. The production of IL-8 was suppressed in EBV-HONE-1cells after Zn-BC-AM PDT. Our results indicate that the response of HONE-1 cells to Zn-BC-AM PDT depends on the presence of latent EBV infection. Since IL-8 is a cytokine with angiogenic activity, Zn-BC-AM PDT may exert an anti-angiogenic effect through the suppression of IL-8 production by the EBV-infected cells.

  18. Identification of acute phase reactants and cytokines useful for monitoring infliximab therapy in ankylosing spondylitis.

    Science.gov (United States)

    Romero-Sánchez, Consuelo; Robinson, William H; Tomooka, Beren H; Londoño, John; Valle-Oñate, Rafael; Huang, Feng; Deng, Xiaohu; Zhang, Liyun; Yang, Chunhua; Yu, David Tak Yan

    2008-11-01

    Although most ankylosing spondylitis patients show an apparent clinical response to infliximab therapy, there is considerable individual variation. Because current clinical assessment relies heavily on subjective patient self-evaluation, biomarkers of high sensitivity and specificity are much needed. Here, we assessed potential biomarkers in 47 ankylosing spondylitis patients who received three standard pulses of infliximab. Before each infusion and at week 10, the following were measured: erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), platelet count, serum levels of metalloproteinase-3 (MMP-3), and 22 different cytokines. We discovered that, 2 weeks after the first infusion, the combination of ESR, CRP, and platelet count distinguished responders from non-responders with 81.3% sensitivity and 72.7% specificity. The distinguishing power was much less when each acute phase reactant was used alone. Among the 22 cytokines, serum IL-1alpha was able to distinguish responders from non-responders at week 6, with sensitivity of 84.9% and specificity of 53.8%. Serum IL-1alpha was probably generated from the joint compartments, as synovial fluid levels were much higher than corresponding serum levels. Although infliximab infusions led to rapid and significant suppression of serum MMP-3 levels, serum MMP-3 levels did not distinguish responders from non-responders. Besides identifying potential biomarkers, our results also demonstrate the usefulness of using sensitivity and specificity to assess usefulness of potential biomarkers.

  19. Insights into cytokine release syndrome and neurotoxicity after CD19-specific CAR-T cell therapy.

    Science.gov (United States)

    Gauthier, Jordan; Turtle, Cameron J

    2018-04-03

    T-cells engineered to express CD19-specific chimeric antigen receptors (CD19 CAR-T cells) can achieve high response rates in patients with refractory/relapsed (R/R) CD19+ hematologic malignancies. Nonetheless, the efficacy of CD19-specific CAR-T cell therapy can be offset by significant toxicities, such as cytokine release syndrome (CRS) and neurotoxicity. In this report of our presentation at the 2018 Second French International Symposium on CAR-T cells (CAR-T day), we describe the clinical presentations of CRS and neurotoxicity in a cohort of 133 adults treated with CD19 CAR-T cells at the Fred Hutchinson Cancer Research Center, and provide insights into the mechanisms contributing to these toxicities. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  20. Antibody-Cytokine Fusion Proteins for the Therapy of Breast Cancer

    National Research Council Canada - National Science Library

    Morrision, Sherie

    2002-01-01

    .... Expression of these cytokines by cancer cells has been shown to render them immunogenic. The anti- HER2/neu antibody fusion proteins were intended to localize the cytokine at the tumor where it is expected to elicit an immune response...

  1. Feasibility of Affibody Molecule-Based PNA-Mediated Radionuclide Pretargeting of Malignant Tumors.

    Science.gov (United States)

    Honarvar, Hadis; Westerlund, Kristina; Altai, Mohamed; Sandström, Mattias; Orlova, Anna; Tolmachev, Vladimir; Karlström, Amelie Eriksson

    2016-01-01

    Affibody molecules are small (7 kDa), non-immunoglobulin scaffold proteins with a potential as targeting agents for radionuclide imaging of cancer. However, high renal re-absorption of Affibody molecules prevents their use for radionuclide therapy with residualizing radiometals. We hypothesized that the use of Affibody-based peptide nucleic acid (PNA)-mediated pretargeting would enable higher accumulation of radiometals in tumors than in kidneys. To test this hypothesis, we designed an Affibody-PNA chimera ZHER2:342-SR-HP1 containing a 15-mer HP1 PNA recognition tag and a complementary HP2 hybridization probe permitting labeling with both (125)I and (111)In. (111)In-ZHER2:342-SR-HP1 bound specifically to HER2-expressing BT474 and SKOV-3 cancer cells in vitro, with a KD of 6±2 pM for binding to SKOV-3 cells. Specific high affinity binding of the radiolabeled complementary PNA probe (111)In-/(125)I-HP2 to ZHER2:342-SR-HP1 pre-treated cells was demonstrated. (111)In-ZHER2:342-SR-HP1 demonstrated specific accumulation in SKOV-3 xenografts in BALB/C nu/nu mice and rapid clearance from blood. Pre-saturation of SKOV-3 with non-labeled anti-HER2 Affibody or the use of HER2-negative Ramos xenografts resulted in significantly lower tumor uptake of (111)In-ZHER2:342-SR-HP1. The complementary PNA probe (111)In/(125)I-HP2 accumulated in SKOV-3 xenografts when ZHER2:342-SR-HP1 was injected 4 h earlier. The tumor accumulation of (111)In/(125)I-HP2 was negligible without ZHER2:342-SR-HP1 pre-injection. The uptake of (111)In-HP2 in SKOV-3 xenografts was 19±2 %ID/g at 1 h after injection. The uptake in blood and kidneys was approximately 50- and 2-fold lower, respectively. In conclusion, we have shown that the use of Affibody-based PNA-mediated pretargeting enables specific delivery of radiometals to tumors and provides higher radiometal concentration in tumors than in kidneys.

  2. Cytokine levels correlate with immune cell infiltration after anti-VEGF therapy in preclinical mouse models of breast cancer.

    Directory of Open Access Journals (Sweden)

    Christina L Roland

    2009-11-01

    Full Text Available The effect of blocking VEGF activity in solid tumors extends beyond inhibition of angiogenesis. However, no studies have compared the effectiveness of mechanistically different anti-VEGF inhibitors with respect to changes in tumor growth and alterations in the tumor microenvironment. In this study we use three distinct breast cancer models, a MDA-MB-231 xenograft model, a 4T1 syngenic model, and a transgenic model using MMTV-PyMT mice, to explore the effects of various anti-VEGF therapies on tumor vasculature, immune cell infiltration, and cytokine levels. Tumor vasculature and immune cell infiltration were evaluated using immunohistochemistry. Cytokine levels were evaluated using ELISA and electrochemiluminescence. We found that blocking the activation of VEGF receptor resulted in changes in intra-tumoral cytokine levels, specifically IL-1beta, IL-6 and CXCL1. Modulation of the level these cytokines is important for controlling immune cell infiltration and ultimately tumor growth. Furthermore, we demonstrate that selective inhibition of VEGF binding to VEGFR2 with r84 is more effective at controlling tumor growth and inhibiting the infiltration of suppressive immune cells (MDSC, Treg, macrophages while increasing the mature dendritic cell fraction than other anti-VEGF strategies. In addition, we found that changes in serum IL-1beta and IL-6 levels correlated with response to therapy, identifying two possible biomarkers for assessing the effectiveness of anti-VEGF therapy in breast cancer patients.

  3. Multivalent interactions between streptavidin-based pretargeting fusion proteins and cell receptors impede efficient internalization of biotinylated nanoparticles.

    Science.gov (United States)

    Parker, Christina L; Yang, Qi; Yang, Bing; McCallen, Justin D; Park, Steven I; Lai, Samuel K

    2017-11-01

    Pretargeting represents a promising strategy to enhance delivery of nanoparticles. The strategy involves first introducing bispecific antibodies or fusion proteins (BFP) that can bind specific epitopes on target cells with one arm, and use the other arm to capture subsequently administered effector molecules, such as radionuclides or drug-loaded nanoparticles. Nevertheless, it remains unclear whether BFP that bind slowly- or non-internalizing epitopes on target cells can facilitate efficient intracellular delivery. Here, we investigated the cellular uptake of biotin-functionalized nanoparticles with streptavidin-scFv against TAG-72, a membrane protein on Jurkat T-cell leukemia cells. Unlike conventional active-targeted nanoparticles, we found that pretargeting resulted in preferential retention of ∼100nm nanoparticles at the plasma membrane rather than internalization into cells. We found no improvement in nanoparticle internalization by simply reducing nanoparticle concentration or surface biotin density. Interestingly, by adding both the BFP and a monoclonal antibody against TAG-72, we observed a twofold improvement in internalization of pretargeted nanoparticles. Our work illustrates that the cellular fate of pretargeted nanoparticles can be controlled by carefully tuning the interactions between pretargeting molecules and nanoparticles on the cell surface. Pretargeting is a multi-step strategy that utilizes bispecific proteins that recognize both cellular epitopes and subsequently administered therapeutic molecules. This approach has been extensively studied for radiotherapy of blood cancers; however, pretargeting remains largely underexplored for nanoparticle targeting, including whether pretargeting can facilitate efficient intracellular delivery. Here, we found that high density of targeting proteins on the cell surface can effectively limit internalization of pretargeted nanoparticles. Our work underscores the need to carefully assess specific cell-pretargeting

  4. CYTOKINE RESPONSE ASSOCIATED WITH HEPATITIS C VIRUS CLEARANCE IN HIV COINFECTED PATIENTS INITIATING PEG INTERFERON- BASED THERAPY.

    Directory of Open Access Journals (Sweden)

    Truong Tam Nguyen

    2016-01-01

    Full Text Available Background: Treatment against hepatitis C virus (HCV infection based on peginterferon-a (pegIFNa and ribavirin induces important changes on cytokine release and T cell activation. Objective: Immune response to pegIFNa-ribavirin therapy was explored in patients coinfected by HCV and HIV. Methods: Concentrations of 25 cytokines and CD8+ T cell activation were monitored in HCV/HIV coinfected patients classified as sustained virological responders (SVR, n=19 and non-responders (NR, n=11.  Results: High pretreatment concentrations of IP-10 (CXCL-10 and MCP-1 (CCL-2 were associated with poor anti-HCV response. PegIFNa-ribavirin therapy increased CD8+ T cell activation and induced significant changes in levels of eleven cytokines related to both Th1 and Th2 responses in SVR (IL-1b, IL-1RA, IL-4, IL-5, IL-6, IL-7, IL-12p40/70, IL-13, IP-10, eotaxin, MCP-1 but only six cytokines in NR (IL-1b, IL-2, IL-5, IL-12p40/70, IL-13, eotaxin. Highest rise in MIP-1b and MCP-1 levels was observed four weeks after anti-HCV treatment initiation in SVR compared to NR (p=0.002 and p=0.03, respectively, whereas a decrease of IL-8 concentration was associated with treatment failure (p= 0.052. Conclusions: Higher and broader cytokine responses to pegIFNa-ribavirin therapy were observed in SVR patients compared to NR. Changes in IL-8, MIP-1b and MCP-1 serum concentrations may be associated with efficacy of pegIFNa- and ribavirin-based therapies in patients coinfected by HCV and HIV.

  5. Cytokine Response Associated with Hepatitis C Virus Clearance in HIV Coinfected Patients Initiating Peg Interferon-α Based Therapy.

    Science.gov (United States)

    Nguyen, Truong Tam; Niloofar, Reihani; Rubbo, Pierre-Alain; Nils, Kuster; Bollore, Karine; Ducos, Jacques; Pageaux, Georges-Philippe; Reynes, Jacques; Van de Perre, Philippe; Tuaillon, Edouard

    2016-01-01

    Treatment of hepatitis C virus (HCV) infection based on peginterferon-α (pegIFNα) and ribavirin induces important changes in cytokine release and T cell activation. Immune response to pegIFNα-ribavirin therapy was explored in patients coinfected by HCV and HIV. Concentrations of 25 cytokines and CD8(+) T cell activation were monitored in HCV/HIV coinfected patients classified as sustained virological responders (SVR, n=19) and non-responders (NR, n=11). High pretreatment concentrations of IP-10 (CXCL-10) and MCP-1 (CCL-2) were associated with a poor anti-HCV response. PegIFNα-ribavirin therapy increased CD8(+) T cell activation and induced significant changes in levels of eleven cytokines related to both Th1 and Th2 responses in SVR (IL-1β, IL-1RA, IL-4, IL-5, IL-6, IL-7, IL-12p40/70, IL-13, IP-10, eotaxin, MCP-1) but of only six cytokines in NR (IL-1β, IL-2, IL-5, IL-12p40/70, IL-13, eotaxin). The highest rise in MIP-1β and MCP-1 levels was observed four weeks after anti-HCV treatment initiation in SVR compared to NR (p=0.002 and p=0.03, respectively), whereas a decrease in IL-8 concentration was associated with treatment failure (p= 0.052). Higher and broader cytokine responses to pegIFNα-ribavirin therapy were observed in SVR patients compared to NR. Changes in IL-8, MIP-1β, and MCP-1 serum concentrations may be associated with efficacy of pegIFNα- and ribavirin-based therapies in patients coinfected by HCV and HIV.

  6. PET imaging of apoptosis with 64Cu-labeled streptavidin following pretargeting of phosphatidylserine with biotinylated annexin-V

    International Nuclear Information System (INIS)

    Cauchon, Nicole; Langlois, Rejean; Rousseau, Jacques A.; Tessier, Guillaume; Cadorette, Jules; Lecomte, Roger; Hunting, Darel J.; Lier, Johan E. van; Pavan, Roberto A.; Zeisler, Stefan K.

    2007-01-01

    In vivo detection of apoptosis is a diagnostic tool with potential clinical applications in cardiology and oncology. Radiolabeled annexin-V (anxV) is an ideal probe for in vivo apoptosis detection owing to its strong affinity for phosphatidylserine (PS), the molecular flag on the surface of apoptotic cells. Most clinical studies performed to visualize apoptosis have used 99m Tc-anxV; however, its poor distribution profile often compromises image quality. In this study, tumor apoptosis after therapy was visualized by positron emission tomography (PET) using 64 Cu-labeled streptavidin (SAv), following pre-targeting of apoptotic cells with biotinylated anxV. Apoptosis was induced in tumor-bearing mice by photodynamic therapy (PDT) using phthalocyanine dyes as photosensitizers, and red light. After PDT, mice were injected i.v. with biotinylated anxV, followed 2 h later by an avidin chase, and after another 2 h with 64 Cu-DOTA-biotin-SAv. PET images were subsequently recorded up to 13 h after PDT. PET images delineated apoptosis in treated tumors as early as 30 min after 64 Cu-DOTA-biotin-SAv administration, with tumor-to-background ratios reaching a maximum at 3 h post-injection, i.e., 7 h post-PDT. Omitting the administration of biotinylated anxV or the avidin chase failed to provide a clear PET image, confirming that all three steps are essential for adequate visualization of apoptosis. Furthermore, differences in action mechanisms between photosensitizers that target tumor cells directly or via initial vascular stasis were clearly recognized through differences in tracer uptake patterns detecting early or delayed apoptosis. This study demonstrates the efficacy of a three-step 64 Cu pretargeting procedure for PET imaging of apoptosis. Our data also confirm the usefulness of small animal PET to evaluate cancer treatment protocols. (orig.)

  7. Comparison of the serum cytokine levels before and after adrenocorticotropic hormone (ACTH) therapy in patients with infantile spasm.

    Science.gov (United States)

    Türe, Esra; Kamaşak, Tülay; Cora, Merve; Şahin, Sevim; Arslan, Elif Acar; Kaklıkaya, Neşe; Cansu, Ali

    2016-10-01

    Infantile spasm is an age-dependent epileptic syndrome seen in infancy or early childhood. Although studies have investigated the epilepsy-cytokine relationship, there has been insufficient research into the relation between cytokines and infantile spasm. The purpose of this study was to examine the role of cytokines in the pathogenesis of infantile spasm by investigating cytokine levels before and 1month after adrenocorticotropic hormone (ACTH) therapy in patients diagnosed with the condition. Twenty patients aged between 1month and 2years and diagnosed with infantile spasm at the Karadeniz Technical University Medical Faculty Department of Child Health and Diseases Pediatric Neurology Clinic, Turkey, and 20 healthy children were included in the study. Patients received 11 doses of ACTH on 2days a week. Levels of TNF-alpha and IL-2, the main cytokines involved in inflammation and recently associated with infantile spasm, and of IL-1beta, IL-6 and IL-17A, associated with epileptic seizures, and serum levels of the IL-17A activator IL-23 were investigated in all patients at the start of treatment and 1month after completion of treatment. No statistically significant difference was observed between pre- and post-treatment patient group and control group IL-1beta, IL-2, IL-23 or TNF-alpha levels. Pre-treatment IL-6 and IL-17A levels were significantly higher in the untreated patient group compared to the healthy control group (pinfantile spasm. Copyright © 2016. Published by Elsevier Ltd.

  8. Intravenous avidin chase improved localization of radiolabeled streptavidin in intraperitoneal xenograft pretargeted with biotinylated antibody

    International Nuclear Information System (INIS)

    Zhang Meili; Sakahara, Harumi; Yao Zhengsheng; Saga, Tsuneo; Nakamoto, Yuhi; Sato, Noriko; Nakada, Hiroshi; Yamashina, Ikuo; Konishi, Junji

    1997-01-01

    In the present study, we examined the effect of avidin administered intravenously (i.v.) on the biodistribution of radiolabeled streptavidin in mice bearing intraperitoneal (IP) xenografts pretargeted with biotinylated antibody. Tumors were established in nude mice by IP inoculation of LS180 human colon cancer cells. Monoclonal antibody MLS128, which recognizes Tn antigen on mucin, was biotinylated and injected IP into the IP tumor-bearing mice. Radioiodinated streptavidin was administered IP or i.v. 48 h after pretargeting of biotinylated antibody. Avidin was administered i.v. 30 min prior to streptavidin injection. The localization of radioiodinated streptavidin in the tumor pretargeted with biotinylated antibody was significantly higher than that without pretargeting and that of radioiodinated MLS128 by the one-step method. Avidin administration significantly accelerated the clearance of radioiodinated streptavidin in blood and other normal tissues and increased the tumor-to-blood radioactivity ratio regardless of administration route of streptavidin. The i.v. avidin chase improved tumor localization of radiolabeled streptavidin in the IP xenografts pretargeted with biotinylated antibody

  9. Trichuris suis ova therapy for allergic rhinitis does not affect allergen-specific cytokine responses despite a parasite-specific cytokine response

    DEFF Research Database (Denmark)

    Bourke, C.D.; Mutapi, F.; Nausch, N.

    2012-01-01

    Parasitic helminths have been shown to reduce inflammation in most experimental models of allergic disease, and this effect is mediated via cytokine responses. However, in humans, the effects of controlled helminth infection on cytokine responses during allergy have not been studied.......Parasitic helminths have been shown to reduce inflammation in most experimental models of allergic disease, and this effect is mediated via cytokine responses. However, in humans, the effects of controlled helminth infection on cytokine responses during allergy have not been studied....

  10. IMPACT OF ANTIVIRAL THERAPY FOR CHRONIC HEPATITIS C ON CYTOKINE SYNTHESIS AND HEPATIC FIBROSING PROCESSES

    Directory of Open Access Journals (Sweden)

    V. V. Shchekotov

    2015-01-01

    Full Text Available Objective: to estimate the time course of changes in the levels of tumor necrosis factor-α (TNF-α, interleukin-4 (IL-4, IL-6, and the hepatic fibrosis indicators hyaluronic acid (HA and liver elasticity index during combined antiviral therapy (AVT with interferon alpha-2b and ribavirin in patients with chronic hepatitis C (CHC. Subjects and methods. Fifty patients with CHC were examined. Serum TNF-α, IL-6, IL-4, and HA were estimated using an enzyme immunoassay. The stage of hepatic fibrosis was determined by fibroelastography with the liver elastic index being measured; the time course of changes in the indicators was assessed in 20 patients at the end of AVT. A virological response was monitored at therapy completion and 6 months later. Results. The patients with CHC in the reactivation phase were found to have enhanced TNF-α, IL-6, and IL-4 activities in 84, 60, and 100 % of the cases, respectively (р < 0.001, р = 0.01, р < 0.001, respectively. The median serum concentration of HA in CHC was 1.8-fold higher than that in the control group (p = 0.03; the liver elastic index averaged 6.5 kPa. TNF-α and IL-6 levels correlated with viremia, transaminases, and hepatic fibrosis indicators. At combined AVT completion, the virological response rate was as high as 85 %, which was attended by a considerable reduction in cytolysis, HA concentrations, and liver density index to 5.4 kPa (3.6–6.8 kPa (p < 0.04, and in the activity of the examined cytokines. The sustained virological response rate was 80 %. Only IL-4 levels decreased and TNF-α and IL-6 concentration remained at the baseline level in patients unresponsive to AVT. Conclusion. It is expedient to monitor TNF-α, IL-4, IL-6, and HA to evaluate the severity of liver involvement in CHC and to predict the efficiency of AVT.

  11. Antibody-Cytokine Fusion Proteins for the Therapy of Breast Cancer

    National Research Council Canada - National Science Library

    Morrison, Sherri

    2000-01-01

    We have proposed to develop novel antibody fusion proteins in which antibodies specific for the breast cancer tumor associated antigen HER2/neu will be genetically fused to the cytokines IL-2, IL-12, and GM-CSF...

  12. Identification of Predictive Biomarkers for Cytokine Release Syndrome after Chimeric Antigen Receptor T cell Therapy for Acute Lymphoblastic Leukemia

    Science.gov (United States)

    Teachey, David T.; Lacey, Simon F.; Shaw, Pamela A.; Melenhorst, J. Joseph; Maude, Shannon L.; Frey, Noelle; Pequignot, Edward; Gonzalez, Vanessa E.; Chen, Fang; Finklestein, Jeffrey; Barrett, David M.; Weiss, Scott L.; Fitzgerald, Julie C.; Berg, Robert A.; Aplenc, Richard; Callahan, Colleen; Rheingold, Susan R.; Zheng, Zhaohui; Rose-John, Stefan; White, Jason C.; Nazimuddin, Farzana; Wertheim, Gerald; Levine, Bruce L.; June, Carl H.; Porter, David L.; Grupp, Stephan A.

    2017-01-01

    Chimeric antigen receptor (CAR)-modified T cells with anti-CD19 specificity are a highly effective novel immune therapy for relapsed/refractory acute lymphoblastic leukemia (ALL). Cytokine release syndrome (CRS) is the most significant and life-threatening toxicity. To improve understanding of CRS, we measured cytokines and clinical biomarkers in 51 CTL019-treated patients. Peak levels of 24 cytokines, including IFNγ, IL6, sgp130, and sIL6R in the first month after infusion were highly associated with severe CRS. Using regression modeling, we could accurately predict which patients would develop severe CRS with a signature composed of three cytokines. Results validated in an independent cohort. Changes in serum biochemical markers, including C-reactive protein and ferritin, were associated with CRS but failed to predict development of severe CRS. These comprehensive profiling data provide novel insights into CRS biology, and importantly represent the first data that can accurately predict which patients have a high probability of becoming critically ill. PMID:27076371

  13. Plasma cytokine profiles in depressed patients who fail to respond to selective serotonin reuptake inhibitor therapy.

    LENUS (Irish Health Repository)

    O'Brien, Sinead M

    2012-02-03

    OBJECTIVE: Approximately 30% of patients with depression fail to respond to a selective serotonin reuptake inhibitor (SSRI). Few studies have attempted to define these patients from a biological perspective. Studies suggest that overall patients with depression show increased production of proinflammatory cytokines. We examined pro- and anti-inflammatory cytokine levels in patients who were SSRI resistant. METHODS: Plasma concentrations of IL-6, IL-8, IL-10, TNF-alpha and sIL-6R were measured with enzyme linked immunosorbent assays (ELISA) in DSM-1V major depressives who were SSRI resistant, in formerly SSRI resistant patients currently euthymic and in healthy controls. RESULTS: Patients with SSRI-resistant depression had significantly higher production of the pro-inflammatory cytokines IL-6 (p=0.01) and TNF-alpha (p=0.004) compared to normal controls. Euthymic patients who were formerly SSRI resistant had proinflammatory cytokine levels which were similar to the healthy subject group. Anti-inflammatory cytokine levels did not differ across the 3 groups. CONCLUSION: Suppression of proinflammatory cytokines does not occur in depressed patients who fail to respond to SSRIs and is necessary for clinical recovery.

  14. Salivary Cytokine Levels and Oral Mucositis in Head and Neck Cancer Patients Treated With Chemotherapy and Radiation Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Bossi, Paolo, E-mail: Paolo.bossi@istitutotumori.mi.it [Department of Head and Neck Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan (Italy); Bergamini, Cristiana [Department of Head and Neck Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan (Italy); Miceli, Rosalba [Clinical Epidemiology and Trial Organization Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan (Italy); Cova, Agata [Unity of Immunotherapy, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan (Italy); Orlandi, Ester [Radiotherapy 2 Unity, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan (Italy); Resteghini, Carlo; Locati, Laura; Alfieri, Salvatore; Imbimbo, Martina; Granata, Roberta [Department of Head and Neck Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan (Italy); Mariani, Luigi [Clinical Epidemiology and Trial Organization Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan (Italy); Iacovelli, Nicola Alessandro [Radiotherapy 2 Unity, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan (Italy); Huber, Veronica [Unity of Immunotherapy, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan (Italy); Cavallo, Anna [Department of Physics and Radiation Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan (Italy); Licitra, Lisa [Department of Head and Neck Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan (Italy); Rivoltini, Licia [Unity of Immunotherapy, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan (Italy)

    2016-12-01

    Purpose: We assessed the presence of salivary cytokines, their modulation during chemoradiation therapy (CTRT), and their association with oral mucositis severity in patients with head and neck cancer (HNC). Methods and Materials: The present prospective observational study enrolled 55 patients with locally advanced HNC requiring CTRT. We also studied 10 healthy volunteers and 10 patients with other cancers. The salivary levels of 13 cytokines were analyzed. We constructed a cytokine predictive score of oral mucositis severity. Results: The baseline salivary cytokine levels were not associated with the severity of treatment-induced oral mucositis. The cytokine levels overall increased during treatment, especially in patients with worse mucositis. In particular, on univariable analysis, an increase of interleukin (IL)-1β (area under the curve [AUC] 0.733; P=.009), IL-6 (AUC 0.746; P=.005), and tumor necrosis factor-α (AUC 0.710; P=.005) at the third week of treatment was significantly associated with the development of severe oral mucositis. On multivariable analysis, the predictive score based on the IL-1β and IL-6 changes from baseline to week 3 was an early strong predictor of higher grade oral mucositis. Conclusions: The treatment of HNC patients with concurrent CTRT induces a significant increase in the salivary levels of IL-1β, IL-6, and tumor necrosis factor-α, all positively associated with the severity of mucosal toxicity. A greater increase of IL-1β and IL-6 3 weeks after treatment initiation is predictive of worse oral mucositis, representing a potential tool for the early identification of patients at risk.

  15. Pretargeted radioimmunotherapy in rapidly progressing, metastatic, medullary thyroid cancer.

    Science.gov (United States)

    Kraeber-Bodéré, Françoise; Salaun, Pierre-Yves; Oudoux, Aurore; Goldenberg, David M; Chatal, Jean-François; Barbet, Jacques

    2010-02-15

    Medullary thyroid cancer (MTC) patients with localized residual disease and/or distant metastases may survive for several years or rapidly progress and die of their disease. Thus, highly reliable prognostic factors are needed for an early distinction between high-risk patients who need to be treated and low-risk patients who warrant a watch-and-wait approach. Calcitonin doubling time is an independent predictor of survival, with a high predictive value in a population of patients who have not normalized their calcitonin, even after repeated surgery. Several imaging methods should be proposed for patients with abnormal residual calcitonin levels persisting after complete surgery: ultrasonography and computed tomography (CT) for neck exploration, and CT for chest, abdomen, and pelvis. Magnetic resonance imaging (MRI) appears to have an advantage over CT for the detection of liver metastases from endocrine tumors. Moreover, MRI appears to be a sensitive imaging technique for detecting the spread of MTC to bone/bone marrow. 2-Fluoro-2-deoxy-D-glucose positron emission tomography/CT could be used for staging patients with progressive MTC, with possible prognostication by standard uptake value quantification. For systemic treatment of patients with rapidly progressing metastatic MTC, chemotherapy is not considered a valid therapeutic option. It is too early to evaluate the potential effectiveness of multikinase inhibitors, although interesting results of phase 2 studies have shown a transient stabilization in 30% to 50% of patients. Pretargeted radioimmunotherapy has been the only innovative treatment modality convincingly showing some survival benefit when compared with a historical untreated control group. (c) 2010 American Cancer Society.

  16. Effect of Maixuekang capsule therapy on optic nerve function, blood coagulation function and cytokines in diabetic optic neuropathy

    Directory of Open Access Journals (Sweden)

    Ya-Li Hao

    2016-12-01

    Full Text Available Objective: To analyze the effect of Maixuekang capsule therapy on optic nerve function, blood coagulation function and cytokines in diabetic optic neuropathy. Methods: A total of 55 patients (82 eyes with diabetic optic neuropathy treated in our hospital between December 2013 and December 2015 were selected, and according to different therapeutic methods, they were divided into observation group (n=38 (49 eyes who received Maixuekang therapy and control group (n=17 (33 eyes who received compound vitamin therapy. Differences in optic nerve function, blood coagulation function and cytokine content were compared between two groups after 3 months of treatment. Results: After 3 months of treatment, optic nerve function indexes MS, RNFL thickness and AP100 levels of observation group were higher than those of control group while MD and LP100 levels were lower than those of control group; blood coagulation indexes WBV, PV and FBG levels were lower than those of control group while TT, PT and APTT levels were higher than those of control group; thrombelastogram parameters R value and K value levels were higher than those of control group while α angle, MA and CI levels were lower than those of control group; oxidative stress indexes ROS, MDA and CAT content in serum were lower than those of control group while SOD content was higher than that of control group. Conclusions: Maixuekang capsule can significantly optimize the optic nerve function in patients with DON, which is specifically directly related to its anticoagulation and anti-oxidative stress effect.

  17. Increased streptavidin uptake in tumors pretargeted with biotinylated antibody using a conjugate of streptavidin-Fab fragment

    International Nuclear Information System (INIS)

    Yao Zhengsheng; Zhang Meili; Sakahara, Harumi; Saga, Tsuneo; Kobayashi, Hisataka; Nakamoto, Yuji; Toyama, Sakuji; Konishi, Junji

    1998-01-01

    Radiolabeled streptavidin accumulated in tumors pretargeted with biotinylated antibody. However, the absolute delivery of radioactivity was limited. To increase the tumor uptake of radioactivity further, we conjugated streptavidin with a mouse monoclonal antibody (MAb) fragment, OST6Fab, which recognizes antigen on human osteosarcoma. Another mouse MAb, OST7, which also reacts with the same tumor but recognizes an epitope different from the OST6 epitope, was biotinylated. The radioiodinated streptavidin-OST6Fab conjugate was administered to tumor-bearing mice after the biotinylated OST7 pretargeting. The uptake of the conjugate in tumors pretargeted with the biotinylated antibody was significantly higher than that of streptavidin and that of the conjugate of streptavidin and irrelevant Fab fragment. Renal uptake of radioactivity was decreased markedly, and the blood clearance was retarded by the conjugation with Fab fragment. In conclusion, the conjugate of streptavidin with specific Fab fragment increased the accumulation of radioactivity in tumors pretargeted with biotinylated antibody

  18. Outcomes of Patients with Renal Cell Carcinoma and Sarcomatoid Dedifferentiation Treated with Nephrectomy and Systemic Therapies: Comparison between the Cytokine and Targeted Therapy Eras.

    Science.gov (United States)

    Keskin, Sarp K; Msaouel, Pavlos; Hess, Kenneth R; Yu, Kai-Jie; Matin, Surena F; Sircar, Kanishka; Tamboli, Pheroze; Jonasch, Eric; Wood, Christopher G; Karam, Jose A; Tannir, Nizar M

    2017-09-01

    We studied overall survival and prognostic factors in patients with sarcomatoid renal cell carcinoma treated with nephrectomy and systemic therapy in the cytokine and targeted therapy eras. This is a retrospective study of patients with sarcomatoid renal cell carcinoma who underwent nephrectomy and received systemic therapy at our center in the cytokine era (1987 to 2005) or the targeted therapy era (2006 to 2015). Multivariate regression models were used to determine the association of covariables with survival. Of the 199 patients with sarcomatoid renal cell carcinoma 167 (83.9%) died (median overall survival 16.5 months, 95% CI 15.2-20.9). Survival of patients with clear cell histology was significantly longer vs those with nonclear cell histology (p = 0.034). Patients with synchronous metastatic disease had significantly shorter survival than patients with metachronous metastatic disease (median 12.1 vs 23.3 months, p = 0.0064). Biopsy of the primary tumor or a metastatic site could detect the presence of sarcomatoid features in only 7.5% of cases. Although a significant improvement in survival rate was observed in the first year in patients treated in the targeted therapy era (p = 0.011), this effect was attenuated at year 2, disappeared at years 3 to 5 after diagnosis and was not evident in patients with poor risk features. Patients with sarcomatoid renal cell carcinoma still have poor prognosis with no clear long-term benefit of targeted therapy. This underscores the need to develop more effective systemic therapies for these patients. Copyright © 2017 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

  19. The effect of beta-interferon therapy on myelin basic protein-elicited CD4+ T cell proliferation and cytokine production in multiple sclerosis

    DEFF Research Database (Denmark)

    Hedegaard, Chris J; Krakauer, Martin; Bendtzen, Klaus

    2008-01-01

    Interferon (IFN)-beta therapy has well-established clinical benefits in multiple sclerosis (MS), but the underlying modulation of cytokine responses to myelin self-antigens remains poorly understood. We analysed the CD4+ T cell proliferation and cytokine responses elicited by myelin basic protein...... (MBP) and a foreign recall antigen, tetanus toxoid (TT), in mononuclear cell cultures from fourteen MS patients undergoing IFN-beta therapy. The MBP-elicited IFN-gamma-, TNF-alpha- and IL-10 production decreased during therapy (p...

  20. Dual Functional Capability of Dendritic Cells - Cytokine-Induced Killer Cells in Improving Side Effects of Colorectal Cancer Therapy.

    Science.gov (United States)

    Mosińska, Paula; Gabryelska, Agata; Zasada, Malwina; Fichna, Jakub

    2017-01-01

    The aim of cancer therapy is to eradicate cancer without affecting healthy tissues. Current options available for treating colorectal cancer (CRC), including surgery, chemotherapy or radiotherapy, usually elicit multiple adverse effects and frequently fail to completely remove the tumor cells. Thus, there is a constant need for seeking cancer cell-specific therapeutics to improve the course of cancer therapy and reduce the risk of relapse. In this review we elaborate on the mechanisms underlying the immunotherapy with dendritic cells (DCs) and cytokine-induced killer (CIK) cells, and summarize their effectiveness and tolerability available clinical studies. Finally, we discuss the up-to-date combinatorial adoptive anti-cancer immunotherapy with CIK cells co-cultured with DCs that recently showed encouraging efficacy and usefulness in treating malignant disease, including CRC.

  1. Cytokines and dendritic cells as adjuvants for therapy of HPV16-associated tumours

    Czech Academy of Sciences Publication Activity Database

    Bubeník, Jan; Mikyšková, Romana; Reiniš, Milan; Mendoza, Luis; Indrová, Marie; Šmahel, M.; Vonka, V.

    2003-01-01

    Roč. 12, Supplement 1 (2003), s. S7 ISSN 1107-3756. [The 8th World Congress on Advances in Oncology and 6th Internationl Symposium on Molecular Medicine . Hernissos, Crete, 16.10.2003-18.10.2003] Institutional research plan: CEZ:AV0Z5052915 Keywords : HPV16 * dendritic cells * cytokines Subject RIV: FD - Oncology ; Hematology Impact factor: 1.940, year: 2003

  2. Cytokine Pattern of T Lymphocytes in Acute Schistosomiasis mansoni Patients following Treated Praziquantel Therapy

    Science.gov (United States)

    Silveira-Lemos, Denise; Fernandes Costa-Silva, Matheus; Cardoso de Oliveira Silveira, Amanda; Azevedo Batista, Mauricio; Alves Oliveira-Fraga, Lúcia; Soares Silveira, Alda Maria; Barbosa Alvarez, Maria Carolina; Martins-Filho, Olindo Assis; Gazzinelli, Giovanni; Corrêa-Oliveira, Rodrigo; Teixeira-Carvalho, Andréa

    2013-01-01

    Acute schistosomiasis is associated with a primary exposure and is more commonly seen in nonimmune individuals traveling through endemic regions. In this study, we have focused on the cytokine profile of T lymphocytes evaluated in circulating leukocytes of acute Schistosomiasis mansoni-infected patients (ACT group) before and after praziquantel treatment (ACT-TR group). Our data demonstrated increased values of total leukocytes, eosinophils, and monocytes in both groups. Interestingly, we have observed that patients treated with praziquantel showed increased values of lymphocytes as compared with noninfected group (NI) or ACT groups. Furthermore, a decrease of neutrophils in ACT-TR was observed when compared to ACT group. Analyses of short-term in vitro whole blood stimulation demonstrated that, regardless of the presence of soluble Schistosoma mansoni eggs antigen (SEA), increased synthesis of IFN-γ and IL-4 by T-cells was observed in the ACT group. Analyses of cytokine profile in CD8 T cells demonstrated higher percentage of IFN-γ and IL-4 cells in both ACT and ACT-TR groups apart from increased percentage of IL-10 cells only in the ACT group. This study is the first one to point out the relevance of CD8 T lymphocytes in the immune response induced during the acute phase of schistosomiasis. PMID:23401741

  3. Phase II trial of yttrium-90-DOTA-biotin pretargeted by NR-LU-10 antibody/streptavidin in patients with metastatic colon cancer

    International Nuclear Information System (INIS)

    Knox, S J.; Goris, M L.; Tempero, M.; Weiden, P L.; Gentner, L.; Breitz, H.; Adams, G. P.; Axworthy, D.; Gaffigan, S.; Bryan, K.; Fisher, Darrell R.; Colcher, D; Horak, I D.; Weiner, L M.

    1999-01-01

    A Phase II study of yttrium-90-tetra-azacyclododecanetetra-acetic acid-biotin (Y-90-DOTA-biotin) pretargeted by NR-LU-10 antibody/streptavidin (SA) was performed. The primary objectives of the study were to evaluate the efficacy and safety of this therapy in patients with metastatic colon cancer. Twenty-five patients were treated with a single dose of 110 mCi/m 2 (mean administered dose, 106.5-10.3 mCi/m 2 ) of Y-90-DOTA-biotin. There were three components of the therapy. Patients first received NR-LU-10/SA on day 1. A clearing agent (biotin-galactose-human serum albumin) was administered 48 h after the NR-LU-10/SA to remove residual circulating unbound NR-LU-10/SA. Lastly, 24 h after administration of clearing agent, patients received biotin-DOTA-labeled with 110 mCi/m 2 Y-90. All three components of the therapy were administered i.v. Both hematological and nonhematological toxicities were observed. Diarrhea was the most frequent grade 4 nonhematological toxicity (16%; with 16% grade 3 diarrhea). Hematological toxicity was less severe with 8% grade 3 and 8% grade 4 neutropenia and 8% grade 3 and 16% grade 4 thrombocytopenia. The overall response rate was 8%. Two partial responders had freedom from progression of 16 weeks. Four patients (16%) had stable disease with freedom from progression of 10-20 weeks. Despite the relatively disappointing results of this study in terms of therapeutic efficacy and toxicity, proof of principle was obtained for the pretargeting approach. In addition, valuable new information was obtained about normal tissue tolerance to low-dose-rate irradiation that will help to provide useful guidelines for future study designs

  4. The Tumor Necrosis Factor Superfamily of Cytokines in the Inflammatory Myopathies: Potential Targets for Therapy

    Directory of Open Access Journals (Sweden)

    Boel De Paepe

    2012-01-01

    Full Text Available The idiopathic inflammatory myopathies (IM represent a heterogeneous group of autoimmune diseases, of which dermatomyositis (DM, polymyositis (PM, and sporadic inclusion body myositis (IBM are the most common. The crucial role played by tumor necrosis factor alpha (TNFα in the IM has long been recognized. However, so far, 18 other members of the TNF superfamily have been characterized, and many of these have not yet received the attention they deserve. In this paper, we summarize current findings for all TNF cytokines in IM, pinpointing what we know already and where current knowledge fails. For each TNF family member, possibilities for treating inflammatory diseases in general and the IM in particular are explored.

  5. Effect of statin therapy on serum activity of proteinases and cytokines in patients with abdominal aortic aneurysm.

    Science.gov (United States)

    Muehling, Bernd; Oberhuber, Alexander; Schelzig, Hubert; Bischoff, Gisela; Marx, Nikolaus; Sunder-Plassmann, Ludger; Orend, Karl H

    2008-01-01

    Metalloproteinases (MMPs) are considered to be key enzymes in the pathogenesis of abdominal aortic aneurysms (AAA), with elevated levels in diseased aorta and in patient sera. Statins seem to exert an inhibitory effect on MMP activity in the aortic wall. No data exist on the effect of statins on serum activity of MMPs and inflammatory cytokines (interleukins, IL). The serum activities of MMP2 and MMP9, osteoprotegerin (OPG), and IL6 and IL10 in 63 patients undergoing elective infrarenal aneurysm repair were measured on the day before surgery. Levels were correlated to statin therapy and aneurysm diameter. There was no significant difference between the two groups in the activity of circulating levels of MMP2/9, OPG, and IL6/10 in patients with infrarenal aortic aneurysm. IL6 levels in patients with AAA larger than 6 cm were significantly elevated; differences in serum activities of MMP2/9, OPG, and IL10 were not related to AAA diameter. Serum activities of MMP2/9, OPG, and IL6/10 are not correlated to statin therapy; IL6 levels are higher in patients with large aneurysms. Hence the effect of statin therapy in the treatment of aneurysmal disease remains to be elucidated.

  6. CLINICAL EFFICIENCY AND INFLUENCE OF COMBINED ANTIHYPERTENSIVE THERAPY UPON CYTOKINE PROFILE IN THE PATIENTS WITH ARTERIAL HYPERTENSION

    Directory of Open Access Journals (Sweden)

    T. A. Dronova

    2009-01-01

    Full Text Available Abstract. We have evaluated effects of combined anti-hypertensive therapy upon the indexes of proinflammatory cytokines and clinical aspects of chronic heart failure among the patients suffering from essential hypertension (stages II-III, high and very high risk groups. The first group (n = 45 was treated with Enalapril + Hydrochlorothiazide, while the second group (n = 41 received Enalapril + Indapamide. Before starting the therapy, a pro-inflammatory cytokinemia was revealed, followed by a significant decrease of IL-6 and TNFαα levels in patients of the first group (p < 0,01, after two weeks of hospital treatment. During combined therapy, showed a sufficient decrease in systolic, diastolic and mean blood pressure levels for the both groups. A more pronounced regression of the mean blood pressure level was detected under Enalapril + Hydrochlorothiazide treatment (p < 0.002, accompanied by clinical improvement of chronic heart failure according to the clinical conditions rating scale (p < 0,001. Due to the correction of the systolic blood pressure level, all the patients showed adecrease in fatal risk of cardiovascular complications: they have left a high-risk group (5 to 10% SCORE for a low risk group (< 5 % SCORE.

  7. Effect of adjuvant levosimendan therapy on neuroendocrine hormones and cytokines in elderly patients with chronic heart failure

    Directory of Open Access Journals (Sweden)

    Li Lei

    2017-11-01

    Full Text Available Objective: To discuss the effect of adjuvant levosimendan therapy on neuroendocrine hormones and cytokines in elderly patients with chronic heart failure. Methods: A total of 100 elderly patients with chronic heart failure who were treated in the hospital between March 2014 and March 2017 were divided into control group and levosimendan group by random number table, each with 50 cases. Control group received clinical routine therapy for chronic heart failure, and levosimendan group received routine therapy combined with adjuvant levosimendan therapy. The differences in serum levels of RAAS indexes, thyroid hormones, myocardial damage indexes and endothelial function indexes were compared between the two groups before and after treatment. Results: At T0, there was no statistically significant difference in serum levels of RAAS indexes, thyroid hormones, myocardial damage indexes and endothelial function indexes between the two groups. At T1, serum RAAS indexes PRA, AngⅡ and ALD levels of levosimendan group were lower than those of control group; serum thyroid hormones TT3, TT4, FT3 and FT4 levels of levosimendan group were higher than those of control group; serum myocardial damage indexes cTnⅠ, H-FABP and NT-proBNP levels of levosimendan group were lower than those of control group; serum endothelial function index NO level of levosimendan group was higher than that of control group while ET-1 level was lower than that of control group. Conclusion: Adjuvant levosimendan therapy for elderly patients with chronic heart failure can effectively adjust the secretion of neuroendocrine hormones and reduce the myocardial and vascular endothelial damage.

  8. Improved pretargeted delivery of radiolabelled hapten to human tumour xenograft in mice by avidin chase of circulating bispecific antibody

    Energy Technology Data Exchange (ETDEWEB)

    Mirallie, Eric; Sai-Maurel, Catherine; Faivre-Chauvet, Alain; Chatal, Jean-Francois; Barbet, Jacques; Thedrez, Philippe [Universite de Nantes, Cancer Research Department, Nantes (France); Regenet, Nicolas [Service de Chirurgie, CHU Nantes, Nantes (France); Chang, Chien-Hsing; Goldenberg, David M. [IBC Pharmaceuticals Inc., Morris Plains, NJ (United States)

    2005-08-01

    Pretargeted therapy with radiolabelled bivalent haptens and bispecific antibodies has shown promising results, but blood clearance of the activity-carrying haptens under conditions designed for radioimmunotherapy is relatively slow. Thus, the chase of excess circulating bispecific antibody by biotinylation of the bispecific antibody and injection of avidin before hapten administration was tested with a view to increasing tumour-to-blood activity ratios. The anti-carcinoembryonic antigen (CEA) x anti-diethylene triamine penta-acetic acid-indium (di-DTPA-indium) bispecific antibody (hMN-14 x 734) was derivatised with NHS-LC-biotin and injected into LS-174T tumour-bearing nude mice at a dose of 3.5 nmol, followed by avidin and finally by the{sup 125}I-labelled di-DTPA-indium hapten (1 nmol). Blood samples were collected, animals sacrificed and tumours and normal tissues counted. Avidin chased up to 72% of the circulating antibody in the liver and the spleen within 30 min. When the labelled hapten was injected 3 h after avidin, tumour to blood ratios measured 3 and 24 h after hapten injection were significantly improved by the chase (3.5-fold), whereas tumour uptake was not significantly reduced. Uptake in normal tissues was unchanged (liver, kidney) or decreased (muscle), with the exception of spleen, in which uptake of both antibody and hapten was increased by the avidin chase. (orig.)

  9. Enhanced antitumor activity of combined pretargeted radioimmunotherapy and paclitaxel in medullary thyroid cancer xenograft.

    Science.gov (United States)

    Kraeber-Bodéré, Françoise; Saï-Maurel, Catherine; Campion, Loïc; Faivre-Chauvet, Alain; Mirallié, Eric; Chérel, Michel; Supiot, Stéphane; Barbet, Jacques; Chatal, Jean-François; Thédrez, Philippe

    2002-02-01

    A significant antitumor effect associated with moderate toxicity was obtained previously with anticarcinoembryonic antigen x antidiethylene-triaminepentaacetic acid (DTPA)-indium F6-734 bispecific antibody and iodine-131-labeled DTPA-indium bivalent hapten in an animal model of medullary thyroid cancer (MTC). The purpose of this study was to determine whether the cytotoxic agents doxorubicin and paclitaxel, also known as radiosensitizers, improve efficacy of pretargeted radioimmunotherapy (RIT) in experimental MTC. Nude mice bearing TT MTC xenograft were treated with F6-734 and iodine-131-labeled DTPA-indium bivalent hapten injected 48 h apart with or without doxorubicin or paclitaxel. The maximum tolerated dose (MTD) of RIT was 92.5 MBq (as determined previously) and that of doxorubicin and paclitaxel 200 and 1000 micrograms, respectively. A control group received no treatment. Animal weight, hematotoxicity, tumor volume, and serum calcitonin were monitored for 5 months. Tumor growth inhibition induced by drugs alone, RIT alone, or combined therapy was characterized by measuring relative tumor volume 20, 40, and 60 days after treatment to detect additivity or synergism. Mean tumor volume doubling time (MTVDT) was 13 +/- 4 days in the control group, 15 +/- 8 days in the group treated with the MTD of doxorubicin, and 32 +/- 13 days in the group treated with the MTD of paclitaxel. After RIT alone at 92.5 MBq, MTVDT was 86 +/- 22 days. After RIT at 74 MBq (80% of MTD), MTVDT was 56 +/- 10 days. MTVDT was not significantly different from this value after RIT plus doxorubicin, 60 +/- 16 days (65 and 100% of the respective single-agent MTDs). Combination of RIT with paclitaxel (65 and 100% of the respective single-agent MTDs) prolonged the suppression of tumor growth. One complete response was observed, and MTVDT was 114 +/- 44 days. This value was significantly longer than the value obtained with RIT alone at 74 MBq (P < 0.05) or with RIT combined with doxorubicin (P

  10. Comparison of IgG and F(ab')2 fragments of bispecific anti-RCCxanti-DTIn-1 antibody for pretargeting purposes.

    NARCIS (Netherlands)

    Schaijk, F.G. van; Boerman, O.C.; Soede, A.C.; McBride, W.J.; Goldenberg, D.M.; Corstens, F.H.M.; Oosterwijk, E.

    2005-01-01

    PURPOSE: An effective pretargeting strategy was developed for renal cell carcinoma (RCC) based on a biologically produced bispecific monoclonal antibody: anti-RCCxanti-DTPA(In) (bsMAb: G250xDTIn-1). Tumour uptake of a (111)In-labelled bivalent peptide after pretargeting with bsMAb G250xDTIn-1 was

  11. Effect of statin therapy on serum activity of proteinases and cytokines in patients with abdominal aortic aneurysm

    Directory of Open Access Journals (Sweden)

    Bernd Muehling

    2008-12-01

    Full Text Available Bernd Muehling1, Alexander Oberhuber1, Hubert Schelzig1, Gisela Bischoff1, Nikolaus Marx2, Ludger Sunder-Plassmann1, Karl H Orend11Department of Thoracic and Vascular surgery; 2Department of Internal Medicine, University of Ulm, Ulm, GermanyBackground and aims: Metalloproteinases (MMPs are considered to be key enzymes in the pathogenesis of abdominal aortic aneurysms (AAA, with elevated levels in diseased aorta and in patient sera. Statins seem to exert an inhibitory effect on MMP activity in the aortic wall. No data exist on the effect of statins on serum activity of MMPs and inflammatory cytokines (interleukins, IL.Methods: The serum activities of MMP2 and MMP9, osteoprotegerin (OPG, and IL6 and IL10 in 63 patients undergoing elective infrarenal aneurysm repair were measured on the day before surgery. Levels were correlated to statin therapy and aneurysm diameter.Results: There was no significant difference between the two groups in the activity of circulating levels of MMP2/9, OPG, and IL6/10 in patients with infrarenal aortic aneurysm. IL6 levels in patients with AAA larger than 6 cm were significantly elevated; differences in serum activities of MMP2/9, OPG, and IL10 were not related to AAA diameter.Conclusion: Serum activities of MMP2/9, OPG, and IL6/10 are not correlated to statin therapy; IL6 levels are higher in patients with large aneurysms. Hence the effect of statin therapy in the treatment of aneurismal disease remains to be elucidated.Keywords: biomarkers, aneurismal disease, statin therapy

  12. Terapia génica con citocinas contra cáncer cervicouterino Gene therapy with cytokines against cervical cancer

    Directory of Open Access Journals (Sweden)

    Víctor Hugo Bermúdez-Morales

    2005-12-01

    Full Text Available La terapia génica es una excelente alternativa para el tratamiento de muchas enfermedades. La capacidad para manipular el DNA ha permitido dirigir la terapia génica para corregir la función de un gen alterado, aumentar la expresión de un gen o activar la respuesta inmune. Así, se puede proponer el uso del DNA como un medicamento capaz de controlar, corregir o curar una enfermedad. La terapia génica contra cáncer tiene un potencial enorme, y en la última década se han obtenido resultados muy alentadores del uso del DNA para controlar diversas neoplasias en modelos animales, lo cual ha permitido su aplicación en protocolos experimentales en humanos. Esta revisión concentra una reseña de los fundamentos de la terapia génica y su aplicación en cáncer cervical, desde el punto de vista de las alteraciones de la respuesta inmune enfocadas al microambiente tumoral y el uso de las citocinas como moduladores de la respuesta inmune.Gene therapy is an excellent alternative for treatment of many diseases. Capacity to manipulate the DNA has allowed direct the gene therapy to correct the function of an altered gene, to increase the expression of a gene and to favour the activation of the immune response. This way, it can intend the use of the DNA like medication able to control, to correct or to cure many diseases. Gene therapy against cancer has an enormous potential, and actually the use of the DNA has increased to control diverse cancer in animal models, with very encouraging results that have allowed its applications in experimental protocols in human. This work concentrates a review of the foundations of the gene therapy and its application on cervical cancer, from the point of view of the alterations of the immune system focused on the tumour micro-environment, and the use of the cytokines as immunomodulators.

  13. Pre-targeted tumor imaging with avidin-McAb and 99Tcm-DTPA-Biotin

    International Nuclear Information System (INIS)

    Zhang Jinming; Tian Jiahe; Wang Yuqi; Liu Xi; Sun Xin

    2002-01-01

    Objective: Biotin-avidin is used as pre-targeting system (BAS) in radioimmunoimaging in order to decrease radiation background and dose associated with the use of directly labelled McAb. The authors tried to use 99 Tc m to substitute 111 In to label DTPA-biotin to evaluate the value of the 99 Tc m -DTPA-biotin in BAS. Methods: DTPA-biotin solution was mixed with SnCl 2 and then fresh eluted 99 Tc m . The solution incubated for 10 min at room temperature. Mice bearing lung tumor (LA-795) with and without metastases in lung underwent 3-step pre-targeting test. Briefly, biotin-C50 was injected first, then avidin and 99 Tc m -DTPA-biotin was respectively given 1 day, 2 days later. Directly labelled C50 with 99 Tc m was used as control agent. Results: The labelling yield of 99 Tc m -DTPA-biotin was over 90%. The amount of SnCl 2 was the key feature in labelling. The tumor could be seen at 2 h after injection of 99 Tc m -DTPA-biotin with γ camera in 3- step groups. The tracer uptake in tumor was (1.35 +- 0.45)% ID/g at 2 h after injection, Tumor/Blood (T/B) was 5.86, T/Muscle (T/M) was 8.43. In control group which received 99 Tc m -DTPA-biotin only, the T/B was 0.85, T/M 1.1. For the directly labelled C50, the T/B was 1.65, T/M was 2.0 at 8 h after injection. Conclusion: Avidin-biotin pre-targeting system can be labelled with 99 Tc m , and the BAS can image the tumor as early as 2 h after injection

  14. Cytokines and intestinal inflammation.

    Science.gov (United States)

    Bamias, Giorgos; Cominelli, Fabio

    2016-11-01

    Cytokines of the intestinal microenvironment largely dictate immunological responses after mucosal insults and the dominance of homeostatic or proinflammatory pathways. This review presents important recent studies on the role of specific cytokines in the pathogenesis of intestinal inflammation. The particular mucosal effects of cytokines depend on their inherent properties but also the cellular origin, type of stimulatory antigens, intermolecular interactions, and the particular immunological milieu. Novel cytokines of the interleukin-1 (IL-1) family, including IL-33 and IL-36, have dominant roles in mucosal immunity, whereas more established ones such as IL-18 are constantly enriched with unique properties. Th17 cells are important mucosal constituents, although their profound plasticity, makes the specific set of cytokines they secrete more important than their mere numbers. Finally, various cytokines, such as tumor necrosis factor-α, IL-6, tumor necrosis factor-like cytokine 1A, and death receptor, 3 demonstrate dichotomous roles with mucosa-protective function in acute injury but proinflammatory effects during chronic inflammation. The role of cytokines in mucosal health and disease is increasingly revealed. Such information not only will advance our understanding of the pathogenesis of gut inflammation, but also set the background for development of reliable diagnostic and prognostic biomarkers and cytokine-specific therapies.

  15. Modulation of cytokine release from human monocytes by drugs used in the therapy of inflammatory bowel diseases

    NARCIS (Netherlands)

    Bruin, K. F.; Hommes, D. W.; Jansen, J.; Tytgat, G. N.; ten Cate, J. Wouter; van Deventer, S. J.

    1995-01-01

    Cytokines produced in the gut mucosa play an important role in the pathogenesis of inflammatory bowel diseases (IBD). To determine whether drugs used in the treatment of these diseases modulate cytokine synthesis, we investigated their effects on endotoxin-induced tumour necrosis factor (TNF)-alpha,

  16. Effect of minimally invasive evacuation of hematoma combined with Xingnaojing therapy on neurological function injury and cytokine level in patients with hypertensive cerebral hemorrhagen

    OpenAIRE

    Yong-Feng Li; Wei Li

    2017-01-01

    Objective: To study the effect of minimally invasive evacuation of hematoma combined with Xingnaojing therapy on neurological function damage and cytokine level in patients with hypertensive cerebral hemorrhage. Methods: A total of 80 patients with hypertensive cerebral hemorrhage treated in our hospital between June 2010 and September 2015 were selected as the research subjects, the treatment methods and test results were reviewed, and then they were divided into the control g...

  17. Measurement of feline cytokines interleukin-12 and interferon- g produced by heat inducible gene therapy adenoviral vector using real time PCR

    International Nuclear Information System (INIS)

    Siddiqui, F.; Avery, P.R.; Ullrich, R.L.; LaRue, S.M.; Dewhirst, M.W.; Li, C.-Y.

    2003-01-01

    Biologic tumor therapy using Interleukin-12 (IL-12) has shown promise as an adjuvant to radiation therapy. The goals for cancer gene immunotherapy include effective eradication of established tumors and generation of a lasting systemic immune response. Among the cytokines, IL-12 has been found to be most effective gene in eradicating experimental tumors, preventing the development of metastases, and eliciting long-term antitumor immunity. Depending on the tumor model, IL-12 can exert antitumor activities via T cells, NK cells or NKT cells. It induces the production of IFN-g and IFN-inducible protein-10. It is also postulated to have antiangiogenic effects, thus inhibiting tumor formation and metastases. However, its use in clinical trials has been restricted largely owing to its systemic hematologic and hepatotoxicity. We tested the efficacy of adenovirus mediated expression of feline IL-12 gene placed under the control of an inducible promoter, the heat shock proteins (hsp70B). This places gene expression under the control of an external physical agent (hyperthermia), thus offering an 'on-off' switch and potentially reducing systemic toxicity by restricting its expression locally to the tumor. Crandell Feline Kidney (CrFK) cells were infected using the construct and the supernatant was then used to stimulate production of interferon g (IFN-g) in feline peripheral blood mononuclear cells (PBMC). As there is no commercially available ELISA kit currently available to detect or measure feline cytokines, we used real time-PCR to measure cytokine mRNA. These results will be used to initiate a clinical trial in cats with soft tissue sarcomas examining hyperthermia Induced gene therapy in conjunction with radiation therapy. The real time- PCR techniques developed here will be used to quantitatively measure cytokine mRNA levels in the punch biopsy samples obtained from the cats during the clinical trial. Support for this study was in part by NCI grant CA72745

  18. Proliferation, migration, and expression of oral-mucosal-healing-related genes by oral fibroblasts receiving low-level laser therapy after inflammatory cytokines challenge.

    Science.gov (United States)

    Basso, Fernanda G; Soares, Diana G; Pansani, Taisa N; Cardoso, Lais M; Scheffel, Débora L; de Souza Costa, Carlos Alberto; Hebling, Josimeri

    2016-12-01

    Increased expression of inflammatory cytokines in the oral cavity has been related to the etiopathogenesis of oral mucositis and to delayed oral mucosal repair. Low-level laser therapy (LLLT) stimulates proliferation and migration of gingival fibroblasts, but the effects of specific inflammatory cytokines on oral mucosal cells and the modulation of these effects by LLLT have not been fully investigated. Therefore, this study investigated the effects of LLLT on oral fibroblasts after being challenged by oral-mucositis-related inflammatory cytokines. Human gingival fibroblasts were seeded in plain culture medium (DMEM) containing 10% fetal bovine serum (FBS) for 24 hours. Then, cells were kept in contact with inflammatory cytokines (TNF-α, IL-1β, IL-6, and IL-8) in serum-free DMEM for 24 hours. After this period, cells were subjected to LLLT with a diode laser device (LaserTABLE, InGaAsP, 780 nm, 25 mW) delivering energy doses from 0.5 to 3 J/cm 2 . Irradiation was repeated for 3 consecutive days. Twenty-four hours after the last irradiation, cell migration (wound-healing and transwell migration assays), cell proliferation (BrdU), gene expression of COL-I and growth factors (real-time PCR), and synthesis of COL-I (Sirius Red assay) and VEGF (ELISA) were assessed. Data were subjected to two-way ANOVA and Tukey's tests or Kruskall-Walis and Mann-Whitney tests (P cytokines decreased the migration capacity of gingival fibroblasts. However, a statistically significant difference was observed only for IL-6, detected by transwell assay, where 30% less cells migrated through the pores (P cytokines, while growth factors and COL-I expression (approximately 80%; P cytokines. The opposite was seen for total collagen synthesis. LLLT promoted an acceleration of fibroblast migration (30%; P cytokines. Gene expression of VEGF (approximately 30%; P cytokines, especially IL-6 and IL-8 on gingival fibroblast functions directly related to the wound-healing process

  19. Improved pretargeted delivery of radiolabelled hapten to human tumour xenograft in mice by avidin chase of circulating bispecific antibody.

    Science.gov (United States)

    Mirallié, Eric; Saï-Maurel, Catherine; Faivre-Chauvet, Alain; Regenet, Nicolas; Chang, Chien-Hsing; Goldenberg, David M; Chatal, Jean-François; Barbet, Jacques; Thedrez, Philippe

    2005-08-01

    Pretargeted therapy with radiolabelled bivalent haptens and bispecific antibodies has shown promising results, but blood clearance of the activity-carrying haptens under conditions designed for radioimmunotherapy is relatively slow. Thus, the chase of excess circulating bispecific antibody by biotinylation of the bispecific antibody and injection of avidin before hapten administration was tested with a view to increasing tumour-to-blood activity ratios. The anti-carcinoembryonic antigen (CEA) x anti-diethylene triamine penta-acetic acid-indium (di-DTPA-indium) bispecific antibody (hMN-14x734) was derivatised with NHS-LC-biotin and injected into LS-174T tumour-bearing nude mice at a dose of 3.5 nmol, followed by avidin and finally by the 125I-labelled di-DTPA-indium hapten (1 nmol). Blood samples were collected, animals sacrificed and tumours and normal tissues counted. Avidin chased up to 72% of the circulating antibody in the liver and the spleen within 30 min. When the labelled hapten was injected 3 h after avidin, tumour to blood ratios measured 3 and 24 h after hapten injection were significantly improved by the chase (3.5-fold), whereas tumour uptake was not significantly reduced. Uptake in normal tissues was unchanged (liver, kidney) or decreased (muscle), with the exception of spleen, in which uptake of both antibody and hapten was increased by the avidin chase. The chase strategy reduces hapten concentration in blood and thus should reduce bone marrow exposure. The use of two different recognition systems limits possible interference between the chase and targeting steps.

  20. Circulating cytokines and procalcitonin in acute Q fever granulomatous hepatitis with poor response to antibiotic and short-course steroid therapy: a case report

    Directory of Open Access Journals (Sweden)

    Chang Lin-Li

    2010-07-01

    Full Text Available Abstract Background Q fever is a zoonosis distributed worldwide that is caused by Coxiella burnetii infection and the defervescence usually occurs within few days of appropriate antibiotic therapy. Whether the changes of cytokine levels are associated with acute Q fever with persistent fever despite antibiotic therapy had not been investigated before. Case Presentation We report a rare case of acute Q fever granulomatous hepatitis remained pyrexia despite several antibiotic therapy and 6-day course of oral prednisolone. During the 18-month follow-up, the investigation of the serum cytokines profile and procalcitonin (PCT revealed that initially elevated levels of interleukin-2 (IL-2, IL-8, IL-10, and PCT decreased gradually, but the IL-6 remained in low titer. No evidence of chronic Q fever was identified by examinations of serum antibodies against C. burnetii and echocardiography. Conclusions The changes of cytokine levels may be associated with acute Q fever with poor response to treatment and PCT may be an indicator for monitoring the response to treatment.

  1. [Development of Researches on Cytokine Mechanisms in Analgesia and Anti-inflammation in Acupuncture Therapy for Rheumatoid Arthritis].

    Science.gov (United States)

    Hong, Shou-Hai; Ding, Sha-Sha; Zhang, Kuo; Xu, Yuan; Zhao, Xue; Xuan, Li-Hua; Guo, Yi

    2016-10-25

    Cytokines are closely related to the occurrence and development of rheumatoid arthritis(RA). Acupuncture exerts anti-inflammatory and analgesic effects via elevating anti-inflammatory cytokine level and reducing pro-inflammatory cytokine level and regulating Th 1/Th 2 balance, which reflects the dual directional regulatory effect of acupuncture. However, problems exist in the current researches, such as inadequate depth, limited breadth and not so up-to-date research focus. The mediocre research level and the phenomena of some contradictory results among studies also need being concerned. Therefore, progress may be attained if a holistic, dynamic and networked study is conducted on the influence of acupuncture on cytokines by combining the latest progress in the mechanisms of network of cytokines and neuroendocrine immune network, and high throughput cytokine capture assay. In this way, the mechanism of cytokines in multi-targets (such as local joints, peripheral blood circulation, central nervous system) involving the effects of acupuncture in improving RA will be known more.

  2. Polymorphisms in Th1/Th2 Cytokine Genes, Hormone Replacement Therapy, and Risk of Non-Hodgkin Lymphoma

    International Nuclear Information System (INIS)

    Zhu, Gongjian; Pan, Dongsheng; Zheng, Tongzhang; Lan, Qing; Chen, Xuezhong; Chen, Yingtai; Kim, Christopher; Bi, Xiaofeng; Holford, Theodore; Boyle, Peter; Leaderer, Brian; Chanock, Stephen J.; Rothman, Nathaniel; Zhang, Yawei

    2011-01-01

    We conducted a population-based case–control study in Connecticut women to test the hypothesis that genetic variations in Th1 and Th2 cytokine genes modify the relationship between hormone replacement therapy (HRT) and risk of non-Hodgkin lymphoma (NHL). Compared to women without a history of HRT use, women with a history of HRT use had a significantly decreased risk of NHL if they carried IFNGR2 (rs1059293) CT/TT genotypes (OR = 0.5, 95%CI: 0.3–0.9), IL13 (rs20541) GG genotype (OR = 0.6, 95%CI: 0.4–0.9), and IL13 (rs1295686) CC genotype (OR = 0.6, 95%CI: 0.4–0.8), but not among women who carried IFNGR2 CC, IL13 AG/AA, and IL13CT/TT genotypes. A similar pattern was also observed for B-cell lymphoma but not for T-cell lymphoma. A statistically significant interaction was observed for IFNGR2 (rs1059293 P for interaction = 0.024), IL13(rs20541 P for interaction = 0.005), IL13 (rs1295686 P for interaction = 0.008), and IL15RA (rs2296135 P for interaction = 0.049) for NHL overall; IL13 (rs20541 P for interaction = 0.0009), IL13(rs1295686 P for interaction = 0.0002), and IL15RA (rs2296135 P for interaction = 0.041) for B-cell lymphoma. The results suggest that common genetic variation in Th1/Th pathway genes may modify the association between HRT and NHL risk.

  3. Cytokines in Sjogren's syndrome: potential therapeutic targets

    NARCIS (Netherlands)

    Roescher, N.; Tak, P.P.; Illei, G.G.

    2010-01-01

    The dysregulated cytokine network in Sjogren's Syndrome (SS) is reflected by local and systemic overexpression of pro-inflammatory cytokines and absent or low levels of anti-inflammatory cytokines. To date, the use of cytokine based therapies in SS has been disappointing. Oral administration of low

  4. Effect of minimally invasive evacuation of hematoma combined with Xingnaojing therapy on neurological function injury and cytokine level in patients with hypertensive cerebral hemorrhagen

    Directory of Open Access Journals (Sweden)

    Yong-Feng Li

    2017-06-01

    Full Text Available Objective: To study the effect of minimally invasive evacuation of hematoma combined with Xingnaojing therapy on neurological function damage and cytokine level in patients with hypertensive cerebral hemorrhage. Methods: A total of 80 patients with hypertensive cerebral hemorrhage treated in our hospital between June 2010 and September 2015 were selected as the research subjects, the treatment methods and test results were reviewed, and then they were divided into the control group (n=45 who accepted minimally invasive evacuation of hematoma alone and the observation group (n=35 who accepted minimally invasive evacuation of hematoma combined with Xingnaojing therapy. Before and after treatment, cerebral blood flow detector was used to detect cerebral blood flow parameters; ELISA method was used to detect serum levels of neurological function indexes and inflammatory cytokines; high performance liquid chromatograph was used to detect serum neurotransmitter levels. Results: Before treatment, the differences in cerebral blood flow parameters, neurological function indexes, inflammatory cytokines and neurotransmitters were not statistically significant between two groups of patients. After treatment, cerebral blood flow parameters Q and V levels of observation group were higher than those of control group while R level was lower than that of control group; serum NSE, NPY, IL-1β, IL-4, IL-6, TNF-α, Glu and Asp contents of observation group were lower than those of control group while BDNF and Gly contents were higher than those of control group. Conclusion: Minimally invasive evacuation of hematoma combined with Xingnaojing therapy can improve the neurological function and regulate the synthesis of inflammatory cytokines and neurotransmitters in patients with hypertension cerebral hemorrhage.

  5. The role of cytokines in development of hematological and immune disorders at radiation therapy for uterine body cancer

    International Nuclear Information System (INIS)

    Sorochan, P.P.; Prokhach, N.E.; Gromakova, Yi.A.; Krugova, Yi.M.; Sukhyin, V.S.

    2013-01-01

    The changes in hematological and immune parameters in patients with uterine body cancer were analyzed by the stages of the combined treatment. The rol of cytokines in the development of hematologic and immune disorders was assessed

  6. Cytokines and Bone Loss in a 5-Year Longitudinal Study—Hormone Replacement Therapy Suppresses Serum Soluble Interleukin-6 Receptor and Increases Interleukin-1-Receptor Antagonist

    DEFF Research Database (Denmark)

    Abrahamsen, B.; Bonnevie-Nielsen, V.; Ebbesen, E.N.

    2000-01-01

    The proinflammatory cytokines interleukin-1 beta (IL-1 beta) and IL-6 may play a central role in the acceleration of postmenopausal bone loss, but observational studies have led to contradictory results. Estrogen-dependent changes in the production of IL-1 receptor antagonist (IL-1ra) and the sol......The proinflammatory cytokines interleukin-1 beta (IL-1 beta) and IL-6 may play a central role in the acceleration of postmenopausal bone loss, but observational studies have led to contradictory results. Estrogen-dependent changes in the production of IL-1 receptor antagonist (IL-1ra......) and the soluble IL-6 receptor (sIL-6R) potentially modify cytokine bioactivity. We therefore assessed the impact of menopause and hormone replacement therapy (HRT) on cytokines and activity modifiers in serum within a 5-year longitudinal study. One hundred sixty perimenopausal women (age 50.1 +/- 2.8 years) were...... randomized to HRT or no treatment. Serum IL-6 increased with age (r = 0.16; p change in IL-1 beta. No changes were...

  7. Effects of combined therapy of traditional Chinese medicine and western medicine on platelets, coagulative functions and inflammatory cytokines with ulcerative colitis

    Directory of Open Access Journals (Sweden)

    Yun-Xia Lei

    2016-07-01

    Full Text Available Objective: To explore the effects of combined therapy of traditional Chinese medicine and western medicine on platelets, coagulative functions and inflammatory cytokines in patients with ulcerative colitis (UC. Methods: A total of 267 patients with UC were collected. 137 patients were treated with combined therapy of traditional Chinese medicine and western medicine as experimental group and 130 patients were treated with only western medicine as controls. Platelet count, coagulation function indexes and inflammatory cytokines were measured before and 15 d after the treatment. Results: No significantly differences were found in all indexes before treatment between two groups. After different treatments, platelet count (PLT, platelet distribution width (PDW were significantly decreased in both groups, but mean platelet volumn (MPV were significantly increased than before treatment. PLT and PDW were significantly lower and MPV were significantly higher in experimental group than control group. Fibrinogen (Fib and D-dimer (DD decreased significantly after treatment. Fib and DD in experimental group were significantly lower than controls. No significantly differences were found in activated partial thromboplastin time (APTT and prothrobin time (PT. Tumor necrosisi factor-α (TNF-α, interleukin-6 (IL-6 and interleukin-8 (IL-8 decreased significantly in both group after treatment. TNF-毩, IL-6 and IL-8 were significantly lower in experimental group than controls. Conclusion: Combined therapy of traditional Chinese medicine and western medicine can more effectively improve the cogulation, fibrinolysis and inflammation in patients with UC than only western medicine therapy.

  8. Targeted Cancer Therapy with Tumor Necrosis Factor-Alpha

    Directory of Open Access Journals (Sweden)

    Weibo Cai Ph.D.

    2008-01-01

    Full Text Available Tumor necrosis factor-alpha (TNF-α, a member of the TNF superfamily, was the first cytokine to be evaluated for cancer biotherapy. However, the clinical use of TNF-α is severely limited by its toxicity. Currently, TNF-α is administered only through locoregional drug delivery systems such as isolated limb perfusion and isolated hepatic perfusion. To reduce the systemic toxicity of TNF-α, various strategies have been explored over the last several decades. This review summarizes current state-of-the-art targeted cancer therapy using TNF-α. Passive targeting, cell-based therapy, gene therapy with inducible or tissue-specific promoters, targeted polymer-DNA complexes, tumor pre-targeting, antibody-TNF-α conjugate, scFv/TNF-α fusion proteins, and peptide/TNF-α fusion proteins have all been investigated to combat cancer. Many of these agents are already in advanced clinical trials. Molecular imaging, which can significantly speed up the drug development process, and nanomedicine, which can integrate both imaging and therapeutic components, has the potential to revolutionize future cancer patient management. Cooperative efforts from scientists within multiple disciplines, as well as close partnerships among many organizations/entities, are needed to quickly translate novel TNF-α-based therapeutics into clinical investigation.

  9. Cytokines, hepatic cell profiling and cell interactions during bone marrow cell therapy for liver fibrosis in cholestatic mice.

    Directory of Open Access Journals (Sweden)

    Daphne Pinheiro

    Full Text Available Bone marrow cells (BMC migrate to the injured liver after transplantation, contributing to regeneration through multiple pathways, but mechanisms involved are unclear. This work aimed to study BMC migration, characterize cytokine profile, cell populations and proliferation in mice with liver fibrosis transplanted with GFP+ BMC. Confocal microscopy analysis showed GFP+ BMC near regions expressing HGF and SDF-1 in the fibrotic liver. Impaired liver cell proliferation in fibrotic groups was restored after BMC transplantation. Regarding total cell populations, there was a significant reduction in CD68+ cells and increased Ly6G+ cells in transplanted fibrotic group. BMC contributed to the total populations of CD144, CD11b and Ly6G cells in the fibrotic liver, related to an increment of anti-fibrotic cytokines (IL-10, IL-13, IFN-γ and HGF and reduction of pro-inflammatory cytokines (IL-17A and IL-6. Therefore, HGF and SDF-1 may represent important chemoattractants for transplanted BMC in the injured liver, where these cells can give rise to populations of extrahepatic macrophages, neutrophils and endothelial progenitor cells that can interact synergistically with other liver cells towards the modulation of an anti-fibrotic cytokine profile promoting the onset of liver regeneration.

  10. Reduced Fc∊RI-Mediated Release of Asthma-Promoting Cytokines and Chemokines from Human Basophils during Omalizumab Therapy

    Science.gov (United States)

    Oliver, Janet M.; Tarleton, Christy A.; Gilmartin, Laura; Archibeque, Tereassa; Qualls, Clifford R.; Diehl, Lorena; Wilson, Bridget S.; Schuyler, Mark

    2010-01-01

    Background Treating asthmatics with the humanized IgE-scavenging antibody, omalizumab (rhuMAb-E25, Xolair®), reduces airways inflammation and asthma symptoms. Previously, omalizumab was shown to cause a dramatic and reversible loss of cell surface high-affinity IgE receptors, Fc∊RI, from the peripheral blood basophils of asthmatics. The consequences of receptor loss for the Fc∊RI-mediated synthesis and release of cytokines implicated in allergic asthma have not been examined. Methods Fifteen asthmatic volunteers each received omalizumab for 12 weeks. Peripheral blood basophils were isolated before, during, 2 weeks after and 6 months after omalizumab. Basophils were assayed for the basal and anti-IgE-stimulated release of cytokines, chemokines and histamine. Pooled data were analyzed by repeated measures ANOVA and by paired t tests. Results Anti-IgE-stimulated human basophils synthesize and release Th2 cytokines (IL-4, IL-13) and chemokines (IL-8, RANTES). The anti-IgE-stimulated release of IL-4, IL-13 and IL-8 was reduced during omalizumab treatment and returned to pretreatment levels after omalizumab withdrawal. Omalizumab did not alter basophil histamine levels or basal and anti-IgE-stimulated histamine release. Conclusions Omalizumab may reduce asthma symptoms in part by suppressing the Fc∊RI-mediated production by basophils of Th2 cytokines and selected chemokines. Anti-IgE-stimulated basophil cytokine synthesis appears more sensitive than histamine release to the loss of Fc∊RI caused by omalizumab treatment. PMID:19844128

  11. Herpes Simplex Virus Suppressive Therapy in Herpes Simplex Virus-2/Human Immunodeficiency Virus-1 Coinfected Women Is Associated With Reduced Systemic CXCL10 But Not Genital Cytokines.

    Science.gov (United States)

    Andersen-Nissen, Erica; Chang, Joanne T; Thomas, Katherine K; Adams, Devin; Celum, Connie; Sanchez, Jorge; Coombs, Robert W; McElrath, M Juliana; Baeten, Jared M

    2016-12-01

    Herpes simplex virus type-2 (HSV-2) may heighten immune activation and increase human immunodeficiency virus 1 (HIV-1) replication, resulting in greater infectivity and faster HIV-1 disease progression. An 18-week randomized, placebo-controlled crossover trial of 500 mg valacyclovir twice daily in 20 antiretroviral-naive women coinfected with HSV-2 and HIV-1 was conducted and HSV-2 suppression was found to significantly reduce both HSV-2 and HIV-1 viral loads both systemically and the endocervical compartment. To determine the effect of HSV-2 suppression on systemic and genital mucosal inflammation, plasma specimens, and endocervical swabs were collected weekly from volunteers in the trial and cryopreserved. Plasma was assessed for concentrations of 31 cytokines and chemokines; endocervical fluid was eluted from swabs and assayed for 14 cytokines and chemokines. Valacyclovir significantly reduced plasma CXCL10 but did not significantly alter other cytokine concentrations in either compartment. These data suggest genital tract inflammation in women persists despite HSV-2 suppression, supporting the lack of effect on transmission seen in large scale efficacy trials. Alternative therapies are needed to reduce persistent mucosal inflammation that may enhance transmission of HSV-2 and HIV-1.

  12. Changes in T-cell subpopulations and cytokine network during early period of ibrutinib therapy in chronic lymphocytic leukemia patients: the significant decrease in T regulatory cells number.

    Science.gov (United States)

    Podhorecka, Monika; Goracy, Aneta; Szymczyk, Agnieszka; Kowal, Malgorzata; Ibanez, Blanca; Jankowska-Lecka, Olga; Macheta, Arkadiusz; Nowaczynska, Aleksandra; Drab-Urbanek, Elzbieta; Chocholska, Sylwia; Jawniak, Dariusz; Hus, Marek

    2017-05-23

    B cell receptor (BCR) stimulation signal plays an important role in the pathogenesis of chronic lymphocytic leukemia (CLL), and kinase inhibitors directed toward the BCR pathway are now the promising anti-leukemic drugs. Ibrutinib, a Bruton tyrosine kinase inhibitor, demonstrates promising clinical activity in CLL. It is reported that ibrutinib, additionally to directly targeting leukemic cells, also inhibits the interactions of these cells with T cells, macrophages and accessory cells. Assessment of these mechanisms is important because of their non -direct anti-leukemic effects and to identify possible side effects connected with long-term drug administration.The aim of this study was to assess the in vivo effects of ibrutinib on T-cell subpopulations and cytokine network in CLL. The analysis was performed on a group of 19 patients during first month of ibrutinib therapy. The standard multicolor flow cytometry and cytometric bead array methods were used for assessment of T-cell subsets and cytokines/chemokines, respectively.The data obtained indicates that Ibrutinib treatment results in changes in T-cell subpopulations and cytokine network in CLL patients. Particularly, a significant reduction of T regulatory cells in peripheral blood was observed. By targeting these populations of T cells Ibrutinib can stimulate rejection of tumor cells by the immune system.

  13. Evaluation of a new biotin-DOTA conjugate for pretargeted antibody-guided radioimmunotherapy (PAGRIT {sup registered})

    Energy Technology Data Exchange (ETDEWEB)

    Urbano, Nicoletta; Papi, Stefano; Paganelli, Giovanni; Chinol, Marco [European Institute of Oncology, Division of Nuclear Medicine, Milan (Italy); Ginanneschi, Mauro [University of Florence and CNR-ICOM, Polo Scientifico, Laboratory of Peptides and Proteins, Chemistry and Biology, Sesto Fiorentino (Italy); De Santis, Rita; Pace, Silvia; Lindstedt, Ragnar; Ferrari, Liliana [Sigma Tau SpA R and D, Pomezia, Rome (Italy); Choi, Sun Ju [Korea Atomic Energy Research Institute, Taejeon (Korea)

    2007-01-15

    A novel biotin-DOTA conjugate (r-BHD: reduced biotinamidohexylamine-DOTA) was investigated in order to provide an efficient pretargeted antibody-guided radioimmunotherapy (PAGRIT {sup registered}) application. Preclinical and clinical results are described. {sup 90}Y and {sup 177}Lu were used to label r-BHD. The effect of pH and a wide range of specific activities were studied. Radiolabelled r-BHD was tested for affinity towards avidin and for stability in saline or in human serum with and without ascorbic acid. Pharmacokinetic data were collected and organ biodistribution evaluated in a tumour-bearing pretargeted animal model. A pilot study was performed in a metastatic melanoma patient and dosimetry was estimated. High radiochemical purity (>99%) was routinely achieved with {sup 90}Y or {sup 177}Lu in sodium acetate buffer (1.0 M, pH 5.0) at a specific activity of 2.6 MBq/nmol. Both {sup 90}Y- and {sup 177}Lu-r-BHD were also prepared at higher specific activities. Radiolabelled r-BHD was stable up to 96 h in human serum and saline with the addition of ascorbic acid. The structural modifications proposed for the r-BHD stabilised it against enzymatic degradation while retaining high binding affinity for avidin. Renal clearance appeared to be the main route of excretion in animals, and high tumour uptake was observed in the pretargeted animals. The patient study showed a total body clearance of {proportional_to}85% in 24 h, with a kidney absorbed dose of 1.5 mGy/MBq. Tumour uptake was rapid and the calculated dose to a 10-mm tumour lesion was {proportional_to}12 mGy/MBq. These results indicate that the new biotin-DOTA conjugate may be a suitable candidate for pretargeting trials. (orig.)

  14. Pretargeted radioimmunotherapy of colorectal cancer metastases: models and pharmacokinetics predict influence of the physical and radiochemical properties of the radionuclide

    Energy Technology Data Exchange (ETDEWEB)

    Frampas, Eric; Maurel, Catherine; Remaud-Le Saec, Patricia; Mauxion, Thibault; Faivre-Chauvet, Alain; Davodeau, Francois; Bardies, Manuel; Barbet, Jacques [Universite de Nantes, Inserm, UMR 892, Centre de Recherche en Cancerologie Nantes-Angers (CRCNA), Nantes (France); Goldenberg, David M. [Immunomedics, Inc., Morris Plains, NJ (United States); Center for Molecular Medicine and Immunology, Garden State Cancer Center, Morris Plains, NJ (United States)

    2011-12-15

    We investigated influences of pretargeting variables, tumor location, and radionuclides in pretargeted radioimmunotherapy (PRIT) as well as estimated tumor absorbed doses. LS-174T human colonic carcinoma cells expressing carcinoembryonic antigen (CEA) were inoculated in nude mice. Biodistribution of a bispecific anti-CEA x anti-hapten antibody, TF2, and of a TF2-pretargeted peptide was assessed and a multi-compartment pharmacokinetic model was devised. Tissue absorbed doses were calculated for {sup 131}I, {sup 177}Lu, {sup 90}Y, {sup 211}At, and {sup 213}Bi using realistic specific activities. Under conditions optimized for tumor imaging (10:1 TF2 to peptide molar ratio, interval time 15-24 h), tumor uptake reached {proportional_to}9 ID/g in subcutaneous tumors at 2 h with very low accretion in normal tissues (tumor to blood ratio >20:1 after 2 h). For a low dose of peptide (0.04 nmol), {sup 211}At is predicted to deliver a high absorbed dose to tumors [41.5 Gy considering a relative biologic effect (RBE) of 5], kidneys being dose-limiting. {sup 90}Y and {sup 213}Bi would also deliver high absorbed doses to tumor (18.6 for {sup 90}Y and 26.5 Gy for {sup 213}Bi, taking RBE into account, for 0.1 nmol) and acceptable absorbed doses to kidneys. With hepatic metastases, a twofold higher tumor absorbed dose is expected. Owing to the low activities measured in blood, the bone marrow absorbed dose is expected to be without significant toxicity. Pretargeting achieves high tumor uptake and higher tumor to background ratios compared to direct RIT. Short-lived radionuclides are predicted to deliver high tumor absorbed doses especially {sup 211}At, with kidneys being the dose-limiting organ. {sup 177}Lu and {sup 131}I should be considered for repeated injections. (orig.)

  15. Manipulation of pre-target activity on the right frontal eye field enhances conscious visual perception in humans.

    Directory of Open Access Journals (Sweden)

    Lorena Chanes

    Full Text Available The right Frontal Eye Field (FEF is a region of the human brain, which has been consistently involved in visuo-spatial attention and access to consciousness. Nonetheless, the extent of this cortical site's ability to influence specific aspects of visual performance remains debated. We hereby manipulated pre-target activity on the right FEF and explored its influence on the detection and categorization of low-contrast near-threshold visual stimuli. Our data show that pre-target frontal neurostimulation has the potential when used alone to induce enhancements of conscious visual detection. More interestingly, when FEF stimulation was combined with visuo-spatial cues, improvements remained present only for trials in which the cue correctly predicted the location of the subsequent target. Our data provide evidence for the causal role of the right FEF pre-target activity in the modulation of human conscious vision and reveal the dependence of such neurostimulatory effects on the state of activity set up by cue validity in the dorsal attentional orienting network.

  16. Synthesis and evaluation of 99mTc/99Tc-MAG3-biotin conjugates for antibody pretargeting strategies

    International Nuclear Information System (INIS)

    Gog, Frank B. van; Visser, Gerard W.M.; Gowrising, Radjish W.A.; Snow, Gordon B.; Dongen, Guus A.M.S. van

    1998-01-01

    Four 99m Tc-MAG3-biotin conjugates were synthesized to determine their potential use in antibody pretargeting strategies for radioimmunoscintigraphy (RIS). To use these 99m Tc-MAG3-biotin conjugates as model compounds for 186 Re-MAG3-biotin conjugates for radioimmunotherapy (RIT), nanomolar amounts of 99 Tc were added as carrier to 99m Tc. The biotin derivatives used for the preparation of the conjugates - biocytin, biotin hydrazide, biotinyl-piperazine, and biotinyl-diaminosuccinic acid - differed at the site that is regarded to be susceptible to hydrolysis by biotinidase present in human plasma. All four conjugates were produced with high radiochemical purity, were stable in PBS, and demonstrated full binding capacity to streptavidin. The 99m Tc/ 99 Tc-MAG3-labeled biotinyl-piperazine and biotinyl-diaminosuccinic acid conjugates were stable in mouse as well as human plasma, whereas the corresponding biocytin and biotin hydrazide conjugates were rapidly degraded. The biodistribution in nude mice at 30 min after injection was similar for all conjugates, and a rapid blood clearance and high intestinal excretion were both observed. It is concluded that the metabolic routing of a conjugate containing biotin and MAG3 is dominated by these two moieties. For this reason, MAG3-biotin conjugates do not seem suited for pretargeted RIT, for which quantitative and fast renal excretion is a prerequisite to minimize radiation toxicity. However, in a pretargeted RIS approach the 99m Tc-MAG3-biotin conjugates might have potential

  17. Predominant cerebral cytokine release syndrome in CD19-directed chimeric antigen receptor-modified T cell therapy

    Directory of Open Access Journals (Sweden)

    Yongxian Hu

    2016-08-01

    Full Text Available Abstract Chimeric antigen receptor-modified (CAR T cells targeting CD19 (CART19 have shown therapeutical activities in CD19+ malignancies. However, the etiological nature of neurologic complications remains a conundrum. In our study, the evidence of blood-brain barrier (BBB-penetrating CAR T cells as a culprit was revealed. A patient with acute lymphocytic leukemia developed sustained pyrexia with tremors about 6 h after CART19 infusion, followed by a grade 2 cytokine release syndrome (CRS and neurological symptoms in the next 3 days. Contrast-enhanced magnetic resonance showed signs of intracranial edema. Lumbar puncture on day 5 showed an over 400-mmH2O cerebrospinal pressure. The cerebrospinal fluid (CSF contained 20 WBCs/μL with predominant CD3+ T cells. qPCR analysis for CAR constructs showed 3,032,265 copies/μg DNA in CSF and 988,747 copies/μg DNA in blood. Cytokine levels including IFN-γ and IL-6 in CSF were extremely higher than those in the serum. Methyprednisone was administrated and the symptoms relieved gradually. The predominance of CART19 in CSF and the huge discrepancies in cytokine distributions indicated the development of a cerebral CRS, presumably featured as CSF cytokines largely in situ produced by BBB-penetrating CAR T cells. For the first time, we reported the development of cerebral CRS triggered by BBB-penetrating CAR T cells. Trial registration: ChiCTR-OCC-15007008 .

  18. ¹⁸F-FDG PET predicts survival after pretargeted radioimmunotherapy in patients with progressive metastatic medullary thyroid carcinoma.

    Science.gov (United States)

    Salaun, Pierre-Yves; Campion, Loïc; Ansquer, Catherine; Frampas, Eric; Mathieu, Cédric; Robin, Philippe; Bournaud, Claire; Vuillez, Jean-Philippe; Taieb, David; Rousseau, Caroline; Drui, Delphine; Mirallié, Eric; Borson-Chazot, Françoise; Goldenberg, David M; Chatal, Jean-François; Barbet, Jacques; Kraeber-Bodéré, Françoise

    2014-08-01

    PET is a powerful tool for assessing targeted therapy. Since (18)F-FDG shows a potential prognostic value in medullary thyroid carcinoma (MTC), this study evaluated (18)F-FDG PET alone and combined with morphological and biomarker evaluations as a surrogate marker of overall survival (OS) in patients with progressive metastatic MTC treated with pretargeted anti-CEA radioimmunotherapy (pRAIT) in a phase II clinical trial. Patients underwent PET associated with morphological imaging (CT and MRI) and biomarker evaluations, before and 3 and 6 months, and then every 6 months, after pRAIT for 36 months. A combined evaluation was performed using anatomic, metabolic and biomarker methods. The prognostic value of the PET response was compared with demographic parameters at inclusion including age, sex, RET mutation, time from initial diagnosis, calcitonin and CEA concentrations and doubling times (DT), SUVmax, location of disease and bone marrow involvement, and with response using RECIST, biomarker concentration variation, impact on DT, and combined methods. Enrolled in the study were 25 men and 17 women with disease progression. The median OS from pRAIT was 3.7 years (0.2 to 6.5 years) and from MTC diagnosis 10.9 years (1.7 to 31.5 years). After pRAIT, PET/CT showed 1 patient with a complete response, 4 with a partial response and 24 with disease stabilization. The combined evaluation showed 20 responses. For OS from pRAIT, univariate analysis showed the prognostic value of biomarker DT (P = 0.011) and SUVmax (P = 0.038) calculated before pRAIT and impact on DT (P = 0.034), RECIST (P = 0.009), PET (P = 0.009), and combined response (P = 0.004) measured after pRAIT. PET had the highest predictive value with the lowest Akaike information criterion (AIC 74.26) as compared to RECIST (AIC 78.06), biomarker variation (AIC 81.94) and impact on DT (AIC 79.22). No benefit was obtained by combining the methods (AIC 78.75). This result was confirmed by the

  19. {sup 18}F-FDG PET predicts survival after pretargeted radioimmunotherapy in patients with progressive metastatic medullary thyroid carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Salaun, Pierre-Yves; Robin, Philippe [University Hospital, Nuclear Medicine Department, Brest (France); Campion, Loic [ICO-Gauducheau Cancer Institute, Statistical Department, Nantes (France); Ansquer, Catherine; Mathieu, Cedric [University Hospital, Nuclear Medicine Department, Nantes (France); Frampas, Eric [University Hospital, Radiology Department, Nantes (France); Universite de Nantes, Nantes-Angers Cancer Research Center, Inserm, U 892, CNRS, UMR 6299, Nantes (France); Bournaud, Claire [University Hospital, Nuclear Medicine Department, Lyon (France); Vuillez, Jean-Philippe [University Hospital, Nuclear Medicine Department, Grenoble (France); Taieb, David [University Hospital, Nuclear Medicine Department, Marseille (France); Rousseau, Caroline [Universite de Nantes, Nantes-Angers Cancer Research Center, Inserm, U 892, CNRS, UMR 6299, Nantes (France); ICO-Rene Gauducheau, Nuclear Medicine Department, Nantes (France); Drui, Delphine [University Hospital, Endocrinology Department, Nantes (France); Mirallie, Eric [University Hospital, Surgery Department, Nantes (France); Borson-Chazot, Francoise [University Hospital, Endocrinology Department, Lyon (France); Goldenberg, David M. [IBC Pharmaceuticals, Inc., and Immunomedics, Inc., Morris Plains, NJ (United States); Center for Molecular Medicine and Immunology, Garden State Cancer Center, Morris Plains, NJ (United States); Chatal, Jean-Francois [GIP ARRONAX, Saint-Herblain (France); Barbet, Jacques [Universite de Nantes, Nantes-Angers Cancer Research Center, Inserm, U 892, CNRS, UMR 6299, Nantes (France); GIP ARRONAX, Saint-Herblain (France); Kraeber-Bodere, Francoise [University Hospital, Nuclear Medicine Department, Nantes (France); Universite de Nantes, Nantes-Angers Cancer Research Center, Inserm, U 892, CNRS, UMR 6299, Nantes (France); ICO-Rene Gauducheau, Nuclear Medicine Department, Nantes (France); Hotel Dieu University Hospital, Nuclear Medicine Department, Nantes (France)

    2014-08-15

    PET is a powerful tool for assessing targeted therapy. Since {sup 18}F-FDG shows a potential prognostic value in medullary thyroid carcinoma (MTC), this study evaluated {sup 18}F-FDG PET alone and combined with morphological and biomarker evaluations as a surrogate marker of overall survival (OS) in patients with progressive metastatic MTC treated with pretargeted anti-CEA radioimmunotherapy (pRAIT) in a phase II clinical trial. Patients underwent PET associated with morphological imaging (CT and MRI) and biomarker evaluations, before and 3 and 6 months, and then every 6 months, after pRAIT for 36 months. A combined evaluation was performed using anatomic, metabolic and biomarker methods. The prognostic value of the PET response was compared with demographic parameters at inclusion including age, sex, RET mutation, time from initial diagnosis, calcitonin and CEA concentrations and doubling times (DT), SUV{sub max}, location of disease and bone marrow involvement, and with response using RECIST, biomarker concentration variation, impact on DT, and combined methods. Enrolled in the study were 25 men and 17 women with disease progression. The median OS from pRAIT was 3.7 years (0.2 to 6.5 years) and from MTC diagnosis 10.9 years (1.7 to 31.5 years). After pRAIT, PET/CT showed 1 patient with a complete response, 4 with a partial response and 24 with disease stabilization. The combined evaluation showed 20 responses. For OS from pRAIT, univariate analysis showed the prognostic value of biomarker DT (P = 0.011) and SUV{sub max} (P = 0.038) calculated before pRAIT and impact on DT (P = 0.034), RECIST (P = 0.009), PET (P = 0.009), and combined response (P = 0.004) measured after pRAIT. PET had the highest predictive value with the lowest Akaike information criterion (AIC 74.26) as compared to RECIST (AIC 78.06), biomarker variation (AIC 81.94) and impact on DT (AIC 79.22). No benefit was obtained by combining the methods (AIC 78.75). This result was confirmed by the

  20. Novel carcinoembryonic-antigen-(CEA)-specific pretargeting system to assess tumor cell viability after irradiation of colorectal cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Meller, Birgit [Univ. Medical Center, Goettingen Univ. (Germany). Dept. of Nuclear Medicine; Halle Univ. (Germany). Dept. of Nuclear Medicine; Rave-Fraenck, Margarete [Univ. Medical Center, Goettingen Univ. (Germany). Dept. of Radiotherapy and Radiation Oncology; Breunig, Christian [Luebeck Univ. (Germany). Dept. of Radiology and Nuclear Medicine; Schirmer, Markus [Univ. Medical Center, Goettingen Univ. (Germany). Dept. of Clinical Pharmacology; Baehre, Manfred [Halle Univ. (Germany). Dept. of Nuclear Medicine; Nadrowitz, Roger [Luebeck Univ. (Germany). Dept. of Radiotherapy; Liersch, Torsten [Univ. Medical Center, Goettingen Univ. (Germany). Dept. of General Surgery; Meller, Johannes [Univ. Medical Center, Goettingen Univ. (Germany). Dept. of Nuclear Medicine

    2011-02-15

    Purpose: To date, no valid imaging modality exists for early response prediction to neoadjuvant radiochemotherapy in carcinoembryonic-antigen-(CEA)-expressing rectal cancers (UICC stages II and III). It is hypothesized that the uptake of an anti-CEA antibody is directly related to the number of viable tumor cells and may be quantified by immuno-positron emission tomography (immuno-PET). Therefore, we evaluated a novel pretargeting system using TF2, a humanized bispecific trivalent monoclonal antibody (mAb), directed against CEA and the IMP-288-peptide, a hapten for binding radiometals for imaging. Uptake and kinetics of the pretargeting system were investigated in vitro prior to and after irradiation. Methods: TF2 was labeled with {sup 131}I and IMP-288 with {sup 111}InCl{sub 3}. The colorectal cancer cell lines HT29, SW480, and T84 with known varying CEA expression were incubated ({<=} 72 hours) with {sup 131}I-TF2 or the TF2-{sup 111}In-IMP-288 pretargeting system. Parallel cultures were irradiated with 2-10 Gy high-energy photons. Tracer uptake, proliferation, apoptosis, and CEA-RNA expression of cancer cells were investigated. Results: The uptake of tracers was dependent on CEA expression and cell count of the cell lines (uptake/106 cells: 0.3% in HT29, 1.5% in SW480, and 14% in T84, p < 0.001). The TF2-{sup 111}In-IMP-288 pretargeting system showed a higher uptake after 4 and 72 hours compared to {sup 131}I-TF2 in parallel cultures. Only in one cell line (SW480) an increased apoptosis after irradiation could be detected. Irradiation increased dose dependently both the specific uptake of {sup 131}I-TF2 and of the TF2-{sup 111}In-IMP-288 system (4-fold in HT29 and T84 after 10 Gy (72 hours), p < 0.001). These results were CEA-mRNA independent. Conclusion: This novel pretargeting system allows the quantitative analysis of CEA-expressing colorectal cancer cells and represents a promising tool for evaluation of tumor cell viability after irradiation. (orig.)

  1. Affinity enhancement bivalent morpholino for pretargeting: initial evidence by surface plasmon resonance.

    Science.gov (United States)

    He, Jiang; Liu, Guozheng; Vanderheyden, Jean-Luc; Dou, Shuping; Mary, Rusckoswki; Hnatowich, Donald J

    2005-01-01

    Pretargeting with bivalent effectors capable of bridging antitumor antibodies has been reported to provide superior results by affinity enhancement. Morpholinos (MORFs) and other DNA analogues used for pretargeting are ideally suited as bivalent effectors since they are easily synthesized and the distance between binding regions, likely to be a determinant of binding, may be adjusted simply by lengthening the chain. The goal of this investigation was to synthesize a bivalent MORF and to determine by surface plasmon resonance (SPR) whether the bivalent MORF exhibited bimolecular binding and whether the MORFs showed improved in vitro hybridization affinity in its bivalent form compared to its monovalent form. An 18 mer amino-derivitized MORF was made bivalent by dimerizing with disuccinimidyl suberate (DSS) in 1-methyl-2-pyrrolidinone (NMP) with N,N-diisopropylethylamine (DIEA) followed by purification by ion exchange chromatography. The in vitro hybridization affinity of bivalent compared to monovalent MORF was then measured by SPR. For these measurements, the complementary biotinylated cDNA was immobilized at coating densities that provided an average spacing of 20-100 angstroms and used to investigate the influence of this spacing on binding of the bivalent MORF with its binding regions separated by 25 A. The yield of bivalent MORF was as high as 45%, and the structure was confirmed by MALDI-TOF mass spectroscopy. When the sensograms obtained by SPR were analyzed using different binding models, the evidence was consistent with bimolecular binding of the bivalent MORF. The dissociation rate constant of the bivalent compared to monovalent MORF was more than 10-fold lower at 2.14 compared to 0.27 x 10(-5) (1/s) (p < 0.05), and since the association rate constants were similar at 8.53 and 5.64 x 10(5) (1/M.s) (p = 0.08), the equilibrium constant for hybridization to the immobilized cDNA of the bivalent compared to the monovalent MORF was almost 20-fold higher at 3

  2. Effect of olanzapine combined with modified electroconvulsive therapy on cytokines, sTNFRs and neural electrophysiological characteristics in patients with schizophrenia

    Directory of Open Access Journals (Sweden)

    Wei Cheng

    2016-12-01

    Full Text Available Objective: To analyze the effect of olanzapine combined with modified electroconvulsive therapy on cytokines, sTNFRs and neural electrophysiological characteristics in patients with schizophrenia. Methods: Patients with schizophrenia treated in our hospital between March 2013 and March 2016 were selected and randomly divided into two groups, the observation group received olanzapine combined with modified electroconvulsive therapy, and the control group received olanzapine therapy. After 6 weeks of treatment, serum levels of soluble tumor necrosis factor receptor (sTNFR, acute phase reaction proteins and brain function indexes as well as the neural electrophysiological characteristics were compared between the two groups. Results: After 6 weeks of treatment, serum sTNFRs, CRP, CER and AAG content of observation group were lower than those of control group while TRF content was higher than that of control group; serum brain function indexes NGF and BDNF content were higher than those of control group while GFAP, S100B, NSE and Hcy content were lower than those of control group; nerve electrophysiology indexes P300, LPP and ERN amplitude were higher than those of control group while LPP amplitude was lower than that of control group. Conclusions: Olanzapine combined with modified electroconvulsive therapy can optimize the condition of schizophrenia, reduce the abnormal degree of nerve electrophysiology and help to improve treatment outcome.

  3. Adaptive T cell responses induced by oncolytic Herpes Simplex Virus-granulocyte macrophage-colony-stimulating factor therapy expanded by dendritic cell and cytokine-induced killer cell adoptive therapy.

    Science.gov (United States)

    Ren, Jun; Gwin, William R; Zhou, Xinna; Wang, Xiaoli; Huang, Hongyan; Jiang, Ni; Zhou, Lei; Agarwal, Pankaj; Hobeika, Amy; Crosby, Erika; Hartman, Zachary C; Morse, Michael A; H Eng, Kevin; Lyerly, H Kim

    2017-01-01

    Purpose : Although local oncolytic viral therapy (OVT) may enhance tumor lysis, antigen release, and adaptive immune responses, systemic antitumor responses post-therapy are limited. Adoptive immunotherapy with autologous dendritic cells (DC) and cytokine-induced killer cells (DC-CIK) synergizes with systemic therapies. We hypothesized that OVT with Herpes Simplex Virus-granulocyte macrophage-colony-stimulating factor (HSV-GM-CSF) would induce adaptive T cell responses that could be expanded systemically with sequential DC-CIK therapy. Patients and Methods : We performed a pilot study of intratumoral HSV-GM-CSF OVT followed by autologous DC-CIK cell therapy. In addition to safety and clinical endpoints, we monitored adaptive T cell responses by quantifying T cell receptor (TCR) populations in pre-oncolytic therapy, post-oncolytic therapy, and after DC-CIK therapy. Results : Nine patients with advanced malignancy were treated with OVT (OrienX010), of whom seven experienced stable disease (SD). Five of the OVT treated patients underwent leukapheresis, generation, and delivery of DC-CIKs, and two had SD, whereas three progressed. T cell receptor sequencing of TCR β sequences one month after OVT therapy demonstrates a dynamic TCR repertoire in response to OVT therapy in the majority of patients with the systematic expansion of multiple T cell clone populations following DC-CIK therapy. This treatment was well tolerated and long-term event free and overall survival was observed in six of the nine patients. Conclusions : Strategies inducing the local activation of tumor-specific immune responses can be combined with adoptive cellular therapies to expand the adaptive T cell responses systemically and further studies are warranted.

  4. Experimental study of biotin-avidin pretargeting technique for anti-CEA McAb radioimmunoimaging

    International Nuclear Information System (INIS)

    Sun Jianzhong; Zhu Chengmo; Guan Liang; Li Biao; Zhang Jixian; Shi Ailan; Zhang Suyin

    1996-01-01

    Biotin-avidin pretargeting technique was used in promoting the diagnostic efficacy of anti-CEA McAb radioimmunoimaging. CEA McAb was conjugated with biotin McAb (B-McAb), streptavidin (SA) was labeled with 131 I ( 131 I-SA) and DTPA-biotin with 111 In( 111 In-DTPA-B). Experimental human colonic tumor bearing nude mice were used. Two step method: B-McAb was preinjected, followed by 131 I SA 48h later, 24, 48, 96 and 120 h postinjection, γ-imaging and biodistribution were studied. Three step method: B-McAb was preinjected, followed by cold SA 24h later and 111 In-DTPA-B another 24h later. 2,6,24 and 48h postinjection, γ-imaging and biodistribution were also studied. Two step method: T/NT of all organs in experimental group was significantly increased compared with controls. The blood T/NT in experimental group and control group at 24 and 120h was 1.11:0.42 and 8.58:3.51, respectively. Tumor % ID/g in all organs slightly decreased compared with direct group. In γ-imaging radioactivity has been accumulated in tumor site as early as 24h, while only slightly visualized or non-visualized in controls. Three step method: in experimental group the blood T/NT reached 4.19 at 2 h, whereas all was < 1.37 at each phase of controls, the T/NT of all organs was also higher in experimental grouped than in controls. The tumor % ID/g in experimental group was 9.72% at 2h and 3.65% at 48h whereas % ID/g in controls in all phases was <3.07. The tumor clearly visualized at 2h and clearer at 48h in γ-imaging. In controls, the tumor was slightly visualized also to early stage, but faded away later on. Biotin-avidin pretargeting technique can elevate the T/NT ratio and decrease the blood background. Early imaging was obtained with better imaging quality

  5. Twelve-Month Antiretroviral Therapy Suppresses Plasma and Genital Viral Loads but Fails to Alter Genital Levels of Cytokines, in a Cohort of HIV-Infected Rwandan Women.

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    Pascale Ondoa

    Full Text Available Genital viral load (GVL is the main determinant of sexual transmission of human immune-deficiency virus (HIV. The effect of antiretroviral therapy (ART on local cervico-vaginal immunological factors associated with GVL is poorly described. We aimed to identify the risk factors of detectable GVL, and the impact of ART on HIV genital shedding and its correlates in a cohort of HIV-infected women, attending HIV care in Kigali, Rwanda.All participants were evaluated for GVL, plasma viral load (PVL, CD4 count, various sexually-transmitted infections (STIs at baseline and at month 12. Genital concentration of 19 cytokines and mRNA expression of APOBEC3G and BST2, two host HIV restriction factors, were evaluated at baseline in all participants. Cytokine levels were re-assessed at month 12 only in participants eligible for ART at baseline. Risk factors of GVL ≥ 40 copies/mL at baseline and month 12 were assessed using logistic regression. Effect of 12-month ART on various local and systemic immunological parameters was examined using a paired t-test and McNemar as appropriate.96 of the 247 women enrolled in the study were eligible for ART. After 12 months of ART, PVL and GVL decreased to undetectable level in respectively 74 and 88% of treated participants. ART did not affect cytokine levels. HIV genital shedding occurred only when PVL was detectable. At baseline, GVL was independently associated with IL-1β after controlling for PVL, age and N. gonorrhea infection (95% CI 1.32-2.15 and at month 12 with MIP-1β (95% CI 0.96-21.32 after controlling for baseline GVL, PVL and month 12 IL-8.Suppressive ART does not necessarily reduce genital level of immune activation. Minimizing all conditions favoring genital inflammation, including active detection and treatment of STIs, might reduce the risk of HIV transmission as supplement to the provision of potent ART.

  6. Pretargeting CD45 enhances the selective delivery of radiation to hematolymphoid tissues in nonhuman primates

    Energy Technology Data Exchange (ETDEWEB)

    Green, Damian J.; Pagel, John M.; Nemecek, Eneida R.; Lin, Yukang; Kenoyer, Aimee L.; Pantelias, Anastasia; Hamlin, Donald K.; Wilbur, D. S.; Fisher, Darrell R.; Rajendran, Joseph G.; Gopal, Ajay K.; Park, Steven I.; Press, Oliver W.

    2009-08-06

    Pretargeted radioimmunotherapy (PRIT) is designed to enhance the directed delivery of radionuclides to malignant cells. Through a series of studies in nineteen nonhuman primates (M. fascicularis) the potential therapeutic advantage of anti-CD45 PRIT was evaluated. Anti-CD45 PRIT demonstrated a significant improvement in target-to-normal organ ratios of absorbed radiation when compared to directly radiolabeled bivalent antibody (conventional radioimmunotherapy [RIT]). Radio-DOTA-biotin administered 48 hours after anti-CD45 streptavidin fusion protein (FP) [BC8 (scFv)4SA] produced markedly lower concentrations of radiation in non-target tissues when compared to conventional RIT. PRIT generated superior target:normal organ ratios in the blood, lung and liver (10.3:1, 18.9:1 and 9.9:1 respectively) when compared to the conventional RIT controls (2.6:1, 6.4:1 and 2.9:1 respectively). The FP demonstrated superior retention in target tissues relative to comparable directly radiolabeled bivalent anti-CD45 RIT. The time-point of administration of the second step radiolabeled ligand (radio-DOTA-biotin) significantly impacted the biodistribution of radioactivity in target tissues. Rapid clearance of the FP from the circulation rendered unnecessary the addition of a synthetic clearing agent in this model. These results support proceeding to anti-CD45 PRIT clinical trials for patients with both leukemia and lymphoma.

  7. Effect of rehabilitation training combined with hyperbaric oxygen therapy on the nerve cytokine secretion and oxidative stress in rehabilitation period of patients with cerebral infarction

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    Ling Kong

    2017-11-01

    Full Text Available Objective: To discuss the influence of rehabilitation training combined with hyperbaric oxygen therapy on the nerve cytokine secretion and oxidative stress in rehabilitation period of patients with cerebral infarction. Methods: A total of 110 patients with cerebral infarction who received rehabilitation therapy in the hospital between January 2015 and May 2017 were divided into routine group (n=55 and hyperbaric oxygen group (n=55 according to random number table. Routine group received regular rehabilitation training, and hyperbaric oxygen group underwent rehabilitation training combined with hyperbaric oxygen therapy. The differences in the serum contents of nerve factors, neurotransmitters and oxidative stress indexes were compared between the two groups at immediately after admission (T0 and after 14 d of treatment (T1. Results: At T0, there was no statistically significant difference in the serum contents of nerve factors, neurotransmitters and oxidative stress indexes between the two groups. At T1, serum nerve factors MBP and NSE contents of hyperbaric oxygen group were lower than those of routine group while NGF content was higher than that of routine group; serum neurotransmitter Glu content was lower than that of routine group while GABA content was higher than that of routine group; serum oxidative stress indexes ROS and LHP contents were lower than those of routine group while CAT and SOD contents were higher than those of routine group. Conclusion: Rehabilitation training combined with hyperbaric oxygen therapy can effectively optimize the nerve function and inhibit the systemic oxidative stress response in rehabilitation period of patients with cerebral infarction.

  8. Reaming in treatment of non-unions in long bones: cytokine expression course as a tool for evaluation of non-union therapy.

    Science.gov (United States)

    Westhauser, Fabian; Zimmermann, Gerald; Moghaddam, Sanaz; Bruckner, Tom; Schmidmaier, Gerhard; Biglari, Bahram; Moghaddam, Arash

    2015-08-01

    The analysis of peripheral serum cytokine expression patterns has been shown to be a possible method for demonstrating changes in bone metabolism. The aim of this study is to evaluate the effectiveness of this method within the treatment of long bone non-union with intramedullary reaming, a well-established non-union treatment concept. Three groups were added to this study: group one (G1) suffered from long bone non-unions, treated successfully with intramedullary reaming; group two (G2) consisted of long bone fractures with proper fracture healing; and group three (G3) included long bone fractures resulting in non-unions. We took blood samples on day 2, and after week 1, 4, 6, month 3 and 6 after initial treatment. Clinical and radiological follow-up were provided for 6 months. We measured transforming growth factor ß-1 (TGFß-1), platelet-derived growth factor (PDGF-AB), and insulin like growth factor-1 (IGF-1) at all-time points. TGF-ß1 levels in G1 and G2 increased from day 2 to 6 weeks after surgery. In general, G1 and G2 showed parallel TGF-ß1 expression patterns, and G3 had a significant peak during first week compared to G1 (p = 0.023). PDGF peaked in G3 during first week after treatment, whereas G1 had its maximum after 4 weeks and G2 after 6 weeks. We were able to detect a significantly lower PDGF concentration at 3 months in G1 compared to G3 (p = 0.029). IGF-1 showed a peak concentration in G1 during the first 4 weeks. Afterwards, concentration levels in both G1 and G2 were higher. Our study was able to show that the cytokine expression pattern in physiological bone healing is similar to that in successful non-union treatment with intramedullary reaming. Our results show that the effect of non-union therapy could be observed objectively by measuring cytokine expression patterns in peripheral blood even in a small group of patients.

  9. Restoring Lost Anti-HER-2 Th1 Immunity in Breast Cancer: A Crucial Role for Th1 Cytokines in Therapy and Prevention.

    Science.gov (United States)

    Nocera, Nadia F; Lee, M Catherine; De La Cruz, Lucy M; Rosemblit, Cinthia; Czerniecki, Brian J

    2016-01-01

    The ErbB/B2 (HER-2/neu) oncogene family plays a critical role in the development and metastatic spread of several tumor types including breast, ovarian and gastric cancer. In breast cancer, HER-2/neu is expressed in early disease development in a large percentage of DCIS lesions and its expression is associated with an increased risk of invasion and recurrence. Targeting HER-2 with antibodies such as trastuzumab or pertuzumab has improved survival, but patients with more extensive disease may develop resistance to therapy. Interestingly, response to HER-2 targeted therapies correlates with presence of immune response genes in the breast. Th1 cell production of the cytokines interferon gamma (IFNγ) and TNFα can enhance MHC class I expression, PD-L1 expression, augment apoptosis and tumor senescence, and enhances growth inhibition of many anti-breast cancer agents, including anti-estrogens and HER-2 targeted therapies. Recently, we have identified that a loss of anti-HER-2 CD4 Th1 in peripheral blood occurs during breast tumorigenesis and is dramatically diminished, even in Stage I breast cancers. The loss of anti-HER-2 Th1 response is specific and not readily reversed by standard therapies. In fact, this loss of anti-HER-2 Th1 response in peripheral blood correlates with lack of complete response to neoadjuvant therapy and diminished disease-free survival. This defect can be restored with HER-2 vaccinations in both DCIS and IBC. Correcting the anti-HER-2 Th1 response may have significant impact in improving response to HER-2 targeted therapies. Development of immune monitoring systems for anti-HER-2 Th1 to identify patients at risk for recurrence could be critical to improving outcomes, since the anti-HER-2 Th1 response can be restored by vaccination. Correction of the cellular immune response against HER-2 may prevent recurrence in high-risk patients with DCIS and IBC at risk of developing new or recurrent breast cancer.

  10. Restoring Lost Anti-HER-2 Th1 Immunity in Breast Cancer: A Crucial Role for Th1 Cytokines in Therapy and Prevention

    Directory of Open Access Journals (Sweden)

    Nadia F Nocera

    2016-10-01

    Full Text Available The ErbB/B2 (HER-2/neu oncogene family plays a critical role in the development and metastatic spread of several tumor types including breast, ovarian and gastric cancer. In breast cancer, HER-2/neu is expressed in early disease development in a large percentage of DCIS lesions and its expression is associated with an increased risk of invasion and recurrence. Targeting HER-2 with antibodies such as trastuzumab or pertuzumab has improved survival, but patients with more extensive disease may develop resistance to therapy. Interestingly, response to HER-2 targeted therapies correlates with presence of immune response genes in the breast. Th1 cell production of the cytokines interferon gamma (IFNγ and TNFα can enhance MHC class I expression, PD1L expression, augment apoptosis and tumor senescence, and enhances growth inhibition of many anti-breast cancer agents, including anti-estrogens and HER-2 targeted therapies. Recently, we have identified that a loss of anti-HER-2 CD4 Th1 in peripheral blood occurs during breast tumorigenesis and is dramatically diminished, even in Stage I breast cancers. The loss of anti-HER-2 Th1 response is specific and not readily reversed by standard therapies. In fact, this loss of anti-HER-2 Th1 response in peripheral blood correlates with lack of complete response to neoadjuvant therapy and diminished disease-free survival. This defect can be restored with HER-2 vaccinations in both DCIS and IBC. Correcting the anti-HER-2 Th1 response may have significant impact in improving response to HER-2 targeted therapies. Development of immune monitoring systems for anti-HER-2 Th1 to identify patients at risk for recurrence could be critical to improving outcomes, since the anti-HER-2 Th1 response can be restored by vaccination. Correction of the cellular immune response against HER-2 may prevent recurrence in high-risk patients with DCIS and IBC at risk of developing new or recurrent breast cancer.

  11. Anti-CD45 pretargeted radioimmunotherapy using bismuth-213: high rates of complete remission and long-term survival in a mouse myeloid leukemia xenograft model

    Science.gov (United States)

    Kenoyer, Aimee L.; Bäck, Tom; Hamlin, Donald K.; Wilbur, D. Scott; Fisher, Darrell R.; Park, Steven I.; Frayo, Shani; Axtman, Amanda; Orgun, Nural; Orozco, Johnnie; Shenoi, Jaideep; Lin, Yukang; Gopal, Ajay K.; Green, Damian J.; Appelbaum, Frederick R.; Press, Oliver W.

    2011-01-01

    Pretargeted radioimmunotherapy (PRIT) using an anti-CD45 antibody (Ab)–streptavidin (SA) conjugate and DOTA-biotin labeled with β-emitting radionuclides has been explored as a strategy to decrease relapse and toxicity. α-emitting radionuclides exhibit high cytotoxicity coupled with a short path length, potentially increasing the therapeutic index and making them an attractive alternative to β-emitting radionuclides for patients with acute myeloid leukemia. Accordingly, we have used 213Bi in mice with human leukemia xenografts. Results demonstrated excellent localization of 213Bi-DOTA-biotin to tumors with minimal uptake into normal organs. After 10 minutes, 4.5% ± 1.1% of the injected dose of 213Bi was delivered per gram of tumor. α-imaging demonstrated uniform radionuclide distribution within tumor tissue 45 minutes after 213Bi-DOTA-biotin injection. Radiation absorbed doses were similar to those observed using a β-emitting radionuclide (90Y) in the same model. We conducted therapy experiments in a xenograft model using a single-dose of 213Bi-DOTA-biotin given 24 hours after anti-CD45 Ab-SA conjugate. Among mice treated with anti-CD45 Ab-SA conjugate followed by 800 μCi of 213Bi- or 90Y-DOTA-biotin, 80% and 20%, respectively, survived leukemia-free for more than 100 days with minimal toxicity. These data suggest that anti-CD45 PRIT using an α-emitting radionuclide may be highly effective and minimally toxic for treatment of acute myeloid leukemia. PMID:21613259

  12. Survival improvement in patients with medullary thyroid carcinoma who undergo pretargeted anti-carcinoembryonic-antigen radioimmunotherapy: a collaborative study with the French Endocrine Tumor Group.

    Science.gov (United States)

    Chatal, Jean-François; Campion, Loïc; Kraeber-Bodéré, Françoise; Bardet, Stephane; Vuillez, Jean-Philippe; Charbonnel, Bernard; Rohmer, Vincent; Chang, Chien-Hsing; Sharkey, Robert M; Goldenberg, David M; Barbet, Jacques

    2006-04-10

    No effective therapy is currently available for the management of patients with metastatic medullary thyroid carcinoma (MTC). The efficacy of pretargeted radioimmunotherapy (pRAIT) with bispecific monoclonal antibody (BsMAb) and a iodine-131 (131I) -labeled bivalent hapten is evaluated. Twenty-nine patients with advanced, progressive MTC, as documented by short serum calcitonin doubling times (Ct DTs), received an anti-carcinoembryonic antigen (CEA)/anti-diethylenetriamine pentaacetic acid (DTPA) -indium BsMAb, followed 4 days later by a 131I-labeled bivalent hapten. Overall survival (OS) was compared with 39 contemporaneous untreated MTC patients with comparable prognostic indicators. OS was significantly longer in high-risk, treated patients (Ct DT < 2 years) than in high-risk, untreated patients (median OS, 110 v 61 months; P < .030). Forty-seven percent of patients, defined as biologic responders by a more than 100% increase in CtDT, experienced significantly longer survival than nonresponders (median OS, 159 v 109 months; P < .035) and untreated patients (median OS, 159 v 61 months; P < .010). Treated patients with bone/bone-marrow disease had a longer survival than patients without such involvement (10-year OS, 83% v 14%; P < .023). Toxicity was mainly hematologic and related to bone/bone-marrow tumor spread. pRAIT against CEA induced long-term disease stabilization and a significantly longer survival in high-risk patients with Ct DTs less than 2 years, compared with similarly high-risk, untreated patients. Ct DT and bone-marrow involvement appear to be prognostic indicators in MTC patients who undergo pRAIT.

  13. SMAC mimetic BV6 enables sensitization of resistant tumor cells but also affects cytokine-induced killer (CIK cells: a potential challenge for combination therapy

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    Eva eRettinger

    2014-07-01

    Full Text Available Allogeneic hematopoietic stem cell transplantation (HSCT is an established treatment option for high-risk hematological malignancies, and may also be offered to patients with solid malignancies refractory to conventional therapies. In case of patients’ relapse, refractory tumor cells may then be targeted by cellular therapy-based combination strategies. Here, we investigated the potential of small molecule IAP inhibitor (SMAC mimetic BV6 in increasing cytokine-induced killer (CIK cell-mediated cytotoxicity against different tumor targets. Four hour pre-incubation with 2.5 μMol BV6 moderately enhanced CIK cell-mediated lysis of hematological (H9, THP-1, Tanoue and solid malignancies (RH1, RH30, TE671. However, BV6 also increased apoptosis of non-malignant cells like peripheral blood mononuclear cells and most notably had an inhibitory effect on immune cells potentially limiting their cytotoxic potential. Hence, cytotoxicity increased in a dose dependent manner when BV6 was removed before CIK cells were added to tumor targets. However, cytotoxic potential was not further increasable by extending BV6 pre-incubation period of target cells from four to 12 hours. Molecular studies revealed that BV6 sensitization of target cells involved activation of caspases. Here we provide evidence that SMAC mimetic may sensitize targets cells for CIK cell-induced cell death. However, BV6 also increased apoptosis of non-malignant cells like CIK cells and peripheral mononuclear cells. These findings may therefore be important for cell- and small molecule IAP inhibitor- based combination therapies of resistant cancers after allogeneic HSCT.

  14. Patient-Specific Dosimetry of Pretargeted Radioimmunotherapy Using CC49 Fusion Protein in Patients with Gastrointestinal Malignancies

    International Nuclear Information System (INIS)

    Shen, Shang; Forero, Andres; LoBuglio, Albert F.; Breitz, H.; Khazaeli, M. B.; Fisher, Darrell R.; Wang, W. Q.; Meredith, Ruby F.

    2005-01-01

    Patient-Specific Dosimetry of Pretargeted Radioimmunotherapy Using CC49 Fusion Protein in Patients with Gastrointestinal Malignancies. Shen S, Forero A, Lobuglio AF, Breitz H, Khazaeli MB, Fisher DR, Wang W, Meredith RF. Department of Radiation Oncology, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama, and Radioisotopes Program at Pacific Northwest National Laboratory, Richland, Washington. Pretargeted radioimmunotherapy (RIT) using CC49 fusion protein, comprised of CC49-(scFv)(4) and streptavidin, in conjunction with (90)Y/(111)In-DOTA-biotin (DOTA = dodecanetetraacetic acid) provides a new opportunity to improve efficacy by increasing the tumor-to-normal tissue dose ratio. To our knowledge, the patient-specific dosimetry of pretargeted (90)Y/(111)In-DOTA-biotin after CC49 fusion protein in patients has not been reported previously. METHODS: Nine patients received 3-step pretargeted RIT: (a) 160 mg/m(2) of CC49 fusion protein, (b) synthetic clearing agent (sCA) at 48 or 72 h later, and (c) (90)Y/(111)In-DOTA-biotin 24 h after the sCA administration. Sequential whole-body (111)In images were acquired immediately and at 2-144 h after injection of (90)Y/(111)In-DOTA-biotin. Geometric-mean quantification with background and attenuation correction was used for liver and lung dosimetry. Effective point source quantification was used for spleen, kidneys, and tumors. Organ and tumor (90)Y doses were calculated based on (111)In imaging data and the MIRD formalism using patient-specific organ masses determined from CT images. Patient-specific marrow doses were determined based on radioactivity concentration in the blood. RESULTS: The (90)Y/(111)In-DOTA-biotin had a rapid plasma clearance, which was biphasic with <10% residual at 8 h. Organ masses ranged from 1,263 to 3,855 g for liver, 95 to 1,009 g for spleen, and 309 to 578 g for kidneys. The patient-specific mean (90)Y dose (cGy/37 MBq, or rad/mCi) was 0.53 (0.32-0.78) to whole body

  15. Non-unions treated with bone morphogenic protein 7: introducing the quantitative measurement of human serum cytokine levels as promising tool in evaluation of adjunct non-union therapy.

    Science.gov (United States)

    Moghaddam, Arash; Breier, Lisa; Haubruck, Patrick; Bender, Daniel; Biglari, Bahram; Wentzensen, Andreas; Zimmermann, Gerald

    2016-01-01

    In this study we sought to determine if application of bone morphogenic protein 7 (BMP-7) promotes physiological bone healing of non-unions and to investigate if serum cytokine analysis may serve as a promising tool in the analysis of adjunct non-union therapy. Therefore we analyzed the influence of BMP-7 application on the serum cytokine expression patterns on patients with impaired bone healing compared to patients that showed proper bone healing. Our study involved analyzing blood samples from 208 patients with long bone fractures together with patients that subsequently developed non-unions. From this large pool, 15 patients with atrophic non-union were matched to 15 patients with atrophic non-union treated with local application of BMP-7 as well as normal bone healing. Changes in the cytokine expression patterns were monitored during the 1st, 2nd, 4th, 8th, 12th and 52nd week. The patients were followed both clinically and radiologically for the entire duration of the study. Serum cytokine expression levels of transforming growth factor beta (TGF-β), platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF) were analyzed and compared. Serum expression of TGF-β were nearly parallel in all three groups, however serum concentrations were significantly higher in patients with proper bone healing and those treated with BMP-7 than in patients with non-unions (p unions (p unions led to similar cytokine expression patterns after treatment as those found in patients with proper bone healing. Our results suggest that treatment with BMP-7 promote healing of non-unions. Furthermore, quantitative measurement of serum cytokine expression is a promising tool for evaluating the effectiveness of additional non-union therapies such as adjunct application of growth factors.

  16. Evaluation on the Clinical Efficacy of Dendritic Cell-Activated Cytokine-Induced Killer Cells Combined with Conventional Therapy in the Treatment of Malignant Tumors

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    Hong WEI

    2016-06-01

    Full Text Available Objective: To evaluate the clinical efficacy of dendritic cell-activated cytokine-induced killer (DC-CIK cells combined with conventional therapy in the treatment of malignant tumors.Methods: A total of 100 patients with malignant tumors were randomly divided into two groups. Treatment group received conventional therapy combined with DC-CIK while control group received conventional therapy alone. The short-term efficacy, adverse reactions and changes of lymphocyte subpopulation were all compared between two groups after treatment.Results: The overall response rate (ORR was higher in treatment group (86.00% than in control group (54.00%, the difference was statistically significant (P<0.05. White blood cell count (WBC reduced after treatment when compared with treatment before (P=0.001, but liver and kidney function had no obvious change in treatment group (P>0.05. WBC reduced markedly, but the level of alanine aminotransferase (ALT increased obviously after treatment in control group (P<0.001. WBC was higher, but the level of ALT was lower in treatment group than in control group (P<0.001. However, there was no difference between two groups regarding serum creatinine (Scr and blood urea nitrogen (BUN (P>0.05. In treatment group, the levels of CD3+, CD3+CD4+, CD3+CD8+, and CD3+CD56+ increased (P<0.05, but the level of CD4+/CD8+ had no significant change (P>0.05. In control group, the levels of CD3+ and CD3+CD4+ reduced (P<0.05, while the levels of CD3+CD8+, CD3+CD56+ and CD4+/CD8+ had no significant change (P>0.05. The levels of CD3+, CD3+CD4+, CD3+CD8+ and CD3+CD56+ in treatment group were higher than those in control group (P<0.01, whereas CD4+/CD8+ was lower than that in control group (P<0.01.Conclusion: DC-CIK combined with conventional therapy, safe and effective, is capable of promoting the recovery of leukocytes and liver and kidney function, and improving the cellular immune function, which may provide a new therapeutic regimen for

  17. Co-Expansion of Cytokine-Induced Killer Cells and Vγ9Vδ2 T Cells for CAR T-Cell Therapy.

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    Shou-Hui Du

    Full Text Available Gamma delta (γδ T cells and cytokine-induced killer (CIK cells, which are a heterogeneous population of T lymphocytes and natural killer T (NKT cells, have been separately expanded ex vivo and shown to be capable of targeting and mediating cytotoxicity against various tumor cells in a major histocompatibility complex-unrestricted manner. However, the co-expansion and co-administration of these immune cells have not been explored. In this study we describe an efficient method to expand simultaneously both CIK and Vγ9Vδ2 T cells, termed as CIKZ cells, from human peripheral blood mononuclear cells (PBMCs using Zometa, interferon-gamma (IFN-γ, interleukin 2 (IL-2, anti-CD3 antibody and engineered K562 feeder cells expressing CD64, CD137L and CD86. A 21-day culture of PBMCs with this method yielded nearly 20,000-fold expansion of CIKZ cells with γδ T cells making up over 20% of the expanded population. The expanded CIKZ cells exhibited antitumor cytotoxicity and could be modified to express anti-CD19 chimeric antigen receptor (CAR, anti-CEA CAR, and anti-HER2 CAR to enhance their specificity and cytotoxicity against CD19-, CEA-, or HER2-positive tumor cells. The tumor inhibitory activity of anti-CD19 CAR-modified CIKZ cells was further demonstrated in vivo in a Raji tumor mouse model. The findings herein substantiate the feasibility of co-expanding CIK and γδ cells for adoptive cellular immunotherapy applications such as CAR T-cell therapy against cancer.

  18. The biodistribution and pretargeting radioimmunoimaging of the fusion protein of anti-CEA single-chain antibody and core-streptavidin in human rectocolonic tumor bearing nude mice

    International Nuclear Information System (INIS)

    Yang Weidong; Li Biao; Zhu Chengmo; Jiang Xufeng; Feng Guowei; Wu Xiangpu

    2002-01-01

    Objective: To investigate the biodistribution and two-step pretargeting radioimmunoimaging of the fusion protein of anti-carcinoembryonic antigen (CEA) single-chain antibody (ScFv) and core-streptavidin in human rectocolonic tumor bearing nude mice. Methods: Before the injection of 153 Sm-biotin, the fusion protein of ScFv-core-streptavidin was pretargeted for 24 h (200 μg every nude mouse), 24 h later 153 Sm-biotin was injected. The uptake of radioactivity in tumor and normal tissues in 20 nude mice was measured at 1, 4, 8 and 24 h and the other 3 nude mice was scanned at 8 and 24 h after peritoneal injection of 153 Sm-biotin. Results: The tumor to blood ratio (tumor/blood) reached 0.49 , 1.21, 1.56 and 3.09 at 1, 4, 8 and 24 h respectively. Radioactivity concentration peaked at 8 h in tumor site and demonstrated a 'hot' area, with significant decreasing its background at 24 h. Conclusion: The fusion protein can elevate the tumor/blood ratio, shorten pretargeting and imaging process and also improve image quality

  19. Cytokine patterns in a prospective cohort of HIV-infected patients with cryptococcal meningitis following initiation of antifungal and antiretroviral therapy

    Science.gov (United States)

    Ferreira-Paim, Kennio; Andrade-Silva, Leonardo Eurípedes; Bragine, Thatiane; Rocha, Ivonete Helena; Ribeiro, Barbara de Melo; Machado, Guilherme Henrique; Rodrigues Junior, Virmondes; Silva-Teixeira, David Nascimento; Meyer, Wieland; Silva-Vergara, Mario León

    2017-01-01

    Cryptococcal meningitis (CM) is a life-threatening infection in HIV-infected patients, especially in resource-limited settings. Cytokine patterns in the cerebrospinal fluid (CSF) and sera may be related to clinical outcomes. This study aimed to evaluate cytokine patterns in the CSF and sera of HIV-infected patients with CM as well as the cytokines produced by peripheral blood mononuclear cells (PBMCs) when stimulated with LPS and cryptococcal GXM. CSF and serum levels of IL-2, IL-4, IL-8, IL-10, IL-12p40, IL-17A, INF-γ, TNF-α and CXCL-10 were measured in HIV-infected patients with CM (CM+ HIV+) at various time points. Cytokine levels were evaluated in the PBMC culture supernatants and the baseline values were compared to those of HIV-infected patients without CM (CM- HIV+) and healthy controls (CM- HIV-). CSF cytokine levels at admission (n = 33) were higher than levels among the 23 survivors at week 2, but statistically significant differences were observed for IL-8 and IFN-γ (pcryptococcal infection. A better understanding of the protective immune response against Cryptococcus neoformans will help to develop novel strategies to improve the outcomes of patients with cryptococcosis. PMID:28486489

  20. Use of cytokines in infection.

    Science.gov (United States)

    Aoki, Naoko; Xing, Zhou

    2004-11-01

    Infectious disease remains an ever-growing health concern worldwide due to increasing antibiotic-resistant microbial strains, immune-compromised populations, international traffic and globalisation, and bioterrorism. There exists an urgent need to develop novel prophylactic and therapeutic strategies. In addition to classic antibiotic therapeutics, immune-modulatory molecules such as cytokines or their inhibitors represent a promising form of antimicrobial therapeutics or immune adjuvant used for the purpose of vaccination. These molecules, in the form of either recombinant protein or transgene, exert their antimicrobial effect by enhancing infectious agent-specific immune activation or memory development, or by dampening undesired inflammatory and immune responses resulting from infection and host defence mechanisms. In the last two decades, a number of cytokine therapy-based experimental and clinical trials have been conducted, and some of these efforts have led to the routine clinical use of cytokines. For instance, although IFNs have been used to treat hepatitis C with great success, many other cytokines are yet to be fully evaluated for their antimicrobial potential. This review discusses the biology and therapeutic potential of selected immune modulatory cytokines and their inhibitors, including granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, IFN-gamma, IL-12 and TNF.

  1. Antigen-specific CD4 T cells are induced after intravesical BCG-instillation therapy in patients with bladder cancer and show similar cytokine profiles as in active tuberculosis.

    Directory of Open Access Journals (Sweden)

    Julia Elsäßer

    Full Text Available Specific T cell immunity in patients with active tuberculosis is associated with a decrease in multifunctionality. However, it is unknown whether cytokine profiles differ in patients with primary infection and those with prior contact. We therefore used intravesical immunotherapy with attenuated live Bacille Calmette-Guérin (BCG in patients with urothelial carcinoma as a model to characterise the induction of systemic immunity towards purified protein derivate (PPD and to study whether cytokine profiles differ depending on pre-existing immunity. Eighteen patients with non-muscle invasive bladder cancer were recruited during the BCG-induction course. Fifty-four healthy individuals served as controls. Interferon (IFN-γ and interleukin (IL-2 producing PPD-specific CD4 T cells were analysed longitudinally before each instillation using a rapid flow-cytometric whole blood immunoassay. Baseline levels of IFN-γ producing PPD-specific T cells were comparable to controls. T cells showed a 5-fold increase to 0.23% by week 2/3, and further increased 8-fold by week 4/5 (to 0.42%, p=0.0007. Systemic immunity was induced in all patients, although the increase was less pronounced in patients with pre-existing immunity. As in active TB, cytokine profiling during therapy revealed a lower percentage of multifunctional IFN-γ/IL-2 double-positive T cells compared to controls (60.2% vs. 71.9%, p=0.0003. Of note, when comparing patients with and without pre-existing immunity, cytokine profiles in patients with primary immunity were shifted towards IL-2 single producing T cells (p=0.02, whereas those in patients with pre-existing immunity were shifted towards IFN-γ single-positivity (p=0.01. In conclusion, systemic T cell responses were induced after BCG-therapy, and their kinetics and cytokine profile depended on pre-existing immunity. Decreased functionality is a typical feature of specific immunity in both patients with active tuberculosis and BCG-therapy

  2. Changes in the levels of kynurenic acid and selected proinflammatory cytokines after pharmacological treatment and electroconvulsive therapy (ECT in patients with depressive disorder

    Directory of Open Access Journals (Sweden)

    Olajossy Marcin

    2016-06-01

    Full Text Available The aim of the present study was to compare the concentrations of KYNA, 3-OH-KYN and the cytokines TNF-α and IL-6 in patients with depression vs. healthy controls as well as in patients with depression treated pharmacologically vs. those treated using ECT. We also evaluated the relationship between the concentrations of KYNA, 3-OH-KYN and the cytokines TNF-α and IL-6 and clinical improvement measured on the MADRS scale in patients treated pharmacologically and those treated with ECT.

  3. Characterization and potential clinical applications of autoantibodies against cytokines

    DEFF Research Database (Denmark)

    de Lemos Rieper, Carina; Galle, Pia; Hansen, Morten Bagge

    2009-01-01

    Autoantibodies recognizing cytokines arise in certain patients during the course of therapy with recombinant cytokines, although they may arise spontaneously as well. They are typically high avidity and in vitro neutralizing IgG antibodies present in picomolar to nanomolar concentrations. Methodo....... There are many ways in which the autoantibodies could be naturally induced, and they have been experimentally induced with ease. Therefore, a new therapeutic concept of inducing cytokine autoantibodies via anti-cytokine vaccination is currently rapidly emerging....

  4. Cytokines as cellular communicators

    Directory of Open Access Journals (Sweden)

    R. Debets

    1996-01-01

    Full Text Available Cytokines and their receptors are involved in the pathophysiology of many diseases. Here we present a detailed review on cytokines, receptors and signalling routes, and show that one important lesson from cytokine biology is the complex and diverse regulation of cytokine activity. The activity of cytokines is controlled at the level of transcription, translation, storage, processing, posttranslational modification, trapping, binding by soluble proteins, and receptor number and/or function. Translation of this diverse regulation in strategies aimed at the control of cytokine activity will result in the development of more specific and selective drugs to treat diseases.

  5. Predictive patient-specific dosimetry and individualized dosing of pretargeted radioimmunotherapy in patients with advanced colorectal cancer

    Energy Technology Data Exchange (ETDEWEB)

    Schoffelen, Rafke; Woliner-van der Weg, Wietske; Visser, Eric P.; Oyen, Wim J.G.; Boerman, Otto C. [Radboud University Medical Center, Department of Radiology and Nuclear Medicine, PO Box 9101, Nijmegen (Netherlands); Goldenberg, David M. [Garden State Cancer Center, Morris Plains, NJ (United States); Immunomedics, Inc., Morris Plains, NJ (United States); IBC Pharmaceuticals, Inc., Morris Plains, NJ (United States); Sharkey, Robert M.; McBride, William J.; Chang, Chien-Hsing [Immunomedics, Inc., Morris Plains, NJ (United States); Rossi, Edmund A. [IBC Pharmaceuticals, Inc., Morris Plains, NJ (United States); Graaf, Winette T.A. van der [Radboud University Medical Center, Department of Medical Oncology, Nijmegen (Netherlands)

    2014-08-15

    Pretargeted radioimmunotherapy (PRIT) with bispecific antibodies (bsMAb) and a radiolabeled peptide reduces the radiation dose to normal tissues. Here we report the accuracy of an {sup 111}In-labeled pretherapy test dose for personalized dosing of {sup 177}Lu-labeled IMP288 following pretargeting with the anti-CEA x anti-hapten bsMAb, TF2, in patients with metastatic colorectal cancer (CRC). In 20 patients bone marrow absorbed doses (BMD) and doses to the kidneys were predicted based on blood samples and scintigrams acquired after {sup 111}In-IMP288 injection for individualized dosing of PRIT with {sup 177}Lu-IMP288. Different dose schedules were studied, varying the interval between the bsMAb and peptide administration (5 days vs. 1 day), increasing the bsMAb dose (75 mg vs. 150 mg), and lowering the peptide dose (100 μg vs. 25 μg). TF2 and {sup 111}In/{sup 177}Lu-IMP288 clearance was highly variable. A strong correlation was observed between peptide residence times and individual TF2 blood concentrations at the time of peptide injection (Spearman's ρ = 0.94, P < 0.0001). PRIT with 7.4 GBq {sup 177}Lu-IMP288 resulted in low radiation doses to normal tissues (BMD <0.5 Gy, kidney dose <3 Gy). Predicted {sup 177}Lu-IMP288 BMD were in good agreement with the actual measured doses (mean ± SD difference -0.0026 ± 0.028 mGy/MBq). Hematological toxicity was mild in most patients, with only two (10 %) having grade 3-4 thrombocytopenia. A correlation was found between platelet toxicity and BMD (Spearman's ρ = 0.58, P = 0.008). No nonhematological toxicity was observed. These results show that individual high activity doses in PRIT in patients with CEA-expressing CRC could be safely administered by predicting the radiation dose to red marrow and kidneys, based on dosimetric analysis of a test dose of TF2 and {sup 111}In-IMP288. (orig.)

  6. Upregulation of proinflammatory cytokine production in response to bacterial pathogen-associated molecular patterns in dogs with diabetes mellitus undergoing insulin therapy.

    Science.gov (United States)

    DeClue, Amy E; Nickell, Jordan; Chang, Chee-hoon; Honaker, Allison

    2012-05-01

    Metabolic alterations associated with diabetes mellitus alter innate immunity. Dogs often develop infectious or inflammatory complications related to diabetes mellitus, yet little is known about the effects of diabetes mellitus on the immune system in this species. Prospective evaluation in dogs with poorly regulated spontaneous type 1 diabetes mellitus (T1DM). In vitro leukocyte cytokine response to lipopolysaccharide (LPS), lipoteichoic acid (LTA), and peptidoglycan (PG) was compared between dogs with T1DM and healthy dogs. Additionally, the effect of acute in vitro glucose exposure on leukocyte tumor necrosis factor (TNF) production from healthy dogs was measured. Leukocytes from dogs with T1DM had significantly greater TNF production after LTA and PG stimulation compared with leukocytes from healthy dogs. Leukocyte interleukin (IL)-6 production was greater after stimulation with LPS, LTA, PG, and phosphate-buffered saline in the T1DM group. No such difference was noted when evaluating IL-10 production between groups regardless of stimulant. Dogs with T1DM had significantly greater IL-6 to IL-10 production ratios than healthy dogs. Acute exposure to dextrose did not augment cytokine production from healthy canine leukocytes. Dogs with T1DM have altered innate immunity characterized by upregulation of proinflammatory cytokine production without a concurrent change in anti-inflammatory cytokine production. This may be one explanation for the common infectious and inflammatory complications associated with T1DM in dogs. © 2012 Diabetes Technology Society.

  7. Cytokine patterns in a prospective cohort of HIV-infected patients with cryptococcal meningitis following initiation of antifungal and antiretroviral therapy.

    Science.gov (United States)

    Mora, Delio José; Ferreira-Paim, Kennio; Andrade-Silva, Leonardo Eurípedes; Bragine, Thatiane; Rocha, Ivonete Helena; Ribeiro, Barbara de Melo; Machado, Guilherme Henrique; Rodrigues Junior, Virmondes; Silva-Teixeira, David Nascimento; Meyer, Wieland; Silva-Vergara, Mario León

    2017-01-01

    Cryptococcal meningitis (CM) is a life-threatening infection in HIV-infected patients, especially in resource-limited settings. Cytokine patterns in the cerebrospinal fluid (CSF) and sera may be related to clinical outcomes. This study aimed to evaluate cytokine patterns in the CSF and sera of HIV-infected patients with CM as well as the cytokines produced by peripheral blood mononuclear cells (PBMCs) when stimulated with LPS and cryptococcal GXM. CSF and serum levels of IL-2, IL-4, IL-8, IL-10, IL-12p40, IL-17A, INF-γ, TNF-α and CXCL-10 were measured in HIV-infected patients with CM (CM+ HIV+) at various time points. Cytokine levels were evaluated in the PBMC culture supernatants and the baseline values were compared to those of HIV-infected patients without CM (CM- HIV+) and healthy controls (CM- HIV-). CSF cytokine levels at admission (n = 33) were higher than levels among the 23 survivors at week 2, but statistically significant differences were observed for IL-8 and IFN-γ (p<0.05). CSF and serum levels of IL-4 and IL-17A at week 10 (n = 16) were lower than the baseline values, whereas IL-2 levels increased compared to week 2 (p<0.05). At week 16 (n = 15), CSF and serum levels of IL-4, IL-10 and CXCL-10 were decreased compared to the baseline values (p<0.05). PBMCs from CM- HIV- individuals produced significantly higher levels of proinflammatory cytokines in response to LPS, with the exception of TNF-α, which showed higher levels among CM+ HIV+ patients. The PBMCs of CM patients produced higher levels of IL-4 than those of CM- HIV- patients in response to GXM stimulation, and levels progressively decreased during treatment (p<0.05). Then, a progressive shift in cytokine expression favoring a Th1 pattern was observed, which is crucial in controlling cryptococcal infection. A better understanding of the protective immune response against Cryptococcus neoformans will help to develop novel strategies to improve the outcomes of patients with cryptococcosis.

  8. Cytokines in Drosophila immunity.

    Science.gov (United States)

    Vanha-Aho, Leena-Maija; Valanne, Susanna; Rämet, Mika

    2016-02-01

    Cytokines are a large and diverse group of small proteins that can affect many biological processes, but most commonly cytokines are known as mediators of the immune response. In the event of an infection, cytokines are produced in response to an immune stimulus, and they function as key regulators of the immune response. Cytokines come in many shapes and sizes, and although they vary greatly in structure, their functions have been well conserved in evolution. The immune signaling pathways that respond to cytokines are remarkably conserved from fly to man. Therefore, Drosophila melanogaster, provides an excellent platform for studying the biology and function of cytokines. In this review, we will describe the cytokines and cytokine-like molecules found in the fly and discuss their roles in host immunity. Copyright © 2015 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

  9. Cytokines: applications in domestic food animals.

    Science.gov (United States)

    Blecha, F

    1991-01-01

    Cytokines such as human, bovine, and porcine interferons and human and bovine interleukin-1 and interleukin-2 have been used in vivo in cattle and pigs. Colony-stimulating factors and tumor necrosis factor alpha have been evaluated in vitro in food animals. Studies to evaluate cytokines in domestic food animals have shown that specific and nonspecific immunomodulation is possible in immunosuppressed or pathogen-exposed animals. Cytokine prophylaxis or therapy in food animals may have the greatest potential for control of respiratory disease and mastitis.

  10. Safety study: is there a pathologic IGF-1, PDGF and TGF-ß cytokine expression caused by adjunct BMP-7 in tibial and femoral non-union therapy?

    Directory of Open Access Journals (Sweden)

    Fischer C

    2018-04-01

    Full Text Available Christian Fischer,1 Christian Reiner,2 Gerhard Schmidmaier,1 Julian Doll,1 Christopher Child,3 Paul Alfred Grützner,4 Bahram Biglari,4 Sonja Boxriker,5 Arash Moghaddam5 1Center for Orthopedics, Trauma Surgery and Spinal Cord Injury, HTRG – Heidelberg Trauma Research Group, Heidelberg University Hospital, Heidelberg, Germany; 2Department of Trauma and Orthopedic Surgery, Paracelsus Medical University, Nuremberg Hospital South, Nuremberg, Germany; 3Department of Trauma Surgery, University Hospital Zurich, Zurich, Switzerland; 4Trauma and Orthopedics, BG Trauma Center Ludwigshafen, Ludwigshafen, Germany; 5Center of Orthopedics, Trauma Surgery and Sport Medicine, ATORG Aschaffenburg-Alzenau, Aschaffenburg, Germany Background: In this prospective safety study, we investigated if the characteristic cytokine expression during bone regeneration is manipulated by the local application of bone morphogenetic protein-7 (BMP-7 in non-union surgery. Therefore, the levels of insulin like growth factor 1 (IGF-1, platelet-derived growth factor AB (PDGF-AB and transforming growth factor beta (TGF-β were compared between patients with the gold standard use of autologous bone graft (ABG and those with additional application of BMP-7 as part of the diamond concept.Patients and methods: Between 2009 and 2014, of the 153 patients with tibial and femoral non-unions, a matched pair analysis was performed to compare the serological cytokine expressions. Blood samples were collected preoperatively, 1, 2 and 6 weeks as well as 3 and 6 months after non-union surgery. Matching criteria were smoking status, fracture location, gender, age and body mass index (BMI. Patients in G1 (n=10 were treated with ABG and local BMP-7 while their matching partners in G2 (n=10 received ABG only. The routine clinical and radiologic follow-up was 1 year.Results: Although the IGF-1 quantification in G2 showed higher pre- and postoperative values compared to G1 (p<0.05, the courses of both

  11. Biotinidase Resistant 68Gallium-Radioligand Based on Biotin/Avidin Interaction for Pretargeting: Synthesis and Preclinical Evaluation.

    Science.gov (United States)

    Prakash, Surbhi; Hazari, Puja Panwar; Meena, Virendra Kumar; Jaswal, Ambika; Khurana, Harleen; Kukreti, Shrikant; Mishra, Anil Kumar

    2016-11-16

    A new macrocyclic system 2,2'-(12-amino-11,13-dioxo-1,4,7,10-tetraazacyclotridecane-4,7-diyl)diacetic acid (ATRIDAT) was designed for coordinating metals in +2 and +3 oxidation states particularly 68 Ga(III), for PET imaging. ATRIDAT was conjugated to d-biotin for pretargeting via biotin-avidin interaction. This model provides high tumor targeting efficiency and stability to biotinidase activity leading to modest signal amplification at the tumor site. Cyclization of triethylenetetramine with protected diethylamino malonate resulted in the formation of 13 membered diamide ring. d-Biotin was then anchored on the pendant amine rendering α-methyne carbon to the biotinamide bond which blocks the biotinidase enzyme activity. Biotinidase stability assay showed remarkable stability toward the action of biotinidase with ∼95% remaining intact after treatment following 4 h. Binding affinity experiments such as HABA assay, competitive displacement studies with d-biotin and CD showed high binding affinity of the molecule with avidin in nanomolar range. Biotin conjugate was successfully radiolabeled with 68 Ga(III) with radiolabeling efficiency of ∼70% and then purified to get 99.9% radiochemical yield. IC 50 of the compound was found to be 2.36 mM in HEK cell line and 0.82 mM in A549 as assessed in MTT assay. In biodistribution studies, the major route of excretion was found to be renal. Significant uptake of 4.15 ± 0.35% was observed in tumor in the avidin pretreated mouse at 1 h. μPET images also showed a high tumor to muscle ratio of 26.8 and tumor to kidney ratio of 1.74 at 1 h post-injection after avidin treatment.

  12. Phase II trial of anticarcinoembryonic antigen pretargeted radioimmunotherapy in progressive metastatic medullary thyroid carcinoma: biomarker response and survival improvement.

    Science.gov (United States)

    Salaun, Pierre-Yves; Campion, Loïc; Bournaud, Claire; Faivre-Chauvet, Alain; Vuillez, Jean-Philippe; Taieb, David; Ansquer, Catherine; Rousseau, Caroline; Borson-Chazot, Françoise; Bardet, Stéphane; Oudoux, Aurore; Cariou, Bertrand; Mirallié, Eric; Chang, Chien-Hsing; Sharkey, Robert M; Goldenberg, David M; Chatal, Jean-François; Barbet, Jacques; Kraeber-Bodéré, Françoise

    2012-08-01

    The prognosis of medullary thyroid carcinoma (MTC) varies from long- to short-term survival based on such prognostic factors as serum calcitonin and carcinoembryonic antigen (CEA) doubling times (DTs). This prospective phase II multicenter trial evaluated the efficacy and safety of anti-CEA pretargeted radioimmunotherapy (pRAIT) in rapidly progressing metastatic MTC patients and also how serum biomarker DTs correlate with clinical outcome. From June 2004 to January 2008, 42 patients were treated with anti-CEA × anti-diethylenetriaminepentaacetic acid (DTPA) bispecific antibody (hMN-14 × m734) (40 mg/m(2)), followed by (131)I-di-DTPA-indium bivalent hapten (1.8 GBq/m(2)) 4-6 d later. The disease control rate (durable stabilization plus objective response) was 76.2%. Grade 3-4 hematologic toxicity was observed in 54.7% of patients and myelodysplastic syndrome in 2, including 1 heavily treated previously. After pRAIT, 21 of 37 assessed patients (56.7%) showed a significant impact on DT (≥100% increase of pre-pRAIT calcitonin or CEA DT or prolonged decrease of the biomarker concentration after pRAIT). Pre-pRAIT DT and post-pRAIT DT were significant independent predictors for overall survival (OS) from pRAIT (pre-pRAIT: hazard ratio [HR], 0.46; 95% confidence interval [CI], 0.24-0.86; P = 0.016; and post-pRAIT: HR, 5.32; 95% CI, 1.63-17.36; P = 0.006) and OS from diagnosis (pre-pRAIT: HR, 0.21; 95% CI, 0.08-0.51; P = 0.001; and post-pRAIT: HR, 6.16; 95% CI, 1.81-20.98; P = 0.004). pRAIT showed antitumor activity, with manageable hematologic toxicity in progressive MTC. Increased biomarker DT after treatment correlated with increased OS.

  13. Cytokines and intraocular inflammation

    NARCIS (Netherlands)

    Hoekzema, R.; Murray, P. I.; Kijlstra, A.

    1990-01-01

    Although new endogenous mediators of inflammatory and immune responses are reported almost on a monthly basis, the cytokines IL-1, TNF, and IL-6 have emerged as the primary regulators of local inflammation in man. In this paper, uveitogenic and other properties of these particular cytokines are

  14. What is the best treatment to decrease pro-inflammatory cytokine release in acute skeletal muscle injury induced by trauma in rats: low-level laser therapy, diclofenac, or cryotherapy?

    Science.gov (United States)

    de Almeida, Patrícia; Tomazoni, Shaiane Silva; Frigo, Lucio; de Carvalho, Paulo de Tarso Camillo; Vanin, Adriane Aver; Santos, Larissa Aline; Albuquerque-Pontes, Gianna Móes; De Marchi, Thiago; Tairova, Olga; Marcos, Rodrigo Labat; Lopes-Martins, Rodrigo Álvaro Brandão; Leal-Junior, Ernesto Cesar Pinto

    2014-03-01

    Currently, treatment of muscle injuries represents a challenge in clinical practice. In acute phase, the most employed therapies are cryotherapy and nonsteroidal anti-inflammatory drugs. In the last years, low-level laser therapy (LLLT) has becoming a promising therapeutic agent; however, its effects are not fully known. The aim of this study was to analyze the effects of sodium diclofenac (topical application), cryotherapy, and LLLT on pro-inflammatory cytokine levels after a controlled model of muscle injury. For such, we performed a single trauma in tibialis anterior muscle of rats. After 1 h, animals were treated with sodium diclofenac (11.6 mg/g of solution), cryotherapy (20 min), or LLLT (904 nm; superpulsed; 700 Hz; 60 mW mean output power; 1.67 W/cm(2); 1, 3, 6 or 9 J; 17, 50, 100 or 150 s). Assessment of interleukin-1β and interleukin-6 (IL-1β and IL-6) and tumor necrosis factor-alpha (TNF-α) levels was performed at 6 h after trauma employing enzyme-linked immunosorbent assay method. LLLT with 1 J dose significantly decreased (p cryotherapy groups. On the other hand, treatment with diclofenac and cryotherapy does not decrease pro-inflammatory cytokine levels compared to the non-treated injured group. Therefore, we can conclude that 904 nm LLLT with 1 J dose has better effects than topical application of diclofenac or cryotherapy in acute inflammatory phase after muscle trauma.

  15. Assessment of cytokine values in serum by RT-PCR in HIV-1 infected individuals with and without highly active anti-retroviral therapy (HAART

    Directory of Open Access Journals (Sweden)

    DA Meira

    2008-01-01

    Full Text Available A cross-sectional study was performed on HIV-1 infected individuals with or without antiretroviral treatment (ARV in the AIDS Day Hospital, Botucatu Medical School, UNESP. Between August 2004 and October 2005, 73 HIV-1 infected individuals were divided into three groups: infected individuals with or without AIDS who had never received ARV (G1 = 15; patients on HAART that had had plasma HIV-1 RNA viral load (VL equal to or greater than 50 copies/mL (G2 = 27; and patients on HAART with undetectable VL for at least the past six months (G3 = 31. There was also an additional group that comprised blood donors without any sign of the disease and with negative HIV serum tests (G4 = 20, which was the control group. Serum cytokine levels (values in pg/mL were measured by enzyme-linked immunosorbent assay (ELISA and specific mRNA expression by reverse transcription polymerase chain reaction (RT-PCR. Both techniques were performed on the four groups for TNF-α, IL-2, INF-γ, IL-4 and IL-10. All patients were submitted to VL determination and CD4+ and CD8+T lymphocyte counts. The analysis of the results revealed a significant comparison among groups for both methods and an association between the latter (> 80% r² > 0.80. There was only one exception, in control individuals for IL-2 by ELISA. The cytokine profiles, in both methods, for the three patient groups, were mature Th-0. The behaviors of IL-2 and INF-γ required emphasis due to consequent expression of dominant Th profile. Both methods showed low IL-2 and high mean values of INF-γ in the three groups. Several authors have recently drawn attention to the substantial apoptosis of infected and non-infected CD4+T cells, mainly during primary infection, persisting only in those with INF-γ phenotype producer and not IL-2. HIV infected individuals submitted to HAART are expected to produce IL-2 in an attempt to present Th-1 profile, but in most cases this did not occur.

  16. Twelve-Month Antiretroviral Therapy Suppresses Plasma and Genital Viral Loads but Fails to Alter Genital Levels of Cytokines, in a Cohort of HIV-Infected Rwandan Women

    NARCIS (Netherlands)

    Ondoa, Pascale; Gautam, Raju; Rusine, John; Lutter, Rene; Jurriaans, Suzanne; Kootstra, Neeltje; Karita, Etienne; van de Wijgert, Janneke

    2015-01-01

    Genital viral load (GVL) is the main determinant of sexual transmission of human immune-deficiency virus (HIV). The effect of antiretroviral therapy (ART) on local cervico-vaginal immunological factors associated with GVL is poorly described. We aimed to identify the risk factors of detectable GVL,

  17. Adjuvant cytokine treatment of minimal residual disease after surgical therapy in mice carrying HPV16-associated tumours: Cytolytic activity of spleen cells from tumour regressors

    Czech Academy of Sciences Publication Activity Database

    Indrová, Marie; Mikyšková, Romana; Jandlová, Táňa; Vonka, V.; Bubeník, Jan; Bieblová, Jana

    2003-01-01

    Roč. 2003, č. 49 (2003), s. 217-222 ISSN 0015-5500 Institutional research plan: CEZ:AV0Z5052915 Keywords : HPV16 * gene therapy * IL-2 Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 0.527, year: 2003

  18. Role of serum levels of angiogenic cytokines in assessment of angiogenesis after stem cell therapy of diabetic patients with critical limb ischemia

    Czech Academy of Sciences Publication Activity Database

    Dubský, M.; Jirkovská, A.; Bém, R.; Fejfarová, V.; Varga, M.; Kolesar, L.; Pagocová, L.; Syková, Eva; Jude, E. B.

    2014-01-01

    Roč. 23, č. 12 (2014), s. 1517-1523 ISSN 0963-6897 Grant - others:GA UK(CZ) 362311; GA MZd(CZ) 00023001IKEM Institutional support: RVO:68378041 Keywords : systemic vasculogenesis * stem cell therapy * critical limp ischemia Subject RIV: FH - Neurology Impact factor: 3.127, year: 2014

  19. Cytokines in bipolar disorder

    DEFF Research Database (Denmark)

    Munkholm, Klaus; Vinberg, Maj; Vedel Kessing, Lars

    2012-01-01

    to affective state. METHODS: We conducted a systemtic review of studies measuring endogenous cytokine concentrations in patients with bipolar disorder and a meta-analysis, reporting results according to the PRISMA statement. RESULTS: Thirteen studies were included, comprising 556 bipolar disorder patients......BACKGROUND: Current research and hypothesis regarding the pathophysiology of bipolar disorder suggests the involvement of immune system dysfunction that is possibly related to disease activity. Our objective was to systematically review evidence of cytokine alterations in bipolar disorder according...

  20. Amniotic fluid inflammatory cytokines

    DEFF Research Database (Denmark)

    Abdallah, Morsi; Larsen, Nanna; Grove, Jakob

    2013-01-01

    The aim of the study was to analyze cytokine profiles in amniotic fluid (AF) samples of children developing autism spectrum disorders (ASD) and controls, adjusting for maternal autoimmune disorders and maternal infections during pregnancy.......The aim of the study was to analyze cytokine profiles in amniotic fluid (AF) samples of children developing autism spectrum disorders (ASD) and controls, adjusting for maternal autoimmune disorders and maternal infections during pregnancy....

  1. Censored correlated cytokine concentrations

    DEFF Research Database (Denmark)

    Andersen, Andreas; Benn, Christine Stabell; Jørgensen, Mathias J

    2013-01-01

    Interest in cytokines as markers for the function of the immune system is increasing. Methods quantifying cytokine concentrations are often subject to detection limits, which lead to non-detectable observations and censored distributions. When distributions are skewed, geometric mean ratios (GMRs...... stacking method that uses clustered variance-covariance estimation allowing homogeneous (Stackc) or inhomogeneous (Stackh) variances. We compare it with direct estimation of the bivariate Tobit likelihood function (Bitobit) and multiple imputation. We assess sensitivity to inhomogeneity and non...

  2. Treatment of minimal residual disease after surgery or chemotherapy in mice carrying HPV16-associated tumours: cytokine and gene therapy with IL-2 and GM-CSF

    Czech Academy of Sciences Publication Activity Database

    Mikyšková, Romana; Indrová, Marie; Šímová, Jana; Jandlová, Táňa; Bieblová, Jana; Jinoch, P.; Bubeník, Jan; Vonka, V.

    2004-01-01

    Roč. 24, č. 1 (2004), s. 161-167 ISSN 1019-6439 R&D Projects: GA MZd NC7148; GA MZd NC7552; GA ČR GA301/01/0985 Institutional research plan: CEZ:AV0Z5052915 Keywords : HPV16 * gene therapy * minimal residual tumour disease Subject RIV: FD - Oncology ; Hematology Impact factor: 3.056, year: 2004

  3. Tuberculosis Therapy Modifies the Cytokine Profile, Maturation State, and Expression of Inhibitory Molecules on Mycobacterium tuberculosis-Specific CD4+ T-Cells.

    Directory of Open Access Journals (Sweden)

    Kapil K Saharia

    Full Text Available Little is known about the expression of inhibitory molecules cytotoxic T-lymphocyte antigen-4 (CTLA-4 and programmed-death-1 (PD-1 on Mycobacterium tuberculosis (Mtb-specific CD4 T-cells and how their expression is impacted by TB treatment.Cryopreserved PBMCs from HIV-TB co-infected and TB mono-infected patients with untreated and treated tuberculosis (TB disease were stimulated for six hours with PPD and stained. Using polychromatic flow cytometry, we characterized the differentiation state, cytokine profile, and inhibitory molecule expression on PPD-specific CD4 T-cells.In our HIV-TB co-infected cohort, TB treatment increased the proportion of PPD-specific CD4 T-cells co-producing IFN-γ+IL-2+TNF-α+ and IFN-γ+IL-2+ (p = 0.0004 and p = 0.0002, respectively while decreasing the proportion of PPD-specific CD4 T-cells co-producing IFN-γ+MIP1-β+TNF-α+ and IFN-γ+MIP1-β+. The proportion of PPD-specific CD4 T-cells expressing an effector memory phenotype decreased (63.6% vs 51.6%, p = 0.0015 while the proportion expressing a central memory phenotype increased (7.8% vs. 21.7%, p = 0.001 following TB treatment. TB treatment reduced the proportion of PPD-specific CD4 T-cells expressing CTLA-4 (72.4% vs. 44.3%, p = 0.0005 and PD-1 (34.5% vs. 29.2%, p = 0.03. Similar trends were noted in our TB mono-infected cohort.TB treatment alters the functional profile of Mtb-specific CD4 T-cells reflecting shifts towards a less differentiated maturational profile and decreases PD-1 and CTLA-4 expression. These could serve as markers of reduced mycobacterial burden. Further study is warranted.

  4. [Cytokine imbalance in critically ill patients: SIRS and CARS].

    Science.gov (United States)

    Murata, A; Kikuchi, M; Mishima, S; Sakaki, S; Goto, H; Matsuoka, T; Tanaka, H; Yukioka, T; Shimazaki, S

    1999-07-01

    It remains difficult to treat severely ill patients, especially those who have sepsis and subsequent multiple organ dysfunction syndrome. We propose the hypothesis that the pathophysiology in the sequential sepsis and multiple organ dysfunction syndrome may be strongly related to the imbalance between inflammatory cytokines and antiinflammatory cytokines induced for the host defense to active neutrophils and endothelial cells. Thus we attempted to develop cytokine modulation therapy to normalize the cytokine balance in the host defense system. In this review, we elucidate the relationship between cytokine imbalance and SIRS/CARS in patients with severe burn injury. Furthermore, we examine the possible usage of G-CSF to amplify neutrophil function, and clarify the reasons why various innovative therapies against sepsis have failed.

  5. Modulation of Cytokine and Cytokine Receptor/Antagonist by Treatment with Doxycycline and Tetracycline in Patients with Dengue Fever

    Directory of Open Access Journals (Sweden)

    J. E. Z. Castro

    2011-01-01

    Full Text Available Dengue virus infection can lead to dengue fever (DF or dengue hemorrhagic fever (DHF. Disease severity has been linked to an increase in various cytokine levels. In this study, we evaluated the effectiveness of doxycycline and tetracycline to modulate serum levels of IL-6, IL-1B, and TNF and cytokine receptor/receptor antagonist TNF-R1 and IL-1RA in patients with DF or DHF. Hospitalized patients were randomized to receive standard supportive care or supportive care combined with doxycycline or tetracycline therapy. Serum cytokine and cytokine receptor/antagonist levels were determined at the onset of therapy and after 3 and 7 days. Cytokine and cytokine receptor/antagonist levels were substantially elevated at day 0. IL-6, IL-1β, and TNF remained at or above day 0 levels throughout the study period in untreated patients. Treatment with tetracycline or doxycycline resulted in a significant decline in cytokine levels. Similarly, IL-1RA and TNF-R1 serum concentrations were elevated at baseline and showed a moderate increase among untreated patients. Both drugs resulted in a significant rise in IL-1Ra levels by day 3 in patients. In contrast, treatment did not affect a similar result for TNF-R1. When compared to the control group, however, a significant rise post-treatment was seen upon intragroup analysis. Further analysis demonstrated that doxycycline was significantly more effective at modulating cytokine and cytokine receptor/antagonist levels than tetracycline.

  6. Modulation of cytokine and cytokine receptor/antagonist by treatment with doxycycline and tetracycline in patients with dengue fever.

    Science.gov (United States)

    Castro, J E Z; Vado-Solis, I; Perez-Osorio, C; Fredeking, T M

    2011-01-01

    Dengue virus infection can lead to dengue fever (DF) or dengue hemorrhagic fever (DHF). Disease severity has been linked to an increase in various cytokine levels. In this study, we evaluated the effectiveness of doxycycline and tetracycline to modulate serum levels of IL-6, IL-1B, and TNF and cytokine receptor/receptor antagonist TNF-R1 and IL-1RA in patients with DF or DHF. Hospitalized patients were randomized to receive standard supportive care or supportive care combined with doxycycline or tetracycline therapy. Serum cytokine and cytokine receptor/antagonist levels were determined at the onset of therapy and after 3 and 7 days. Cytokine and cytokine receptor/antagonist levels were substantially elevated at day 0. IL-6, IL-1β, and TNF remained at or above day 0 levels throughout the study period in untreated patients. Treatment with tetracycline or doxycycline resulted in a significant decline in cytokine levels. Similarly, IL-1RA and TNF-R1 serum concentrations were elevated at baseline and showed a moderate increase among untreated patients. Both drugs resulted in a significant rise in IL-1Ra levels by day 3 in patients. In contrast, treatment did not affect a similar result for TNF-R1. When compared to the control group, however, a significant rise post-treatment was seen upon intragroup analysis. Further analysis demonstrated that doxycycline was significantly more effective at modulating cytokine and cytokine receptor/antagonist levels than tetracycline.

  7. The role of cytokines in postmenopausal osteoporosis.

    Science.gov (United States)

    Brincat, S D; Borg, M; Camilleri, G; Calleja-Agius, J

    2014-08-01

    Postmenopausal osteoporosis is a silent systemic progressive disease characterised by a decrease in bone mass per unit volume. This condition compromises the physical strength of the skeleton and increases the susceptibility to fractures on minor trauma. The imbalance between bone formation and bone resorption is known to be responsible for postmenopausal bone loss. Estrogen deficiency contributes to bone loss by increasing the production of pro-inflammatory cytokines by bone marrow and bone cells. Clinical and molecular evidence indicates that estrogen-regulated cytokines exert regulatory effects on bone turnover implicating their role as being the primary mediators of the accelerated bone loss at menopause. The current perspective on the role and interaction of cytokines such as IL-1, IL-4, IL-6, IL-17, TNF, IFN-γ and TGF-β in bone loss linked with estrogen deficiency is reviewed. Current treatment options and emerging drug therapies in the management of postmenopausal osteoporosis are also evaluated.

  8. Visualizing the Acute Effects of Vascular-Targeted Therapy In Vivo Using Intravital Microscopy and Magnetic Resonance Imaging: Correlation with Endothelial Apoptosis, Cytokine Induction, and Treatment Outcome

    Directory of Open Access Journals (Sweden)

    Mukund Seshadri

    2007-02-01

    Full Text Available The acute effects of the vascular-disrupting agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA were investigated in vivo using intravital microscopy (IVM and magnetic resonance imaging (MRI. Changes in vascular permeability and blood flow of syngeneic CT-26 murine colon adenocarcinomas were assessed at 4 and 24 hours after DMXAA treatment (30 mg/kg, i.p. and correlated with induction of tumor necrosis factor-α (TNF-α, endothelial damage [CD31/terminal deoxynucleotidyl transferase (TdT], and treatment outcome. Intravital imaging revealed a marked increase in vascular permeability 4 hours after treatment, consistent with increases in intratumoral mRNA and protein levels of TNF-α. Parallel contrast-enhanced MRI studies showed a ~ 4-fold increase in longitudinal relaxation rates (ΔR1, indicative of increased contrast agent accumulation within the tumor. Dualimmunostained tumor sections (CD31/TdT revealed evidence of endothelial apoptosis at this time point. Twenty-four hours after treatment, extensive hemorrhage and complete disruption of vascular architecture were observed with IVM, along with a significant reduction in ΔR1 and virtual absence of CD31 immunostaining. DMXAA-induced tumor vascular damage resulted in significant long-term (60-day cures compared to untreated controls. Multimodality imaging approaches are useful in visualizing the effects of antivascular therapy in vivo. Such approaches allow cross validation and correlation of findings with underlying molecular changes contributing to treatment outcome.

  9. Biologics for Targeting Inflammatory Cytokines, Clinical Uses, and Limitations

    Directory of Open Access Journals (Sweden)

    Peleg Rider

    2016-01-01

    Full Text Available Proinflammatory cytokines are potent mediators of numerous biological processes and are tightly regulated in the body. Chronic uncontrolled levels of such cytokines can initiate and derive many pathologies, including incidences of autoimmunity and cancer. Therefore, therapies that regulate the activity of inflammatory cytokines, either by supplementation of anti-inflammatory recombinant cytokines or by neutralizing them by using blocking antibodies, have been extensively used over the past decades. Over the past few years, new innovative biological agents for blocking and regulating cytokine activities have emerged. Here, we review some of the most recent approaches of cytokine targeting, focusing on anti-TNF antibodies or recombinant TNF decoy receptor, recombinant IL-1 receptor antagonist (IL-1Ra and anti-IL-1 antibodies, anti-IL-6 receptor antibodies, and TH17 targeting antibodies. We discuss their effects as biologic drugs, as evaluated in numerous clinical trials, and highlight their therapeutic potential as well as emphasize their inherent limitations and clinical risks. We suggest that while systemic blocking of proinflammatory cytokines using biological agents can ameliorate disease pathogenesis and progression, it may also abrogate the hosts defense against infections. Moreover, we outline the rational need to develop new therapies, which block inflammatory cytokines only at sites of inflammation, while enabling their function systemically.

  10. Cytokiner og osteoporose

    DEFF Research Database (Denmark)

    Jørgensen, N R

    1997-01-01

    During the last few years, progress has been made towards the understanding of local regulation of bone remodelling especially in relation to osteoporosis. Cytokines have shown to be powerful regulators of bone resorption and formation, though under superior control from oestrogen/testosterone, p...

  11. Recombinant Cytokines from Plants

    Czech Academy of Sciences Publication Activity Database

    Sirko, A.; Vaněk, Tomáš; Gora-Sochacka, A.; Redkiewicz, P.

    2011-01-01

    Roč. 12, č. 6 (2011), s. 3536-3552 ISSN 1661-6596 Institutional research plan: CEZ:AV0Z50380511 Keywords : cytokines * pharmaceutical proteins * plant-based production systems Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.598, year: 2011

  12. Cytokines in human milk.

    Science.gov (United States)

    Garofalo, Roberto

    2010-02-01

    Epidemiologic studies conducted in the past 30 years to investigate the protective functions of human milk strongly support the notion that breastfeeding prevents infantile infections, particularly those affecting the gastrointestinal and respiratory tracts. However, more recent clinical and experimental observations also suggest that human milk not only provides passive protection, but also can directly modulate the immunological development of the recipient infant. The study of this remarkable defense system in human milk has been difficult because of its biochemical complexity, the small concentration of certain bioactive components, the compartmentalization of some of these agents, the dynamic quantitative and qualitative changes of milk during lactation, and the lack of specific reagents to quantify these agents. However, a host of bioactive substances, including hormones, growth factors, and immunological factors such as cytokines, have been identified in human milk. Cytokines are pluripotent polypeptides that act in autocrine/paracrine fashions by binding to specific cellular receptors. They operate in networks and orchestrate the development and functions of immune system. Several different cytokines and chemokines have been discovered in human milk in the past years, and the list is growing very rapidly. This article will review the current knowledge about the increasingly complex network of chemoattractants, activators, and anti-inflammatory cytokines present in human milk and their potential role in compensating for the developmental delay of the neonate immune system. Copyright 2010. Published by Mosby, Inc.

  13. Cytokiner og osteoporose

    DEFF Research Database (Denmark)

    Jørgensen, N R

    1997-01-01

    /testosterone, parathyroidhormone and 1,25(OH)2D3. Some of the cytokines primarily enhance osteoclastic bone resorption e.g. IL-1 (Interleukin-1), TNF (Tumor Necrosis Factor) and IL-6 (Interleukin-6), while others primarily stimulate bone formation e.g. TGF-beta (Transforming Growth Factor), IGF (Insulin-like Growth Factor...

  14. Detection of autoantibodies to cytokines

    DEFF Research Database (Denmark)

    Bendtzen, K; Hansen, M B; Ross, C

    2000-01-01

    Autoantibodies to various cytokines have been reported in normal individuals and in patients with various infectious and immunoinflammatory disorders, and similar antibodies (Ab) may be induced in patients receiving human recombinant cytokines. The clinical relevance of these Ab is often difficult...... to evaluate. Not only are in vitro neutralizing cytokine Ab not necessarily neutralizing in vivo, but assays for binding and neutralizing Ab to cytokines are often difficult to interpret. For example, denaturation of immobilized cytokines in immunoblotting techniques and immunometric assays may leave Ab...

  15. Cytokines as Biomarkers in Rheumatoid Arthritis

    Directory of Open Access Journals (Sweden)

    Agata Burska

    2014-01-01

    Full Text Available RA is a complex disease that develops as a series of events often referred to as disease continuum. RA would benefit from novel biomarker development for diagnosis where new biomarkers are still needed (even if progresses have been made with the inclusion of ACPA into the ACR/EULAR 2010 diagnostic criteria and for prognostic notably in at risk of evolution patients with autoantibody-positive arthralgia. Risk biomarkers for rapid evolution or cardiovascular complications are also highly desirable. Monitoring biomarkers would be useful in predicting relapse. Finally, predictive biomarkers for therapy outcome would allow tailoring therapy to the individual. Increasing numbers of cytokines have been involved in RA pathology. Many have the potential as biomarkers in RA especially as their clinical utility is already established in other diseases and could be easily transferable to rheumatology. We will review the current knowledge’s relation to cytokine used as biomarker in RA. However, given the complexity and heterogeneous nature of RA, it is unlikely that a single cytokine may provide sufficient discrimination; therefore multiple biomarker signatures may represent more realistic approach for the future of personalised medicine in RA.

  16. Cytokines as Biomarkers in Rheumatoid Arthritis

    Science.gov (United States)

    Burska, Agata; Boissinot, Marjorie; Ponchel, Frederique

    2014-01-01

    RA is a complex disease that develops as a series of events often referred to as disease continuum. RA would benefit from novel biomarker development for diagnosis where new biomarkers are still needed (even if progresses have been made with the inclusion of ACPA into the ACR/EULAR 2010 diagnostic criteria) and for prognostic notably in at risk of evolution patients with autoantibody-positive arthralgia. Risk biomarkers for rapid evolution or cardiovascular complications are also highly desirable. Monitoring biomarkers would be useful in predicting relapse. Finally, predictive biomarkers for therapy outcome would allow tailoring therapy to the individual. Increasing numbers of cytokines have been involved in RA pathology. Many have the potential as biomarkers in RA especially as their clinical utility is already established in other diseases and could be easily transferable to rheumatology. We will review the current knowledge's relation to cytokine used as biomarker in RA. However, given the complexity and heterogeneous nature of RA, it is unlikely that a single cytokine may provide sufficient discrimination; therefore multiple biomarker signatures may represent more realistic approach for the future of personalised medicine in RA. PMID:24733962

  17. Cytokine regulation of immune tolerance

    OpenAIRE

    Wu, Jie; Xie, Aini; Chen, Wenhao

    2014-01-01

    The immune system provides defenses against invading pathogens while maintaining immune tolerance to self-antigens. This immune homeostasis is harmonized by the direct interactions between immune cells and the cytokine environment in which immune cells develop and function. Herein, we discuss three non-redundant paradigms by which cytokines maintain or break immune tolerance. We firstly describe how anti-inflammatory cytokines exert direct inhibitory effects on immune cells to enforce immune ...

  18. Class I Cytokine Receptors

    DEFF Research Database (Denmark)

    Steinocher, Helena

    , the minimal determinants for specificity between membrane spanning helices were investigated with small artificial low complexity peptides, prior found to activate the EPOR in cells. The placement of single methyl group in the so called transmembrane aptamers (traptamers) determined the stabilizing effect...... characteristics of membrane spanning helices, was designed and hGHR TMD and hEPOR TMD produced in sufficient amounts for spectroscopic investigations. The isolated hGHR TMD was revealed to associate in dimeric complexes in detergent micelles and first presumptions about the dimer interface could be made. Further...... the traptamers on the hEPOR TMD dimeric complex in detergent micelles. To gain a better understanding of hGHR regulation a point mutation in the hGHR intracellular domain (ICD), which has recently been linked to lung cancer, was characterized. The mutation was found to decrease binding of suppressor of cytokine...

  19. Inflammasome-independent regulation of IL-1-family cytokines.

    Science.gov (United States)

    Netea, Mihai G; van de Veerdonk, Frank L; van der Meer, Jos W M; Dinarello, Charles A; Joosten, Leo A B

    2015-01-01

    Induction, production, and release of proinflammatory cytokines are essential steps to establish an effective host defense. Cytokines of the interleukin-1 (IL-1) family induce inflammation and regulate T lymphocyte responses while also displaying homeostatic and metabolic activities. With the exception of the IL-1 receptor antagonist, all IL-1 family cytokines lack a signal peptide and require proteolytic processing into an active molecule. One such unique protease is caspase-1, which is activated by protein platforms called the inflammasomes. However, increasing evidence suggests that inflammasomes and caspase-1 are not the only mechanism for processing IL-1 cytokines. IL-1 cytokines are often released as precursors and require extracellular processing for activity. Here we review the inflammasome-independent enzymatic processes that are able to activate IL-1 cytokines, paying special attention to neutrophil-derived serine proteases, which subsequently induce inflammation and modulate host defense. The inflammasome-independent processing of IL-1 cytokines has important consequences for understanding inflammatory diseases, and it impacts the design of IL-1-based modulatory therapies.

  20. Pre-targeted immunodetection in glioma patients: tumour localization and single-photon emission tomography imaging of [[sup 99m]Tc ]PnAO-biotin

    Energy Technology Data Exchange (ETDEWEB)

    Paganelli, G. (INB-CNR, Milan Univ. (Italy). Dept. of Nuclear Medicine Scientific Inst. H San Raffaele, Milan (Italy)); Magnani, P. (INB-CNR, Milan Univ. (Italy). Dept. of Nuclear Medicine Scientific Inst. H San Raffaele, Milan (Italy)); Zito, F. (INB-CNR, Milan Univ. (Italy). Dept. of Nuclear Medicine Scientific Inst. H San Raffaele, Milan (Italy)); Lucignani, G. (INB-CNR, Milan Univ. (Italy). Dept. of Nuclear Medicine Scientific Inst. H San Raffaele, Milan (Italy)); Sudati, F. (INB-CNR, Milan Univ. (Italy). Dept. of Nuclear Medicine Scientific Inst. H San Raffaele, Milan (Italy)); Truci, G. (Div. of Neurology, Milan Univ. (Italy) Scientific Inst. H San Raffaele, Milan (Italy)); Motti, E. (Div. of Neurosurgery, Milan Univ. (Italy) Scientific Inst. H San Raffaele, Milan (Italy)); Terreni, M. (Dept. of Pathology, Scientific Inst. H San Raffaele, Milan (Italy)); Pollo, B. (Dept. of Pathology, Scientific Inst. G. Besta, Milan (Italy)); Giovanelli, M. (Div. of Neurosurgery, Milan

    1994-04-01

    We have developed a three-step pre-targeting method using the avidin-biotin system. The rationale of this technique consists in vivo labelling of biotinylated MoAbs targeted onto tumour deposits, when most of the unbound antibodies have been cleared from the bloodstream as avidin-bound complexes. The anti-tenascin MoAb BC2, specific for the majority of gliomas, was biotinylated and 1 mg was administered i.v. in 20 patients with histologically documented cerebral lesions. After 24-36 h, 5 mg avidin was injected i.v. followed 24 h later by a third i.v. injection of 0.2 mg PnAO-biotin labelled with 15-20 mCi technetium-99m. No evidence of toxicity was observed. Whole-body biodistribution was measured at 20 min, 3 h and 5 h post-injection. [[sup 99m]Tc]PnAO-biotin had a fast blood clearance and was primarily excreted through the biliary system. A dedicated single-photon emission tomography system was used to acquire brain tomographic images 1-2 h after the administration of [[sup 99m]Tc]PnAO-biotin. Tumours were detected in 15/18 glioma patients with a tumour to non-tumour ratio of up 14:1. This three-step method, based on the sequential adminsitration of anti-tenascin MoAb BC2, avidin and [[sup 99m]Tc]PnAO-biotin, can support computed tomography or magnetic resonance imaging for the diagnosis and follow-up of patients with glioma. (orig./MG)

  1. Prospects for cytokine and chemokine biotherapy.

    Science.gov (United States)

    Oppenheim, J J; Murphy, W J; Chertox, O; Schirrmacher, V; Wang, J M

    1997-12-01

    Cytokines with immunostimulating effects have the capacity to induce tumor immunity in animal models, whereas some cytokines interfere with tumor growth based on their angiostatic effects. Despite these capabilities, cytokines, such as IFN-, IFN-, tumor necrosis factor, interleukin (IL)-1, and IL-2, have had limited clinical efficacy and many undesirable side effects. In preclinical models, cytokines can even promote tumor growth and increase metastatic spread. Although chemokines have had limited clinical evaluation, studies of animal models show that they can also have tumor-suppressive or tumor-enhancing effects. In mice, chemokines, such as IP-10, RANTES, and TCA3, have resulted in tumor regression and immunity to subsequent tumor challenge. Those chemokines that are angiostatic (e.g., PF4, IP-10, and MIG) can also induce tumor regression by reducing the tumor blood supply. Conversely, IL-8, which is angiogenic, can promote tumor growth. Our studies show that nasopharyngeal cell line cells (FADU) show a chemotactic as well as a proliferative response to MCP-1. In addition, a variant murine T cell lymphoma cell line Esb-MP, unlike the parental variant Esb, was selectively chemoattracted by murine MCP-1/JE. When injected s.c. into mice, the Esb-MP variant metastasized to the kidney with much higher frequency than the Esb variant. Both cultured kidneys from normal mice and a mesangial cell line constitutively produced chemoattractants that acted on Esb-MP but not Esb parental cells. Purification to homogeneity of these chemoattractants led to the identification of RANTES and JE. These results demonstrate that some chemokines may promote tumor growth and organ-specific metastatic spread of those tumors that have adapted and become responsive to chemokines. Finally, tumors appear to use numerous adaptive mechanisms to subvert and suppress the immune system. More effective therapy with cytokines and chemokines will require better characterization of the means by

  2. Markers of liver function and inflammatory cytokines modulation by ...

    African Journals Online (AJOL)

    Background: Non-alcoholic steatohepatitis is a growing public health problem with no approved therapy; as cytokines and other pro-inflammatory mediators may each play a role in transition of steatosis to NASH which is projected to be the leading cause of liver transplantation in the United States by 2020. Objective: The ...

  3. Impact of genetic polymorphisms of four cytokine genes on treatment ...

    African Journals Online (AJOL)

    Manar Obada

    2016-04-25

    Apr 25, 2016 ... TGF-b. Abstract Background: Many factors contribute for viral clearance and response to antiviral therapy. Genetic polymorphisms of cytokines, ... (HCC) [2]. Interferon had been the cornerstone of HCV ther- apy for almost two decades [3]. Direct-acting anti-viral (DAA) drugs active against different targets of ...

  4. Impact of genetic polymorphisms of four cytokine genes on treatment ...

    African Journals Online (AJOL)

    Background: Many factors contribute for viral clearance and response to antiviral therapy. Genetic polymorphisms of cytokines, chemokines, and their receptors can alter the immune response against Hepatitis C virus (HCV). Aim of the study: The aim of the current study is to assess single nucleotide polymorphism (SNP) in ...

  5. The relationship between IL-2 cytokine secretion and CD4 T ...

    African Journals Online (AJOL)

    Concentration of IL-2 cytokine was determined using ELISA technique, while CD4 T-lymphocyte count was done with C6 Acurri flow cytometer system. Levels ... Although there was elevation of IL-2 cytokine secretion during highly active antiretroviral therapy (HAART), with down regulation of viral burden, no corresponding ...

  6. Skin as a Psychoneuroendocrine Immunology Microcosm: The New Frontier of Low Dose Therapy With Cytokines and Growth Factors in the Systemic Treatment of Chronic Autoimmune Inflammatory Diseases in Dermatology

    Directory of Open Access Journals (Sweden)

    Lotti

    2016-04-01

    Full Text Available In recent years, the central role of signaling molecules, such as hormones, cytokines and growth factors, has become evident in both physiological and pathological processes; these signaling molecules are the main regulating effectors of whole body biological functions, in accordance with the guiding principle of psychoneuroendocrine immunology (PNEI. Low dose medicine (LDM represents an innovative medical approach in which the latest evidence in the fields of molecular biology, PNEI and nano-concentration pharmacology are merged. LDM suggests the use of low-doses of activated biological molecules in order to manage PNEI homeostasis, and this approach represents a new opportunity for the development of therapeutic strategies based on immune balancing interventions. Scientific evidence regarding the efficacy and safety of the LDM approach in the treatment of psoriasis vulgaris, and positive preliminary data regarding the oral administration of low dose activated cytokines for vitiligo and atopic dermatitis treatment, support the LDM-based therapeutic approach for many dermatological diseases.

  7. Cytokines as biomarkers in depressive disorder: current standing and prospects.

    Science.gov (United States)

    Lichtblau, Nicole; Schmidt, Frank M; Schumann, Robert; Kirkby, Kenneth C; Himmerich, Hubertus

    2013-10-01

    The frequently observed co-occurrence of depressive disorders and inflammatory diseases suggests a close connection between the nervous and the immune systems. Increased pro-inflammatory and type 1 cytokines, such as interleukin (IL)-1, tumour necrosis factor (TNF)-α and interferon (IFN)-γ, appear to be an important link. Cytokines are synthesized by immune cells in the blood and peripheral tissues and by glial cells in the central nervous system (CNS). Evidence suggests that the blood-brain barrier (BBB) is permeable to cytokines and immune cells, and that afferent nerves, e.g. the vagus nerve, mediate the communication between peripheral inflammatory processes and CNS. Cytokines such as IL-1ß, TNF-α and IFN-γ seem to contribute to the pathophysiology of depression by activating monoamine reuptake, stimulating the hypothalamic-pituitary-adrenocortical (HPA) axis and decreasing production of serotonin due to increased activity of indolamine-2,3-dioxygenase (IDO). However, critical appraisal of these hypotheses is required, because cytokine elevation is not specific to depression. Moreover, several effective antidepressants such as amitriptyline and mirtazapine have been shown to increase cytokine production. When applying immunomodulatory therapies, these drugs may increase the risk of specific side effects such as infections or interact with antidepressant drugs on important functions of the body such as the coagulation system.

  8. Leucocytes, cytokines and satellite cells

    DEFF Research Database (Denmark)

    Paulsen, Gøran; Mikkelsen, Ulla Ramer; Raastad, Truls

    2012-01-01

    -damaging exercise', primarily eccentric exercise. We review the evidence for the notion that the degree of muscle damage is related to the magnitude of the cytokine response. In the third and final section, we look at the satellite cell response to a single bout of eccentric exercise, as well as the role...... variation in individual responses to a given exercise should, however be expected. The link between cytokine and satellite cell responses and exercise-induced muscle damage is not so clear The systemic cytokine response may be linked more closely to the metabolic demands of exercise rather than muscle...... damage. With the exception of IL-6, the sources of systemic cytokines following exercise remain unclear The satellite cell response to severe muscle damage is related to regeneration, whereas the biological significance of satellite cell proliferation after mild damage or non-damaging exercise remains...

  9. Hypothyroidism and depression: Are cytokines the link?

    Directory of Open Access Journals (Sweden)

    Parimal S Tayde

    2017-01-01

    Full Text Available Context: Primary hypothyroidism has been thought of as an inflammatory condition characterized by raised levels of cytokines such as C-reactive protein (CRP, interleukin-6 (IL-6, and tumor necrosis factor-alpha (TNF-α. Depression is also well known to occur in hypothyroidism. Depression is also characterized by elevated inflammatory cytokines. We planned to study whether cytokines play an important part in linking these two conditions. Objectives: (1 To know the prevalence of depression in overt hypothyroidism due to autoimmune thyroid disease. (2 To correlate the levels of inflammatory markers with the occurrence of depression. (3 To study the effect of levothyroxine on inflammatory markers and depression. Materials and Methods: In this longitudinal, case–controlled study, 33 patients with autoimmune hypothyroidism (thyroid-stimulating hormone >10 uIU/ml were included with 33 age-, sex-, and body max index-matched healthy controls. Individuals were tested for Serum TNF-α, IL-6, high-sensitivity-CRP (hs-CRP. They were assessed for depression using Montgomery Asberg Depression Rating Scale (MADRS and World Health Organization Quality of Life (QOL Scale. Patients received L Thyroxine titrated to achieve euthyroidism and were reassessed for inflammatory markers and cognitive dysfunction. Results: Nineteen patients (57% had mild to moderate depression (MADRS >11. After 6 months of treatment, eight patients (42% had remission of depression with significant improvement in QOL scores (P < 0.05. TNF-α, IL-6, and hs-CRP were significantly elevated in patients compared with controls and reduced with therapy but did not reach baseline as controls. The change in inflammatory markers correlated with improvement in QOL scores in social and environmental domains (P < 0.01. Conclusions: Primary autoimmune hypothyroidism is an inflammatory state characterized by elevated cytokines which decline with LT4 therapy. It is associated with depression and poor

  10. Targeting, toxicity, and efficacy of 2-step, pretargeted radioimmunotherapy using a chimeric bispecific antibody and 131I-labeled bivalent hapten in a phase I optimization clinical trial.

    Science.gov (United States)

    Kraeber-Bodéré, Françoise; Rousseau, Caroline; Bodet-Milin, Caroline; Ferrer, Ludovic; Faivre-Chauvet, Alain; Campion, Loïc; Vuillez, Jean-Philippe; Devillers, Anne; Chang, Chien-Hsing; Goldenberg, David M; Chatal, Jean-François; Barbet, Jacques

    2006-02-01

    Safety, targeting, and antitumor efficacy of pretargeted radioimmunotherapy using anti-carcinoembryonic antigen (CEA) hMN-14 x m734 bispecific antibody (BsmAb) and 131I-di-diethylenetriamine pentaacetic acid (DTPA)-indium hapten were evaluated in a phase I study performed on patients with CEA-expressing tumors. Twenty-two patients with nonmedullary thyroid carcinoma (non-MTC) (group I, 13 patients) or medullary thyroid carcinoma (MTC) (group II, 9 patients) were enrolled. These patients received a 75 mg/m2 (11 patients) or 40 mg/m2 (11 patients) dose of BsmAb and escalating activities of (131)I-di-DTPA-indium 5 d later. Toxicity and tumor response were assessed in 20 patients who received a therapeutic (>2.2 GBq) hapten dose of radioactivity. The percentage of lesions detected by immunoscintigraphy after injection of the therapeutic dose of hapten was 70% on an anatomic-site basis. High bone uptake was relatively frequent. A transient grade I or II hepatic toxicity was observed in 5 patients (45%) injected with 75 mg/m2 of BsmAb and in 1 patient (11%) injected with 40 mg/m2. No other nonhematologic toxicity was observed. With 75 mg/m2 of BsmAb, hematologic toxicity was high: 5 cases of grade III or IV leukopenia (45%) and 5 cases of grade III or IV thrombopenia (45%). With a 40 mg/m2 dose of BsmAb, hematologic toxicity was reduced significantly: 3 cases of grade III or IV leukopenia (33%) and 1 case of grade III or IV thrombopenia (11%) (P = 0.02). Toxicity was significantly higher in MTC patients than in non-MTC patients (P = 0.019). Nine cases of tumor stabilization of 3 mo to more than 12 mo were observed (45%), 6 in the MTC group and 3 in the non-MTC group. The rate of disease stabilization was significantly higher with 75 mg/m2 of BsmAb (64%) than with 40 mg/m2 (22%) (P = 0.04). Human antimouse antibody elevation was observed in 1 patient (8%) and human antihuman antibody in 4 (33%). A BsmAb dose of 40 mg/m2 and a 5-d interval appeared to be a better dose

  11. Cytokine network in psoriasis revisited.

    Science.gov (United States)

    Michalak-Stoma, Anna; Pietrzak, Aldona; Szepietowski, Jacek C; Zalewska-Janowska, Anna; Paszkowski, Tomasz; Chodorowska, Grażyna

    2011-12-01

    Psoriasis is a chronic genetically determined, erythemato-squamous disease associated with many comorbidities. Evidence from clinical studies and experimental models support the concept that psoriasis is a T cell-mediated inflammatory skin disease and T helper (Th) cells - Th1, Th17 and Th22 - play an important role in the pathogenesis. Th1 cytokines IFNγ, IL-2, as well as Th17 cytokines IL-17A, IL-17F, IL-22, IL-26, and TNFα (Th1 and Th17 cytokine) are increased in serum and lesional skin. IL-22 produced by Th17 and new subset of T helper cells, Th22, is also increased within psoriatic lesions and in the serum. Other recently recognized cytokines of significant importance in psoriasis are IL-23, IL-20 and IL-15. The IL-23/Th17 pathway plays a dominant role in psoriasis pathogenesis. Currently due to enormous methodological progress, more and more clinical and histopathological psoriatic features could be explained by particular cytokine imbalance, which still is one of the most fascinating dermatological research fields stimulating new and new generations of researchers.

  12. Anti-cytokine autoantibodies in autoimmune diseases

    Science.gov (United States)

    Cappellano, Giuseppe; Orilieri, Elisabetta; Woldetsadik, Abiy D; Boggio, Elena; Soluri, Maria F; Comi, Cristoforo; Sblattero, Daniele; Chiocchetti, Annalisa; Dianzani, Umberto

    2012-01-01

    An overview of the current literature is showing that autoantibodies (AutoAbs) against cytokines are produced in several pathological conditions, including autoimmune diseases, but can also be detected in healthy individuals. In autoimmune diseases, these AutoAbs may also be prognostic markers, either negative (such as AutoAbs to IL-8 and IL-1α in rheumatoid arthritis) or positive (such as AutoAbs to IL-6 in systemic sclerosis and those to osteopontin in rheumatoid arthritis). They may have neutralizing activity and influence the course of the physiological and pathological immune responses. High levels of AutoAbs against cytokines may even lead to immunodeficiency, such as those to IL-17 in autoimmune polyendocrine syndrome type I or those to IFN-γ in mycobacterial infections. Their role in human therapy may be exploited not only through passive immunization but also through vaccination, which may improve the costs for long lasting treatments of autoimmune diseases. Detection and quantification of these AutoAbs can be profoundly influenced by the technique used and standardization of these methods is needed to increase the value of their analysis. PMID:23885320

  13. CYTOKINES GENETIC POLYMORPHISM: THE PAST AND THE FUTURE

    Directory of Open Access Journals (Sweden)

    L. V. Puzyryova

    2016-01-01

    Full Text Available The molecular genetics opens the new horizons in modern medicine, especially now when many diseases are given huge value in a type of their prevalence among various groups of population. Extremely high interleukin genes polymorphism degrees are studied well especially genetic polymorphism of tumor necrosis factor. Patients with HIV infection in the territory of Russia cause now the highest degree of mortality that is the most actual and socially significant problem of healthcare. This problems studying attracts many researchers. Works in respect of genetic immunity to a virus and influence of cytokines production on the disease forecast are especially interesting. One of the HIV replication influencing factors are cytokines, some of which, including the tumor necrosis factor and interleukin-6 can promote replication of HIV, raising an expression of virus regulatory genes. During disease progress in parallel of anti-inflammatory cytokines level increase (causing in this case rather ineffective antibodies level increase there is an T-helpers suppression stimulating a strong cellular component. Cytokine network functioning during HIV infection depends on many reasons which the individual variation in cytokine production caused by a number of genetic features, as well as an existence of opportunistic infection. Cytokines polymorphism determination in HIV infected patients is necessary in clinical practice for disease progression forecast to adverse fast transition to AIDS that it is important to consider in a choice of tactics of the supporting therapy of HIV-positive patients. Considering insufficient efficiency of modern methods of treatment, restoration and modulation of cytokines balance will increase anti-virus activity of immune system, influencing the factors blocking replication of a HIV.

  14. Malaria: toxins, cytokines and disease

    DEFF Research Database (Denmark)

    Jakobsen, P H; Bate, C A; Taverne, J

    1995-01-01

    In this review the old concept of severe malaria as a toxic disease is re-examined in the light of recent discoveries in the field of cytokines. Animal studies suggest that the induction of TNF by parasite-derived molecules may be partly responsible for cerebral malaria and anemia, while hypoglyc......In this review the old concept of severe malaria as a toxic disease is re-examined in the light of recent discoveries in the field of cytokines. Animal studies suggest that the induction of TNF by parasite-derived molecules may be partly responsible for cerebral malaria and anemia, while...

  15. Cytokines and Pancreatic β-Cell Apoptosis

    DEFF Research Database (Denmark)

    Berchtold, L A; Prause, M; Størling, J

    2016-01-01

    in the low to the high picomolar-femtomolar range and vary exposure time for up to 14-16h to reproduce the acute regulatory effects of systemic inflammation on β-cell secretory responses, with a shift to inhibition at high picomolar concentrations or more than 16h of exposure to illustrate adverse effects...... of anticytokine therapies has yet to be shown by testing the incremental effects of appropriate dosing, timing, and combinations of treatments. Due to the considerable translational importance of enhancing the precision, specificity, and safety of antiinflammatory treatments of diabetes, we review here......The discovery 30 years ago that inflammatory cytokines cause a concentration, activity, and time-dependent bimodal response in pancreatic β-cell function and viability has been a game-changer in the fields of research directed at understanding inflammatory regulation of β-cell function and survival...

  16. Targeting the Binding Interface on a Shared Receptor Subunit of a Cytokine Family Enables the Inhibition of Multiple Member Cytokines with Selectable Target Spectrum*

    Science.gov (United States)

    Nata, Toshie; Basheer, Asjad; Cocchi, Fiorenza; van Besien, Richard; Massoud, Raya; Jacobson, Steven; Azimi, Nazli; Tagaya, Yutaka

    2015-01-01

    The common γ molecule (γc) is a shared signaling receptor subunit used by six γc-cytokines. These cytokines play crucial roles in the differentiation of the mature immune system and are involved in many human diseases. Moreover, recent studies suggest that multiple γc-cytokines are pathogenically involved in a single disease, thus making the shared γc-molecule a logical target for therapeutic intervention. However, the current therapeutic strategies seem to lack options to treat such cases, partly because of the lack of appropriate neutralizing antibodies recognizing the γc and, more importantly, because of the inherent and practical limitations in the use of monoclonal antibodies. By targeting the binding interface of the γc and cytokines, we successfully designed peptides that not only inhibit multiple γc-cytokines but with a selectable target spectrum. Notably, the lead peptide inhibited three γc-cytokines without affecting the other three or non-γc-cytokines. Biological and mutational analyses of our peptide provide new insights to our current understanding on the structural aspect of the binding of γc-cytokines the γc-molecule. Furthermore, we provide evidence that our peptide, when conjugated to polyethylene glycol to gain stability in vivo, efficiently blocks the action of one of the target cytokines in animal models. Collectively, our technology can be expanded to target various combinations of γc-cytokines and thereby will provide a novel strategy to the current anti-cytokine therapies against immune, inflammatory, and malignant diseases. PMID:26183780

  17. Leucocytes, cytokines and satellite cells

    DEFF Research Database (Denmark)

    Paulsen, Gøran; Mikkelsen, Ulla Ramer; Raastad, Truls

    2012-01-01

    damage. With the exception of IL-6, the sources of systemic cytokines following exercise remain unclear The satellite cell response to severe muscle damage is related to regeneration, whereas the biological significance of satellite cell proliferation after mild damage or non-damaging exercise remains...

  18. Targeted radionuclide therapies for pancreatic cancer.

    Science.gov (United States)

    Shah, M; Da Silva, R; Gravekamp, C; Libutti, S K; Abraham, T; Dadachova, E

    2015-08-01

    Pancreatic malignancies, the fourth leading cause of cancer deaths, have an aggressive behavior with poor prognosis, resulting in a 5-year survival rate of only 4%. It is typically a silent malignancy until patients develop metastatic disease. Targeted radionuclide therapies of cancer such as radiolabeled peptides, which bind to the receptors overexpressed by cancer cells and radiolabeled antibodies to tumor-specific antigens provide a viable alternative to chemotherapy and external beam radiation of metastatic cancers. Multiple clinical trials of targeted radionuclide therapy of pancreatic cancer have been performed in the last decade and demonstrated safety and potential efficacy of radionuclide therapy for treatment of this formidable disease. Although a lot of progress has been made in treatment of pancreatic neuroendocrine tumors with radiolabeled (90)Y and (177)Lu somatostatin peptide analogs, pancreatic adenocarcinomas remain a major challenge. Novel approaches such as peptides and antibodies radiolabeled with alpha emitters, pre-targeting, bispecific antibodies and biological therapy based on the radioactive tumorlytic bacteria might offer a potential breakthrough in treatment of pancreatic adenocarcinomas.

  19. Cytokine Correlations in Youth with Tic Disorders

    OpenAIRE

    Parker-Athill, E. Carla; Ehrhart, Jared; Tan, Jun; Murphy, Tanya K.

    2015-01-01

    Background: Studies have noted immunological disruptions in patients with tic disorders, including increased serum cytokine levels. This study aimed to determine whether or not cytokine levels could be correlated with tic symptom severity in patients with a diagnosed tic disorder.

  20. Cytokines and mood in healthy young adults

    NARCIS (Netherlands)

    Jansen, J.; Fernstrand, A.M.; Van De Loo, A.J.A.E.; Garssen, J.; Verster, J.C.

    2015-01-01

    Purpose: A link between chronic inflammation and neuropsychiatric disorders has been demonstrated previously. For example, pro- and anti-inflammatory cytokines have shown to impact neurocircuits relevant to mood regulation. Elevated levels of inflammatory cytokines have been associated with the

  1. Vaginal cytokines do not correlate with postmenopausal vulvovaginal symptoms.

    Science.gov (United States)

    Kollmann, Zahraa; Bersinger, Nick; von Wolff, Michael; Thurman, Andrea R; Archer, David F; Stute, Petra

    2015-04-01

    Exploratory pilot study to determine the correlation between postmenopausal vulvovaginal symptoms and vaginal cytokine levels. Postmenopausal women (n = 34) not using menopausal hormone therapy and presenting with or without symptoms of vulvovaginal irritation were screened. Each participant underwent a vaginal examination and screening for vaginitis. A cervicovaginal lavage (CVL) with sterile saline and a peripheral blood sample were obtained. Main outcome measures were assessed by Luminex® X-map method on the Bio-Plex® platform. Main outcome measures were cervicovaginal and serum interleukin (IL)-4, IL-5, IL-10, IL-12, IL-13, TNF-α, GM-CSF, MIP-1-alpha and RANTES level. Cervicovaginal cytokines were adjusted to total protein concentration [pg/mcg protein]. Twenty-six postmenopausal women were enrolled (symptomatic: n = 15; asymptomatic: n = 11). There were no significant differences between groups: age, age at menopause, vaginal pH and all CVL and serum cytokines (IL-4, IL-5, IL-10, IL-12, IL-13, TNF-α, GM-CSF, MIP-1-alpha and RANTES). GM-CSF was the most abundant vaginal cytokine (symptomatic: 146.5 ± 165.6 pg/mcg protein; asymptomatic: 146.0 ± 173.5 pg/mcg protein; p = 0.99). Postmenopausal vulvovaginal symptoms did not correlate with vaginal inflammatory marker. There was no difference in serum or CVL cytokines between symptomatic and asymptomatic postmenopasual women. Vaginal symptoms after menopause are not related to the vaginal cytokine changes associated with loss of estrogen.

  2. Avian cytokines in health and disease

    Directory of Open Access Journals (Sweden)

    Wigley P

    2003-01-01

    Full Text Available Cytokines are proteins secreted by cells that play an important role in the activation and regulation of other cells and tissues during inflammation and immune responses. Although well described in several mammalian species, the role of cytokines and other related proteins is poorly understood in avian species. Recent advances in avian genetics and immunology have begun to allow the exploration of cytokines in health and disease. Cytokines may be classified in a number of ways, but may be conveniently arranged into four broad groups on the basis of their function. Proinflammatory cytokines such as interleukin-6 and interleukin-1beta play a role in mediating inflammation during disease or injury. Th1 cytokines, including interleukin-12 and interferon-gamma, are involved in the induction of cell-mediated immunity, whereas Th2 cytokines such as interleukin-4 are involved in the induction of humoral immunity. The final group Th3 or Tr cytokines play a role in regulation of immunity. The role of various cytokines in infectious and non-infectious diseases of chickens and turkeys is now being investigated. Although there are only a few reliable ELISAs or bioassays developed for avian cytokines, the use of molecular techniques, and in particular quantitative RT-PCR (Taqman has allowed investigation of cytokine responses in a number of diseases including salmonellosis, coccidiosis and autoimmune thyroiditis. In addition the use of recombinant cytokines as therapeutic agents or as vaccine adjuvants is now being explored.

  3. Cytokine determinants of viral tropism

    Science.gov (United States)

    McFadden, Grant; Mohamed, Mohamed R.; Rahman, Masmudur M.; Bartee, Eric

    2015-01-01

    The specificity of a given virus for a ceil type, tissue or species — collectively known as viral tropism — is an important factor in determining the outcome of viral infection in any particular host. Owing to the increased prevalence of zoonotic infections and the threat of emerging and re-emerging pathogens, gaining a better understanding of the factors that determine viral tropism has become particularly important. In this Review, we summarize our current understanding of the central role of antiviral and pro-inflammatory cytokines, particularly the interferons and tumour necrosis factor, in dictating viral tropism and how these cytokine pathways can be exploited therapeutically for cancer treatment and to better counter future threats from emerging zoonotic pathogens. PMID:19696766

  4. Cytokine profile in children with newly diagnosed tuberculosis

    Directory of Open Access Journals (Sweden)

    O. M. Raznatovska

    2017-10-01

    Full Text Available Nowadays, the most important task of children's phthisiology is to increase the effectiveness of children with tuberculosis treatment, and in the first priority should be given to the first time diagnosed tuberculosis (FTDTB. Examination of the immune system state by cytokine profile in blood serum studying is paid to sufficient attention, as cytokines are the system which regulates the entire complex of organism protective reactions, and immunological dysregulation is the cause of pathological process increasing. There few data of the cytokine profile state studying in children with FTDTB inUkraine in the available literature and various combinations of cytokines comprehensively with other immunological parameters are studied. According to our studies of the blood serum cytokine profile state in adult patients with tuberculosis, the reliable indices of immune system changes are interleukin (IL-2, IL-6, IL-4 and IL-10. The aim of the work is to study the indicators of blood serum cytokine profile (IL-2, IL-6, IL-4, IL-10 in children with FTDTB. Materials and methods. The study of the cytokine profile indicators has been performed in 28 children with FTDTB, aged from 1 to 16 years old (an average age was 9.2 ± 1.1 years. The indicators of the cytokine profile were studied by researching the levels of IL-2, IL-6, IL-4, IL-10 in blood serum by ELISA technique on the equipment of Sirio S immuno-enzyme reader using “Bender MedSystems GmbH” (Austria kit (pkg/ml. These indicators were evaluated at the beginning of antimycobacterial therapy intensive phase. Results. Despite the fact that according to the data from BCG vaccination, 42.8 % of children suffering from FTDTB had full immunity, the changes of cytokine profile indicators at the beginning of the disease were determined in 96.4 % of cases. The peculiarities of cytokine profile changes in sick children were a significant decrease in the content of anti-inflammatory cytokine IL-4, increase in

  5. Cytokine Profiles of Severe Influenza Virus-Related Complications in Children

    Directory of Open Access Journals (Sweden)

    Andrew Fiore-Gartland

    2017-11-01

    Full Text Available RationaleEffective immunomodulatory therapies for children with life-threatening “cytokine storm” triggered by acute influenza infection are lacking. Understanding the immune profiles of children progressing to severe lung injury and/or septic shock could provide insight into pathogenesis.ObjectivesTo compare the endotracheal and serum cytokine profiles of children with influenza-related critical illness and to identify their associations with severe influenza-associated complications.MethodsChildren with influenza-related critical illness were enrolled across 32 hospitals in development (N = 171 and validation (N = 73 cohorts (December 2008 through May 2016. Concentrations of 42 cytokines were measured in serum and endotracheal samples and clustered into modules of covarying cytokines. Relative concentrations of cytokines and cytokine modules were tested for associations with acute lung injury (ALI, shock requiring vasopressors, and death/ECMO.Measurements and main resultsModules of covarying cytokines were more significantly associated with disease severity than individual cytokines. In the development cohort, increased levels of a serum module containing IL6, IL8, IL10, IP10, GCSF, MCP1, and MIP1α [shock odds ratio (OR = 3.37, family-wise error rate (FWER p < 10−4], and decreased levels of a module containing EGF, FGF2, SCD40L, and PAI-1 (shock OR = 0.43, FWER p = 0.002, were both associated with ALI, shock, and death-ECMO independent of age and bacterial coinfection. Both of these associations were confirmed in the validation cohort. Endotracheal and serum cytokine associations differed markedly and were differentially associated with clinical outcomes.ConclusionWe identified strong positive and negative associations of cytokine modules with the most severe influenza-related complications in children, providing new insights into the pathogenesis of influenza-related critical illness in children. Effective

  6. The role of cytokine deficiencies and cytokine autoantibodies in clinical dermatology

    DEFF Research Database (Denmark)

    Liszewski, Walter; Gniadecki, Robert

    2016-01-01

    Cytokines are small, secreted proteins that are essential for promoting and maintaining a normal immune response. Upregulation of cytokines frequently occurs in autoimmune and inflammatory diseases. Conversely, several immunodeficiency, autoimmune and autoinflammatory disorders are known to occur...... review the role of cytokine deficiencies and cytokine autoantibodies in immunodeficiency syndromes, as well as in autoimmune disorders. Finally, we will examine autoinflammatory disorders due to cytokine deficiencies....

  7. Corticosteroid-Induced MKP-1 Represses Pro-Inflammatory Cytokine Secretion by Enhancing Activity of Tristetraprolin (TTP) in ASM Cells

    NARCIS (Netherlands)

    Prabhala, Pavan; Ammit, Alaina; Bunge, Kristin; Ge, Qi

    2016-01-01

    Exaggerated cytokine secretion drives pathogenesis of a number of chronic inflammatory diseases, including asthma. Anti-inflammatory pharmacotherapies, including corticosteroids, are front-line therapies and although they have proven clinical utility, the molecular mechanisms responsible for their

  8. Plasma cytokines in acute stroke

    DEFF Research Database (Denmark)

    Christensen, Hanne Krarup; Boysen, Gudrun; Christensen, Erik

    2011-01-01

    GOALS: The aim of this study was to test the relations between plasma cytokines and the clinical characteristics, course, and risk factors in acute stroke. PATIENTS AND METHODS: The analysis was based on 179 patients with acute stroke included within 24 hours of stroke onset. On inclusion and 3...... months later plasma levels of interleukin 1 beta (IL-1beta), tumor necrosis factor alpha (TNF-alpha), interleukin-1 receptor antagonist (IL-1RA), interleukin 6 (IL-6), interleukin 10 (IL-10), soluble tumor necrosis factor receptor 1 (sTNF-R1), and soluble tumor necrosis factor receptor 2 (sTNF-R2) were...

  9. Cytokines and cytokine networks target neurons to modulate long-term potentiation.

    Science.gov (United States)

    Prieto, G Aleph; Cotman, Carl W

    2017-04-01

    Cytokines play crucial roles in the communication between brain cells including neurons and glia, as well as in the brain-periphery interactions. In the brain, cytokines modulate long-term potentiation (LTP), a cellular correlate of memory. Whether cytokines regulate LTP by direct effects on neurons or by indirect mechanisms mediated by non-neuronal cells is poorly understood. Elucidating neuron-specific effects of cytokines has been challenging because most brain cells express cytokine receptors. Moreover, cytokines commonly increase the expression of multiple cytokines in their target cells, thus increasing the complexity of brain cytokine networks even after single-cytokine challenges. Here, we review evidence on both direct and indirect-mediated modulation of LTP by cytokines. We also describe novel approaches based on neuron- and synaptosome-enriched systems to identify cytokines able to directly modulate LTP, by targeting neurons and synapses. These approaches can test multiple samples in parallel, thus allowing the study of multiple cytokines simultaneously. Hence, a cytokine networks perspective coupled with neuron-specific analysis may contribute to delineation of maps of the modulation of LTP by cytokines. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. Dissecting innate immune signaling in viral evasion of cytokine production.

    Science.gov (United States)

    Zhang, Junjie; Zhu, Lining; Feng, Pinghui

    2014-03-02

    In response to a viral infection, the host innate immune response is activated to up-regulate gene expression and production of antiviral cytokines. Conversely, viruses have evolved intricate strategies to evade and exploit host immune signaling for survival and propagation. Viral immune evasion, entailing host defense and viral evasion, provides one of the most fascinating and dynamic interfaces to discern the host-virus interaction. These studies advance our understanding in innate immune regulation and pave our way to develop novel antiviral therapies. Murine γHV68 is a natural pathogen of murine rodents. γHV68 infection of mice provides a tractable small animal model to examine the antiviral response to human KSHV and EBV of which perturbation of in vivo virus-host interactions is not applicable. Here we describe a protocol to determine the antiviral cytokine production. This protocol can be adapted to other viruses and signaling pathways. Recently, we have discovered that γHV68 hijacks MAVS and IKKβ, key innate immune signaling components downstream of the cytosolic RIG-I and MDA5, to abrogate NFΚB activation and antiviral cytokine production. Specifically, γHV68 infection activates IKKβ and that activated IKKβ phosphorylates RelA to accelerate RelA degradation. As such, γHV68 efficiently uncouples NFΚB activation from its upstream activated IKKβ, negating antiviral cytokine gene expression. This study elucidates an intricate strategy whereby the upstream innate immune activation is intercepted by a viral pathogen to nullify the immediate downstream transcriptional activation and evade antiviral cytokine production.

  11. Targeting cytokine networks in KRAS-driven tumorigenesis.

    Science.gov (United States)

    Golay, Hadrien G; Barbie, David A

    2014-08-01

    KRAS is one of the most commonly mutated oncogenes in human tumors, and is typically associated with aggressive disease. Despite intensive study and years of effort, KRAS has remained refractory to targeted inhibition. Given the challenge of inhibiting KRAS directly, current approaches to KRAS targeted therapy have involved the disruption of downstream signaling pathways. However, combinations of drugs that target RAF/MEK and PI3K/AKT signaling have failed to live up to expectations in the clinic. Here we summarize the evidence that the cytokine signaling circuitry of KRAS-driven tumors represents an equally tractable drug target. Indeed, the incorporation of novel therapeutics that disrupts these cytokine signaling networks may hold the key to overcoming this seemingly impenetrable treatment barrier.

  12. Bioanalytical Chemistry of Cytokines-A Review

    Science.gov (United States)

    Stenken, Julie A.; Poschenrieder, Andreas J.

    2014-01-01

    Cytokines are bioactive proteins produced by many different cells of the immune system. Due to their role in different inflammatory disease states and maintaining homeostasis, there is enormous clinical interest in the quantitation of cytokines. The typical standard methods for quantitation of cytokines are immunoassay-based techniques including enzyme-linked immusorbent assays (ELISA) and bead-based immunoassays read by either standard or modified flow cytometers. A review of recent developments in analytical methods for measurements of cytokine proteins is provided. This review briefly covers cytokine biology and the analysis challenges associated with measurement of these biomarker proteins for understanding both health and disease. New techniques applied to immunoassay-based assays are presented along with the uses of aptamers, electrochemistry, mass spectrometry, optical resonator-based methods. Methods used for elucidating the release of cytokines from single cells as well as in vivo collection methods are described. PMID:25467452

  13. Cancer Cytokines and the Relevance of 3D Cultures for Studying Those Implicated in Human Cancers.

    Science.gov (United States)

    Maddaly, Ravi; Subramaniyan, Aishwarya; Balasubramanian, Harini

    2017-09-01

    Cancers are complex conditions and involve several factors for oncogenesis and progression. Of the various factors influencing the physiology of cancers, cytokines are known to play significant roles as mediators of functions. Intricate cytokine networks have been identified in cancers and interest in cytokines associated with cancers has been gaining ground. Of late, some of these cytokines are even identified as potential targets for cancer therapy apart from a few others such as IL-6 being identified as markers for disease prognosis. Of the major contributors to cancer research, cancer cell lines occupy the top slot as the most widely used material in vitro. In vitro cell cultures have seen significant evolution by the introduction of 3-dimensional (3D) culture systems. 3D cell cultures are now widely accepted as excellent material for cancer research which surpass the traditional monolayer cultures. Cancer research has benefited from 3D cell cultures for understanding the various hallmarks of cancers. However, the potential of these culture systems are still unexploited for cancer cytokine research compared to the other aspects of cancers such as gene expression changes, drug-induced toxicity, morphology, angiogenesis, and invasion. Considering the importance of cancer cytokines, 3D cell cultures can be better utilized in understanding their roles and functions. Some of the possibilities where 3D cell cultures can contribute to cancer cytokine research arise from the distinct morphology of the tumor spheroids, the extracellular matrix (ECM), and the spontaneous occurrence of nutrient and oxygen gradients. Also, the 3D culture models enable one to co-culture different types of cells as a simulation of in vivo conditions, enhancing their utility to study cancer cytokines. We review here the cancer associated cytokines and the contributions of 3D cancer cell cultures for studying cancer cytokines. J. Cell. Biochem. 118: 2544-2558, 2017. © 2017 Wiley Periodicals

  14. Radiolabeled antibodies for cancer imaging and therapy.

    Science.gov (United States)

    Barbet, Jacques; Bardiès, Manuel; Bourgeois, Mickael; Chatal, Jean-François; Chérel, Michel; Davodeau, François; Faivre-Chauvet, Alain; Gestin, Jean-François; Kraeber-Bodéré, Françoise

    2012-01-01

    Radiolabeled antibodies were studied first for tumor detection by single-photon imaging, but FDG PET stopped these developments. In the meantime, radiolabeled antibodies were shown to be effective in the treatment of lymphoma. Radiolabeling techniques are well established and radiolabeled antibodies are a clinical and commercial reality that deserves further studies to advance their application in earlier phase of the diseases and to test combination and adjuvant therapies including radiolabeled antibodies in hematological diseases. In solid tumors, more resistant to radiations and less accessible to large molecules such as antibodies, clinical efficacy remains limited. However, radiolabeled antibodies used in minimal or small-size metastatic disease have shown promising clinical efficacy. In the adjuvant setting, ongoing clinical trials show impressive increase in survival in otherwise unmanageable tumors. New technologies are being developed over the years: recombinant antibodies and pretargeting approaches have shown potential in increasing the therapeutic index of radiolabeled antibodies. In several cases, clinical trials have confirmed preclinical studies. Finally, new radionuclides, such as lutetium-177, with better physical properties will further improve the safety of radioimmunotherapy. Alpha particle and Auger electron emitters offer the theoretical possibility to kill isolated tumor cells and microscopic clusters of tumor cells, opening the perspective of killing the last tumor cell, which is the ultimate challenge in cancer therapy. Preliminary preclinical and preliminary clinical results confirm the feasibility of this approach.

  15. CYTOKINE DISBALANCE AT HERPESVIRUS MYOCARDITIS

    Directory of Open Access Journals (Sweden)

    Peremot S. D

    2016-12-01

    Full Text Available Viral myocarditis is a heterogeneous group of diseases not only by etiologic factors, which belong to different families of Vira kingdom, but is also characterized by a unique mechanism of inflammatory process and cytokine levels specific for each of them. According to numerous researches in сardio-immunology, at herpesvirus infection of the cardiovascular system occur both systemic and localized violations of the immune response. Unfortunately, the accessible literature did not provide the data analysis of complex cardio-immunological research that would take into account the features of herpesvirus myocarditis clinical course. This grounds relevance of immunodiagnosis directed on the exposure of dysimmunities by study of indices of general and local immunity with the estimation of the immune status in patients depending on the stage of exasperation or relapse of chronic herpetic infection in the complex of diagnostic tests. The purpose of our research was to determine features of the state of the immune system with the complex analysis of cytokine profile data, immune and interferon statuses in subacute and chronic forms of herpesvirus myocarditis. Materials and methods. 87 myocarditis patients who were receiving inpatient treatment in medical establishments of Kharkiv were examined. The average age was (M ± m 36 ± 3,46 years old. The diagnosis of myocarditis was established according to the order № 436 by the Ministry of Healthcare of Ukraine from 03.07.2006 of clinical findings protocol. In accordance with the term of myocarditis clinical course, the patients were divided in two sub-groups: 44 patients with subacute (from 2 to 6 months, and 43 patients with chronic (over 6 months clinical course of viral myocarditis. The control group correlated with patients of basic group by age and gender and consisted of 40 practically healthy persons without implications of cardial pathology. Definition of cytokine concentration: IL-2, IL-4, IL-6

  16. Advances in Proteomic Techniques for Cytokine Analysis: Focus on Melanoma Research

    Directory of Open Access Journals (Sweden)

    Helena Kupcova Skalnikova

    2017-12-01

    Full Text Available Melanoma is a skin cancer with permanently increasing incidence and resistance to therapies in advanced stages. Reports of spontaneous regression and tumour infiltration with T-lymphocytes makes melanoma candidate for immunotherapies. Cytokines are key factors regulating immune response and intercellular communication in tumour microenvironment. Cytokines may be used in therapy of melanoma to modulate immune response. Cytokines also possess diagnostic and prognostic potential and cytokine production may reflect effects of immunotherapies. The purpose of this review is to give an overview of recent advances in proteomic techniques for the detection and quantification of cytokines in melanoma research. Approaches covered span from mass spectrometry to immunoassays for single molecule detection (ELISA, western blot, multiplex assays (chemiluminescent, bead-based (Luminex and planar antibody arrays, ultrasensitive techniques (Singulex, Simoa, immuno-PCR, proximity ligation/extension assay, immunomagnetic reduction assay, to analyses of single cells producing cytokines (ELISpot, flow cytometry, mass cytometry and emerging techniques for single cell secretomics. Although this review is focused mainly on cancer and particularly melanoma, the discussed techniques are in general applicable to broad research field of biology and medicine, including stem cells, development, aging, immunology and intercellular communication.

  17. Cytokines during periodontal wound healing: potential application for new therapeutic approach.

    Science.gov (United States)

    Morand, D N; Davideau, J-L; Clauss, F; Jessel, N; Tenenbaum, H; Huck, O

    2017-04-01

    Regeneration of periodontal tissues is one of the main goals of periodontal therapy. However, current treatment, including surgical approach, use of membrane to allow maturation of all periodontal tissues, or use of enamel matrix derivatives, presents limitations in their indications and outcomes leading to the development of new tissue engineering strategies. Several cytokines are considered as key molecules during periodontal destruction process. However, their role during each phase of periodontal wound healing remains unclear. Control and modulation of the inflammatory response and especially, release of cytokines or activation/inhibition in a time- and spatial-controlled manner may be a potential perspective for periodontal tissue engineering. The aim of this review was to summarize the specific role of several cytokines during periodontal wound healing and the potential therapeutic interest of inflammatory modulation for periodontal regeneration especially related to the expression sequence of cytokines. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  18. Cytokine profile of cervical cancer cells

    NARCIS (Netherlands)

    Hazelbag, S.; Fleuren, G. J.; Baelde, J. J.; Schuuring, E.; Kenter, G. G.; Gorter, A.

    2001-01-01

    OBJECTIVE: In patients with cervical carcinoma, the presence of cytokines produced by T(H)2 cells, and the presence of an eosinophilic inflammatory infiltrate, has been associated with a less effective immune response and tumor progression. In the present study, we have investigated the cytokine

  19. Cytokine profile of cervical cancer cells

    NARCIS (Netherlands)

    Hazelbag, S; Fleuren, GJ; Baelde, JJ; Schuuring, E; Kenter, GG; Gorter, A

    2001-01-01

    Objective. In patients with cervical carcinoma, the presence of cytokines produced by T(H)2 cells, and the presence of an eosinophilic inflammatory infiltrate, has been associated with a less effective immune response and tumor progression. In the present study, we have investigated the cytokine

  20. Cytokines and organ failure in acute pancreatitis

    DEFF Research Database (Denmark)

    Malmstrøm, Marie Louise; Hansen, Mark Berner; Andersen, Anders Møller

    2012-01-01

    We aimed at synchronously examining the early time course of 4 proinflammatory cytokines as predictive factors for development of organ failure in patients with acute pancreatitis (AP).......We aimed at synchronously examining the early time course of 4 proinflammatory cytokines as predictive factors for development of organ failure in patients with acute pancreatitis (AP)....

  1. Cytokine gene expression of peripheral blood lymphocytes ...

    African Journals Online (AJOL)

    Lipopolysaccharide (LPS) is a predominant glycolipid in the outer membranes of gam-negative bacteria that stimulates monocytes, macrophages, and neutrophils to produce cytokines. The aim was to study the expression profile of TLRs and cytokines and determine the role of LPS in the peripheral blood lymphocytes.

  2. Cytokine orchestration in post-operative peritoneal adhesion formation.

    LENUS (Irish Health Repository)

    Cahill, Ronan A

    2012-02-03

    Peritoneal adhesions are a near inevitable occurrence after laparotomy and a major cause of both patient and physician misery. To date, clinical attempts at their amelioration have concentrated on manipulating the physical factors that affect their development despite a wealth of experimental data elucidating the molecular mechanisms that underlie their initiation, development and maturation. However, the advent of targeted, specific anti-cytokine agents as directed therapy for inflammatory and neoplastic conditions raises the prospect of a new era for anti-adhesion strategies. To harness this potential will require considerable cross-disciplinary collaboration and that surgeon-scientists propel themselves to the forefront of this emerging field.

  3. Cytokines and Growth Factors Expressed by Human Cutaneous Melanoma

    Directory of Open Access Journals (Sweden)

    Elias G. Elias

    2010-05-01

    Full Text Available Cytokines and growth factors have biologic effects that could stimulate tumor growth, invasion and angiogenesis. The incidence of 24 factors was investigated in 25 cultured human melanoma cell lines and in 62 fixed tissues at different stages of the disease. Over 80% of the human melanoma cell lines expressed TGF-β, IL-8, IL-6, VEGF, PDGF-AA and OPN. Significantly higher TGF-β, IGF-1 and IL-15 were determined in primary lesions compared to distant metastases by immunohistochemistry. Illustrating the complexity of the milieu of the tumor microenvironment, some of these factors may have to be considered in targeted therapy.

  4. Interactions between Autophagy and Inhibitory Cytokines.

    Science.gov (United States)

    Wu, Tian-Tian; Li, Wei-Min; Yao, Yong-Ming

    2016-01-01

    Autophagy is a degradative pathway that plays an essential role in maintaining cellular homeostasis. Most early studies of autophagy focused on its involvement in age-associated degeneration and nutrient deprivation. However, the immunological functions of autophagy have become more widely studied in recent years. Autophagy has been shown to be an intrinsic cellular defense mechanism in the innate and adaptive immune responses. Cytokines belong to a broad and loose category of proteins and are crucial for innate and adaptive immunity. Inhibitory cytokines have evolved to permit tolerance to self while also contributing to the eradication of invading pathogens. Interactions between inhibitory cytokines and autophagy have recently been reported, revealing a novel mechanism by which autophagy controls the immune response. In this review, we discuss interactions between autophagy and the regulatory cytokines IL-10, transforming growth factor-β, and IL-27. We also mention possible interactions between two newly discovered cytokines, IL-35 and IL-37, and autophagy.

  5. Novel methods of cytokine detection: Real-time PCR, ELISPOT, and intracellular cytokine staining

    Directory of Open Access Journals (Sweden)

    Eliza Turlej

    2009-05-01

    Full Text Available Cytokines are small hormone-like proteins that play important roles in immune system control. Cytokines regulate the proliferation and differentiation of cells and hematopoiesis and act as mediators in the inflammatory reaction. Changes in cytokine levels are found in many diseases, such as sepsis, bowel inflammatory disease, autoimmune diseases, as well as graft-versus-host disease. Cytokines levels can be detected using in vivo, in vitro, and ex vivo techniques. The level of cytokine produced can be measured by immunoenzymatic test (ELISA in supernatant after cell culture with the addition of stimulant and in plasma by techniques that measure the level of cytokine secretion in cells (e.g. immunohistochemical staining, ELISPOT, and intracellular cytokine staining, and by molecular biological methods (RPA, real-time PCR, in situ hybridization, and Northern blot. Detection of cytokine mRNA in tissues is useful in the direct determination of heterogenic populations of cytokine-producing cells. Nowadays the most frequently used methods for measuring cytokine level are ELISPOT, intracellular cytokine staining with flow cytometry detection, and real-time PCR. These methods have an important clinical role in vaccine efficacy, in viral, bacterial, and verminous diagnostics, and in determining the efficacy of cancer treatment.

  6. Modulation of cytokine production by carnitine

    Directory of Open Access Journals (Sweden)

    Nicola M. Kouttab

    1993-01-01

    Full Text Available The ability of carnitine congeners to modulate cytokine production by human peripheral blood mononuclear cells (PBMC was investigated. Modulation of cytokine production by PBMC of young (30 years of age or younger and old (70 years of age or older normal donors was first compared. The PBMC were collected over Ficoll–Hypaque and incubated in the presence of various concentrations of acetyl L-carnitine for 24 h. Subsequently the supernatants were collected and examined for cytokine production. The presence of cytokines in tissue culture supernatants was examined by ELISA. The cytokines measured included IL-1α, IL-1β, IL-2, IL-4, IL-6, TNFα, GM–CSF, and IFNγ. The results showed that at 50 μg/ml of acetyl L-carnitine the most significant response was obtained for TNFα. In this regard four of five young donors responded, but only one of five old donors responded. More recently these studies were expanded to examine the ability of L-carnitine to modulate cytokine production at higher doses, 200 and 400 μg/ml, in young donors. The results of these studies showed that in addition to TNFα, significant production of IL-1β and IL-6 was observed. These preliminary studies provide evidence that carnitine may modulate immune functions through the production of selected cytokines.

  7. Cytokines in Radiobiological Responses: A Review

    Science.gov (United States)

    Schaue, Dörthe; Kachikwu, Evelyn L.; McBride, William H.

    2013-01-01

    Cytokines function in many roles that are highly relevant to radiation research. This review focuses on how cytokines are structurally organized, how they are induced by radiation, and how they orchestrate mesenchymal, epithelial and immune cell interactions in irradiated tissues. Pro-inflammatory cytokines are the major components of immediate early gene programs and as such can be rapidly activated after tissue irradiation. They converge with the effects of ionizing radiation in that both generate free radicals including reactive oxygen and nitrogen species (ROS/RNS). “Self” molecules secreted or released from cells after irradiation feed the same paradigm by signaling for ROS and cytokine production. As a result, multilayered feedback control circuits can be generated that perpetuate the radiation tissue damage response. The pro-inflammatory phase persists until such times as perceived challenges to host integrity are eliminated. Antioxidant, anti-inflammatory cytokines then act to restore homeostasis. The balance between pro-inflammatory and anti-inflammatory forces may shift to and fro for a long time after radiation exposure, creating waves as the host tries to deal with persisting pathogenesis. Individual cytokines function within socially interconnected groups to direct these integrated cellular responses. They hunt in packs and form complex cytokine networks that are nested within each other so as to form mutually reinforcing or antagonistic forces. This yin-yang balance appears to have redox as a fulcrum. Because of their social organization, cytokines appear to have a considerable degree of redundancy and it follows that an elevated level of a specific cytokine in a disease situation or after irradiation does not necessarily implicate it causally in pathogenesis. In spite of this, “driver” cytokines are emerging in pathogenic situations that can clearly be targeted for therapeutic benefit, including in radiation settings. Cytokines can greatly

  8. Spironolactone inhibits production of proinflammatory cytokines, including tumour necrosis factor-alpha and interferon-gamma, and has potential in the treatment of arthritis

    DEFF Research Database (Denmark)

    Bendtzen, K; Hansen, P R; Rieneck, K

    2003-01-01

    and interleukin 6 (70-90% inhibition). Release of these cytokines was also suppressed when testing whole blood from RA patients receiving 50 mg spironolactone twice daily, indicating that pharmaceutical use of the drug may suppress the release of inflammatory cytokines. Spironolactone therapy was generally well...

  9. Cytokines: Roles in atherosclerosis disease progression and potential therapeutic targets

    Science.gov (United States)

    Moss, Joe W. E.; Ramji, Dipak P.

    2017-01-01

    Atherosclerosis, the primary cause of cardiovascular disease (CVD), is a chronic inflammatory disorder in the walls of medium and large arteries. CVD is currently responsible for about one in three global deaths and this is expected to rise in the future due to an increase in the prevalence of obesity and diabetes. Current therapies for atherosclerosis mainly modulate lipid homeostasis and whilst successful at reducing the risk of a CVD-related death, they are associated with considerable residual risk and various side effects. There is therefore a need for alternative therapies aimed at regulating inflammation in order to reduce atherogenesis. This review will highlight the key role cytokines play during disease progression as well as potential therapeutic strategies to target them. PMID:27357616

  10. Th17 cytokines induce pro-fibrotic cytokines release from human eosinophils

    Science.gov (United States)

    2013-01-01

    Background Subepithelial fibrosis is one of the most critical structural changes affecting bronchial airway function during asthma. Eosinophils have been shown to contribute to the production of pro-fibrotic cytokines, TGF-β and IL-11, however, the mechanism regulating this process is not fully understood. Objective In this report, we investigated whether cytokines associated with inflammation during asthma may induce eosinophils to produce pro-fibrotic cytokines. Methods Eosinophils were isolated from peripheral blood of 10 asthmatics and 10 normal control subjects. Eosinophils were stimulated with Th1, Th2 and Th17 cytokines and the production of TGF-β and IL-11 was determined using real time PCR and ELISA assays. Results The basal expression levels of eosinophil derived TGF-β and IL-11 cytokines were comparable between asthmatic and healthy individuals. Stimulating eosinophils with Th1 and Th2 cytokines did not induce expression of pro-fibrotic cytokines. However, stimulating eosinophils with Th17 cytokines resulted in the enhancement of TGF-β and IL-11 expression in asthmatic but not healthy individuals. This effect of IL-17 on eosinophils was dependent on p38 MAPK activation as inhibiting the phosphorylation of p38 MAPK, but not other kinases, inhibited IL-17 induced pro-fibrotic cytokine release. Conclusions Th17 cytokines might contribute to airway fibrosis during asthma by enhancing production of eosinophil derived pro-fibrotic cytokines. Preventing the release of pro-fibrotic cytokines by blocking the effect of Th17 cytokines on eosinophils may prove to be beneficial in controlling fibrosis for disorders with IL-17 driven inflammation such as allergic and autoimmune diseases. PMID:23496774

  11. Mycobacteria-specific cytokine responses as correlates of treatment response in active and latent tuberculosis.

    Science.gov (United States)

    Clifford, Vanessa; Tebruegge, Marc; Zufferey, Christel; Germano, Susie; Forbes, Ben; Cosentino, Lucy; McBryde, Emma; Eisen, Damon; Robins-Browne, Roy; Street, Alan; Denholm, Justin; Curtis, Nigel

    2017-08-01

    A biomarker indicating successful tuberculosis (TB) therapy would assist in determining appropriate length of treatment. This study aimed to determine changes in mycobacteria-specific antigen-induced cytokine biomarkers in patients receiving therapy for latent or active TB, to identify biomarkers potentially correlating with treatment success. A total of 33 adults with active TB and 36 with latent TB were followed longitudinally over therapy. Whole blood stimulation assays using mycobacteria-specific antigens (CFP-10, ESAT-6, PPD) were done on samples obtained at 0, 1, 3, 6 and 9 months. Cytokine responses (IFN-γ, IL-1ra, IL-2, IL-10, IL-13, IP-10, MIP-1β, and TNF-α) in supernatants were measured by Luminex xMAP immunoassay. In active TB cases, median IL-1ra (with CFP-10 and with PPD stimulation), IP-10 (CFP-10, ESAT-6), MIP-1β (ESAT-6, PPD), and TNF-α (ESAT-6) responses declined significantly over the course of therapy. In latent TB cases, median IL-1ra (CFP-10, ESAT-6, PPD), IL-2 (CFP-10, ESAT-6), and IP-10 (CFP-10, ESAT-6) responses declined significantly. Mycobacteria-specific cytokine responses change significantly over the course of therapy, and their kinetics in active TB differ from those observed in latent TB. In particular, mycobacteria-specific IL-1ra responses are potential correlates of successful therapy in both active and latent TB. Copyright © 2017 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

  12. Theranostic pretargeted radioimmunotherapy of colorectal cancer xenografts in mice using picomolar affinity {sup 86}Y- or {sup 177}Lu-DOTA-Bn binding scFv C825/GPA33 IgG bispecific immunoconjugates

    Energy Technology Data Exchange (ETDEWEB)

    Cheal, Sarah M.; Lee, Sang-gyu; Punzalan, Blesida; Larson, Steven M. [Memorial Sloan Kettering Cancer Center, Department of Radiology, New York, NY (United States); Memorial Sloan Kettering Cancer Center, Molecular Pharmacology and Chemistry Program, New York, NY (United States); Xu, Hong; Guo, Hong-fen [Memorial Sloan Kettering Cancer Center, Department of Pediatrics, New York, NY (United States); Chalasani, Sandhya; Carrasquillo, Jorge A. [Memorial Sloan Kettering Cancer Center, Department of Radiology, New York, NY (United States); Fung, Edward K. [Memorial Sloan Kettering Cancer Center, Molecular Pharmacology and Chemistry Program, New York, NY (United States); Memorial Sloan Kettering Cancer Center, Department of Medical Physics, New York, NY (United States); Jungbluth, Achim [Memorial Sloan Kettering Cancer Center, Department of Pathology, New York, NY (United States); Zanzonico, Pat B.; O' Donoghue, Joseph [Memorial Sloan Kettering Cancer Center, Department of Medical Physics, New York, NY (United States); Smith-Jones, Peter M. [Stony Brook University, Department of Psychiatry and Behavioral Science, Stony Brook, NY (United States); Stony Brook University, Department of Radiology, Stony Brook, NY (United States); Wittrup, K.D. [Massachusetts Institute of Technology, Department of Chemical Engineering, Cambridge, MA (United States); Massachusetts Institute of Technology, Department of Biological Engineering, Cambridge, MA (United States); Massachusetts Institute of Technology, Koch Institute for Integrative Cancer Research, Cambridge, MA (United States); Cheung, Nai-Kong V. [Memorial Sloan Kettering Cancer Center, Molecular Pharmacology and Chemistry Program, New York, NY (United States); Memorial Sloan Kettering Cancer Center, Department of Pediatrics, New York, NY (United States)

    2016-05-15

    GPA33 is a colorectal cancer (CRC) antigen with unique retention properties after huA33-mediated tumor targeting. We tested a pretargeted radioimmunotherapy (PRIT) approach for CRC using a tetravalent bispecific antibody with dual specificity for GPA33 tumor antigen and DOTA-Bn-(radiolanthanide metal) complex. PRIT was optimized in vivo by titrating sequential intravenous doses of huA33-C825, the dextran-based clearing agent, and the C825 haptens {sup 177}Lu-or {sup 86}Y-DOTA-Bn in mice bearing the SW1222 subcutaneous (s.c.) CRC xenograft model. Using optimized PRIT, therapeutic indices (TIs) for tumor radiation-absorbed dose of 73 (tumor/blood) and 12 (tumor/kidney) were achieved. Estimated absorbed doses (cGy/MBq) to tumor, blood, liver, spleen, and kidney for single-cycle PRIT were 65.8, 0.9 (TI 73), 6.3 (TI 10), 6.6 (TI 10), and 5.3 (TI 12), respectively. Two cycles of PRIT (66.6 or 111 MBq {sup 177}Lu-DOTA-Bn) were safe and effective, with a complete response of established s.c. tumors (100 - 700 mm{sup 3}) in nine of nine mice, with two mice alive without recurrence at >140 days. Tumor log kill in this model was estimated to be 2.1 - 3.0 based on time to 500-mm{sup 3} tumor recurrence. In addition, PRIT dosimetry/diagnosis was performed by PET imaging of the positron-emitting DOTA hapten {sup 86}Y-DOTA-Bn. We have developed anti-GPA33 PRIT as a triple-step theranostic strategy for preclinical detection, dosimetry, and safe targeted radiotherapy of established human colorectal mouse xenografts. (orig.)

  13. Dynamical Systems, Cytokine Storms, and Blood Filtration

    Science.gov (United States)

    Foster, Glenn; Hubler, Alfred

    2008-03-01

    Various infections and non-infectious diseases can trigger immune cells and the proteins (cytokines) the cells use to communicate with each other to be caught in a positive feedback loop; this ``cytokine storm'' is frequently fatal. By examining the network of cytokine-immune cell interactions we will illustrate why anti-mediator drugs have been generally ineffective in stopping this feedback. A more effective approach may be to try and reduce interactions by dampening many signals at once by filtering the cytokines out of the blood directly (think dialysis). We will argue that feedback on an out of control nonlinear dynamical system is easier to understand than its normal healthy state and apply filtration to a toy model of immune response.

  14. Eosinophil cytokines: Emerging roles in immunity

    Directory of Open Access Journals (Sweden)

    Paige eLacy

    2014-11-01

    Full Text Available Eosinophils derive from the bone marrow and circulate at low levels in the blood in healthy individuals. These granulated cells preferentially leave the circulation and marginate to tissues, where they are implicated in the regulation of innate and adaptive immunity. In diseases such as allergic inflammation, eosinophil numbers escalate markedly in the blood and tissues where inflammatory foci are located. Eosinophils possess a range of immunomodulatory factors that are released upon cell activation, including over 35 cytokines, growth factors, and chemokines. Unlike T and B cells, eosinophils can rapidly release cytokines within minutes in response to stimulation. While some cytokines are stored as preformed mediators in crystalloid granules and secretory vesicles, eosinophils are also capable of undergoing de novo synthesis and secretion of these immunological factors. Some of the molecular mechanisms that coordinate the final steps of cytokine secretion are hypothesized to involve binding of membrane fusion complexes comprised of soluble N-ethylmaleimide sensitive factor attachment protein receptors (SNAREs. These intracellular receptors regulate the release of granules and vesicles containing a range of secreted proteins, among which are cytokines and chemokines. Emerging evidence from both human and animal model-based research has suggested an active participation of eosinophils in several physiological/pathological processes such as immunomodulation and tissue remodeling. The observed eosinophil effector functions in health and disease implicate eosinophil cytokine secretion as a fundamental immunoregulatory process. The focus of this review is to describe the cytokines, growth factors, and chemokines that are elaborated by eosinophils, and to illustrate some of the intracellular events leading to the release of eosinophil-derived cytokines.

  15. Cytokine and gene therapy of minimal residual tumour disease

    Czech Academy of Sciences Publication Activity Database

    Bubeník, Jan; Šímová, Jana; Mikyšková, Romana; Mendoza, Luis; Jandlová, Táňa

    1999-01-01

    Roč. 4, Suppl. 1 (1999), s. S10 ISSN 1107-3756. [World Congress on Advances in Oncology /4./, International Symposium on Molecular Medicine /2./. 07.10.1999-09.10.1999, Vouliagmeni, Atény] Subject RIV: EC - Immunology

  16. Influence of DC-CIK in advanced colorectal cancer patients on T lymphocyte subsets and cytokines

    Directory of Open Access Journals (Sweden)

    Rong Wang

    2016-07-01

    Full Text Available Objective: To explore the effects of dendritic cells (DC-cytokine induced killer cells (CIK treatment on T lymphocyte subsets and cytokines in patients with advanced colorectal cancer. Methods: A total of 84 cases patients with advanced colorectal cancer were divided into two groups according to random number table method, each 42 cases, both two groups were given FOLFOX scheme chemotherapy, on the basis, the observation group were given supplementary DC-CIK treatment, compared the T lymphocy te subgroup: CD3+, CD4+, CD8+, CD4+/CD8+, Th1 cytokines, interleukin-2 (IL-2 and interferon gamma-γ (FN-γ, Th2 cytokines: interleukin 6 (IL-6, interleukin 4 (IL-4 of the two groups before and after treatment. Results: Compared with before treatment, the CD3+, CD4+, CD8+, CD4+/CD8+, Th1 cytokines IL-2 and IFN-γ in observation group were significantly higher than after treatment , the CD3+, CD4+, CD8+, CD4+/CD8+, Th1 cytokines IL-2 and IFN-γ in control group were significantly lower than after treatment, and the differences were all statistically significant; The CD3+, CD4+, CD8+, CD4+/CD8+, Th1 cytokines IL-2 and IFN-γ in observation group after treatment were significantly higher than those in control group after treatment with statistical difference; CD8+, Th2 cytokines IL-4, IL-6 in two groups had no statistical significance before and after treatment. Conclusion: Chemotherapy can cause the immune function restrained in patients with advanced colorectal cancer, and DC-CIK supplementary therapy can significantly improve the immune function, enhance the anti tumor immune responses.

  17. A review of the relationship between proinflammatory cytokines and major depressive disorder.

    Science.gov (United States)

    Young, Juan Joseph; Bruno, Davide; Pomara, Nunzio

    2014-12-01

    Determining etiological factors and reviewing advances in diagnostic modalities sensitive and specific to Major Depressive Disorder (MDD) is of importance in its evaluation and treatment. The inflammatory hypothesis is one of the most prevalent topics concerning MDD and may provide insight into the pathogenesis of depression, development of biomarkers, and ultimately production of more effective depression therapies. We reviewed several studies to evaluate contemporary concepts concerning proinflammatory cytokines and their relationship to various depressive disorders, the use of anti-inflammatory therapies in MDD treatment, and the application of neuroimaging in conjunction with cytokine profiles from both plasma and CSF as possible diagnostic tools. Proinflammatory cytokines in both plasma and CSF have been found to influence the progression and severity of depressive disorders in different populations. Studies have shown elevated serum levels of IL-1, IL-6, TNF-α, CRP, and MCP-1 in depressed patients, but have presented mixed results with IL-8 serum levels, and with IL-6 and MCP-1 CSF levels. Anti-inflammatory treatment of MDD may have adjuvant properties with current depression medications. MRI and NIRS neuroimaging confirm neurological abnormalities in the presence of elevated proinflammatory cytokines in depressed or stressed patients. Heterogeneity of MDD and limited CSF cytokine research complicate the study of MDD pathogenesis. There is significant evidence that inflammatory processes influence the development and progression of MDD. Future studies with larger arrays of cytokine profiles aided by neuroimaging may provide more sensitive and specific modes of diagnostics in determining MDD etiology and provide guidance in individual therapies. Copyright © 2014 Elsevier B.V. All rights reserved.

  18. Cytokine profiles show heterogeneity of interferon-β response in multiple sclerosis patients

    DEFF Research Database (Denmark)

    Hegen, Harald; Adrianto, Indra; Lessard, Christopher J

    2016-01-01

    OBJECTIVE: To evaluate serum cytokine profiles for their utility to determine the heterogeneous responses to interferon (IFN)-β treatment in patients with multiple sclerosis (MS). METHODS: Patients with relapsing-remitting MS (RRMS) or clinically isolated syndrome receiving de novo IFN-β treatment...... were included in this prospective, observational study. Number of relapses and changes in disability were assessed 2 years prior to and 2 years after initiation of treatment. Sera were collected at baseline and after 3 months on therapy. Cytokine levels in sera were assessed by Luminex multiplex assays...

  19. Th17-Associated Cytokines as a Therapeutic Target for Steroid-Insensitive Asthma

    Directory of Open Access Journals (Sweden)

    Yuko Morishima

    2013-01-01

    Full Text Available Steroid-insensitive asthma is an infrequent but problematic airway disease that presents with persistent symptoms, airflow limitation, or recurrent exacerbations even when treated with steroid-based therapies. Because of unsatisfactory results obtained from currently available therapies for steroid-insensitive asthma, a better understanding of its pathogenesis and the development of new targeted molecular therapies are warranted. Recent studies indicated that levels of interleukin (IL-17 are increased and both eosinophils and neutrophils infiltrate the airways of severe asthmatics. IL-17 is a proinflammatory cytokine mainly secreted from helper T (Th 17 cells and is important for the induction of neutrophil recruitment and migration at sites of inflammation. This review focuses on the pathogenetic role of Th17 cells and their associated cytokines in steroid-insensitive asthma and discusses the prospects of novel therapeutic options targeting the Th17 signaling pathway.

  20. Eosinophil secretion of granule-derived cytokines

    Directory of Open Access Journals (Sweden)

    Lisa A Spencer

    2014-10-01

    Full Text Available Eosinophils are tissue-dwelling leukocytes, present in the thymus, and gastrointestinal and genitourinary tracts of healthy individuals at baseline, and recruited, often in large numbers, to allergic inflammatory foci and sites of active tissue repair. The biological significance of eosinophils is vast and varied. In health, eosinophils support uterine and mammary gland development, and maintain bone marrow plasma cells and adipose tissue alternatively activated macrophages, while in response to tissue insult eosinophils function as inflammatory effector cells, and, in the wake of an inflammatory response, promote tissue regeneration and wound healing. One common mechanism driving many of the diverse eosinophil functions is the regulated and differential secretion of a vast array of eosinophil-derived cytokines. Eosinophils are distinguished from most other leukocytes in that many, if not all, of the over three dozen eosinophil-derived cytokines are pre-synthesized and stored within intracellular granules, poised for very rapid, stimulus-induced secretion. Eosinophils engaged in cytokine secretion in situ utilize distinct pathways of cytokine release that include: classical exocytosis, whereby granules themselves fuse with the plasma membrane and release their entire contents extracellularly; piecemeal degranulation, whereby granule-derived cytokines are selectively mobilized into vesicles that emerge from granules, traverse the cytoplasm and fuse with the plasma membrane to release discrete packets of cytokines; and eosinophil cytolysis, whereby intact granules are extruded from eosinophils, and deposited within tissues. In this latter scenario, extracellular granules can themselves function as stimulus-responsive secretory-competent organelles within the tissue. Here we review the distinctive processes of differential secretion of eosinophil granule-derived cytokines.

  1. IL-17 and related cytokines involved in the pathology and immunotherapy of multiple sclerosis: Current and future developments.

    Science.gov (United States)

    Luchtman, Dirk W; Ellwardt, Erik; Larochelle, Catherine; Zipp, Frauke

    2014-08-01

    Multiple sclerosis (MS), an autoimmune neurological disorder, is driven by self-reactive T helper (Th) cells. Research on the role of Th17 lymphocytes in MS pathogenesis has made significant progress in identifying various immunological as well as environmental factors that induce the differentiation and expansion of these cells, different subsets of Th17 cells with varying degrees of pathogenicity, and the role of the secreted effector cytokines. While approved therapies for MS offer significant benefit to patients, there remain unmet needs. Ongoing clinical trials aim to translate the advanced knowledge of Th17 cytokines to improved therapies. This review discusses the current status and future developments of research into the role of Th17 and related cytokines in MS pathogenesis and therapy. Copyright © 2014. Published by Elsevier Ltd.

  2. Regulation of human cytokines by Cordyceps militaris.

    Science.gov (United States)

    Sun, Yong; Shao, Yani; Zhang, Zhiguo; Wang, Lianfen; Mariga, Alfred M; Pang, Guangchang; Geng, Chaoyu; Ho, Chi-Tang; Hu, Qiuhui; Zhao, Liyan

    2014-12-01

    Cordyceps (Cordyceps militaris) exhibits many biological activities including antioxidant, inhibition of inflammation, cancer prevention, hypoglycemic, and antiaging properties, etc. However, a majority of studies involving C. militaris have focused only on in vitro and animal models, and there is a lack of direct translation and application of study results to clinical practice (e.g., health benefits). In this study, we investigated the regulatory effects of C. militaris micron powder (3 doses) on the human immune system. The study results showed that administration of C. militaris at various dosages reduced the activity of cytokines such as eotaxin, fibroblast growth factor-2, GRO, and monocyte chemoattractant protein-1. In addition, there was a significant decrease in the activity of various cytokines, including GRO, sCD40L, and tumor necrosis factor-α, and a significant downregulation of interleukin-12(p70), interferon-γ inducible protein 10, and macrophage inflammatory protein-1β activities, indicating that C. militaris at all three dosages downregulated the activity of cytokines, especially inflammatory cytokines and chemokines. Different dosages of C. militaris produced different changes in cytokines. Copyright © 2014. Published by Elsevier B.V.

  3. Regulation of human cytokines by Cordyceps militaris

    Directory of Open Access Journals (Sweden)

    Yong Sun

    2014-12-01

    Full Text Available Cordyceps (Cordyceps militaris exhibits many biological activities including antioxidant, inhibition of inflammation, cancer prevention, hypoglycemic, and antiaging properties, etc. However, a majority of studies involving C. militaris have focused only on in vitro and animal models, and there is a lack of direct translation and application of study results to clinical practice (e.g., health benefits. In this study, we investigated the regulatory effects of C. militaris micron powder (3 doses on the human immune system. The study results showed that administration of C. militaris at various dosages reduced the activity of cytokines such as eotaxin, fibroblast growth factor-2, GRO, and monocyte chemoattractant protein-1. In addition, there was a significant decrease in the activity of various cytokines, including GRO, sCD40L, and tumor necrosis factor-α, and a significant downregulation of interleukin-12(p70, interferon-γ inducible protein 10, and macrophage inflammatory protein-1β activities, indicating that C. militaris at all three dosages downregulated the activity of cytokines, especially inflammatory cytokines and chemokines. Different dosages of C. militaris produced different changes in cytokines.

  4. [Attachment style and cytokine levels in patients with fibromyalgia. A prospective longitudinal study].

    Science.gov (United States)

    Wang, H; Weber, A; Schiltenwolf, M; Amelung, D

    2014-10-01

    The association between attachment style and subjective pain is controversially discussed and the influence of attachment styles on cytokine levels in chronic pain has received little attention in research. In this prospective longitudinal clinical study, we evaluated the relationship between cytokines, attachment style and subjective pain intensity as well as pain-related functioning in patients with fibromyalgia (FM) who underwent a 4-week multidisciplinary pain therapy. The attachment style was determined in 43 patients with FM using the relationship questionnaire (RQ-2) and subjective pain with the German version of the West Haven-Yale multidimensional pain inventory. Serum levels of the proinflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin 8 (IL-8) and the anti-inflammatory cytokines IL-4 and IL-10 were assessed before and after treatment and additionally once only in 18 healthy controls (Bio-Plex system). Patients with FM syndrome were significantly more often insecurely attached than healthy controls (p = 0.001). Serum levels of TNF-α (p = 0.001) and IL-10 (p = 0.039) were significantly higher in FM patients compared to controls. Attachment was unrelated to IL-4, IL-8, and IL-10 levels. Insecurely attached FM patients had significantly higher levels of TNF-α (p = 0.002). than securely attached patients. Insecurely and securely attached patients did not differ in subjective levels of pain severity, activity or functional interference. Cytokine levels were not correlated with subjective levels of pain severity or functional interference. Multidisciplinary pain therapy significantly reduced cytokine levels, pain severity, anxiety and depression independent of attachment style.

  5. Cytokines in the management of rotavirus infection: A systematic review of in vivo studies.

    Science.gov (United States)

    Gandhi, Gopalsamy Rajiv; Santos, Victor Santana; Denadai, Marina; da Silva Calisto, Valdete Kaliane; de Souza Siqueira Quintans, Jullyana; de Oliveira E Silva, Ana Mara; de Souza Araújo, Adriano Antunes; Narain, Narendra; Cuevas, Luis Eduardo; Júnior, Lucindo José Quintans; Gurgel, Ricardo Queiroz

    2017-08-01

    Rotavirus is a leading cause of childhood diarrhoea. Rotavirus vaccines are effective against severe rotavirus gastroenteritis, but have lower efficacy in low income countries in Africa. Anti-rotavirus treatment is not available. This study reviews the literature of animal studies evaluating whether cytokine mediated pathways of immune activation could improve rotavirus therapy. We performed a systematic review of articles in English published from 2010 to 2016 reporting agents with in vivo antirotavirus activity for the management of rotavirus infection. The search was carried in PubMed, EMBASE, Scopus and Web of Science. Animal experiments where cytokines were investigated to assess the outcome of rotavirus therapy were included. A total of 869 publications were identified. Of these, 19 pertained the objectives of the review, and 11 articles described the effect of probiotics/commensals on rotavirus infection and immune responses in animals. Eight further in vivo studies evaluated the immunomodulating effects of herbs, secondary metabolites and food-derived products on cytokine responses of rotavirus-infected animals. Studies extensively reported the regulatory roles for T-helper (Th)1 (interferon gamma (IFN-γ), interleukin (IL)-2, IL-12) and Th2 (IL-4, IL-6, IL-10) cytokines responses to rotavirus pathogenesis and immunity, inhibiting rotavirus infection through suppression of inflammation by viral inhibition. Th1 and Th2 cytokines stimulate the immune system, inhibiting rotavirus binding and/or replication in animal models. Th1/Th2 cytokine responses have optimal immunomodulating effects to reduce rotavirus diarrhoea and enhance immune responses in experimental rotavirus infection. Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. Cytokine Regulation of Microenvironmental Cells in Myeloproliferative Neoplasms

    Directory of Open Access Journals (Sweden)

    Gregor Hoermann

    2015-01-01

    Full Text Available The term myeloproliferative neoplasms (MPN refers to a heterogeneous group of diseases including not only polycythemia vera (PV, essential thrombocythemia (ET, and primary myelofibrosis (PMF, but also chronic myeloid leukemia (CML, and systemic mastocytosis (SM. Despite the clinical and biological differences between these diseases, common pathophysiological mechanisms have been identified in MPN. First, aberrant tyrosine kinase signaling due to somatic mutations in certain driver genes is common to these MPN. Second, alterations of the bone marrow microenvironment are found in all MPN types and have been implicated in the pathogenesis of the diseases. Finally, elevated levels of proinflammatory and microenvironment-regulating cytokines are commonly found in all MPN-variants. In this paper, we review the effects of MPN-related oncogenes on cytokine expression and release and describe common as well as distinct pathogenetic mechanisms underlying microenvironmental changes in various MPN. Furthermore, targeting of the microenvironment in MPN is discussed. Such novel therapies may enhance the efficacy and may overcome resistance to established tyrosine kinase inhibitor treatment in these patients. Nevertheless, additional basic studies on the complex interplay of neoplastic and stromal cells are required in order to optimize targeting strategies and to translate these concepts into clinical application.

  7. Gingival fluid cytokine expression and subgingival bacterial counts during pregnancy and postpartum: a case series.

    Science.gov (United States)

    Bieri, Regina Alessandri; Adriaens, Laurence; Spörri, Stefan; Lang, Niklaus P; Persson, G Rutger

    2013-01-01

    The aim of this study was to assess gingival fluid (GCF) cytokine messenger RNA (mRNA) levels, subgingival bacteria, and clinical periodontal conditions during a normal pregnancy to postpartum. Subgingival bacterial samples were analyzed with the checkerboard DNA-DNA hybridization method. GCF samples were assessed with real-time PCR including five proinflammatory cytokines and secretory leukocyte protease inhibitor. Nineteen pregnant women with a mean age of 32 years (S.D. ± 4 years, range 26-42) participated in the study. Full-mouth bleeding scores (BOP) decreased from an average of 41.2% (S.D. ± 18.6%) at the 12th week of pregnancy to 26.6% (S.D. ± 14.4%) at the 4-6 weeks postpartum (p counts of Eubacterium saburreum, Parvimonas micra, Selenomonas noxia, and Staphylococcus aureus were found at week 12 of pregnancy than at the 4-6 weeks postpartum examinations (p counts were observed. BOP scores and GCF levels of selected cytokines were not related to each other and no differences in GCF levels of the cytokines were observed between samples from the 12th week of pregnancy to 4-6 weeks postpartum. Decreasing postpartum counts of Porphyromonas endodontalis and Pseudomonas aeruginosa were associated with decreasing levels of Il-8 and Il-1β. BOP decreased after pregnancy without any active periodontal therapy. Associations between bacterial counts and cytokine levels varied greatly in pregnant women with gingivitis and a normal pregnancy outcome. Postpartum associations between GCF cytokines and bacterial counts were more consistent. Combined assessments of gingival fluid cytokines and subgingival bacteria may provide important information on host response.

  8. Cytokines: muscle protein and amino acid metabolism

    DEFF Research Database (Denmark)

    van Hall, Gerrit

    2012-01-01

    raises TNF-α and IL-6 to moderate levels, has only identified IL-6 as a potent cytokine, decreasing systemic amino acid levels and muscle protein metabolism. The marked decrease in circulatory and muscle amino acid concentrations was observed with a concomitant reduction in both the rates of muscle...... of IL-6 on the regulation of muscle protein metabolism but indirectly via IL-6 reducing amino acid availability. SUMMARY: Recent studies suggest that the best described cytokines TNF-α and IL-6 are unlikely to be the major direct mediators of muscle protein loss in inflammatory diseases. However...

  9. Cytokines and Organ Failure in Acute Pancreatitis

    DEFF Research Database (Denmark)

    Malmstrøm, Marie Louise; Hansen, Mark Berner; Andersen, Anders Møller

    2012-01-01

    renal, respiratory, and circulatory failure, as was the case for patients with multiorgan failure. Interleukin 18 levels were significantly elevated in renal and respiratory failure only. Tumor necrosis factor > was significantly elevated in all types of organ failures, except for intestinal failure....... Conclusions: Synchronous measurements of 4 cytokines demonstrated IL-6 and IL-8 to be predictive as early surrogate markers with regard to organ failures in AP. The fact that all of the cytokines were particularly elevated in patients with organ failures calls for evaluation of agents modifying the severe...

  10. Proinflammatory Cytokines as Regulators of Vaginal Microbiota.

    Science.gov (United States)

    Kremleva, E A; Sgibnev, A V

    2016-11-01

    It was shown that IL-1β, IL-8, and IL-6 in concentrations similar to those in the vagina of healthy women stimulated the growth of normal microflora (Lactobacillus spp.) and suppressed the growth and biofilm production by S. aureus and E. coli. On the contrary, these cytokines in higher concentrations typical of vaginal dysbiosis suppressed normal microflora and stimulated the growth of opportunistic microorganisms. TGF-β1 in both doses produced a stimulating effects on study vaginal microsymbionts. It is hypothesized that pro-inflammatory cytokines serve as the molecules of interspecies communication coordinating the interactions of all components of the vaginal symbiotic system.

  11. Misoprostol Inhibits Lipopolysaccharide-Induced Pro-inflammatory Cytokine Production by Equine Leukocytes

    Directory of Open Access Journals (Sweden)

    Emily Medlin Martin

    2017-09-01

    Full Text Available Pro-inflammatory cytokines including tumor necrosis factor α (TNFα, IL-1β, IL-6, and IL-8 are potent immune mediators that exacerbate multiple equine diseases such as sepsis and laminitis. Unfortunately, safe and effective cytokine-targeting therapies are lacking in horses; therefore, novel mechanisms of inhibiting cytokine production are critically needed. One potential mechanism for inhibiting cytokine synthesis is elevation of intracellular cyclic AMP (cAMP. In human leukocytes, intracellular cAMP production is induced by activation of E-prostanoid (EP receptors 2 and 4. These receptors can be targeted by the EP2/4 agonist and prostaglandin E1 analog, misoprostol. Misoprostol is currently used as a gastroprotectant in horses but has not been evaluated as a cytokine-targeting therapeutic. Thus, we hypothesized that misoprostol treatment would inhibit pro-inflammatory cytokine production by lipopolysaccharide (LPS-stimulated equine leukocytes in an in vitro inflammation model. To test this hypothesis, equine leukocyte-rich plasma (LRP was collected from 12 healthy adult horses and used to model LPS-mediated inflammatory signaling. LRP was treated with varying concentrations of misoprostol either before (pretreated or following (posttreated LPS stimulation. LRP supernatants were assayed for 23 cytokines using an equine-specific multiplex bead immunoassay. Leukocytes were isolated from LRP, and leukocyte mRNA levels of four important cytokines were evaluated via RT-PCR. Statistical differences between treatments were determined using one-way RM ANOVA (Holm–Sidak post hoc testing or Friedman’s RM ANOVA on Ranks (SNK post hoc testing, where appropriate (p < 0.05, n = 3–6 horses. These studies revealed that misoprostol pre- and posttreatment inhibited LPS-induced TNFα and IL-6 protein production in equine leukocytes but had no effect on IL-8 protein. Interestingly, misoprostol pretreatment enhanced IL-1β protein synthesis

  12. Misoprostol Inhibits Lipopolysaccharide-Induced Pro-inflammatory Cytokine Production by Equine Leukocytes

    Science.gov (United States)

    Martin, Emily Medlin; Messenger, Kristen M.; Sheats, Mary Katherine; Jones, Samuel L.

    2017-01-01

    Pro-inflammatory cytokines including tumor necrosis factor α (TNFα), IL-1β, IL-6, and IL-8 are potent immune mediators that exacerbate multiple equine diseases such as sepsis and laminitis. Unfortunately, safe and effective cytokine-targeting therapies are lacking in horses; therefore, novel mechanisms of inhibiting cytokine production are critically needed. One potential mechanism for inhibiting cytokine synthesis is elevation of intracellular cyclic AMP (cAMP). In human leukocytes, intracellular cAMP production is induced by activation of E-prostanoid (EP) receptors 2 and 4. These receptors can be targeted by the EP2/4 agonist and prostaglandin E1 analog, misoprostol. Misoprostol is currently used as a gastroprotectant in horses but has not been evaluated as a cytokine-targeting therapeutic. Thus, we hypothesized that misoprostol treatment would inhibit pro-inflammatory cytokine production by lipopolysaccharide (LPS)-stimulated equine leukocytes in an in vitro inflammation model. To test this hypothesis, equine leukocyte-rich plasma (LRP) was collected from 12 healthy adult horses and used to model LPS-mediated inflammatory signaling. LRP was treated with varying concentrations of misoprostol either before (pretreated) or following (posttreated) LPS stimulation. LRP supernatants were assayed for 23 cytokines using an equine-specific multiplex bead immunoassay. Leukocytes were isolated from LRP, and leukocyte mRNA levels of four important cytokines were evaluated via RT-PCR. Statistical differences between treatments were determined using one-way RM ANOVA (Holm–Sidak post hoc testing) or Friedman’s RM ANOVA on Ranks (SNK post hoc testing), where appropriate (p equine leukocytes but had no effect on IL-8 protein. Interestingly, misoprostol pretreatment enhanced IL-1β protein synthesis following 6 h of LPS stimulation, while misoprostol posttreatment inhibited IL-1β protein production after 24 h of LPS stimulation. At the mRNA level, misoprostol pre

  13. EFFECT OF CURCUMIN LIPOSOMAL FORM ON ANGIOTENSIN CONVERTING ACTIVITY, CYTOKINES AND COGNITIVE CHARACTERISTICS OF THE RATS WITH ALZHEIMER’S DISEASE MODEL

    Directory of Open Access Journals (Sweden)

    V.V.

    2015-12-01

    Full Text Available The purpose of the study was the investigation of curcumin liposome form effect on angiotensinconverting enzyme activity, cytokines and mnestic features of rats with experimental model of Alzheimer’s disease. In the animals with intrahippocampal injection of Аβ42_Human, nasal therapy with curcumin liposome form was used. Cytokine concentration and angiotensin converting enzyme activity in brain regions (cerebral cortex and hippocampus and in blood serum as well as indicators of conditioned avoidance response were registered. It was found that as a result of curcumin therapy the rats with Alzheimer’s disease had suppressed cytokine and angiotensin converting enzyme activities and recovered mnestic indices. Nasal therapy with curcumin liposome form gave reduction of angiotensin-converting enzyme activity and anti-cytokine effect in the target regions of the brain (cerebral cortex and hippocampus, which helped the rats mnestic features and memory recovery.

  14. Inflammatory Cytokine Pattern Is Sex-Dependent in Mouse Cutaneous Melanoma Experimental Model

    Directory of Open Access Journals (Sweden)

    Mihaela Surcel

    2017-01-01

    Full Text Available We present the evaluation of inflammatory cytokines in mouse cutaneous melanoma experimental model, as markers of disease evolution. Moreover, to test our experimental model, we have used low doses of dacarbazine (DTIC. C57 BL/6J mouse of both sexes were subjected to experimental cutaneous melanoma and treated with low doses of DTIC. Clinical parameters and serum cytokines were followed during tumor evolution and during DTIC therapy. Cytokine/chemokine pattern was assessed using xMAP technology and the following molecules were quantified: interleukins (IL-1-beta, IL-6, IL-10, IL-12 (p70, interferon (IFN-gamma, granulocyte macrophage colony-stimulating factor (GM-CSF, tumor necrosis factor (TNF-alpha, macrophage inflammatory protein (MIP-1alpha, monocyte chemoattractant protein (MCP-1, and keratinocyte-derived chemokine (KC. Significant differences were found between normal females and males mice, female mice having a statistically higher serum concentration of IL-1-beta compared to male mice, while males have a significantly higher concentration of MIP-1-alpha. During melanoma evolution in the female group, IL-1-beta, MIP-1-alpha, and KC circulatory levels were found 10-fold increased, while other cytokines doubled their values. In the male mice group, only circulatory KC increased 4 times, while IL-1-beta and TNF-alpha doubled their circulatory values. Various serum cytokines correlated with the disease evolution in cutaneous melanoma mouse model.

  15. Higher Baseline Proinflammatory Cytokines Mark Poor Antidepressant Response in Bipolar Disorder.

    Science.gov (United States)

    Benedetti, Francesco; Poletti, Sara; Hoogenboezem, Thomas A; Locatelli, Clara; de Wit, Harm; Wijkhuijs, Annemarie J M; Colombo, Cristina; Drexhage, Hemmo A

    The clinical relevance of raised levels of circulating cytokines in bipolar disorder is still unclear. Cytokines influence neurotransmitters, neuroplasticity, and white matter integrity. An inconsistent literature suggests that higher cytokine levels could hamper antidepressant response. Total sleep deprivation (TSD) and light therapy (LT) prompt a rapid antidepressant response and can provide a model treatment to study predictors of response. We studied at baseline 15 immune-regulating compounds in 37 consecutively admitted inpatients with a major depressive episode in the course of bipolar disorder (DSM-5 criteria) and in 24 controls. Thirty-one patients (84%) had a lifetime history of drug resistance. Patients were administered 3 TSD + LT cycles in 1 week (study period: 2010-2012). Data were analyzed with age- and false-discovery-rate-corrected analysis of variance and were tested as predictors in a regressive model. Twenty-three patients (62%) responded to treatment (Inventory of Depressive Symptomatology IDS-C score cytokines (Q² = 0.15), and a high factor score significantly predicted worse response (b = -0.692; W = 4.34, P = .037). A higher body mass index correlated with higher cytokines (r = 0.430, P = .010), indirectly hampering response (b = -0.0192, P = .013). Proinflammatory compounds reflecting an M1-like proinflammatory state of monocytes/macrophages are associated with a poor response to antidepressant TSD + LT treatment in bipolar depression.

  16. Pharmacokinetics and dosimetry studies for optimization of anti-carcinoembryonic antigen x anti-hapten bispecific antibody-mediated pretargeting of Iodine-131-labeled hapten in a phase I radioimmunotherapy trial.

    Science.gov (United States)

    Kraeber-Bodéré, Françoise; Faivre-Chauvet, Alain; Ferrer, Ludovic; Vuillez, Jean-Philippe; Brard, Pierre-Yves; Rousseau, Caroline; Resche, Isabelle; Devillers, Anne; Laffont, Sophie; Bardiès, Manuel; Chang, Ken; Sharkey, Robert M; Goldenberg, David M; Chatal, Jean-François; Barbet, Jacques

    2003-09-01

    Pharmacokinetics and dosimetry of hMN-14 x m734 bispecific monoclonal antibody (BsMAb) and (131)I-labeled di-diethylenetriaminepentaacetic acid-indium ((131)I-hapten) were studied to optimize pretargeted radioimmunotherapy. Thirty-five patients with carcinoembryonic antigen-expressing tumors were included. In a first group of 12 patients, (131)I-trace-labeled BsMAb doses were escalated from 10 to 100 mg/m(2), and 3.7 GBq of (131)I-hapten were administered 7 days later. In a second group, 12 patients received 75 mg/m(2) BsMAb and 2.6-4.2 GBq of (131)I-hapten 5 days later. The BsMAb dose was then reduced to 40 mg/m(2), and 10 patients received 1.9-5.5 GBq of (131)I-hapten. Blood samples were collected. Biodistribution was monitored by quantitative scintigraphy. Directly labeled BsMAb pharmacokinetics was described by two exponentials: half-lives were 8.1 h (2.0-18.1 h) and 48.2 h (22.8-79.4 h); blood clearance was 123 ml/h (64-195 ml/h). With a 7-day interval, 10 or 30 mg/m(2) BsMAb resulted in fast elimination and very low tumor uptake of hapten, whereas 50 or 100 mg/m(2) resulted in favorable tumor accretion. With 75 mg/m(2) BsMAb and a 5-day interval, hapten clearance was 152 ml/h (81-298 ml/h). Calculated radiation dose to tumor was 3.9 Gy/GBq (0.4-22.4 Gy/GBq) for the hapten, compared with 2.0 Gy/GBq (0.3-3.8 Gy/GBq) for the BsMAb, but hematological toxicity prevented dose escalation. Reduction of the BsMAb dose to 40 mg/m(2) accelerated hapten clearance to 492 ml/h (113-2544 ml/h) and reduced hematological toxicity without compromising tumor uptake [5.2 Gy/GBq (0.5-12.6 Gy/GBq)]. Optimized BsMAb doses and time interval will allow for the administration of higher, tumoricidal, activity doses.

  17. Characterization of Serum Cytokine Profile in Predominantly Colonic Inflammatory Bowel Disease to Delineate Ulcerative and Crohn's Colitides

    Directory of Open Access Journals (Sweden)

    Olga Y. Korolkova

    2015-08-01

    Full Text Available Background As accessible diagnostic approaches fail to differentiate between ulcerative colitis (UC and Crohn's colitis (CC in one-third of patients with predominantly colonic inflammatory bowel disease (IBD, leading to inappropriate therapy, we aim to investigate the serum cytokine levels in these patients in search of molecular biometric markers delineating UC from CC. Methods We measured 38 cytokines, chemokines, and growth factors using magnetic-bead-based multiplex immunoassay in 25 UC patients, 28 CC patients, and 30 controls. Our results are compared with those from a review of current literature regarding advances in serum cytokine profiles and associated challenges preventing their use for diagnostic/prognostic purposes. Results Univariate analysis showed statistically significant increases of eotaxin, GRO, and TNF-α in UC patients compared to controls (Ctrl; interferon γ, interleukin (IL-6, and IL-7 in CC group compared to Ctrl; and IL-8 in both UC and CC versus Ctrl. No cytokines were found to be different between UC and CC. A generalized linear model identified combinations of cytokines, allowing the identification of UC and CC patients, with area under the curve (AUC = 0.936, as determined with receiver operating characteristic (ROC analysis. Conclusions The current knowledge available about circulating cytokines in IBD is often contradictory. The development of an evidence-based tool using cytokines for diagnostic accuracy is still preliminary.

  18. Inflammatory and Anti-Inflammatory Equilibrium, Proliferative and Antiproliferative Balance: The Role of Cytokines in Multiple Myeloma

    Directory of Open Access Journals (Sweden)

    Caterina Musolino

    2017-01-01

    Full Text Available Multiple myeloma (MM is typically exemplified by a desynchronized cytokine system with increased levels of inflammatory cytokines. We focused on the contrast between inflammatory and anti-inflammatory systems by assessing the role of cytokines and their influence on MM. The aim of this review is to summarize the available information to date concerning this equilibrium to provide an overview of the research exploring the roles of serum cytokines in MM. However, the association between MM and inflammatory cytokines appears to be inadequate, and other functions, such as pro-proliferative or antiproliferative effects, can assume the role of cytokines in the genesis and progression of MM. It is possible that inflammation, when guided by cancer-specific Th1 cells, may inhibit tumour onset and progression. In a Th1 microenvironment, proinflammatory cytokines (e.g., IL-6 and IL-1 may contribute to tumour eradication by attracting leucocytes from the circulation and by increasing CD4 + T cell activity. Hence, caution should be used when considering therapies that target factors with pro- or anti-inflammatory activity. Drugs that may reduce the tumour-suppressive Th1-driven inflammatory immune response should be avoided. A better understanding of the relationship between inflammation and myeloma will ensure more effective therapeutic interventions.

  19. Cytokines in atherosclerosis: an intricate balance

    NARCIS (Netherlands)

    Boshuizen, M.C.S.

    2016-01-01

    Atherosclerosis is the underlying pathology in the majority of clinical manifestations of cardiovascular diseases, which are nowadays the main global cause of mortality. Atherosclerosis is a lipid-driven chronic inflammatory disease of the arterial wall. This inflammatory response, with cytokines as

  20. Cytokine gene expression of peripheral blood lymphocytes ...

    African Journals Online (AJOL)

    STORAGESEVER

    2009-03-20

    Mar 20, 2009 ... Key words: Lipopolysaccharide, lymphocytes, TLRs, cytokines. INTRODUCTION. Lipopolysaccharide (LPS), a predominant glycolipid in the outer membranes of Gam-negative bacteria, stimulates monocyte, macrophages, and neutrophils and increase expression of cell adhesion molecules (Trent et al., ...

  1. Study of cytokines microenvironment during autoimmune diseases ...

    African Journals Online (AJOL)

    22, IL-23, TNF-α and TGF-β) were determined. We used the immunoenzymatic technology to assess the titer of cytokines. We found that there was no significant variation of TNF-α level in normal controls and autoimmune diseases ...

  2. Current status and challenges of cytokine pharmacology

    Czech Academy of Sciences Publication Activity Database

    Zídek, Zdeněk; Anzenbacher, P.; Kmoníčková, Eva

    2009-01-01

    Roč. 157, č. 3 (2009), s. 342-361 ISSN 0007-1188 R&D Projects: GA ČR GA305/08/0535; GA MŠk 1M0508 Institutional research plan: CEZ:AV0Z50390512 Keywords : cytokines * immunotherapy * immunopharmacology Subject RIV: FR - Pharmacology ; Medidal Chemistry Impact factor: 5.204, year: 2009

  3. Immunodeficiency secondary to anti-cytokine autoantibodies

    Science.gov (United States)

    Browne, Sarah K.; Holland, Steven M.

    2011-01-01

    Purpose of review Anti-cytokine autoantibodies are an important and emerging mechanism of disease pathogenesis. We will review the clinical and laboratory features of syndromes in which immunodeficiency is caused by or associated with neutralizing anti-cytokine autoantibodies. Recent findings A growing number of patients have been described who demonstrate unique infectious phenotypes associated with neutralizing autoantibodies that target a particular cytokine known to participate in host defense against the offending organism. Examples include anti-granulocyte macrophage-colony stimulating factor (GM-CSF) autoantibodies and pulmonary alveolar proteinosis; anti-interferon(IFN)-γ autoantibodies and disseminated nontuberculous mycobacteria(NTM); anti-(interleukin)IL-6 autoantibodies and severe staphylococcal skin infection; anti-IL-17A, antiIL-17F or anti-IL-22 autoantibodies in patients with mucocutaneous candidiasis in the setting of both the autoimmune polyendocrinopathy, candidiasis, ectodermal dystrophy (APECED) syndrome and in cases of thymoma. Summary Anti-cytokine autoantibodies have manifestations that are diverse, ranging from asymptomatic to life-threatening. These emerging and fascinating causes of acquired immunodeficiency may explain some previously idiopathic syndromes. PMID:20966748

  4. Omics and cytokine discovery in fish

    NARCIS (Netherlands)

    Jacobson, Gregory; Muncaster, Simon; Mensink, Koen; Forlenza, Maria; Elliot, Nick; Broomfield, Grant; Signal, Beth; Bird, Steve

    2017-01-01

    A continued programme of research is essential to overcome production bottlenecks in any aquacultured fish species. Since the introduction of genetic and molecular techniques, the quality of immune research undertaken in fish has greatly improved. Thousands of species specific cytokine genes have

  5. Proinflammatory cytokine responses in patients with psoriasis.

    Science.gov (United States)

    Kouris, Anargyros; Pistiki, Aikaterini; Katoulis, Alexandros; Georgitsi, Marianna; Giatrakou, Sofia; Papadavid, Evangelia; Netea, Mihai G; Stavrianeas, Nikolaos; Giamarellos-Bourboulis, Evangelos J

    2014-01-01

    Psoriasis is one of the most common, immune-mediated, chronic inflammatory skin diseases. Proinflammatory cytokines play an important pathogenetic role at a local level. To assess whether the proinflammatory cytokines IL-1β, IL-6, IL-17, IL-22 and TNF-α are released systemically during psoriasis. Peripheral blood mononuclear cells (PBMCs) were isolated from 30 patients with psoriasis and 30 healthy volunteers. Cytokine production was assessed in supernatants using an enzyme immunoassay after stimulation of PBMCs with microbial stimuli. In addition, flow cytometry was used to determine the subsets of monocytes involved and the intracellular TNF-α production in monocytes. IL-17 levels were significantly higher in the supernatants of PBMCs from psoriatic patients after stimulation with phytohemagglutinin. TNF-α production was also significantly higher in cells from psoriatic patients after stimulation with all stimuli, as compared with health volunteers. Similar changes were not found for the other cytokines. A statistically significant difference was observed between patients and controls for inflammatory CD14(+)/CD16(+) monocytes (ppsoriasis. These results support the concept that there is a systemic, proinflammatory component in psoriasis.

  6. Cytokines and Immune Responses in Murine Atherosclerosis

    NARCIS (Netherlands)

    Kusters, Pascal J. H.; Lutgens, Esther

    2015-01-01

    Atherosclerosis is an inflammatory disease of the vessel wall characterized by activation of the innate immune system, with macrophages as the main players, as well as the adaptive immune system, characterized by a Th1-dominant immune response. Cytokines play a major role in the initiation and

  7. Cytokines as biomarkers of nanoparticle immunotoxicity.

    Science.gov (United States)

    Elsabahy, Mahmoud; Wooley, Karen L

    2013-06-21

    Nanoscale objects, whether of biologic origin or synthetically created, are being developed into devices for a variety of bionanotechnology diagnostic and pharmaceutical applications. However, the potential immunotoxicity of these nanomaterials and mechanisms by which they may induce adverse reactions have not received sufficient attention. Nanomaterials, depending on their characteristics and compositions, can interact with the immune system in several ways and either enhance or suppress immune system function. Cytokines perform pleiotropic functions to mediate and regulate the immune response and are generally recognized as biomarkers of immunotoxicity. While the specificity and validity of certain cytokines as markers of adverse immune response has been established for chemicals, small and macromolecular drugs, research on their applicability for predicting and monitoring the immunotoxicity of engineered nanomaterials is still ongoing. The goal of this review is to provide guidelines as to important cytokines that can be utilized for evaluating the immunotoxicity of nanomaterials and to highlight the role of those cytokines in mediating adverse reactions, which is of particular importance for the clinical development of nanopharmaceuticals and other nanotechnology-based products. Importantly, the rational design of nanomaterials of low immunotoxicity will be discussed, focusing on synthetic nanodevices, with emphasis on both the nanoparticle-forming materials and the embedded cargoes.

  8. Cytokines and immune surveillance in humans

    Science.gov (United States)

    Sonnenfeld, Gerald

    1994-01-01

    Evidence from both human and rodent studies has indicated that alterations in immunological parameters occur after space flight. Among the parameters shown, by us and others, to be affected is the production of interferons. Interferons are a family of cytokines that are antiviral and play a major role in regulating immune responses that control resistance to infection. Alterations in interferon and other cytokine production and activity could result in changes in immunity and a possible compromise of host defenses against both opportunistic and external infections. The purpose of the present study is to explore further the effects of space flight on cyotokines and cytokine-directed immunological function. Among the tests carried out are interferon-alpha production, interferon-gamma production, interleukin-1 and -2 production, signal transduction in neutrophils, signal transduction in monocytes, and monocyte phagocytic activity. The experiments will be performed using peripheral blood obtained from human subjects. It is our intent to eventually carry out these experiments using astronauts as subjects to determine the effects of space flight on cytokine production and activity. However, these subjects are not currently available. Until they become available, we will carry out these experiments using subjects maintained in the bed-rest model for microgravity.

  9. Cytokines as biomarkers of nanoparticle immunotoxicity

    Science.gov (United States)

    Elsabahy, Mahmoud; Wooley, Karen L.

    2013-01-01

    Nanoscale objects, whether of biologic origin or synthetically created, are being developed into devices for a variety of bionanotechnology diagnostic and pharmaceutical applications. However, the potential immunotoxicity of these nanomaterials and mechanisms by which they may induce adverse reactions have not received sufficient attention. Nanomaterials, depending on their characteristics and compositions, can interact with the immune system in several ways and either enhance or suppress immune system function. Cytokines perform pleiotropic functions to mediate and regulate the immune response and are generally recognized as biomarkers of immunotoxicity. While the specificity and validity of certain cytokines as markers of adverse immune response has been established for chemicals, small and macromolecular drugs, research on their applicability for predicting and monitoring the immunotoxicity of engineered nanomaterials is still ongoing. The goal of this review is to provide guidelines as to important cytokines that can be utilized for evaluating the immunotoxicity of nanomaterials and to highlight the role of those cytokines in mediating adverse reactions, which is of particular importance for the clinical development of nanopharmaceuticals and other nanotechnology-based products. Importantly, the rational design of nanomaterials of low immunotoxicity will be discussed, focusing on synthetic nanodevices, with emphasis on both the nanoparticle-forming materials and the embedded cargoes. PMID:23549679

  10. Cytokines in Sjögren's syndrome

    NARCIS (Netherlands)

    Roescher, N.; Tak, P. P.; Illei, G. G.

    2009-01-01

    Cytokines play a central role in the regulation of immunity and are often found to be deregulated in autoimmune diseases. Sjögren's syndrome is a chronic autoimmune disease characterized by inflammation and loss of secretory function of the salivary and lachrymal glands. This review highlights the

  11. Pre-targeted radioimmunotherapy of solid tumors: A multidisciplinary approach; La radio-immunotherapie preciblee des tumeurs solides: une demarche pluridisciplinaire

    Energy Technology Data Exchange (ETDEWEB)

    Barbet, J.; Kraber-Bodere, F.; Faivre-Chauvet, A.; Gestin, J.F.; Bardies, M.; Chatal, J.F. [Institut National de la Sante et de la Recherche Medicale (INSERM), U601, Institut de Biologie, Dept. de Recherche en Cancerologie, 44 - Nantes (France); Nantes Univ., U601, Dept. de Recherche en Cancerologie, 44 (France); Campion, L. [Institut National de la Sante et de la Recherche Medicale (INSERM), U601, Institut de Biologie, Dept. de Recherche en Cancerologie, 44 - Nantes (France); Centre de lutte contre le cancer Rene-Gauducheau, 44 - Saint-Herblain (France)

    2007-09-15

    No effective therapy is currently available for the management of patients with metastases of most solid tumors. Thus, pre targeted radioimmunotherapy approaches have been developed that have shown promises. One of these techniques uses bi specific monoclonal antibody and radiolabeled bivalent haptens injected sequentially. In two clinical trials, 29 patients with advanced, progressive medullary thyroid carcinoma, as documented by short serum calcitonin doubling times, received an anti-carcinoembryonic antigen x anti-diethylenetriamine pentaacetic acid (DTPA)-indium) bi specific monoclonal antibody, followed four to five days later by an {sup 131}I-labeled bivalent hapten. Overall survival was significantly longer in high-risk, treated patients than in high-risk, untreated patients (110 versus 61 months; P < 0.030). Forty-seven percent of patients, defined as biologic responders by a more than 100% increase in calcitonin doubling time, experienced significantly longer survival than non-responders (159 versus 109 months; P < 0.035) and untreated patients (159 versus 61 months; P < 0.010). Toxicity was mainly hematologic and related to bone/bone-marrow tumor spread. Various multidisciplinary aspects of this long-term endeavor that resulted in long-term disease stabilization and a significantly longer survival in high-risk patients are described and discussed with respect to future directions of research on pre targeted radioimmunotherapy. (authors)

  12. Neuropathic pain and cytokines: current perspectives

    Directory of Open Access Journals (Sweden)

    Clark AK

    2013-11-01

    Full Text Available Anna K Clark, Elizabeth A Old, Marzia Malcangio Wolfson Centre for Age Related Diseases, King's College London, London, UK Abstract: Neuropathic pain represents a major problem in clinical medicine because it causes debilitating suffering and is largely resistant to currently available analgesics. A characteristic of neuropathic pain is abnormal response to somatic sensory stimulation. Thus, patients suffering peripheral neuropathies may experience pain caused by stimuli which are normally nonpainful, such as simple touching of the skin or by changes in temperature, as well as exaggerated responses to noxious stimuli. Convincing evidence suggests that this hypersensitivity is the result of pain remaining centralized. In particular, at the first pain synapse in the dorsal horn of the spinal cord, the gain of neurons is increased and neurons begin to be activated by innocuous inputs. In recent years, it has become appreciated that a remote damage in the peripheral nervous system results in neuronal plasticity and changes in microglial and astrocyte activity, as well as infiltration of macrophages and T cells, which all contribute to central sensitization. Specifically, the release of pronociceptive factors such as cytokines and chemokines from neurons and non-neuronal cells can sensitize neurons of the first pain synapse. In this article we review the current evidence for the role of cytokines in mediating spinal neuron–non-neuronal cell communication in neuropathic pain mechanisms following peripheral nerve injury. Specific and selective control of cytokine-mediated neuronal–glia interactions results in attenuation of the hypersensitivity to both noxious and innocuous stimuli observed in neuropathic pain models, and may represent an avenue for future therapeutic intervention. Keywords: anti-inflammatory cytokines, proinflammatory cytokines, microglia, astrocytes, first pain synapse

  13. Inflammatory cytokines as biomarkers in heart failure.

    Science.gov (United States)

    Ueland, Thor; Gullestad, Lars; Nymo, Ståle H; Yndestad, Arne; Aukrust, Pål; Askevold, Erik T

    2015-03-30

    Inflammation has been implicated in the pathogenesis of heart failure (HF). In addition to their direct involvement as mediators in the pathogenesis of HF, inflammatory cytokines and related mediators could also be suitable markers for risk stratification and prognostication in HF patients. Many reports have suggested that inflammatory cytokines may predict adverse outcome in these patients. However, most studies have been limited in sample size and lacking full adjustment with the most recent and strongest biochemical predictor such as NT-proBNP and high sensitivity troponins. Furthermore, a number of pre-analytical and analytical aspects of cytokine measurements may limit their use as biomarkers. This review focuses on technical, informative and practical considerations concerning the clinical use of inflammatory cytokines as prognostic biomarkers in HF. We focus on the predictive value of tumor necrosis factor (TNF) α, the TNF family receptors sTNFR1 and osteoprotegerin, interleukin (IL)-6 and its receptor gp130, the chemokines MCP-1, IL-8, CXCL16 and CCL21 and the pentraxin PTX-3 in larger prospective fully adjusted studies. No single inflammatory cytokine provides sufficient discrimination to justify the transition to everyday clinical use as a prognosticator in HF. However, while subjecting potential new HF markers to rigorous comparisons with "gold-standard" markers, such as NT-proBNP, using receiver operating characteristics (ROCs) and HF risk models, makes sense from a clinical standpoint, it may pose a threat to a broadening of mechanistic insight if the new markers are dismissed solely on account of lower statistical power. Copyright © 2014. Published by Elsevier B.V.

  14. Cytokine Status, Thyroid Autoantibodies and Their Dynamic Changes During the Treatment of Graves' Disease

    Directory of Open Access Journals (Sweden)

    V V Lazanovich

    2008-09-01

    Full Text Available It has been found during the research that the changes of Th1 and Th2 marker cytokine content in Graves Disease are dynamic and are directly correlated not only with the severity of autoimmune thyrotoxicosis, but also with the method of treatment used and duration of Thiamazole therapy. The beginning of autoimmune thyrotoxicosis shows the largest amounts of both pro-inflammatory (IL-1a, IL-8, IFN-γ and anti-inflammatory (IL-10 cytokines which are significantly reduced during Thiamazole therapy, with the exception of the cases of severe disease course. Thyroid resection does not result in immunologic remission either, which is confirmed by persisting high serum levels of IL-1a, IL-8, IFN-γ, IL-10 and TSH antibodies in the severe GBD group. Among the unfavorable prognostic factors for recurrent disease are high serum levels of TSH antibodies, IL-1a and IFN-γ during pre-surgery period.

  15. Cytokine-Induced Killer Cells As Pharmacological Tools for Cancer Immunotherapy

    Science.gov (United States)

    Gao, Xingchun; Mi, Yajing; Guo, Na; Xu, Hao; Xu, Lixian; Gou, Xingchun; Jin, Weilin

    2017-01-01

    Cytokine-induced killer (CIK) cells are a heterogeneous population of effector CD3+CD56+ natural killer T cells, which can be easily expanded in vitro from peripheral blood mononuclear cells. CIK cells work as pharmacological tools for cancer immunotherapy as they exhibit MHC-unrestricted, safe, and effective antitumor activity. Much effort has been made to improve CIK cells cytotoxicity and treatments of CIK cells combined with other antitumor therapies are applied. This review summarizes some strategies, including the combination of CIK with additional cytokines, dendritic cells, check point inhibitors, antibodies, chemotherapeutic agents, nanomedicines, and engineering CIK cells with a chimeric antigen receptor. Furthermore, we briefly sum up the clinical trials on CIK cells and compare the effect of clinical CIK therapy with other immunotherapies. Finally, further research is needed to clarify the pharmacological mechanism of CIK and provide evidence to formulate uniform culturing criteria for CIK expansion. PMID:28729866

  16. Cytokine-Induced Killer Cells As Pharmacological Tools for Cancer Immunotherapy

    Directory of Open Access Journals (Sweden)

    Xingchun Gao

    2017-07-01

    Full Text Available Cytokine-induced killer (CIK cells are a heterogeneous population of effector CD3+CD56+ natural killer T cells, which can be easily expanded in vitro from peripheral blood mononuclear cells. CIK cells work as pharmacological tools for cancer immunotherapy as they exhibit MHC-unrestricted, safe, and effective antitumor activity. Much effort has been made to improve CIK cells cytotoxicity and treatments of CIK cells combined with other antitumor therapies are applied. This review summarizes some strategies, including the combination of CIK with additional cytokines, dendritic cells, check point inhibitors, antibodies, chemotherapeutic agents, nanomedicines, and engineering CIK cells with a chimeric antigen receptor. Furthermore, we briefly sum up the clinical trials on CIK cells and compare the effect of clinical CIK therapy with other immunotherapies. Finally, further research is needed to clarify the pharmacological mechanism of CIK and provide evidence to formulate uniform culturing criteria for CIK expansion.

  17. Inflammasome-independent regulation of IL-1-family cytokines

    NARCIS (Netherlands)

    Netea, M.G.; Veerdonk, F.L. van de; Meer, J.W.M. van der; Dinarello, C.A.; Joosten, L.A.B.

    2015-01-01

    Induction, production, and release of proinflammatory cytokines are essential steps to establish an effective host defense. Cytokines of the interleukin-1 (IL-1) family induce inflammation and regulate T lymphocyte responses while also displaying homeostatic and metabolic activities. With the

  18. Cytokine Correlations in Youth with Tic Disorders

    Science.gov (United States)

    Parker-Athill, E. Carla; Ehrhart, Jared; Tan, Jun

    2015-01-01

    Abstract Background: Studies have noted immunological disruptions in patients with tic disorders, including increased serum cytokine levels. This study aimed to determine whether or not cytokine levels could be correlated with tic symptom severity in patients with a diagnosed tic disorder. Methods: Twenty-one patients, ages 4–17 years (average 10.63±2.34 years, 13 males), with a clinical diagnosis of Tourette's syndrome (TS) or chronic tic disorder (CTD), were selected based on having clinic visits that coincided with a tic symptom exacerbation and a remission. Ratings of tic severity were assessed using the Yale Global Tic Severity Scale (YGTSS) and serum cytokine levels (interleukin [IL]-2, IL-4, IL-5, IL-10, IL-12p70, IL-13, interferon [IFN]-γ, tumor necrosis factor [TNF]-α, and granulocyte macrophage-colony stimulating factor [GM-CSF]) were measured using Luminex xMAP technology. Results: During tic symptom exacerbation, patients had higher median serum TNF-α levels (z=−1.962, p=0.05), particularly those on antipsychotics (U=9.00, p=0.033). Increased IL-13 was also associated with antipsychotic use during exacerbation (U=4.00, p=0.043) despite being negatively correlated to tic severity scores (ρ=−0.599, p=018), whereas increased IL-5 was associated with antibiotic use (U=6.5, p=0.035). During tic symptom remission, increased serum IL-4 levels were associated with antipsychotic (U=6.00, p=0.047) and antibiotic (U=1.00, p=0.016) use, whereas increased IL-12p70 (U=4.00, p=0.037) was associated with antibiotic use. Conclusions: These findings suggest a role for cytokine dysregulation in the pathogenesis of tic disorders. It also points toward the mechanistic involvement and potential diagnostic utility of cytokine monitoring, particularly TNF-α levels. Larger, systematic studies are necessary to further delineate the role of cytokines and medication influences on immunological profiling in tic disorders. PMID:25658821

  19. Cytokine correlations in youth with tic disorders.

    Science.gov (United States)

    Parker-Athill, E Carla; Ehrhart, Jared; Tan, Jun; Murphy, Tanya K

    2015-02-01

    Studies have noted immunological disruptions in patients with tic disorders, including increased serum cytokine levels. This study aimed to determine whether or not cytokine levels could be correlated with tic symptom severity in patients with a diagnosed tic disorder. Twenty-one patients, ages 4-17 years (average 10.63±2.34 years, 13 males), with a clinical diagnosis of Tourette's syndrome (TS) or chronic tic disorder (CTD), were selected based on having clinic visits that coincided with a tic symptom exacerbation and a remission. Ratings of tic severity were assessed using the Yale Global Tic Severity Scale (YGTSS) and serum cytokine levels (interleukin [IL]-2, IL-4, IL-5, IL-10, IL-12p70, IL-13, interferon [IFN]-γ, tumor necrosis factor [TNF]-α, and granulocyte macrophage-colony stimulating factor [GM-CSF]) were measured using Luminex xMAP technology. During tic symptom exacerbation, patients had higher median serum TNF-α levels (z=-1.962, p=0.05), particularly those on antipsychotics (U=9.00, p=0.033). Increased IL-13 was also associated with antipsychotic use during exacerbation (U=4.00, p=0.043) despite being negatively correlated to tic severity scores (ρ=-0.599, p=018), whereas increased IL-5 was associated with antibiotic use (U=6.5, p=0.035). During tic symptom remission, increased serum IL-4 levels were associated with antipsychotic (U=6.00, p=0.047) and antibiotic (U=1.00, p=0.016) use, whereas increased IL-12p70 (U=4.00, p=0.037) was associated with antibiotic use. These findings suggest a role for cytokine dysregulation in the pathogenesis of tic disorders. It also points toward the mechanistic involvement and potential diagnostic utility of cytokine monitoring, particularly TNF-α levels. Larger, systematic studies are necessary to further delineate the role of cytokines and medication influences on immunological profiling in tic disorders.

  20. IL-12 Family Cytokines: General Characteristics, Pathogenic Microorganisms, Receptors, and Signalling Pathways.

    Science.gov (United States)

    Behzadi, Payam; Behzadi, Elham; Ranjbar, Reza

    2016-03-01

    Among a wide range of cytokines, the Interleukin 12 (IL-12) family has its unique structural, functional, and immunological characteristics that have made this family as important immunological playmakers. Because of the importance of IL-12 heterodimeric cytokines in microbial infections, autoimmune diseases, and cancers, the authors of this literature discuss about the general characteristics of IL-12 family members, the interactions between IL-12 cytokines and pathogenic microorganisms, the interleukins receptors and their strategies for selecting different signalling pathways. IL-12 and IL-23 are similar in p40 subunits and both are involved in proinflammatory responses while, IL-27 and IL-35 contribute to anti-inflammatory activities; however, IL-27 is also involved in pro-inflammatory responses. There are some similarities and dissimilarities among IL-12 family members which make them a unique bridge between innate and adaptive immune systems. The bioactivities of IL-12 family indicate a brilliant promise for their applications in different fields of medicine. The members of IL-12 family are candidate for several therapeutics including gene therapy, cancer therapy, tumour therapy, and vaccination. To have an accurate diagnostic technique and definite treatment regarding to infectious diseases, the playmakers of IL-12 family as effective criteria together with microarray technology are the best choices for current and future applications.

  1. Evaluation of inflammatory cytokines and oxidative stress markers in prostate cancer patients undergoing curative radiotherapy

    Directory of Open Access Journals (Sweden)

    Phebe L. Abdel-Messeih

    2017-05-01

    Full Text Available Prostate cancer is the second leading cause of cancer-related death in men. The present study was carried out to investigate the radiation response of serum cytokines and oxidative markers to find out if these novel biomarkers have significant applications regarding radiation outcome in prostate cancer patients. Significant elevations of prostatic specific antigen (PSA, asymmetric dimethyl arginine (ADMA and nitric oxide (NO were recorded in cancer prostate patients at the time of diagnosis compared to controls. Patients were subjected to radiotherapy post prostatectomy with a total dose of 66 Gy in 33 fractions (5 sessions/week for 7 weeks. At the end of the seventh week post radiotherapy, ADMA levels were accentuated while the levels of PSA and NO were lower than before therapy. The level of inflammatory cytokines (interleukins IL-4, IL-5 and interferon-gamma in post radiation therapy patients were significantly elevated compared to both controls and prostate cancer patients. A significant inverse correlation was observed in prostate cancer patients between ADMA and NO. Moreover, a significant inverse correlation in post radiation therapy patients was observed between IL-5 and PSA. These results are highly suggestive that there is a specific cytokine response in patients undergoing curative radiotherapy for prostate cancer.

  2. Evaluation of serum cytokines in cats with and without degenerative joint disease and associated pain.

    Science.gov (United States)

    Gruen, Margaret E; Messenger, Kristen M; Thomson, Andrea E; Griffith, Emily H; Aldrich, Lauren A; Vaden, Shelly; Lascelles, B Duncan X

    2017-01-01

    Degenerative joint disease is common in cats, with signs of pain frequently found on orthopedic examination and radiographs often showing evidence of disease. However, understanding of the pathophysiology of degenerative joint disease and associated pain remains limited. Several cytokines have been identified as having a role in pain in humans, but this has not been investigated in cats. The present study was performed to use a multiplex platform to evaluate the concentration of 19 cytokines and chemokines in serum samples obtained from cats with and without degenerative joint disease and associated pain. Samples from a total of 186 cats were analyzed, with cats representing a range of severity on radiographic and orthopedic evaluations and categorized by degenerative joint disease scores and pain scores. Results showed that cats with higher radiographic degenerative joint disease scores have higher serum concentrations of IL-4 and IL-8, while cats with higher orthopedic exam pain scores have higher concentrations of IL-8, IL-2, and TNF-α; increased concentration of IL-8 in degenerative joint disease and pain may be confounded by the association with age. Discriminant analysis was unable to identify one or more cytokines that distinguish between groups of cats classified based on degenerative joint disease score category or pain score category. Finally, cluster analysis driven by analyte concentrations shows separation of groups of cats, but features defining the groups remain unknown. Further studies are warranted to investigate any changes in cytokine concentrations in response to analgesic therapies, and further evaluate the elevations in cytokine concentrations found here, particularly focused on studies of local cytokines present in synovial fluid. Copyright © 2016 Elsevier B.V. All rights reserved.

  3. Inhibitory effects of bisbenzylisoquinolines on synthesis of the inflammatory cytokines interleukin-1 and tumour necrosis factor-alpha

    Directory of Open Access Journals (Sweden)

    W. Kim Seow

    1993-01-01

    Full Text Available Synthesis of IL-1β and TNFα by human monocytesmacrophages was significantly inhibited by eleven bisbenzylisoquinolines and one half-molecule (benzylisoquinoline, with IC50 values in the μM range. The results indicate that these compounds may have value in the therapy of human diseases where these inflammatory cytokines have a central role in pathogenesis.

  4. Analysis of Th Cell-related Cytokine Production in Behçet Disease Patients with Uveitis Before and After Infliximab Treatment.

    Science.gov (United States)

    Takeuchi, Masaru; Karasawa, Yoko; Harimoto, Kohzou; Tanaka, Atsushi; Shibata, Masaki; Sato, Tomohito; Caspi, Rachel R; Ito, Masataka

    2017-02-01

    To examine antigen-stimulated cytokine production by Behçet disease patients (BD) before and after infliximab infusion. PBMCs were obtained before and after infliximab infusion in BD patients with or without recurrent uveitis during at least 1 year of infliximab therapy, and from healthy subjects. PBMCs were cultured with IRBP, and Th-related cytokines in cultures were measured. Levels of IL-4, IL-6, IL-10 IL-17A, IL-17F, IL-31, IFN-γ, and TNFα were higher in BD before infliximab infusion than in healthy subjects, and these levels were the highest in BD with recurrent uveitis. After infliximab infusion, these cytokine levels were reduced to a greater extent in BD without recurrent uveitis than in BD with recurrence. Th-related cytokines produced by IRBP-stimulated PBMCs were elevated in BD, and infliximab infusion suppressed these cytokines to a greater extent in BD without recurrent uveitis than in those with recurrence.

  5. Cytokine-producing T cell subsets in human leishmaniasis

    DEFF Research Database (Denmark)

    Kemp, Kåre

    2000-01-01

    Leishmania specific Th1/Th2 cells have been identified in humans as well as in mice. There is a correlation between the clinical outcome of the infection and the cytokine response profile. Generally, the production of Th2 cytokines leads to severe infection, whereas the production of Th1 cytokine...

  6. Cytokines as Immunological Markers for Follow up of Disease ...

    African Journals Online (AJOL)

    Background: Cytokines play a major role in protection against Mycobacterium tuberculosis infection and regulate the immune responses at a cellular level. Cytokine profile determines clinical outcome of the disease and responses to treatment as well. A T helper 1 (Th1) cytokine interferon gamma (IFN-U) is one of the most ...

  7. Cytokines and Other Mediators in Alopecia Areata

    Directory of Open Access Journals (Sweden)

    Stamatis Gregoriou

    2010-01-01

    Full Text Available Alopecia areata, a disease of the hair follicles with multifactorial etiology and a strong component of autoimmune origin, has been extensively studied as far as the role of several cytokines is concerned. So far, IFN-, interleukins, TNF-, are cytokines that are well known to play a major role in the pathogenesis of the disease, while several studies have shown that many more pathways exist. Among them, MIG, IP-10, BAFF, HLA antigens, MIG, as well as stress hormones are implicated in disease onset and activity. Within the scope of this paper, the authors attempt to shed light upon the complexity of alopecia areata underlying mechanisms and indicate pathways that may suggest future treatments.

  8. Rosacea: the Cytokine and Chemokine Network

    Science.gov (United States)

    Gerber, Peter Arne; Buhren, Bettina Alexandra; Steinhoff, Martin; Homey, Bernhard

    2013-01-01

    Rosacea is one of the most common dermatoses of adults. Recent studies have improved our understanding of the pathophysiology of rosacea. Current concepts suggest that known clinical trigger factors of rosacea such as UV radiation, heat, cold, stress, spicy food, and microbes modulate Toll-like receptor signaling, induce reactive oxygen species, as well as enhance antimicrobial peptide and neuropeptide production. Downstream of these events cytokines and chemokines orchestrate an inflammatory response that leads to the recruitment and activation of distinct leukocyte subsets and induces the characteristic histopathological features of rosacea. Here we summarize the current knowledge of the cytokine and chemokine network in rosacea and propose pathways that may be of therapeutic interest. PMID:22076326

  9. Original Research Rotavirus antigen, cytokine, and neutralising ...

    African Journals Online (AJOL)

    cytokines examined were IL-1β, IL-2, IL-7, IL-12, IL-. 17, IFN-γ, TNF-α, IL-4, IL-5, IL-6, IL-10, IL-13, IL-8,. G-CSF, GM-CSF, MCP-1(MCAF), and MIP-1β. Rotavirus-. Table 1: Comparison of demographic and rotavirus antigenaemia data by HIV status among children with rotavirus diarrhoea in Blantyre, Malawi. Variables.

  10. Cytokine Expression in Homozygous Sickle Cell Anaemia

    Directory of Open Access Journals (Sweden)

    Nnodim Johnkennedy

    2015-01-01

    Full Text Available Background: Sickle cell anaemia is an inherited disease in which the red blood cells become rigid and sticky, and change from being disc-shaped to being crescent-shaped. The change in shape is due to the presence of an abnormal form of haemoglobin. This results in severe pain and damage to some organs. Aim and Objective: The study was carried out to determine the levels of cytokine in sickle cell anemia. Material and Methods: Thirty confirmed sickle cell patients in steady state (HbSS-SS and thirty persons with normal haemoglobin (HbAA as well as sixteen sickle cell disease in crises (HbSS-cr between the ages of 15 to 30 years were selected in this study. Cytokines including interleukin 1 beta (IL- 1β, interleukin 2 (IL- 2, interleukin (IL-6, tumour necrosis factor alpha (TNF-α, and interferon gamma (IFN- λ were measured by commercially available ELISA kits. Results: The results obtained showed that the levels of TNF-α and IL-6 in sickle cell anaemia patients in crisis were significantly elevated when compared with sickle cell in steady state (P<0.05. Similarly, the levels of IL-1β, IL-6, and IFN- λ were significantly increased in sickle cell anaemia stable state when compared to HbAA subjects (P<0.05. Conclusion: This may probably implies that cytokine imbalance is implicated in the pathogenesis of sickle cell crisis. Also, cytokines could be used as an inflammatory marker as well as related marker in disease severity and hence therapeutic intervention.

  11. Cytokines in systemic lupus erythematosus: far beyond Th1/Th2 dualism lupus: cytokine profiles.

    Science.gov (United States)

    Guimarães, Poliana Macedo; Scavuzzi, Bruna Miglioranza; Stadtlober, Nicole Perugini; Franchi Santos, Lorena Flor da Rosa; Lozovoy, Marcell Alysson Batisti; Iriyoda, Tatiana Mayumi Veiga; Costa, Neide Tomimura; Reiche, Edna Maria Vissoci; Maes, Michael; Dichi, Isaias; Simão, Andréa Name Colado

    2017-10-01

    The aims of this study were to delineate cytokine profiles of systemic lupus erythematosus (SLE), construct prediction models for diagnosis and disease activity using those profiles, and to examine the associations between TNFB Ncol polymorphism, body mass index (BMI) and vitamin D levels with cytokine levels. Two hundred SLE patients and 196 healthy controls participated in this case-control study. Plasma cytokines levels of tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-1β, IL- 4, IL-6, IL-10, IL-12 and IL-17 were measured and cytokines profiles were computed. IL-6, IL-12, IL-17, IFN-γ and IL-10 levels were significantly higher in SLE, while IL-4 was lower in SLE. The Th1/Th2 and Th1+Th17/Th2 profiles were significantly higher in SLE than in healthy controls, whereas there were no significant differences in the proinflammatory cytokine profile (TNFα+IL-6+IL-1β). In total, 90.4% of all subjects were correctly classified using Th1+Th17 profile and IL-10 (positively associated) and IL-4 (negatively associated) as predictor variables (sensitivity=66.7% and specificity=96.9%). In all, 20.9% of the variance in the SLE Disease Activity Index was predicted by the Th1+Th17/Th2 ratio, IL-10 and BMI (all positively) and proinflammatory profile (inversely associated). B1/B1 genotype is accompanied by increased IL-17 and Th17/Th2 ratio, while B1/B2 genotype is accompanied by higher IL-4 and IFNγ values. 25-OH vitamin D was inversely associated with IFN-γ levels. SLE is accompanied by Th1, Th17 and Treg profile and lowered IL-4 production. Lowered vitamin D levels and B1/B1 genotype, but not BMI, contribute to changes in cytokines profiles. Future treatments should target Th1, Th2 and Th17 profiles rather than inflammatory cytokines.

  12. The role of cytokines in skin aging.

    Science.gov (United States)

    Borg, M; Brincat, S; Camilleri, G; Schembri-Wismayer, P; Brincat, M; Calleja-Agius, J

    2013-10-01

    Cutaneous aging is one of the major noticeable menopausal complications that most women want to fight in their quest for an eternally youthful skin appearance. It may contribute to some maladies that occur in aging which, despite not being life-threatening, affect the well-being, psychological state and quality of life of aged women. Skin aging is mainly affected by three factors: chronological aging, decreased levels of estrogen after menopause, and environmental factors. Aged skin is characterized by a decrease in collagen content and skin thickness which result in dry, wrinkled skin that is easily bruised and takes a longer time to heal. Cytokines play a crucial role in the manifestation of these features of old skin. The pro-inflammatory cytokine tumor necrosis factor-alpha inhibits collagen synthesis and enhances collagen degradation by increasing the production of MMP-9. It also lowers the skin immunity and thus increases the risk of cutaneous infections in old age. Deranged levels of several interleukins and interferons also affect the aging process. The high level of CCN1 protein in aged skin gives dermal fibroblasts an 'age-associated secretory phenotype' that causes abnormal homeostasis of skin collagen and leads to the loss of the function and integrity of skin. Further research is required especially to establish the role of cytokines in the treatment of cutaneous aging.

  13. Influence of androgen deprivation therapy on the uptake of PSMA-targeted agents: Emerging opportunities challenges

    Energy Technology Data Exchange (ETDEWEB)

    Bakht, Martin K.; Oh, So Won; Youn, Hye Won; Cheon, Gi Jeong; Kwak, Cheol; Kang, Keon Wook [Seoul National University College of Medicine, Seoul (Korea, Republic of)

    2017-09-15

    Prostate-specific membrane antigen (PSMA) is an attractive target for both diagnosis and therapy because of its high expression in the vast majority of prostate cancers. Development of small molecules for targeting PSMA is important for molecular imaging and radionuclide therapy of prostate cancer. Recent evidence implies that androgen-deprivation therapy increase PSMA-ligand uptake in some cases. The reported upregulations in PSMA-ligand uptake after exposure to second-generation antiandrogens such as enzalutamide and abiraterone might disturb PSMA-targeted imaging for staging and response monitoring of patients undergoing treatment with antiandrogen-based drugs. On the other hand, second-generation antiandrogens are emerging as potential endoradio-/chemosensitizers. Therefore, the enhancement of the therapeutic efficiency of PSMA-targeted theranostic methods can be listed as a new capability of antiandrogens. In this manuscript, we will present what is currently known about the mechanism of increasing PSMA uptake following exposure to antiandrogens. In addition, we will discuss whether these above-mentioned antiandrogens could play the role of endoradio-/chemosensitizers in combination with the well-established PSMA-targeted methods for pre-targeting of prostate cancer.

  14. Gene therapy pf HPV-16 induced tumours in rodents

    Czech Academy of Sciences Publication Activity Database

    Vonka, V.; Sobotková, E.; Šmahel, M.; Žák, R.; Hamšíková, E.; Bubeník, Jan

    1999-01-01

    Roč. 19, - (1999), s. 2014 ISSN 0250-7005. [Symposium on Local Cytokine Therapy of Cancer: Interleukin-2, Interferon and Related Cytokines /1./. Hamburg, 29.04.1999-01.05.1999] Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 1.375, year: 1999

  15. Cytokines, cytokine antagonists, and soluble adhesion molecules in pediatric OMS and other neuroinflammatory disorders.

    Science.gov (United States)

    Pranzatelli, Michael R; Tate, Elizabeth D; McGee, Nathan R; Colliver, Jerry A

    2013-03-15

    To test for hypothesized disease- and treatment-induced changes in cytokines and adhesion molecules in children with opsoclonus-myoclonus syndrome (OMS). Multiplex bead assay technology was used for simultaneous measurement of 34 soluble cytokines in cerebrospinal fluid (CSF) and serum. Soluble intercellular adhesion molecule-1 (sICAM-1) and vascular cell adhesion molecule-1 (sVCAM-1) were measured by ELISA. In total, there were 388 children (239 OMS, 114 controls, and 35 other inflammatory neurological disorders (OIND)). In untreated OMS, mean CSF IL-6 was elevated 2.3-fold, but 67-fold in OIND, without significant differences in other CSF cytokines. Mean serum concentrations of sIL-2Ra (+50%) and CXCL1 (+70%) (pOMS than controls (p=0.005), as was serum CCL11 and IL-13 in treated OMS. Mean CSF CCL4 and IL-1Ra were selectively higher in IVIg-treated OMS (p≤0.0001). CSF sICAM-1 was elevated only in OIND (3.3-fold); serum sICAM-1 was higher in untreated OMS (+21%); and sVCAM-1 was not affected. No correlations with OMS severity or duration were identified. Novel cytokine, cytokine antagonist, and soluble adhesion molecule abnormalities due to OMS or treatment were found. However, the normality of much of the data strengthens previous findings implicating B cell mechanisms. Copyright © 2013 Elsevier B.V. All rights reserved.

  16. EFFECT OF CURCUMIN LIPOSOMAL FORM ON ANGIOTENSIN CONVERTING ACTIVITY, CYTOKINES AND COGNITIVE CHARACTERISTICS OF THE RATS WITH ALZHEIMER’S DISEASE MODEL

    OpenAIRE

    V.V.; S.М.

    2015-01-01

    The purpose of the study was the investigation of curcumin liposome form effect on angiotensinconverting enzyme activity, cytokines and mnestic features of rats with experimental model of Alzheimer’s disease. In the animals with intrahippocampal injection of А42_Human, nasal therapy with curcumin liposome form was used. Cytokine concentration and angiotensin converting enzyme activity in brain regions (cerebral cortex and hippocampus) and in blood serum as well as indicators of conditioned a...

  17. Regulation of cytokines by small RNAs during skin inflammation

    Directory of Open Access Journals (Sweden)

    Mikkelsen Jacob G

    2010-07-01

    Full Text Available Abstract Intercellular signaling by cytokines is a vital feature of the innate immune system. In skin, an inflammatory response is mediated by cytokines and an entwined network of cellular communication between T-cells and epidermal keratinocytes. Dysregulated cytokine production, orchestrated by activated T-cells homing to the skin, is believed to be the main cause of psoriasis, a common inflammatory skin disorder. Cytokines are heavily regulated at the transcriptional level, but emerging evidence suggests that regulatory mechanisms that operate after transcription play a key role in balancing the production of cytokines. Herein, we review the nature of cytokine signaling in psoriasis with particular emphasis on regulation by mRNA destabilizing elements and the potential targeting of cytokine-encoding mRNAs by miRNAs. The proposed linkage between mRNA decay mediated by AU-rich elements and miRNA association is described and discussed as a possible general feature of cytokine regulation in skin. Moreover, we describe the latest attempts to therapeutically target cytokines at the RNA level in psoriasis by exploiting the cellular RNA interference machinery. The applicability of cytokine-encoding mRNAs as future clinical drug targets is evaluated, and advances and obstacles related to topical administration of RNA-based drugs targeting the cytokine circuit in psoriasis are described.

  18. Targeting an IKBKE cytokine network impairs triple-negative breast cancer growth.

    Science.gov (United States)

    Barbie, Thanh U; Alexe, Gabriela; Aref, Amir R; Li, Shunqiang; Zhu, Zehua; Zhang, Xiuli; Imamura, Yu; Thai, Tran C; Huang, Ying; Bowden, Michaela; Herndon, John; Cohoon, Travis J; Fleming, Timothy; Tamayo, Pablo; Mesirov, Jill P; Ogino, Shuji; Wong, Kwok-Kin; Ellis, Matthew J; Hahn, William C; Barbie, David A; Gillanders, William E

    2014-12-01

    Triple-negative breast cancers (TNBCs) are a heterogeneous set of cancers that are defined by the absence of hormone receptor expression and HER2 amplification. Here, we found that inducible IκB kinase-related (IKK-related) kinase IKBKE expression and JAK/STAT pathway activation compose a cytokine signaling network in the immune-activated subset of TNBC. We found that treatment of cultured IKBKE-driven breast cancer cells with CYT387, a potent inhibitor of TBK1/IKBKE and JAK signaling, impairs proliferation, while inhibition of JAK alone does not. CYT387 treatment inhibited activation of both NF-κB and STAT and disrupted expression of the protumorigenic cytokines CCL5 and IL-6 in these IKBKE-driven breast cancer cells. Moreover, in 3D culture models, the addition of CCL5 and IL-6 to the media not only promoted tumor spheroid dispersal but also stimulated proliferation and migration of endothelial cells. Interruption of cytokine signaling by CYT387 in vivo impaired the growth of an IKBKE-driven TNBC cell line and patient-derived xenografts (PDXs). A combination of CYT387 therapy with a MEK inhibitor was particularly effective, abrogating tumor growth and angiogenesis in an aggressive PDX model of TNBC. Together, these findings reveal that IKBKE-associated cytokine signaling promotes tumorigenicity of immune-driven TNBC and identify a potential therapeutic strategy using clinically available compounds.

  19. Dietary factors regulate cytokines in murine models of systemic lupus erythematosus.

    Science.gov (United States)

    Hsieh, Chia-Chien; Lin, Bi-Fong

    2011-11-01

    Cytokines play the active roles in the pathogenesis of systemic lupus erythematosus (SLE) and contribute significantly to the immune imbalance in this disease. Conservative therapeutic approaches, such as dietary modifications have been shown to have some beneficial impact on the disease activity of the SLE. Over the past years, accumulating evidences have supported a major role for specific dietary factors, including calorie restriction, n-3/n-6 fatty acids, vitamin A, vitamin D, vitamin E, phytoestrogens or herbal medicine in the regulation of cytokines involved in SLE development. Although there are many reviews that discuss the issue of nutrition and immunity, there are relatively few articles that focus on the regulation of cytokines by dietary factors. This concise review will summarize those animal studies that investigated not only the outcome of autoantibody production and proteinuria, but also cytokines production. However, the field of dietary factors in the immunomodulation of SLE is still in its infancy. More clinical studies are needed to confirm the preliminary results and advance the knowledge in this field. Lifestyle modification and adjustments in diet are important and encouraged to be suggested as an adjuvant therapy for SLE. Copyright © 2011 Elsevier B.V. All rights reserved.

  20. Scanning for Therapeutic Targets within the Cytokine Network of Idiopathic Inflammatory Myopathies

    Directory of Open Access Journals (Sweden)

    Boel De Paepe

    2015-08-01

    Full Text Available The idiopathic inflammatory myopathies (IIM constitute a heterogeneous group of chronic disorders that include dermatomyositis (DM, polymyositis (PM, sporadic inclusion body myositis (IBM and necrotizing autoimmune myopathy (NAM. They represent distinct pathological entities that, most often, share predominant inflammation in muscle tissue. Many of the immunopathogenic processes behind the IIM remain poorly understood, but the crucial role of cytokines as essential regulators of the intramuscular build-up of inflammation is undisputed. This review describes the extensive cytokine network within IIM muscle, characterized by strong expression of Tumor Necrosis Factors (TNFα, LTβ, BAFF, Interferons (IFNα/β/γ, Interleukins (IL-1/6/12/15/18/23 and Chemokines (CXCL9/10/11/13, CCL2/3/4/8/19/21. Current therapeutic strategies and the exploration of potential disease modifying agents based on manipulation of the cytokine network are provided. Reported responses to anti-TNFα treatment in IIM are conflicting and new onset DM/PM has been described after administration of anti-TNFα agents to treat other diseases, pointing to the complex effects of TNFα neutralization. Treatment with anti-IFNα has been shown to suppress the IFN type 1 gene signature in DM/PM patients and improve muscle strength. Beneficial effects of anti-IL-1 and anti-IL-6 therapy have also been reported. Cytokine profiling in IIM aids the development of therapeutic strategies and provides approaches to subtype patients for treatment outcome prediction.

  1. Interaction of Dietary Fatty Acids with Tumour Necrosis Factor Family Cytokines during Colon Inflammation and Cancer

    Science.gov (United States)

    Straková, Nicol; Vaculová, Alena Hyršlová; Tylichová, Zuzana; Šafaříková, Barbora; Kozubík, Alois

    2014-01-01

    Intestinal homeostasis is precisely regulated by a number of endogenous regulatory molecules but significantly influenced by dietary compounds. Malfunction of this system may result in chronic inflammation and cancer. Dietary essential n-3 polyunsaturated fatty acids (PUFAs) and short-chain fatty acid butyrate produced from fibre display anti-inflammatory and anticancer activities. Both compounds were shown to modulate the production and activities of TNF family cytokines. Cytokines from the TNF family (TNF-α, TRAIL, and FasL) have potent inflammatory activities and can also regulate apoptosis, which plays an important role in cancer development. The results of our own research showed enhancement of apoptosis in colon cancer cells by a combination of either docosahexaenoic acid (DHA) or butyrate with TNF family cytokines, especially by promotion of the mitochondrial apoptotic pathway and modulation of NFκB activity. This review is focused mainly on the interaction of dietary PUFAs and butyrate with these cytokines during colon inflammation and cancer development. We summarised recent knowledge about the cellular and molecular mechanisms involved in such effects and outcomes for intestinal cell behaviour and pathologies. Finally, the possible application for the prevention and therapy of colon inflammation and cancer is also outlined. PMID:24876678

  2. Phenotype and influx kinetics of leukocytes and inflammatory cytokine production in kidney ischemia/reperfusion injury.

    Science.gov (United States)

    Williams, Timothy M; Wise, Andrea F; Layton, Daniel S; Ricardo, Sharon D

    2018-01-01

    Kidney ischemia/reperfusion (IR) injury is characterized by tubular epithelial cell (TEC) death and an inflammatory response involving cytokine production and immune cell infiltration. In various kidney diseases, increased macrophage numbers correlate with injury severity and poor prognosis. However, macrophage plasticity enables a diverse range of functions, including wound healing, making them a key target for novel therapies. This study aimed to comprehensively characterize the changes in myeloid and epithelial cells and the production of cytokines throughout the experimental IR model of acute kidney injury to aid in the identification of targets to promote and enhance kidney regeneration and repair. Flow cytometric analysis of murine unilateral IR injury was used to assess TEC and myeloid cell subpopulations in conjunction with histological analysis and cytokine production at 6 h, 1, 3, 5 and 7 days post IR injury, spanning the initial inflammatory phase and the following reparative phase. IR injury resulted in a rapid infiltration of Ly6C high monocytes and neutrophils with a steady rise in F4/80 high MHCII high macrophages over the injury time. The production of the inflammatory cytokines IL-6, MCP-1 and TNF coincided with an increase in IL-10 production. This characterization will provide a reference point for future studies designed to manipulate immune cell phenotype and function in order to promote endogenous repair of damaged kidneys. © 2016 Asian Pacific Society of Nephrology.

  3. The Role of Cytokine in the Lupus Nephritis

    Directory of Open Access Journals (Sweden)

    Yasunori Iwata

    2011-01-01

    Full Text Available Lupus nephritis (LN is a major clinical manifestation of systemic lupus erythematosus (SLE. Although numerous abnormalities of immune system have been proposed, cytokine overexpression plays an essential role in the pathogenesis of LN. In the initial phase of the disease, the immune deposits and/or autoantibodies induce cytokine production in renal resident cells, leading to further inflammatory cytokine/chemokine expression and leukocyte infiltration and activation. Then, infiltrate leukocytes, such as macrophages (Mφ and dendritic cells (DCs, secrete a variety of cytokines and activate naïve T cells, leading the cytokine profile towards T helper (Th1, Th2, and/or Th17. Recent studies revealed these inflammatory processes in experimental animal models as well as human LN. The cytokine targeted intervention may have the therapeutic potentials for LN. This paper focuses on the expression of cytokine and its functional role in the pathogenesis of LN.

  4. Synergy between Common γ Chain Family Cytokines and IL-18 Potentiates Innate and Adaptive Pathways of NK Cell Activation.

    Science.gov (United States)

    Nielsen, Carolyn M; Wolf, Asia-Sophia; Goodier, Martin R; Riley, Eleanor M

    2016-01-01

    Studies to develop cell-based therapies for cancer and other diseases have consistently shown that purified human natural killer (NK) cells secrete cytokines and kill target cells after in vitro culture with high concentrations of cytokines. However, these assays poorly reflect the conditions that are likely to prevail in vivo in the early stages of an infection and have been carried out in a wide variety of experimental systems, which has led to contradictions within the literature. We have conducted a detailed kinetic and dose-response analysis of human NK cell responses to low concentrations of IL-12, IL-15, IL-18, IL-21, and IFN-α, alone and in combination, and their potential to synergize with IL-2. We find that very low concentrations of both innate and adaptive common γ chain cytokines synergize with equally low concentrations of IL-18 to drive rapid and potent NK cell CD25 and IFN-γ expression; IL-18 and IL-2 reciprocally sustain CD25 and IL-18Rα expression in a positive feedback loop; and IL-18 synergizes with FcγRIII (CD16) signaling to augment antibody-dependent cellular cytotoxicity. These data indicate that NK cells can be rapidly activated by very low doses of innate cytokines and that the common γ chain cytokines have overlapping but distinct functions in combination with IL-18. Importantly, synergy between multiple signaling pathways leading to rapid NK cell activation at very low cytokine concentrations has been overlooked in prior studies focusing on single cytokines or simple combinations. Moreover, although the precise common γ chain cytokines available during primary and secondary infections may differ, their synergy with both IL-18 and antigen-antibody immune complexes underscores their contribution to NK cell activation during innate and adaptive responses. IL-18 signaling potentiates NK cell effector function during innate and adaptive immune responses by synergy with IL-2, IL-15, and IL-21 and immune complexes.

  5. Harmonization of the intracellular cytokine staining assay.

    Science.gov (United States)

    Welters, Marij J P; Gouttefangeas, Cécile; Ramwadhdoebe, Tamara H; Letsch, Anne; Ottensmeier, Christian H; Britten, Cedrik M; van der Burg, Sjoerd H

    2012-07-01

    Active immunotherapy for cancer is an accepted treatment modality aiming to reinforce the T-cell response to cancer. T-cell reactivity is measured by various assays and used to guide the clinical development of immunotherapeutics. However, data obtained across different institutions may vary substantially making comparative conclusions difficult. The Cancer Immunotherapy Immunoguiding Program organizes proficiency panels to identify key parameters influencing the outcome of commonly used T-cell assays followed by harmonization. Our successes with IFNγ-ELISPOT and peptide HLA multimer analysis have led to the current study on intracellular cytokine staining (ICS). We report the results of three successive panels evaluating this assay. At the beginning, 3 out of 9 participants (33 %) were able to detect >6 out of 8 known virus-specific T-cell responses in peripheral blood of healthy individuals. This increased to 50 % of the laboratories in the second phase. The reported percentages of cytokine-producing T cells by the different laboratories were highly variable with coefficients of variation well over 60 %. Variability could partially be explained by protocol-related differences in background cytokine production leading to sub-optimal signal-to-noise ratios. The large number of protocol variables prohibited identification of prime guidelines to harmonize the assays. In addition, the gating strategy used to identify reactive T cells had a major impact on assay outcome. Subsequent harmonization of the gating strategy considerably reduced the variability within the group of participants. In conclusion, we propose that first basic guidelines should be applied for gating in ICS experiments before harmonizing assay protocol variables.

  6. Cytokines in the modulation of eosinophilia

    Directory of Open Access Journals (Sweden)

    Faccioli Lúcia H

    1997-01-01

    Full Text Available In this review we discuss our recently results showing interleukin 5 (IL-5 involvement in eosinophil migration and in the maintenance of eosinophilia in blood, bone marrow, lung and peritoneal cavity, in a visceral larva migrans syndrome model using guinea-pigs infected with Toxocara canis. We also describe the sequential release of TNF-alpha and IL-8 during the course of infection, and the interaction between these cytokines and IL-5 during infection. Finally we propose a new biological role for IL-5, at least in our model, as a modulator of IL-8 release and secretion.

  7. Diabetes, Inflammation, Proinflammatory Cytokines, and Diabetic Nephropathy

    Directory of Open Access Journals (Sweden)

    Juan F. Navarro

    2006-01-01

    Full Text Available Diabetes and its complications have become a public health problem. Diabetic nephropathy is the main cause of renal failure. In spite of our higher knowledge on this complication, the intimate mechanisms leading to the development and progression of renal injury are not yet fully known. Activated innate immunity and inflammation are relevant factors in the pathogenesis of diabetes. Moreover, inflammation, and more specifically proinflammatory cytokines and other molecules with a relevant role within the inflammatory process, may be critical factors in the development of microvascular diabetic complications, including nephropathy. This new pathogenic perspective may lead to important new therapeutic considerations and new therapeutic goals for the treatment of diabetic nephropathy.

  8. Macrophage cytokines: Involvement in immunity and infectious diseases

    Directory of Open Access Journals (Sweden)

    Guillermo eArango Duque

    2014-10-01

    Full Text Available The evolution of macrophages has made them primordial for both development and immunity. Their functions range from the shaping of body plans to the ingestion and elimination of apoptotic cells and pathogens. Cytokines are small soluble proteins that confer instructions and mediate communication among immune and non-immune cells. A portfolio of cytokines is central to the role of macrophages as sentries of the innate immune system that mediate the transition from innate to adaptive immunity. In concert with other mediators, cytokines bias the fate of macrophages into a spectrum of inflammation-promoting ‘classically activated’, to anti-inflammatory or ‘alternatively activated’ macrophages. Deregulated cytokine secretion is implicated in several disease states ranging from chronic inflammation to allergy. Macrophages release cytokines via a series of beautifully orchestrated pathways that are spatiotemporally regulated. At the molecular level, these exocytic cytokine secretion pathways are coordinated by multi-protein complexes that guide cytokines from their point of synthesis to their ports of exit into the extracellular milieu. These trafficking proteins, many of which were discovered in yeast and commemorated in the 2013 Nobel Prize in Physiology or Medicine, coordinate the organelle fusion steps that are responsible for cytokine release. This review discusses the functions of cytokines secreted by macrophages, and summarizes what is known about their release mechanisms. This information will be used to delve into how selected pathogens subvert cytokine release for their own survival.

  9. Macrophage cytokines: involvement in immunity and infectious diseases.

    Science.gov (United States)

    Arango Duque, Guillermo; Descoteaux, Albert

    2014-01-01

    The evolution of macrophages has made them primordial for both development and immunity. Their functions range from the shaping of body plans to the ingestion and elimination of apoptotic cells and pathogens. Cytokines are small soluble proteins that confer instructions and mediate communication among immune and non-immune cells. A portfolio of cytokines is central to the role of macrophages as sentries of the innate immune system that mediate the transition from innate to adaptive immunity. In concert with other mediators, cytokines bias the fate of macrophages into a spectrum of inflammation-promoting "classically activated," to anti-inflammatory or "alternatively activated" macrophages. Deregulated cytokine secretion is implicated in several disease states ranging from chronic inflammation to allergy. Macrophages release cytokines via a series of beautifully orchestrated pathways that are spatiotemporally regulated. At the molecular level, these exocytic cytokine secretion pathways are coordinated by multi-protein complexes that guide cytokines from their point of synthesis to their ports of exit into the extracellular milieu. These trafficking proteins, many of which were discovered in yeast and commemorated in the 2013 Nobel Prize in Physiology or Medicine, coordinate the organelle fusion steps that are responsible for cytokine release. This review discusses the functions of cytokines secreted by macrophages, and summarizes what is known about their release mechanisms. This information will be used to delve into how selected pathogens subvert cytokine release for their own survival.

  10. Inflammatory Cytokines in Depression: Neurobiological Mechanisms and Therapeutic Implications

    Science.gov (United States)

    Felger, Jennifer C.; Lotrich, Francis E.

    2013-01-01

    Mounting evidence indicates that inflammatory cytokines contribute to the development of depression in both medically ill and medically healthy individuals. Cytokines are important for development and normal brain function, and have the ability to influence neurocircuitry and neurotransmitter systems to produce behavioral alterations. Acutely, inflammatory cytokine administration or activation of the innate immune system produces adaptive behavioral responses that promote conservation of energy to combat infection or recovery from injury. However, chronic exposure to elevated inflammatory cytokines and persistent alterations in neurotransmitter systems can lead to neuropsychiatric disorders and depression. Mechanisms of cytokine behavioral effects involve activation of inflammatory signaling pathways in the brain that results in changes in monoamine, glutamate, and neuropeptide systems, and decreases in growth factors, e.g. brain derived neurotrophic factor. Furthermore, inflammatory cytokines may serve as mediators of both environmental (e.g. childhood trauma, obesity, stress, and poor sleep) and genetic (functional gene polymorphisms) factors that contribute to depression’s development. This review explores the idea that specific gene polymorphisms and neurotransmitter systems can confer protection from or vulnerability to specific symptom dimensions of cytokine-related depression. Additionally, potential therapeutic strategies that target inflammatory cytokine signaling or the consequences of cytokines on neurotransmitter systems in the brain to prevent or reverse cytokine effects on behavior are discussed. PMID:23644052

  11. The Cross-talk between Tristetraprolin and Cytokines in Cancer.

    Science.gov (United States)

    Guo, Jian; Wang, Hao; Jiang, Shiyi; Xia, Jiazeng; Jin, Shimao

    2017-11-24

    Cytokines are small secreted proteins serving as vital mediators that mediate the host immune responses. Transcription and post-transcription play a critical role in cytokine expression through the regulation of message RNA (mRNA) cytoplasmic localization, translation initiation and decay. Researches have been conducted to reveal regulatory mechanisms of cytokines production in cells involved in cancer. AU-rich element (ARE) can regulate the degradation and translation of mRNA by connecting with specific ARE binding proteins. It is now clear that tristetraprolin (TTP), as the most common ARE binding protein, negatively regulates many aspects of the cytokines through binding to the AREs in the 3'-untranslated region (3'UTR) of mRNA. Furthermore, some certain cytokines have an impact on TTP expression and function. Therefore, the cross-regulation between cytokines and TTP has come into sight. The complicated regulatory networks between cytokines and TTP are closely related to tumorigenesis. In this review, we summarize specific regulatory mechanisms of cytokine mRNAs. We focus on how TTP negatively regulates inflammatory and oncogenic cytokines expression after combining with AREs, we also pay attention to some cytokines mediating the expression of TTP and their cross-talk in various cancers in detail. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  12. IMMUNE STATUS AND CYTOKINE PROFILE IN CHILDREN WITH PERINATAL DAMAGES OF CNS

    Directory of Open Access Journals (Sweden)

    O. V. Nikogosova

    2005-01-01

    Full Text Available Abstract. The aim of the study was to verify etiological agents of CNS perinatal damages in children of early age and to study peculiarities of immune and cytokine statuses during pathogenetically grounded therapy.618 children aged from 1 month till 3 years were examined. Changes of neurologic status were interrogated and complete standard paraclinical examination was carried out. Basic clinical groups were formed.Immunoassay program, which included verification of a causative agent and determination of indices of cellular and humoral immunities, was used to identify a causative agent and to determin infectious activity. Direct methods of investigation which reveal a causative agent and indirect methods which register specific immune response were used. Patients were divided into groups on the basis of etiological agent.The program of pharmacotherapy was based on findings, immune status and in particular immune mediators. This program included specific anti-infectious therapy and adequate immunorehabilitation. Data analysis was made for groups of patients who got symptomatic therapy in neurologic disease and who got immunocorrective and anti-infectious therapy in addition to standard treatment. Comparison of clinical characteristics showed considerable improvement of patients in the latter group, what correlated with laboratorial data. Normalization of principal indices of immune and cytokine statuses which ensure development of anti-infectious immunity resulted in persistent infectious remission, noticeable improvement of clinical state of the invalidity rate.

  13. Relationship of cytokines and cytokine signaling to immunodeficiency disorders in the mouse

    Directory of Open Access Journals (Sweden)

    Morawetz R.A.

    1998-01-01

    Full Text Available The contributions of cytokines to the development and progression of disease in a mouse model of retrovirus-induced immunodeficiency (MAIDS are controversial. Some studies have indicated an etiologic role for type 2 cytokines, while others have emphasized the importance of type 1 cytokines. We have used mice deficient in expression of IL-4, IL-10, IL-4 and IL-10, IFN-g, or ICSBP - a transcriptional protein involved in IFN signaling - to examine their contributions to this disorder. Our results demonstrate that expression of type 2 cytokines is an epiphenomenon of infection and that IFN-g is a driving force in disease progression. In addition, exogenously administered IL-12 prevents many manifestations of disease while blocking retrovirus expression. Interruption of the IFN signaling pathways in ICSBP-/- mice blocks induction of MAIDS. Predictably, ICSBP-deficient mice exhibit impaired responses to challenge with several other viruses. This immunodeficiency is associated with impaired production of IFN-g and IL-12. Unexpectedly, however, the ICSBP-/- mice also develop a syndrome with many similarities to chronic myelogenous leukemia in humans. The chronic phase of this disease is followed by a fatal blast crisis characterized by clonal expansions of undifferentiated cells. ICSBP is thus an important determinant of hematopoietic growth and differentiation as well as a prominent signaling molecule for IFNs

  14. Evolution of Class I cytokine receptors

    Science.gov (United States)

    Liongue, Clifford; Ward, Alister C

    2007-01-01

    Background The Class I cytokine receptors have a wide range of actions, including a major role in the development and function of immune and blood cells. However, the evolution of the genes encoding them remains poorly understood. To address this we have used bioinformatics to analyze the Class I receptor repertoire in sea squirt (Ciona intestinalis) and zebrafish (Danio rerio). Results Only two Class I receptors were identified in sea squirt, one with homology to the archetypal GP130 receptor, and the other with high conservation with the divergent orphan receptor CLF-3. In contrast, 36 Class I cytokine receptors were present in zebrafish, including representative members for each of the five structural groups found in mammals. This allowed the identification of 27 core receptors belonging to the last common ancestor of teleosts and mammals. Conclusion This study suggests that the majority of diversification of this receptor family occurred after the divergence of urochordates and vertebrates approximately 794 million years ago (MYA), but before the divergence of ray-finned from lobe-finned fishes around 476 MYA. Since then, only relatively limited lineage-specific diversification within the different Class I receptor structural groups has occurred. PMID:17640376

  15. Interplay of cytokines in preterm birth

    Directory of Open Access Journals (Sweden)

    Monika Pandey

    2017-01-01

    Full Text Available Preterm infants (i.e., born before <37 wk of gestation are at increased risk of morbidity and mortality and long-term disabilities. Global prevalence of preterm birth (PTB varies from 5 to 18 per cent. There are multiple aetiological causes and factors associated with PTB. Intrapartum infections are conventionally associated with PTB. However, maternal genotype modulates response to these infections. This review highlights the association of cytokine gene polymorphisms and their levels with PTB. Varying PTB rates across the different ethnic groups may be as a result of genetically mediated varying cytokines response to infections. Studies on genetic variations in tumour necrosis factor-alpha, interleukin-1 alpha (IL-1α, IL-1β, IL-6, IL-10 and toll-like receptor-4 genes and their association with PTB, have been reviewed. No single polymorphism of the studied genes was found to be associated with PTB. However, increased maternal levels of IL-1β and IL-6 and low levels of IL-10 have been found to be associated with PTB.

  16. Radiotherapy- and chemotherapy-induced normal tissue damage. The role of cytokines and adhesion molecules

    International Nuclear Information System (INIS)

    Plevova, P.

    2002-01-01

    Background. Ionising radiation and cytostatic agents used in cancer therapy exert damaging effects on normal tissues and induce a complex response at the cellular and molecular levels. Cytokines and adhesion molecules are involved in this response. Methods. Published data on the given topic have been reviewed. Results and conclusions. Various cytokines and adhesion molecules, including tumor necrosis factor α, interleukins- 1,-2,-4, and -6, interferon γ, granulocyte macrophage- and macrophage- colony stimulating factors, transforming growth factor β, platelet-derived growth factor, insulin-like growth factor I, fibroblast and epidermal growth factors, platelet-activating factor, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, E- and P-selectins are involved in the response of normal tissues to ionizing radiation- and chemotherapy- induced normal tissues damage and are co-responsible for some side effects of these treatment modalities, including fever, anorexia and fatigue, suppression of hematopoiesis, both acute and late local tissue response. (author)

  17. Multiplex array analysis of circulating cytokines and chemokines in natalizumab-treated patients with multiple sclerosis.

    Science.gov (United States)

    Villani, Sonia; Zanotta, Nunzia; Ambrogi, Federico; Comar, Manola; Franciotta, Diego; Dolci, Maria; Cason, Carolina; Ticozzi, Rosalia; Ferrante, Pasquale; Delbue, Serena

    2017-09-15

    Natalizumab greatly reduces inflammatory relapses in multiple sclerosis (MS) by blocking the integrin-mediated leukocyte traffic to the brain, but less is known about its effects on the systemic immunity. We measured 48 cytokines/chemokines in sera from 19 natalizumab-treated MS patients. Serum concentrations of both anti-(IL-10, IL1ra) and pro-inflammatory (IL7, IL16) molecules decreased after 21-month treatment, without associations to unbalanced Th2/Th1cytokine ratios, clinical responses, and blood/urine replication of polyomavirus JC (JCPyV). No patient developed the JCPyV-related progressive multifocal leukoencephalopathy (PML), the major risk factor of natalizumab therapy. Our data suggest that natalizumab has marginal impact on the systemic immunity. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. Cytokine RNA levels in transiliac bone biopsies from healthy early postmenopausal women

    DEFF Research Database (Denmark)

    Abrahamsen, Bo; Shalhoub, V; Larson, E K

    2000-01-01

    be demonstrated in women with rapid bone loss after the menopause. Biopsies were obtained from 23 early postmenopausal women (mean age 53.9 years) who participated in a randomized study of hormone replacement therapy (HRT) and risk factors for osteoporosis. Bone mineral density was assessed by duel energy X......The cytokines interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), and IL-6 induce osteoclast formation and may contribute to the development of postmenopausal osteoporosis. Cross-sectional studies have suggested that both IL-1 and IL-1ra secretion increase on estrogen withdrawal......, and that postmenopausal osteoporosis is associated with an inadequate increase in monocyte IL-1ra secretion with age. We measured cytokine mRNA (IL-1beta, IL-1ra, IL-6, and TNF-alpha) directly in bone biopsies from early postmenopausal women to determine if a lower compensatory increase in IL-1ra mRNA could...

  19. Alzheimer’s disease and cytokine IL-10 gene polymorphisms: is there an association?

    Directory of Open Access Journals (Sweden)

    Carolina Antunes Magalhães

    Full Text Available ABSTRACT Alzheimer’s disease (AD is the most common form of dementia. In the last 15 years, a new theory has proposed the autoimmune mechanism as a trigger for AD. Studies on the association between AD and inflammatory biomarkers have yielded controversial results. Interleukin-10 (IL-10, an anti-inflammatory mediator, has been pointed out as one of the main cytokines associated with the occurrence of AD. Moreover, treatment that increases IL-10 levels could be a potential therapy for AD, since this cytokine acts on amyloid and pro-inflammatory molecule reduction. Based on the current literature, this study reviews evidence regarding the role of IL-10 polymorphisms in the context of AD, which has been shown to be of paramount importance for attenuating neuroinflammation, cognitive dysfunction and neurodegeneration.

  20. Targeting cytokine signaling checkpoint CIS activates NK cells to protect from tumor initiation and metastasis

    Science.gov (United States)

    Putz, Eva M.; Guillerey, Camille; Kos, Kevin; Stannard, Kimberley; Miles, Kim; Delconte, Rebecca B.; Nicholson, Sandra E.; Huntington, Nicholas D.; Smyth, Mark J.

    2017-01-01

    ABSTRACT The cytokine-induced SH2-containing protein CIS belongs to the suppressor of cytokine signaling (SOCS) protein family. Here, we show the critical role of CIS in suppressing natural killer (NK) cell control of tumor initiation and metastasis. Cish-deficient mice were highly resistant to methylcholanthrene-induced sarcoma formation and protected from lung metastasis of B16F10 melanoma and RM-1 prostate carcinoma cells. In contrast, the growth of primary subcutaneous tumors, including those expressing the foreign antigen OVA, was unchanged in Cish-deficient mice. The combination of Cish deficiency and relevant targeted and immuno-therapies such as combined BRAF and MEK inhibitors, immune checkpoint blockade antibodies, IL-2 and type I interferon revealed further improved control of metastasis. The data clearly indicate that targeting CIS promotes NK cell antitumor functions and CIS holds great promise as a novel target in NK cell immunotherapy. PMID:28344878

  1. Proinflammatory cytokines in alcohol or gallstone induced acute pancreatitis. A prospective study

    DEFF Research Database (Denmark)

    Novovic, Srdan; Andersen, Anders Møller; Ersbøll, Annette Kjaer

    2009-01-01

    OBJECTIVES: If differences of inflammatory pathways in acute pancreatitis exist for various etiologies, selective and specific antiinflammatory and other modulatory treatment regimens might be indicated. Circulating levels of prominent proinflammatory cytokines IL-6, 8, 18, and TNF-alpha were...... measured in patients having their first attack of either alcohol- or gallstone-induced acute pancreatitis. METHODS: Seventy-five consecutive patients were prospectively included over a 15-month period, sixty of them being either alcohol- or gallstone-induced. All patients were treated according...... and clinical outcome is independent of the underlying etiology. Revealing the complex spatial and temporal profile of proinflammatory cytokine expression in acute pancreatitis is necessary and important for the development of a more targeted rational therapy....

  2. Cytokine genes as potential biomarkers for muscle weakness in OPMD

    DEFF Research Database (Denmark)

    Riaz, Muhammad; Raz, Yotam; van der Slujis, Barbara

    2016-01-01

    been exploited in the last decade. Cytokines are released from many tissues, including skeletal muscles, but their application to monitor muscle pathology is sparse. We report that the cytokine functional group is altered in the transcriptome of oculopharyngeal muscular dystrophy (OPMD). OPMD...... is a dominant, late-onset myopathy, caused by an alanine-expansion mutation in the gene encoding for poly(A) binding protein nuclear 1 (expPABPN1). Here, we investigated the hypothesis that cytokines could mark OPMD disease state. We determined cytokines levels the vastus lateralis muscle from genetically...... confirmed expPABPN1 carriers at a symptomatic or a presymptomatic stage. We identified cytokine-related genes candidates from a transcriptome study in a mouse overexpressing exp PABPN1 Six cytokines were found to be consistently down-regulated in OPMD vastus lateralis muscles. Expression levels...

  3. FLT3 ligand preserves the uncommitted CD34+CD38- progenitor cells during cytokine prestimulation for retroviral transduction

    DEFF Research Database (Denmark)

    Nielsen, S D; Husemoen, L L; Sørensen, T U

    2000-01-01

    Before stem cell gene therapy can be considered for clinical applications, problems regarding cytokine prestimulation remain to be solved. In this study, a retroviral vector carrying the genes for the enhanced version of green fluorescent protein (EGFP) and neomycin resistance (neo(r)) was used...... (SCF), FLT3 ligand, interleukin-3 (IL-3), IL-6, and IL-7 prior to transduction. Expression of the two genes was assessed by flow cytometry and determination of neomycin-resistant colonies in a selective colony-forming unit (CFU) assay, respectively. The neomycin resistance gene was expressed...... in a higher percentage of cells than the EGFP gene, but there seemed to be a positive correlation between expression of the two genes. The effect of cytokine prestimulation was therefore monitored using EGFP as marker for transduction. When SCF was compared to SCF in combination with more potent cytokines...

  4. Cytokine ratios in chronic periodontitis and type 2 diabetes mellitus.

    Science.gov (United States)

    Acharya, Anirudh B; Thakur, Srinath; Muddapur, M V; Kulkarni, Raghavendra D

    Chronic periodontitis may influence systemic cytokines in type 2 diabetes. This study aimed to evaluate the cytokine ratios in type 2 diabetes with, and without chronic periodontitis. Gingival status, periodontal, glycemic parameters and serum cytokines were evaluated in participants grouped as healthy, chronic periodontitis, and type 2 diabetes with, and without chronic periodontitis. Cytokine ratios showed significant differences in type 2 diabetes and chronic periodontitis, were highest in participants having both type 2 diabetes and chronic periodontitis, with a statistically significant cut-off point and area under curve by receiver operating characteristic. Copyright © 2016 Diabetes India. Published by Elsevier Ltd. All rights reserved.

  5. Pro-inflammatory cytokines in animal and human gestation.

    Science.gov (United States)

    Paulesu, Luana; Bhattacharjee, Jayonta; Bechi, Nicoletta; Romagnoli, Roberta; Jantra, Silke; Ietta, Francesca

    2010-01-01

    The story of cytokines in pregnancy began about 30 years ago, approximately in concomitance with the understanding that cytokines are autocrine-paracrine regulators of physiological processes. Pro-inflammatory cytokines are predominant in the early and late events of gestation, e.g. pregnancy establishment and parturition, both of which have been described as inflammatory-like events. Pro-inflammatory cytokines are also produced in response to microbes constantly in contact with the female reproductive tract. While a pro-inflammatory response is beneficial to successful pregnancy, an exaggerated response, as may occur for an unresolved infection, could result in an unfavorable pregnancy outcome in animals and humans. Therapeutic strategies are required to avoid the risks to the health of fetus and mother. In this review, we discuss the involvement of pro-inflammatory cytokines in pregnancy at implantation and parturition, including the pathologies which might be related to an alteration of the cytokine levels. We also deal with the use of anti-cytokines and/or anti-inflammatory mediators to antagonize the action of pro-inflammatory cytokines. Finally we discuss the potential of animal models to evaluate the association of cytokines in the establishment and maintenance of pregnancy.

  6. Oxidative stress and proinflammatory cytokines contribute to demyelination and axonal damage in a cerebellar culture model of neuroinflammation.

    Science.gov (United States)

    di Penta, Alessandra; Moreno, Beatriz; Reix, Stephanie; Fernandez-Diez, Begoña; Villanueva, Maite; Errea, Oihana; Escala, Nagore; Vandenbroeck, Koen; Comella, Joan X; Villoslada, Pablo

    2013-01-01

    Demyelination and axonal damage are critical processes in the pathogenesis of multiple sclerosis (MS). Oxidative stress and pro-inflammatory cytokines elicited by inflammation mediates tissue damage. To monitor the demyelination and axonal injury associated with microglia activation we employed a model using cerebellar organotypic cultures stimulated with lipopolysaccharide (LPS). Microglia activated by LPS released pro-inflammatory cytokines (IL-1β, IL-6 and TNFα), and increased the expression of inducible nitric oxide synthase (iNOS) and production of reactive oxygen species (ROS). This activation was associated with demyelination and axonal damage in cerebellar cultures. Axonal damage, as revealed by the presence of non-phosphorylated neurofilaments, mitochondrial accumulation in axonal spheroids, and axonal transection, was associated with stronger iNOS expression and concomitant increases in ROS. Moreover, we analyzed the contribution of pro-inflammatory cytokines and oxidative stress in demyelination and axonal degeneration using the iNOS inhibitor ethyl pyruvate, a free-scavenger and xanthine oxidase inhibitor allopurinol, as well as via blockage of pro-inflammatory cytokines using a Fc-TNFR1 construct. We found that blocking microglia activation with ethyl pyruvate or allopurinol significantly decreased axonal damage, and to a lesser extent, demyelination. Blocking TNFα significantly decreased demyelination but did not prevented axonal damage. Moreover, the most common therapy for MS, interferon-beta, was used as an example of an immunomodulator compound that can be tested in this model. In vitro, interferon-beta treatment decreased oxidative stress (iNOS and ROS levels) and the release of pro-inflammatory cytokines after LPS stimulation, reducing axonal damage. The model of neuroinflammation using cerebellar culture stimulated with endotoxin mimicked myelin and axonal damage mediated by the combination of oxidative stress and pro-inflammatory cytokines

  7. An experimental model-based exploration of cytokines in ablative radiation-induced lung injury in vivo and in vitro.

    Science.gov (United States)

    Hong, Zhen-Yu; Song, Kwang Hyun; Yoon, Joo-Heon; Cho, Jaeho; Story, Michael D

    2015-06-01

    Stereotactic ablative radiotherapy is a newly emerging radiotherapy treatment method that, compared with conventionally fractionated radiation therapy (CFRT), allows an ablative dose of radiation to be delivered to a confined area around a tumor. The aim of the present study was to investigate the changes of various cytokines that may be involved in ablative radiation-induced lung injury in vitro and in vivo. In the in vivo study, ablative-dose radiation was delivered to a small volume of the left lung of C3H/HeJCr mice using a small-animal irradiator. The levels of 24 cytokines in the peripheral blood were tested at several time points after irradiation. For the in vitro study, three mouse cell types (type II pneumocytes, alveolar macrophages, and fibroblasts) known to play important roles in radiation-induced pneumonitis and lung fibrosis were analyzed using a co-culture system. In the in vivo study, we found obvious patterns of serum cytokine changes depending on the volume of tissue irradiated (2-mm vs. 3.5-mm collimator). Only the levels of 3 cytokines increased with the 2-mm collimator at the acute phase (1-2 weeks after irradiation), while the majority of cytokines were elevated with the 3.5-mm collimator. In the in vitro co-culture system, after the cells were given an ablative dose of irradiation, the levels of five cytokines (GM-CSF, G-CSF, IL-6, MCP-1, and KC) increased significantly in a dose-dependent manner. The cytokine levels in our radiation-induced lung injury model showed specific changes, both in vivo and in vitro. These results imply that biological studies related to ablative-dose small-volume irradiation should be investigated using the corresponding experimental models rather than on those simulating large-volume CFRT.

  8. Tacrolimus does not alter the production of several cytokines and antimicrobial peptide in Malassezia furfur-infected-keratinocytes.

    Science.gov (United States)

    Balato, Anna; Paoletti, Iole; De Gregorio, Vincenza; Cantelli, Mariateresa; Ayala, Fabio; Donnarumma, Giovanna

    2014-03-01

    Topical immunosuppressant therapy is widely used in the treatment of inflammatory skin diseases, such as atopic dermatitis and psoriasis. Besides its beneficial therapeutic effects, application of topical anti-inflammatory drugs may render the epidermis more vulnerable to invading pathogens by suppressing innate immune responses in keratinocytes (KCs). Cytokines, chemokines and antimicrobial peptides (AMPs) produced by epithelial cells enable them to participate in innate and acquired immune responses. The aim of the present work was to study the influence of tacrolimus (FK506) on KCs infected with Malassezia furfur (M. furfur), evaluating the expression of pro-inflammatory cytokines IL-1α and IL-6, chemokine IL-8, anti-inflammatory cytokines transforming growth factor beta1 (TGF-β1) and IL-10 and AMP β-defensin-2. Human KCs were obtained from surgical specimens of normal adult skin. The expression of mRNAs in KCs: FK506-treated, FK506-treated and M. furfur-infected as well as only M. furfur-infected was quantified by real-time quantitative polymerase chain reaction. Next, the production of the AMP β-defensin-2 and of the above-mentioned pro-inflammatory and anti-inflammatory cytokines was evaluated using enzyme-linked immunosorbent assay. In this study, FK506 did not alter cytokine and AMP production by KCs; this led us to hypothesise that it may not enhance the risk of mycotic skin infections. © 2013 Blackwell Verlag GmbH.

  9. Cytokines and Angiogenesis in the Corpus Luteum

    Directory of Open Access Journals (Sweden)

    António M. Galvão

    2013-01-01

    Full Text Available In adults, physiological angiogenesis is a rare event, with few exceptions as the vasculogenesis needed for tissue growth and function in female reproductive organs. Particularly in the corpus luteum (CL, regulation of angiogenic process seems to be tightly controlled by opposite actions resultant from the balance between pro- and antiangiogenic factors. It is the extremely rapid sequence of events that determines the dramatic changes on vascular and nonvascular structures, qualifying the CL as a great model for angiogenesis studies. Using the mare CL as a model, reports on locally produced cytokines, such as tumor necrosis factor α (TNF, interferon gamma (IFNG, or Fas ligand (FASL, pointed out their role on angiogenic activity modulation throughout the luteal phase. Thus, the main purpose of this review is to highlight the interaction between immune, endothelial, and luteal steroidogenic cells, regarding vascular dynamics/changes during establishment and regression of the equine CL.

  10. STAT3, a Key Parameter of Cytokine-driven Tissue Protection During Sterile Inflammation – the Case of Experimental Acetaminophen (Paracetamol-induced Liver Damage

    Directory of Open Access Journals (Sweden)

    Heiko eMühl

    2016-05-01

    Full Text Available Acetaminophen (APAP, N-acetyl-p-aminophenol, or paracetamol overdosing is a prevalent cause of acute liver injury. While clinical disease is initiated by overt parenchymal hepatocyte necrosis in response to the analgetic, course of intoxication is substantially influenced by associated activation of innate immunity. This process is supposed to be set in motion by release of danger associated molecular patterns (DAMPs from dying hepatocytes and is accompanied by an inflammatory cytokine response. Murine models of APAP-induced liver injury emphasize the complex role that DAMPs and cytokines play in promoting either hepatic pathogenesis or resolution and recovery from intoxication. Whereas the function of key inflammatory cytokines is controversially discussed, a subclass of specific cytokines capable of efficiently activating the hepatocyte signal transducer and activator of transcription (STAT-3 pathway stands out as being consistently protective in murine models of APAP intoxication. Those include foremost interleukin (IL-6, IL-11, IL-13, and IL-22. Above all, activation of STAT3 under the influence of these cytokines has the capability to drive hepatocyte compensatory proliferation, a key principle of the regenerating liver. Herein, the role of these specific cytokines during experimental APAP-induced liver injury is highlighted and discussed in a broader perspective. In hard-to-treat or at-risk patients standard therapy may fail and APAP intoxication can proceed towards a fatal condition. Focused administration of recombinant STAT3-activating cytokines may evolve as novel therapeutic approach under those ill-fated conditions.

  11. Increased Blood Levels of Growth Factors, Proinflammatory Cytokines, and Th17 Cytokines in Patients with Newly Diagnosed Type 1 Diabetes.

    Science.gov (United States)

    Alnek, Kristi; Kisand, Kalle; Heilman, Kaire; Peet, Aleksandr; Varik, Karin; Uibo, Raivo

    2015-01-01

    The production of several cytokines could be dysregulated in type 1 diabetes (T1D). In particular, the activation of T helper (Th) type 1 (Th1) cells has been proposed to underlie the autoimmune pathogenesis of the disease, although roles for inflammatory processes and the Th17 pathway have also been shown. Nevertheless, despite evidence for the role of cytokines before and at the onset of T1D, the corresponding findings are inconsistent across studies. Moreover, conflicting data exist regarding the blood cytokine levels in T1D patients. The current study was performed to investigate genetic and autoantibody markers in association with the peripheral blood cytokine profiles by xMap multiplex technology in newly diagnosed young T1D patients and age-matched healthy controls. The onset of young-age T1D was characterized by the upregulation of growth factors, including granulocyte macrophage-colony stimulating factor (GM-CSF) and interleukin (IL)-7, the proinflammatory cytokine IL-1β (but not IL-6 or tumor necrosis factor [TNF]-α), Th17 cytokines, and the regulatory cytokines IL-10 and IL-27. Ketoacidosis and autoantibodies (anti-IA-2 and -ZnT8), but not human leukocyte antigen (HLA) genotype, influenced the blood cytokine levels. These findings broaden the current understanding of the dysregulation of systemic levels of several key cytokines at the young-age onset of T1D and provide a further basis for the development of novel immunoregulatory treatments in this disease.

  12. Cross-regulation of cytokine signalling: pro-inflammatory cytokines restrict IL-6 signalling through receptor internalisation and degradation.

    Science.gov (United States)

    Radtke, Simone; Wüller, Stefan; Yang, Xiang-ping; Lippok, Barbara E; Mütze, Barbara; Mais, Christine; de Leur, Hildegard Schmitz-Van; Bode, Johannes G; Gaestel, Matthias; Heinrich, Peter C; Behrmann, Iris; Schaper, Fred; Hermanns, Heike M

    2010-03-15

    The inflammatory response involves a complex interplay of different cytokines which act in an auto- or paracrine manner to induce the so-called acute phase response. Cytokines are known to crosstalk on multiple levels, for instance by regulating the mRNA stability of targeted cytokines through activation of the p38-MAPK pathway. In our study we discovered a new mechanism that answers the long-standing question how pro-inflammatory cytokines and environmental stress restrict immediate signalling of interleukin (IL)-6-type cytokines. We show that p38, activated by IL-1beta, TNFalpha or environmental stress, impairs IL-6-induced JAK/STAT signalling through phosphorylation of the common cytokine receptor subunit gp130 and its subsequent internalisation and degradation. We identify MK2 as the kinase that phosphorylates serine 782 in the cytoplasmic part of gp130. Consequently, inhibition of p38 or MK2, deletion of MK2 or mutation of crucial amino acids within the MK2 target site or the di-leucine internalisation motif blocks receptor depletion and restores IL-6-dependent STAT activation as well as gene induction. Hence, a novel negative crosstalk mechanism for cytokine signalling is described, where cytokine receptor turnover is regulated in trans by pro-inflammatory cytokines and stress stimuli to coordinate the inflammatory response.

  13. Proton therapy

    Science.gov (United States)

    Proton beam therapy; Cancer - proton therapy; Radiation therapy - proton therapy; Prostate cancer - proton therapy ... that use x-rays to destroy cancer cells, proton therapy uses a beam of special particles called ...

  14. Controlling neuropathic pain by adeno-associated virus driven production of the anti-inflammatory cytokine, interleukin-10

    Directory of Open Access Journals (Sweden)

    Flotte Terence R

    2005-02-01

    Full Text Available Abstract Despite many decades of drug development, effective therapies for neuropathic pain remain elusive. The recent recognition of spinal cord glia and glial pro-inflammatory cytokines as important contributors to neuropathic pain suggests an alternative therapeutic strategy; that is, targeting glial activation or its downstream consequences. While several glial-selective drugs have been successful in controlling neuropathic pain in animal models, none are optimal for human use. Thus the aim of the present studies was to explore a novel approach for controlling neuropathic pain. Here, an adeno-associated viral (serotype II; AAV2 vector was created that encodes the anti-inflammatory cytokine, interleukin-10 (IL-10. This anti-inflammatory cytokine is known to suppress the production of pro-inflammatory cytokines. Upon intrathecal administration, this novel AAV2-IL-10 vector was successful in transiently preventing and reversing neuropathic pain. Intrathecal administration of an AAV2 vector encoding beta-galactosidase revealed that AAV2 preferentially infects meningeal cells surrounding the CSF space. Taken together, these data provide initial support that intrathecal gene therapy to drive the production of IL-10 may prove to be an efficacious treatment for neuropathic pain.

  15. Glucagon-Like Peptide-1 Protects Human Islets against Cytokine-Mediated β-Cell Dysfunction and Death: A Proteomic Study of the Pathways Involved

    DEFF Research Database (Denmark)

    Rondas, Dieter; Bugliani, Marco; D’Hertog, Wannes

    2013-01-01

    of human islets of Langerhans treated with cytokines (IL-1β and IFN-γ) in the presence or absence of GLP-1 by 2D difference gel electrophoresis and subsequent protein interaction network analysis to understand the molecular pathways involved in GLP-1-mediated β-cell protection. Co-incubation of cytokine......-exposed human islets while protecting them against cytokine-mediated cell death and dysfunction. These data illustrate the beneficial effects of GLP-1 on human islets under immune attack, leading to a better understanding of the underlying mechanisms involved, a prerequisite for improving therapies for diabetic......Glucagon-like peptide-1 (GLP-1) has been shown to protect pancreatic β-cells against cytokine-induced dysfunction and destruction. The mechanisms through which GLP-1 exerts its effects are complex and still poorly understood. The aim of this study was to analyze the protein expression profiles...

  16. T-Cell Cytokines as Predictive Markers of the Risk of Allograft Rejection.

    Science.gov (United States)

    Brunet, Mercè; Millán López, Olga; López-Hoyos, Marcos

    2016-04-01

    Over the last decade, several biomarkers and surrogate markers have surfaced as promising predictive markers of risk of rejection in solid organ transplantation. The monitoring of these markers can help to improve graft and recipient care by personalizing immunomodulatory therapies. The complex immune system response against an implanted graft can change during long-term follow-up, and the dynamic balance between effector and regulatory T-cell populations is a crucial factor in antidonor response, risk of rejection, and immunosuppression requirements. Therefore, at any time before and after transplantation, T-effector activity, which is associated with increased production and release of proinflammatory cytokines, can be a surrogate marker of the risk of rejection and need for immunosuppression. In addition, immunosuppressive drugs may have a different effect in each individual patient. The pharmacokinetics and pharmacodynamics of these drugs show high interpatient variability, and pharmacodynamic markers, strongly associated with the specific mechanism of action, can potentially be used to measure individual susceptibility to a specific immunosuppressive agent. The monitoring of a panel of valid biomarkers can improve patient stratification and the selection of immunosuppressive drugs. After transplantation, therapy can be adjusted based on the prediction of rejection episodes (maintained alloreactivity), the prognosis of allograft damage, and the individual's response to the drugs. This review will focus on current data indicating that changes in the T-cell production of the intracellular cytokines interferon-γ and interleukin-2 could be used to predict the risk of rejection and to guide immunosuppressive therapy in transplant recipients.

  17. Featured Article: Modulation of the OGF-OGFr pathway alters cytokine profiles in experimental autoimmune encephalomyelitis and multiple sclerosis.

    Science.gov (United States)

    Ludwig, Michael D; Zagon, Ian S; McLaughlin, Patricia J

    2018-02-01

    -dose naltrexone modulated IL-6 and IL-10 cytokine expression. Validation in human serum revealed markedly reduced IL-6 cytokine levels in MS patients taking low-dose naltrexone relative to standard care. In summary, modulation of the OGF-OGFr pathway regulates some inflammatory cytokines, and together with opioid growth factor serum levels, may begin to form a panel of valid biomarkers to monitor progression of multiple sclerosis and response to therapy. Impact statement Modulation of the opioid growth factor (OGF)-OGF receptor (OGFr) alters inflammatory cytokine expression in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). Multiplex cytokine assays demonstrated that mice with chronic EAE and treated with either OGF or low-dose naltrexone (LDN) had decreased expression of interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), and the anti-inflammatory cytokine IL-10 within 10 days or treatment, as well as increased serum expression of the pro-inflammatory cytokine IL-6, relative to immunized mice receiving saline. Multiplex data were validated using ELISA kits and serum from MS patients treated with LDN and revealed decreased in IL-6 levels in patients taking LDN relative to standard care alone. These data, along with serum levels of OGF, begin to formulate a selective biomarker profile for MS that is easily measured and effective at monitoring disease progression and response to therapy.

  18. CYTOKINE - The Official Journal of the International Cytokine Society. Volume 11, Number 11

    Science.gov (United States)

    1999-12-09

    AND CHEMOKINE RECEPTORS Disease Targets for Therapeutic Development November 15-16,1999 • The Ritz - Carlton , Tysons Corner • McLean, Virginia As...but rather on the mechanisms involved in the regulation of chemokine biology. Many presentations extended the concept that the signals present at the...Legend. The cover is an original painting commissioned from the artist Tina York. It depicts the artist’s conceptions of cytokines emanating from a

  19. Cytokine Levels in the Serum of Healthy Subjects

    Directory of Open Access Journals (Sweden)

    Giulio Kleiner

    2013-01-01

    Full Text Available Growing knowledge about the cytokine network response has led to a better comprehension of mechanisms of pathologies and to the development of new treatments with biological drugs, able to block specific molecules of the immune response. Indeed, when the cytokine production is deregulated, diseases often occur. The understanding of the physiological mechanism of the cytokine network would be useful to better comprehend pathological conditions. Moreover, since the immune system and response change their properties with development, differences in patients' age should be taken into account, both in physiological and in pathological conditions. In this study, we analyzed the profile of 48 cytokines and chemokines in the serum of healthy subjects, comparing adults (≥18 years with young children and children (1–6 and 7–17 years. We found that a certain number of cytokines were not being produced in healthy subjects; others showed a constant serum level amongst the groups. Certain cytokines exhibited a downward or an upward trend with increasing age. The remaining cytokines were up- or downregulated in the group of the children with respect to the other groups. In conclusion, we drew some kinds of guidelines about the physiological production of cytokines and chemokines, underling the difference caused by aging.

  20. Modulation of cytokine production profiles in splenic dendritic cells ...

    African Journals Online (AJOL)

    We examined the role of splenic dendritic cells in immune response to Toxoplasma gondii infection in SAG1 (P30+) transgenic mice by investigating the kinetics of intracellular cytokines expression of IL-4, IL-10, IL-12 and IFN-γ by intracellular cytokine staining (ICS) using flow cytometry, and compared the results to those of ...

  1. Cytokines and Chemokines Involved in Acute Retinal Necrosis

    NARCIS (Netherlands)

    de Boer, JH; de Visser, L; Rijkers, G.; Wiertz, K.; van den Ham, H.J.; van Loon, A.M.; Rothova, Aniki; Mijnes, JDF

    2017-01-01

    Purpose: To investigate which cytokines and chemokines are involved in the immunopathogenesis of acute retinal necrosis (ARN), and whether cytokine profiles are associated with clinical manifestations, such as visual outcome. Methods: Serum and aqueous humor (AH) samples of 19 patients with ARN were

  2. Cytokines and chemokines involved in acute retinal necrosis

    NARCIS (Netherlands)

    L. De Visser (Lenneke); J.H. de Boer (Joke); G.T. Rijkers; Wiertz, K. (Karin); H.J. van den Ham; de Boer, R. (Rob); van Loon, A.M. (Anton M.); A. Rothová (Aniki); J.D.F. de Groot-Mijnes (Jolanda )

    2017-01-01

    textabstractPURPOSE. To investigate which cytokines and chemokines are involved in the immunopatho-genesis of acute retinal necrosis (ARN), and whether cytokine profiles are associated with clinical manifestations, such as visual outcome. METHODS. Serum and aqueous humor (AH) samples of 19 patients

  3. Peripheral parasitaemia and its association with plasma cytokines ...

    African Journals Online (AJOL)

    Also, plasma levels of cytokines were measured using Th1/Th2 human cytokine ELISA kits (Abcam, UK). Analysis of Variance and Student's t-test were used for Comparison of groups while Pearson's Correlation Coefficient was used for tests of association. Results: The results revealed a mean parasite density of ...

  4. Cytokines and the neurodevelopmental basis of mental illness

    Directory of Open Access Journals (Sweden)

    Udani eRatnayake

    2013-10-01

    Full Text Available Epidemiological studies suggest that prenatal exposure to different types of viral or bacterial infections may be associated with similar outcomes; i.e., an increased risk of mental illness disorders in the offspring. Infections arising from various causes have similar debilitating effects in later life, suggesting that the exact pathogen may not be the critical factor in determining the neurological and cognitive outcome in the offspring. Instead, it is thought that response of the innate immune system, specifically the increased production of inflammatory cytokines, may be the critical mediator in altering fetal brain development pre-disposing the offspring to mental illness disorders later in life. Inflammatory cytokines are essential for normal brain development. Factors such as the site of cytokine production, a change in balance between anti- and pro- inflammatory cytokines, placental transfer of cytokines, the effects of cytokines on glial cells, and the effects of glucocorticoids are important when evaluating the impact of maternal infection on fetal brain development. Although it is clear that cytokines are altered in the fetal brain following maternal infection, further evidence is required to determine if cytokines are the critical factor that alters the trajectory of brain development, subsequently leading to postnatal behavioural and neurological abnormalities.

  5. Autoantibodies induced by chimeric cytokine-HIV envelope glycoprotein immunogens

    NARCIS (Netherlands)

    Isik, Gözde; van Montfort, Thijs; Chung, Nancy P. Y.; Moore, John P.; Sanders, Rogier W.

    2014-01-01

    Cytokines are often used as adjuvants to increase the immunogenicity of vaccines because they can improve the immune response and/or direct it into a desired direction. As an alternative to codelivering Ags and cytokines separately, they can be fused into a composite protein, with the advantage that

  6. Cytokines: abnormalities in major depression and implications for pharmacological treatment.

    LENUS (Irish Health Repository)

    O'Brien, Sinead M

    2012-02-03

    The role of cytokines in depression was first considered when the cytokine interferon resulted in "sickness behaviour", the symptoms of which are similar to those of major depression. The latter is associated with an increase in pro-inflammatory cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6) and tumour necrosis factor alpha (TNF-alpha). These cytokines are potent modulators of corticotropin-releasing hormone (CRH) which produces heightened hypothalamic-pituitary-adrenal axis (HPA) activity characterized by increases in ACTH and cortisol, both of which are reported elevated in major depression. Antidepressant treatment has immunomodulatory effects with increases in the production of IL-10, which is an anti-inflammatory cytokine. This review based on a Medline search from 1980-2003, focuses on the evidence available of cytokine changes in acute stress, chronic stress and major depression. It examines the effects of antidepressant treatment on immune parameters in both animal models and clinical trials. We suggest that future antidepressants may target the immune system by either blocking the actions of pro-inflammatory cytokines or increasing the production of anti-inflammatory cytokines.

  7. Impact of weight loss on oxidative stress and inflammatory cytokines ...

    African Journals Online (AJOL)

    addressed the beneficial effects of weight reduction in modulating biomarkers of inflammatory cytokines and oxidative stress for obesity associated with type 2 diabetes mellitus. Objective: This study was designed to detect the effects of weight loss on the inflammatory cytokines, oxidative stress markers in obese type 2 ...

  8. Cytokines in lethal graft-versus-host disease

    NARCIS (Netherlands)

    Knulst, A.C.; Bril-Bazuin, C.; Tibbe, G.J.M.; Oudenaren, van A.; Savelkoul, H.F.J.; Benner, R.

    1992-01-01

    Graft-versus-host disease (GVHD) is caused by donor T lymphocytes that recognize foreign antigens on host tissues. This leads to T cell activation, which involves a cascade of events including the transcription of genes for cytokines and their receptors and the production of cytokines. One of the

  9. Cytokines and the Risk of Preterm Delivery in Twin Pregnancies

    DEFF Research Database (Denmark)

    Rode, Line; Klein, Katharina; Larsen, Helle

    2012-01-01

    To estimate the association between cytokine levels in twin pregnancies and risk of spontaneous preterm delivery, including the effect of progesterone treatment.......To estimate the association between cytokine levels in twin pregnancies and risk of spontaneous preterm delivery, including the effect of progesterone treatment....

  10. Inflammatory cytokines and risk of coronary heart disease

    DEFF Research Database (Denmark)

    Kaptoge, Stephen; Seshasai, Sreenivasa Rao Kondapally; Gao, Pei

    2014-01-01

    Because low-grade inflammation may play a role in the pathogenesis of coronary heart disease (CHD), and pro-inflammatory cytokines govern inflammatory cascades, this study aimed to assess the associations of several pro-inflammatory cytokines and CHD risk in a new prospective study, including meta...

  11. Spironolactone inhibits production of proinflammatory cytokines by human mononuclear cells

    DEFF Research Database (Denmark)

    Hansen, Peter Riis; Rieneck, Klaus; Bendtzen, Klaus

    2004-01-01

    The mineralocorticoid receptor antagonist spironolactone (SPIR) reduces the mortality and morbidity in patients with congestive heart failure (CHF). Overexpression of proinflammatory cytokines contribute to the development and progression of CHF.......The mineralocorticoid receptor antagonist spironolactone (SPIR) reduces the mortality and morbidity in patients with congestive heart failure (CHF). Overexpression of proinflammatory cytokines contribute to the development and progression of CHF....

  12. Pathogen interactions with cytokines and host defence: an overview.

    Science.gov (United States)

    Seow, H F

    1998-05-15

    This review summarises some of the immune evasion tactics adopted by pathogens. They include the antagonism of immune function through the use of homologues of cytokine receptors, expression of viral proteins which interact with cytokine signal transduction and expression of cytokine mimics and host proteins that influence the Type I or II cytokine responses. Some of the viral defense molecules that interfere with the functions of cytokines include the EBV protein BCRF1 (viral IL-10) which blocks synthesis of cytokines such as IFN-gamma, viral IL-17 and IL-8 receptor encoded by the herpesvirus saimiri genome and chemokine receptor homologues of Epstein-Barr virus, herpesvirus saimiri and cytomegalovirus. These immunomodulatory tactics function to protect the host from the lethal inflammatory effects as well as inhibit the local inflammatory response elicited to kill the foreign pathogen. Other strategies include the alterations in cytokine expression such as demonstrated with the hepatitis B virus (HBV) core protein and terminal protein which can inhibit interferon-beta gene expression, the interactions of the hepatitis C virus core protein to lymphotoxin-beta receptor and the effects of the interferon signal transduction pathway by adenovirus EIA oncogene and HBV by reducing levels or activity of the cytosolic latent transcriptional factors (STATS). Immune evasive strategies of helminth parasites related to cytokine activities will also be briefly discussed.

  13. The cytokines cardiotrophin-like cytokine/cytokine-like factor-1 (CLC/CLF) and ciliary neurotrophic factor (CNTF) differ in their receptor specificities.

    Science.gov (United States)

    Tormo, Aurélie Jeanne; Letellier, Marie-Claude; Lissilaa, Rami; Batraville, Laurie-Anne; Sharma, Mukut; Ferlin, Walter; Elson, Greg; Crabé, Sandrine; Gauchat, Jean-François

    2012-12-01

    Ciliary neurotrophic factor (CNTF) and cardiotrophin-like cytokine (CLC) are two cytokines with neurotrophic and immunomodulatory activities. CNTF is a cytoplasmic factor believed to be released upon cellular damage, while CLC requires interaction with a soluble cytokine receptor, cytokine-like factor 1 (CLF), to be efficiently secreted. Both cytokines activate a receptor complex comprising the cytokine binding CNTF receptor α (CNTFRα) and two signaling chains namely, leukemia inhibitory factor receptor β (LIFRβ) and gp130. Human CNTF can recruit and activate an alternative receptor in which CNTFRα is substituted by IL-6Rα. As both CNTF and CLC have immune-regulatory activities in mice, we compared their ability to recruit mouse receptors comprising both gp130 and LIFRβ signaling chains and either IL-6Rα or IL-11Rα which, unlike CNTFRα, are expressed by immune cells. Our results indicate that 1) mouse CNTF, like its human homologue, can activate cells expressing gp130/LIFRβ with either CNTFRα or IL-6Rα and, 2) CLC/CLF is more restricted in its specificity in that it activates only the tripartite CNTFR. Several gp130 signaling cytokines influence T helper cell differentiation. We therefore investigated the effect of CNTF on CD4 T cell cytokine production. We observed that CNTF increased the number of IFN-γ producing CD4 T cells. As IFN-γ is considered a mediator of the therapeutic effect of IFN-β in multiple sclerosis, induction of IFN-γ by CNTF may contribute to the beneficial immunomodulatory effect of CNTF in mouse multiple sclerosis models. Together, our results indicate that CNTF activates the same tripartite receptors in mouse and human cells and further validate rodent models for pre-clinical investigation of CNTF and CNTF derivatives. Furthermore, CNTF and CLC/CLF differ in their receptor specificities. The receptor α chain involved in the immunomodulatory effects of CLC/CLF remains to be identified. Crown Copyright © 2012. Published by

  14. Cytokines in Bipolar Disorder: Paving the Way for Neuroprogression

    Directory of Open Access Journals (Sweden)

    Izabela Guimarães Barbosa

    2014-01-01

    Full Text Available Bipolar disorder (BD is a severe, chronic, and recurrent psychiatric illness. It has been associated with high prevalence of medical comorbidities and cognitive impairment. Its neurobiology is not completely understood, but recent evidence has shown a wide range of immune changes. Cytokines are proteins involved in the regulation and the orchestration of the immune response. We performed a review on the involvement of cytokines in BD. We also discuss the cytokines involvement in the neuroprogression of BD. It has been demonstrated that increased expression of cytokines in the central nervous system in postmortem studies is in line with the elevated circulating levels of proinflammatory cytokines in BD patients. The proinflammatory profile and the immune imbalance in BD might be regarded as potential targets to the development of new therapeutic strategies.

  15. Role of IL-38 and Its Related Cytokines in Inflammation

    Directory of Open Access Journals (Sweden)

    Xianli Yuan

    2015-01-01

    Full Text Available Interleukin- (IL- 38 is a recently discovered cytokine and is the tenth member of the IL-1 cytokine family. IL-38 shares structural features with IL-1 receptor antagonist (IL-1Ra and IL-36Ra. IL-36R is the specific receptor of IL-38, a partial receptor antagonist of IL-36. IL-38 inhibits the production of T-cell cytokines IL-17 and IL-22. IL-38 also inhibits the production of IL-8 induced by IL-36γ, thus inhibiting inflammatory responses. IL-38-related cytokines, including IL-1Ra and IL-36Ra, are involved in the regulation of inflammation and immune responses. The study of IL-38 and IL-38-related cytokines might provide new insights for developing anti-inflammatory treatments in the near future.

  16. The inflammatory cytokines: molecular biomarkers for major depressive disorder?

    Science.gov (United States)

    Martin, Charlotte; Tansey, Katherine E; Schalkwyk, Leonard C; Powell, Timothy R

    2015-01-01

    Cytokines are pleotropic cell signaling proteins that, in addition to their role as inflammatory mediators, also affect neurotransmitter systems, brain functionality and mood. Here we explore the potential utility of cytokine biomarkers for major depressive disorder. Specifically, we explore how genetic, transcriptomic and proteomic information relating to the cytokines might act as biomarkers, aiding clinical diagnosis and treatment selection processes. We advise future studies to investigate whether cytokine biomarkers might differentiate major depressive disorder patients from other patient groups with overlapping clinical characteristics. Furthermore, we invite future pharmacogenetic studies to investigate whether early antidepressant-induced changes to cytokine mRNA or protein levels precede behavioral changes and act as longer-term predictors of clinical antidepressant response.

  17. Unique Cytokine Signature in the Plasma of Patients with Fibromyalgia

    Directory of Open Access Journals (Sweden)

    Jamie Sturgill

    2014-01-01

    Full Text Available Fibromyalgia (FMS is a chronic pain syndrome with a complex but poorly understood pathogenesis affecting approximately 10 million adults in the United States. The lack of a clear etiology of FMS has limited the effective diagnosis and treatment of this debilitating condition. The objective of this secondary data analysis was to examine plasma cytokine levels in women with FMS using the Bio-Plex Human Cytokine 17-plex Assay. Post hoc analysis of plasma cytokine levels was performed to evaluate patterns that were not specified a priori. Upon examination, patients with FMS exhibited a marked reduction in TH2 cytokines such as IL-4, IL-5, and IL-13. The finding of this pattern of altered cytokine milieu not only supports the role of inflammation in FMS but also may lead to more definitive diagnostic tools for clinicians treating FMS. The TH2 suppression provides strong evidence of immune dysregulation in patients with FMS.

  18. Pro-inflammatory cytokine profile of critically ill septic patients following therapeutic plasma exchange.

    Science.gov (United States)

    Hamishehkar, Hadi; Beigmohammadi, Mohammad Taghi; Abdollahi, Mohammad; Mousavi, Sarah; Ziaie, Shadi; Sharifian, Ramazan Ali; Davoudi, Setareh; Mojtahedzadeh, Mojtaba

    2013-02-01

    Severe sepsis involves a generalized inflammatory response, mediated by a number of various cytokines and factors. Plasma exchange (PE) has been proposed as a therapeutic approach to improve survival of patients with severe sepsis and septic shock. The theory is that removing harmful excessive endogenous inflammatory mediators is beneficial. Upon establishment of a diagnosis of severe sepsis, twelve patients received PE plus conventional sepsis treatment. Interleukin (IL)-6, IL-1β and tumor necrosis factor (TNF)-α were assayed before and after each session of PE. There were no significant changes in cytokine plasma levels after each PE session compared to pre-procedure levels. Among measured pro-inflammatory cytokines, only the plasma levels of IL-6 before the 2nd and 3rd PE sessions were lower than baseline levels (p=0.011 and p=0.012, respectively). All patients tolerated PE therapy well without any adverse effects or homodynamic instability. The results of this study showed that PE does not have a direct and rapid effect on plasma level of TNF-α, IL-1β and IL-6. Copyright © 2012 Elsevier Ltd. All rights reserved.

  19. Gliotransmitters and cytokines in the control of blood-brain barrier permeability.

    Science.gov (United States)

    Osipova, Elena D; Semyachkina-Glushkovskaya, Oxana V; Morgun, Andrey V; Pisareva, Natalia V; Malinovskaya, Natalia A; Boitsova, Elizaveta B; Pozhilenkova, Elena A; Belova, Olga A; Salmin, Vladimir V; Taranushenko, Tatiana E; Noda, Mami; Salmina, Alla B

    2018-01-08

    The contribution of astrocytes and microglia to the regulation of neuroplasticity or neurovascular unit (NVU) is based on the coordinated secretion of gliotransmitters and cytokines and the release and uptake of metabolites. Blood-brain barrier (BBB) integrity and angiogenesis are influenced by perivascular cells contacting with the abluminal side of brain microvessel endothelial cells (pericytes, astrocytes) or by immune cells existing (microglia) or invading the NVU (macrophages) under pathologic conditions. The release of gliotransmitters or cytokines by activated astroglial and microglial cells is provided by distinct mechanisms, affects intercellular communication, and results in the establishment of microenvironment controlling BBB permeability and neuroinflammation. Glial glutamate transporters and connexin and pannexin hemichannels working in the tight functional coupling with the purinergic system serve as promising molecular targets for manipulating the intercellular communications that control BBB permeability in brain pathologies associated with excessive angiogenesis, cerebrovascular remodeling, and BBB-mediated neuroinflammation. Substantial progress in deciphering the molecular mechanisms underlying the (patho)physiology of perivascular glia provides promising approaches to novel clinically relevant therapies for brain disorders. The present review summarizes the current understandings on the secretory machinery expressed in glial cells (glutamate transporters, connexin and pannexin hemichannels, exocytosis mechanisms, membrane-derived microvesicles, and inflammasomes) and the role of secreted gliotransmitters and cytokines in the regulation of NVU and BBB permeability in (patho)physiologic conditions.

  20. Understanding the Role of Chemokines and Cytokines in Experimental Models of Herpes Simplex Keratitis

    Directory of Open Access Journals (Sweden)

    Tayaba N. Azher

    2017-01-01

    Full Text Available Herpes simplex keratitis is a disease of the cornea caused by HSV-1. It is a leading cause of corneal blindness in the world. Underlying molecular mechanism is still unknown, but experimental models have helped give a better understanding of the underlying molecular pathology. Cytokines and chemokines are small proteins released by cells that play an important proinflammatory or anti-inflammatory role in modulating the disease process. Cytokines such as IL-17, IL-6, IL-1α, and IFN-γ and chemokines such as MIP-2, MCP-1, MIP-1α, and MIP-1β have proinflammatory role in the destruction caused by HSV including neutrophil infiltration and corneal inflammation, and other chemokines and cytokines such as IL-10 and CCL3 can have a protective role. Most of the damage results from neutrophil infiltration and neovascularization. While many more studies are needed to better understand the role of these molecules in both experimental models and human corneas, current studies indicate that these molecules hold potential to be targets of future therapy.

  1. [Clinical Applications of Peripheral Markers of Response in Antidepressant Treatment: Neurotrophins and Cytokines].

    Science.gov (United States)

    Bermúdez, Constanza Mendoza

    2012-03-01

    Explanatory theories of depression have advanced in recent decades from the monoaminergic hypothesis to neurogenesis alterations to the neurohormonal hypothesis that includes the dysfunction of the inflammatory response. Currently there is a growing interest in the development of biomarkers that can contribute to diagnosis and proper treatment. To describe the role of neurotrophins such as brain-derived neurotrophic factor (BDNF) and cytokines in the pathophysiology of depressive disorder in addition to reviewing and analyzing evidence about their clinical application as biomarkers of antidepressant therapy. Relevant data research in several databases. In recent years evidence of alterations in neurogenesis mediated by the expression of BDNF in the hippocampus in the pathophysiology of depression has increased and there is ample evidence that BDNF is a marker of the diagnosis of depressive disorder and also of treatment effectiveness. There is little information about other neurotrophins. There has also been increased interest in relation to depression as an "inflammatory disease" and the link with cytokines in its pathogenesis. Evidence has been found for the usefulness of some cytokines especially IL-1 (interleukin 1), IL-6 (interleukin 6), and TNF (tumor necrosis factor) as biomarkers of antidepressant drug response in humans. Copyright © 2012 Asociación Colombiana de Psiquiatría. Publicado por Elsevier España. All rights reserved.

  2. Waste management - cytokines, growth factors and cachexia.

    Science.gov (United States)

    Saini, Amarjit; Al-Shanti, Nasser; Nasser, Al-Shanti; Stewart, Claire E H

    2006-12-01

    Muscle damage with a lack of regeneration, manifests itself in several life-threatening diseases, including cancer cachexia, congestive heart failure, AIDS and sepsis. Often misdiagnosed as a condition simply of weight loss, cachexia is actually a highly complex metabolic disorder involving features of anorexia, anaemia, lipolysis and insulin resistance. A significant loss of lean body mass arises from such conditions, resulting in wasting of skeletal muscle. Unlike starvation, the weight loss seen in chronic illnesses arises equally from loss of muscle and of fat. The cachectic state is particularly problematic in cancer, typifying poor prognosis and often lowering responses to chemotherapy and radiation treatment. More than half of cancer patients suffer from cachexia, and strikingly, nearly one-third of cancer deaths are related to cachexia rather than the tumour burden. In considering this disorder, we are faced with a conundrum; how is it possible for uncontrolled growth to prevail in the tumour, in the face of unrestrained tissue loss in our muscles? Consistently, the catabolic state has been associated with a shift in the homeostatic balance between muscle synthesis and degradation mediated by the actions of growth factors and cytokines. Indeed, tumour necrosis factor-alpha (TNF-alpha) levels are raised in several animal models of cachectic muscle wasting, whereas the insulin-like growth factor (IGF) system acts potently to regulate muscle development, hypertrophy and maintenance. This concept of skeletal muscle homeostasis, often viewed as the net balance between two separate processes of protein synthesis and degradation has however changed. More recently, the view is that these two biochemical processes are not occurring independently of each other but in fact are finely co-ordinated by a web of intricate signalling networks. This review, therefore, aims to discuss data currently available regarding the mechanisms of degeneration and regeneration with

  3. Dosimetry in radionuclide therapies with 90Y-conjugates. The IEO experience

    International Nuclear Information System (INIS)

    Cremonesi, M.; Ferrari, M.; Chinol, M.; Bartolomei, M.; Sacco, E.; Fiorenza, M.; Tosi, G.; Paganelli, G.; Stabin, M. G.

    2000-01-01

    The basis for successful radionuclide therapy is a high and stable uptake of the radiopharmaceutical in the target tissue along with low activity concentration in other normal organs. The contribution of dosimetry in radionuclide therapy is to predict before the treatment the absorbed doses in tumor and normal organs, to identify the critical organs, to minimize any possible toxicity and to evaluate the maximum tolerated dose. In this article is reported the experience concerning pharmacokinetics and dosimetry of two 90 Y-therapeutic protocols: 3-step pretargeting radioimmunotherapy (RIT) according to the biotin-avidin system and receptor mediated radionuclide therapy with the somatostatin analogue (DOTA-D-Phe 1 -Tyr 3 ) octreotide named DOTATOC. For the dosimetric analysis, analogous approaches for the two radiolabeled compounds due to the similar pharmacokinetic characteristics were adopted; the MIRD formalism was applied, taking into account both the physical and the biological characteristics of the radio conjugate and patients' metabolism. In order to determine biological clearance, serial blood samples and complete urine collection were obtained up to 48 hours after injection; to evaluate biodistribution, several whole body scans were acquired. Both therapies showed the advantageous characteristics of a fast blood clearance and a predominantly renal excretion of the radiopharmaceuticals thus lowering the irradiation of the total body. Although pharmacokinetic characteristics were similar, different critical organs were found for the two therapies: in particular, some considerations regarding red marrow, spleen and kidneys were required. The results of the studies indicate that high activities of 90 Y-biotin (3-step RIT) and 90 Y-DOTATOC can be administered with acceptable radiation doses to normal organs

  4. Serum cytokine profiles as predictors of asthma control in adults from the EGEA study.

    Science.gov (United States)

    Akiki, Zeina; Rava, Marta; Diaz Gil, Oscar; Pin, Isabelle; le Moual, Nicole; Siroux, Valérie; Guerra, Stefano; Chamat, Soulaima; Matran, Regis; Fitó, Montserrat; Salameh, Pascale; Nadif, Rachel

    2017-04-01

    To which extent serum cytokines may predict asthma control in adults remains understudied. We investigated cross-sectional and longitudinal associations between cytokine profiles and asthma outcomes. Serum interleukin (IL)-1Ra, IL-5, IL-7, IL-8, IL-10, IL-13 and TNF-α levels were determined in 283 adults with current asthma from the 2nd survey of the Epidemiological Study on the Genetics and Environment of Asthma (EGEA2). Participants were followed-up seven years later. Asthma symptom control was assessed according to GINA 2015 guidelines. Cytokine profiles were identified by principal component (PC) analyses, and expressed as above/below the median. The first two PCs captured 82.5% of the variability. While all seven cytokines scored high on PC1, only IL-1Ra and IL-10 scored high on PC2. At EGEA2, neither PC1 nor PC2 were related to exacerbations, asthma attacks, asthma symptom control, lung function, or allergic diseases. High level of PC1 (above the median) was associated with higher blood neutrophil counts (P = 0.02), while high level of PC2 was associated with lower IgE levels (P = 0.04). High level of PC2 at EGEA2 was associated with lower bronchial hyperresponsiveness (adjusted(a) OR[95%CI] = 0.46[0.23; 0.91]) and with subsequent lower risk of worsening asthma control and attacks (aOR[95%CI] = 0.24[0.09; 0.60]; 0.31[0.11; 0.85] respectively). Serum cytokine profiles with high levels of IL-1Ra and IL-10 were associated with lower subsequent risks of worsening asthma control and attacks in adults. This study adds new findings for the role of serum cytokine profiles to help identifying adults with subsequent risk of asthma burden that could be targeted for specific therapies. Copyright © 2017 Elsevier Ltd. All rights reserved.

  5. Elevated cerebral spinal fluid cytokine levels in boys with cerebral adrenoleukodystrophy correlates with MRI severity.

    Directory of Open Access Journals (Sweden)

    Troy C Lund

    Full Text Available X-linked adrenoleukodystrophy (ALD is a metabolic, peroxisomal disease that results from a mutation in the ABCD1 gene. The most severe course of ALD progression is the cerebral inflammatory and demyelinating form of the disease, cALD. To date there is very little information on the cytokine mediators in the cerebral spinal fluid (CSF of these boys.Measurement of 23 different cytokines was performed on CSF and serum of boys with cerebral ALD and patients without ALD. Significant elevations in CSF IL-8 (29.3±2.2 vs 12.8±1.1 pg/ml, p = 0.0001, IL-1ra (166±30 vs 8.6±6.5 pg/ml, p = 0.005, MCP-1 (610±47 vs 328±34 pg/ml, p = 0.002, and MIP-1b (14.2±1.3 vs 2.0±1.4 pg/ml, p<0.0001 were found in boys with cALD versus the control group. The only serum cytokine showing an elevation in the ALD group was SDF-1 (2124±155 vs 1175±125 pg/ml, p = 0.0001. The CSF cytokines of IL-8 and MCP-1b correlated with the Loes MRI severity score (p = 0.04 and p = 0.008 respectively, as well as the serum SDF-1 level (p = 0.002. Finally, CSF total protein was also significantly elevated in boys with cALD and correlated with both IL-8, MCP-1b (p = 0.0001 for both, as well as Loes MRI severity score (p = 0.0007.IL-8, IL-1ra, MCP-1, MIP-1b and CSF total protein were significantly elevated in patients with cALD; IL-8, MCP-1b, and CSF total protein levels correlated with disease severity determined by MRI. This is the largest report of CSF cytokine levels in cALD to date, and identification of these key cytokines will provide further insight into disease progression and perhaps lead to improved targeted therapies.

  6. Platelet-rich plasma preparation for regenerative medicine: optimization and quantification of cytokines and growth factors

    Science.gov (United States)

    2013-01-01

    Introduction Platelet-rich plasma (PRP) is nowadays widely applied in different clinical scenarios, such as orthopedics, ophthalmology and healing therapies, as a growth factor pool for improving tissue regeneration. Studies into its clinical efficiency are not conclusive and one of the main reasons for this is that different PRP preparations are used, eliciting different responses that cannot be compared. Platelet quantification and the growth factor content definition must be defined in order to understand molecular mechanisms behind PRP regenerative strength. Standardization of PRP preparations is thus urgently needed. Methods PRP was prepared by centrifugation varying the relative centrifugal force, temperature, and time. Having quantified platelet recovery and yield, the two-step procedure that rendered the highest output was chosen and further analyzed. Cytokine content was determined in different fractions obtained throughout the whole centrifugation procedure. Results Our method showed reproducibility when applied to different blood donors. We recovered 46.9 to 69.5% of total initial platelets and the procedure resulted in a 5.4-fold to 7.3-fold increase in platelet concentration (1.4 × 106 to 1.9 × 106 platelets/μl). Platelets were highly purified, because only blood cells and leukocytes was present in the final PRP preparation. We also quantified growth factors, cytokines and chemokines secreted by the concentrated platelets after activation with calcium and calcium/thrombin. High concentrations of platelet-derived growth factor, endothelial growth factor and transforming growth factor (TGF) were secreted, together with the anti-inflammatory and proinflammatory cytokines interleukin (IL)-4, IL-8, IL-13, IL-17, tumor necrosis factor (TNF)-α and interferon (IFN)-α. No cytokines were secreted before platelet activation. TGF-β3 and IFNγ were not detected in any studied fraction. Clots obtained after platelet coagulation retained a high concentration of

  7. Serum Cytokines as Biomarkers in Islet Cell Transplantation for Type 1 Diabetes.

    Science.gov (United States)

    van der Torren, Cornelis R; Verrijn Stuart, Annemarie A; Lee, DaHae; Meerding, Jenny; van de Velde, Ursule; Pipeleers, Daniel; Gillard, Pieter; Keymeulen, Bart; de Jager, Wilco; Roep, Bart O

    2016-01-01

    Islet cell transplantation holds a potential cure for type 1 diabetes, but many islet recipients do not reach long-lasting insulin independence. In this exploratory study, we investigated whether serum cytokines, chemokines and adipokines are associated with the clinical outcome of islet transplantation. Thirteen islet transplant patients were selected on basis of good graft function (reaching insulin independence) or insufficient engraftment (insulin requiring) from our cohort receiving standardized grafts and immune suppressive therapy. Patients reaching insulin independence were divided in those with continued (>12 months) versus transient (cytokines and adipokines was measured in sera taken before and at one year after transplantation using a validated multiplex immunoassay platform. Ninety serum proteins were detectable in concentrations varying markedly among patients at either time point. Thirteen markers changed after transplantation, while another seven markers changed in a clinical subpopulation. All other markers remained unaffected after transplantation under generalized immunosuppression. Patterns of cytokines could distinguish good graft function from insufficient function including IFN-α, LIF, SCF and IL-1RII before and after transplantation, by IL-16, CCL3, BDNF and M-CSF only before and by IL-22, IL-33, KIM-1, S100A12 and sCD14 after transplantation. Three other proteins (Leptin, Cathepsin L and S100A12) associated with loss of temporary graft function before or after transplantation. Distinct cytokine signatures could be identified in serum that predict or associate with clinical outcome. These serum markers may help guiding patient selection and choice of immunotherapy, or act as novel drug targets in islet transplantation.

  8. Cytokine production and visualized effects in the feto-maternal unit. Quantitative and topographic data on cytokines during intrauterine disease.

    Science.gov (United States)

    Stallmach, T; Hebisch, G; Joller-Jemelka, H I; Orban, P; Schwaller, J; Engelmann, M

    1995-09-01

    A large array of cytokines show high activity in amniotic fluid. Attempts have been made to quantify the concentrations or to track rising levels for diagnostic purposes when examining disturbances of the feto-maternal unit. However, the kinetics of cytokine production in the amniotic fluid are not well understood, and there is lack of knowledge about concomitant levels in fetal and maternal blood. The presence of cytokines in fetal and placental cells was demonstrated by immunohistochemistry using mAb. Cytokines were quantified by enzymimmunoassay in amniotic fluid and fetal and maternal blood. This was done with regard to two disease states that quite frequently complicate the course of pregnancy, namely chorioamnionitis and intrauterine growth retardation. The cytokines examined were G-CSF, GM-CSF, TNF-alpha, IL-1, IL-6, and IL-8. In chorioamnionitis, all cytokines, except GM-CSF, were elevated about 100 times in the amniotic fluid. An accompanying increase in maternal and fetal blood was only found for IL-6 and G-CSF; IL-8 was elevated in fetal blood only. Intrauterine growth retardation was characterized by elevated levels of TNF-alpha in the amniotic fluid, whereas G-CSF, GM-CSF, and IL-1 beta were significantly reduced. Immunohistochemistry showed that under normal conditions the cytokines are to be found in a characteristic distribution in certain cell types in the fetus, the placenta, and the placental bed. With rising concentrations, more cells seemed to be recruited for cytokine production, especially macrophages and decidual cells. In chorioamnionitis, fetal extramedullary granulopoiesis was augmented, and in intrauterine growth retardation, erythropoiesis as well as granulopoiesis were depressed. Not only inflammatory disease but also intrauterine growth retardation is characterized by a changing cytokine pattern. Alterations in fetal hematopoiesis observed at postmortem examination of perinatal deaths can be correlated to changes in cytokine

  9. Gliovascular and cytokine interactions modulate brain endothelial barrier in vitro.

    Science.gov (United States)

    Chaitanya, Ganta V; Cromer, Walter E; Wells, Shannon R; Jennings, Merilyn H; Couraud, P Olivier; Romero, Ignacio A; Weksler, Babette; Erdreich-Epstein, Anat; Mathis, J Michael; Minagar, Alireza; Alexander, J Steven

    2011-11-23

    The glio-vascular unit (G-unit) plays a prominent role in maintaining homeostasis of the blood-brain barrier (BBB) and disturbances in cells forming this unit may seriously dysregulate BBB. The direct and indirect effects of cytokines on cellular components of the BBB are not yet unclear. The present study compares the effects of cytokines and cytokine-treated astrocytes on brain endothelial barrier. 3-dimensional transwell co-cultures of brain endothelium and related-barrier forming cells with astrocytes were used to investigate gliovascular barrier responses to cytokines during pathological stresses. Gliovascular barrier was measured using trans-endothelial electrical resistance (TEER), a sensitive index of in vitro barrier integrity. We found that neither TNF-α, IL-1β or IFN-γ directly reduced barrier in human or mouse brain endothelial cells or ECV-304 barrier (independent of cell viability/metabolism), but found that astrocyte exposure to cytokines in co-culture significantly reduced endothelial (and ECV-304) barrier. These results indicate that the barrier established by human and mouse brain endothelial cells (and other cells) may respond positively to cytokines alone, but that during pathological conditions, cytokines dysregulate the barrier forming cells indirectly through astrocyte activation involving reorganization of junctions, matrix, focal adhesion or release of barrier modulating factors (e.g. oxidants, MMPs). © 2011 Chaitanya et al; licensee BioMed Central Ltd.

  10. Radionuclide Therapy of Unresectable Tumors with AvidinOX and (90)Y-biotinDOTA: Tongue Cancer Paradigm.

    Science.gov (United States)

    Albertoni, Claudio; Leoni, Barbara; Rosi, Antonio; D'Alessio, Valeria; Carollo, Valeria; Spagnoli, Luigi Giusto; van Echteld, Cees; De Santis, Rita

    2015-09-01

    Local treatment of unresectable tumors is challenging, particularly with radioactivity. Current practice relies on external beam irradiation or on a variety of medical devices for brachytherapy. Both approaches proved useful in controlling tumor growth, but are characterized by poor compliance of the patient, significant side-effects, high costs, and technological complexity, which hamper widespread use. The authors recently described a novel form of radionuclide therapy based on the oxidized form of avidin that, chemically reacting with tissue proteins, can secure radioactive biotin within the injected tissue, either when precomplexed or when taken from the blood stream after intravenous administration. AvidinOX-pretargeted (177)Lu-biotinDOTA ((177)Lu-ST2210) is currently under clinical investigation for the treatment of liver oligometastases from colorectal cancer (clinicaltrials.gov/NCT02053324). In the present work, the authors show that injected AvidinOX can link tissues of various natures such as prostate, kidney, breast, or brain and can react by contact with scraped tissues such as skin or urinary bladder. AvidinOX injected into human OSC19 tongue cancer masses orthotopically transplanted in nude mice takes up intravenously administered (90)Y-ST2210, which exerts significant antitumor activity, while preserving the integrity and functionality of the tongue. Present data confirm that AvidinOX-based radionuclide therapy is an innovative and promising approach for the local treatment of inoperable tumors.

  11. Changes in levels of cytokines in the treatment of infected wounds and festering in children

    Directory of Open Access Journals (Sweden)

    O. V. Spakhi

    2016-12-01

    Full Text Available Informative and prognostic significance of cytokines in assessing the effectiveness of treatment tactics no doubt. The aim was to study the levels of pro- and anti-inflammatory cytokines in the dynamics of the treatment of infected wounds and purulent (IWP in children using the proposed optimized local treatment compared with standard procedure. Materials and methods. 45 children with IWP who were treated in the department of purulent surgery of Zaporozhye Regional Children's Hospital during the period of 2015-2016 years were divided into main (n = 26 and control groups (n = 19 depending on the tactics of treatment. The therapy of the main group patients were added by optimized integrated local treatment, which included a combination of magnetic therapy, antibacterial drug liposomal solutions and hirudotherapy. Efficacy of treatment was assessed by clinical characteristics and serum levels of IL-1β and IL-10 on the 1st and the 7th day of treatment. Results. The highest levels of pro-inflammatory IL-1β were defined in children with lymphadenitis on the first day of treatment. Common trends in the dynamics of cytokines content changes on the 7th day were in the line with generally accepted: decreased in IL-1β and increased in IL-10 levels. The level of IL-1β was not statistically different on the 7th day only in children with phlegmon. The most significant changes in IL-10 were observed in children with abscesses and lymphadenitis than in children with infected wound and phlegmon. Changes in markers of inflammation conform to positive changes in the clinical course of wound healing in children at the study. Generally, there was a lag dynamics of cytokines changes in the children who received standard therapy compared with the children who received the proposed optimized local treatment. Conclusions. The use of proposed IWP complex treatment in children showed the most significant effect on the anti-inflammatory IL-10 level in children with

  12. Cytokines Elevated in HIV Elite Controllers Reduce HIV ReplicationIn Vitroand Modulate HIV Restriction Factor Expression.

    Science.gov (United States)

    Jacobs, Evan S; Keating, Sheila M; Abdel-Mohsen, Mohamed; Gibb, Stuart L; Heitman, John W; Inglis, Heather C; Martin, Jeffrey N; Zhang, Jinbing; Kaidarova, Zhanna; Deng, Xutao; Wu, Shiquan; Anastos, Kathryn; Crystal, Howard; Villacres, Maria C; Young, Mary; Greenblatt, Ruth M; Landay, Alan L; Gange, Stephen J; Deeks, Steven G; Golub, Elizabeth T; Pillai, Satish K; Norris, Philip J

    2017-03-15

    A subset of HIV-infected individuals termed elite controllers (ECs) maintain CD4 + T cell counts and control viral replication in the absence of antiretroviral therapy (ART). Systemic cytokine responses may differentiate ECs from subjects with uncontrolled viral replication or from those who require ART to suppress viral replication. We measured 87 cytokines in four groups of women: 73 ECs, 42 with pharmacologically suppressed viremia (ART), 42 with uncontrolled viral replication (noncontrollers [NCs]), and 48 HIV-uninfected (NEG) subjects. Four cytokines were elevated in ECs but not NCs or ART subjects: CCL14, CCL21, CCL27, and XCL1. In addition, median stromal cell-derived factor-1 (SDF-1) levels were 43% higher in ECs than in NCs. The combination of the five cytokines suppressed R5 and X4 virus replication in resting CD4 + T cells, and individually SDF-1β, CCL14, and CCL27 suppressed R5 virus replication, while SDF-1β, CCL21, and CCL14 suppressed X4 virus replication. Functional studies revealed that the combination of the five cytokines upregulated CD69 and CCR5 and downregulated CXCR4 and CCR7 on CD4 + T cells. The CD69 and CXCR4 effects were driven by SDF-1, while CCL21 downregulated CCR7. The combination of the EC-associated cytokines induced expression of the anti-HIV host restriction factors IFITM1 and IFITM2 and suppressed expression of RNase L and SAMHD1. These results identify a set of cytokines that are elevated in ECs and define their effects on cellular activation, HIV coreceptor expression, and innate restriction factor expression. This cytokine pattern may be a signature characteristic of HIV-1 elite control, potentially important for HIV therapeutic and curative strategies. IMPORTANCE Approximately 1% of people infected with HIV control virus replication without taking antiviral medications. These subjects, termed elite controllers (ECs), are known to have stronger immune responses targeting HIV than the typical HIV-infected subject, but the

  13. Kaposi Sarcoma Inflammatory Cytokine Syndrome (KICS): A Rare but Potentially Treatable Condition.

    Science.gov (United States)

    Karass, Michael; Grossniklaus, Emily; Seoud, Talal; Jain, Sanjay; Goldstein, Daniel A

    2017-05-01

    Kaposi sarcoma inflammatory cytokine syndrome (KICS) is a newly-described condition affecting individuals who are HIV-positive and are infected with human herpesvirus 8 (HHV-8). This is a syndrome that in some ways mimics severe sepsis with associated acute respiratory distress syndrome, possibly requiring a ventilator and vasopressor support. However, unlike severe sepsis, antibiotics provide no benefit. Management of KICS has not been fully elucidated because of its high mortality rate. However, the syndrome has been successfully treated in some cases with immunomodulatory therapy. It is crucial for oncologists to be able to recognize this syndrome and to institute the appropriate therapy. The Oncologist 2017;22:623-625. © AlphaMed Press 2017.

  14. Polymorphisms in cytokine genes and serum cytokine levels among New Mexican women with and without breast cancer.

    Science.gov (United States)

    Erdei, Esther; Kang, Huining; Meisner, Angela; White, Kirsten; Pickett, Gavin; Baca, Cynthia; Royce, Melanie; Berwick, Marianne

    2010-07-01

    Among New Mexican Hispanic women, breast cancer is detected at a more advanced stage than compared to Non-Hispanic White women. One central factor that has been little studied is the role of critical cytokines. We genotyped incident breast cancer cases and their age-, gender- and smoking-matched controls (N=40 matched pairs) for 25 single nucleotide polymorphisms (SNPs) in cytokine genes. We measured corresponding serum cytokine levels as well. Five cytokines (IL-1beta, IL-5, TNF-alpha, IL-6 and IL-2) were significantly associated with disease and based on their serum levels, concentrations were higher in the cases than in the controls. Disease odds ratios corresponding to one standard deviation change in log-transformed concentrations of these cytokines were 18.87, 4.10, 3.61, 3.27 and 2.52. Three most statistically significant SNPs were rs2069705, located in the promoter region of the interferon gamma gene (INF-gamma); rs2243248, in the promoter of IL-4 (rs2243248); and rs1800925, in the promoter of the IL-13 gene. Increased serum cytokine levels at diagnosis are indicative for immunological alterations and possibly related to genetic susceptibility markers as well. These findings might guide us to understand the presence of SNPs in cytokine genes and serum concentrations among breast cancer patients and potentially in other cancers. Copyright 2010 Elsevier Ltd. All rights reserved.

  15. Increased Blood Levels of Growth Factors, Proinflammatory Cytokines, and Th17 Cytokines in Patients with Newly Diagnosed Type 1 Diabetes.

    Directory of Open Access Journals (Sweden)

    Kristi Alnek

    Full Text Available The production of several cytokines could be dysregulated in type 1 diabetes (T1D. In particular, the activation of T helper (Th type 1 (Th1 cells has been proposed to underlie the autoimmune pathogenesis of the disease, although roles for inflammatory processes and the Th17 pathway have also been shown. Nevertheless, despite evidence for the role of cytokines before and at the onset of T1D, the corresponding findings are inconsistent across studies. Moreover, conflicting data exist regarding the blood cytokine levels in T1D patients. The current study was performed to investigate genetic and autoantibody markers in association with the peripheral blood cytokine profiles by xMap multiplex technology in newly diagnosed young T1D patients and age-matched healthy controls. The onset of young-age T1D was characterized by the upregulation of growth factors, including granulocyte macrophage-colony stimulating factor (GM-CSF and interleukin (IL-7, the proinflammatory cytokine IL-1β (but not IL-6 or tumor necrosis factor [TNF]-α, Th17 cytokines, and the regulatory cytokines IL-10 and IL-27. Ketoacidosis and autoantibodies (anti-IA-2 and -ZnT8, but not human leukocyte antigen (HLA genotype, influenced the blood cytokine levels. These findings broaden the current understanding of the dysregulation of systemic levels of several key cytokines at the young-age onset of T1D and provide a further basis for the development of novel immunoregulatory treatments in this disease.

  16. Curcumin protects against radiation-induced acute and chronic cutaneous toxicity in mice and decreases mRNA expression of inflammatory and fibrogenic cytokines

    International Nuclear Information System (INIS)

    Okunieff, Paul; Xu Jianhua; Hu Dongping; Liu Weimin; Zhang Lurong; Morrow, Gary; Pentland, Alice; Ryan, Julie L.; Ding, Ivan M.D.

    2006-01-01

    Purpose: To determine whether curcumin ameliorates acute and chronic radiation skin toxicity and to examine the expression of inflammatory cytokines (interleukin [IL]-1, IL-6, IL-18, IL-1Ra, tumor necrosis factor [TNF]-α, and lymphotoxin-β) or fibrogenic cytokines (transforming growth factor [TGF]-β) during the same acute and chronic phases. Methods and Materials: Curcumin was given intragastrically or intraperitoneally to C3H/HeN mice either: 5 days before radiation; 5 days after radiation; or both 5 days before and 5 days after radiation. The cutaneous damage was assessed at 15-21 days (acute) and 90 days (chronic) after a single 50 Gy radiation dose was given to the hind leg. Skin and muscle tissues were collected for measurement of cytokine mRNA. Results: Curcumin, administered before or after radiation, markedly reduced acute and chronic skin toxicity in mice (p < 0.05). Additionally, curcumin significantly decreased mRNA expression of early responding cytokines (IL-1 IL-6, IL-18, TNF-α, and lymphotoxin-β) and the fibrogenic cytokine, TGF-β, in cutaneous tissues at 21 days postradiation. Conclusion: Curcumin has a protective effect on radiation-induced cutaneous damage in mice, which is characterized by a downregulation of both inflammatory and fibrogenic cytokines in irradiated skin and muscle, particularly in the early phase after radiation. These results may provide the molecular basis for the application of curcumin in clinical radiation therapy

  17. Selections of appropriate regimen of high-dose chemotherapy combined with adoptive cellular therapy with dendritic and cytokine-induced killer cells improved progression-free and overall survival in patients with metastatic breast cancer: reargument of such contentious therapeutic preferences.

    Science.gov (United States)

    Ren, Jun; Di, Lijun; Song, Guohong; Yu, Jing; Jia, Jun; Zhu, Yuling; Yan, Ying; Jiang, Hanfang; Liang, Xu; Che, Li; Zhang, Jie; Wan, Fengling; Wang, Xiaoli; Zhou, Xinna; Lyerly, Herbert Kim

    2013-10-01

    We hypothesized that combination of dendritic cell (DC) with autologous cytokine-induced killer (CIK) immunotherapy in setting of high-dose chemotherapy (HDC) would be effective for selected metastatic breast cancer (MBC) patients. Our previous work showed thiotepa could eradicate breast cancer stem cells. From 2004 to 2009, 79 patients received standard dose chemotherapy (SDC) of 75 mg/m(2) docetaxel and 75 mg/m(2) thiotepa versus 87 patients of HDC + DC/CIK: 120 mg/m(2) docetaxel to mobilize peripheral CD34(+) progenitor cells, a sequence of HDC (120 mg/m(2) docetaxel, plus 175 mg/m(2) thiotepa) + DC/CIK, with or without 400 mg/m(2) carboplatin depending upon bone marrow function. The endpoints were response rates (RR), progression-free survival (PFS), and overall survival (OS). Compared with SDC, PFS and OS were improved in HDC + DC/CIK (median PFS 10.2 vs. 3.7 months, P < 0.001; median OS 33.1 vs. 15.2 months, P < 0.001). Patients of pre-menopausal, HDC as first-line treatment after metastasis, or with visceral metastasis showed prolonged PFS and OS. SDC group also achieved the similar response as previous reports. Our study demonstrated the novel combination of HDC with DC/CIK to be an effective choice for the selected MBC population, in which choosing appropriate chemo regimens played important roles, and also specific HDC regimen plus DC/CIK immunotherapy showed the clinical benefits compared with chemotherapy alone.

  18. Class I Cytokine Receptors: Structure and function in the Membrane

    DEFF Research Database (Denmark)

    Bugge, Katrine Østergaard

    Class I cytokine receptors are involved in important biological functions of both physiological and pathological nature in mammals. However, the molecular details of the cross-membrane signal transduction through these receptors remain obscure. One of the major reasons for this is the lack...... ample material of high quality for structural studies with NMR spectroscopy of several class I cytokine receptor TMDs. Furthermore, the structure of a class I cytokine receptor TMD in DHPC micelles was solved with solution-state NMR spectroscopy. Additionally, since structural studies of intact proteins...... receptor. This integrative structure opens up for interpreting these receptors in their intact form and offers unique insights on the topology of single-pass transmembrane receptors with intrinsically disordered domains. Dimerization of the TMDs of class I cytokine receptors has been shown to be important...

  19. Cytokine gene polymorphisms and their association with cervical ...

    African Journals Online (AJOL)

    Cytokine gene polymorphisms and their association with cervical cancer: A North Indian study. ... Egyptian Journal of Medical Human Genetics ... factors and adhesion molecules promotes tumor progression and involves inflammation, angiogenesis and thrombosis, thus providing optimal conditions for cancer development.

  20. Influence of phthalates on cytokine production in monocytes and macrophages

    DEFF Research Database (Denmark)

    Hansen, Juliana Frohnert; Bendtzen, Klaus; Boas, Malene

    2015-01-01

    BACKGROUND: Phthalates are a group of endocrine disrupting chemicals suspected to influence the immune system. The aim of this systematic review is to summarise the present knowledge on the influence of phthalates on monocyte and macrophage production and secretion of cytokines, an influence which......://www.crd.york.ac.uk/NIHR_PROSPERO, registration number CRD42013004236). In vivo, ex vivo and in vitro studies investigating the influence of phthalates on cytokine mRNA expression and cytokine secretion in animals and humans were included. A total of 11 reports, containing 12 studies, were found eligible for inclusion. In these, a total of four...... different phthalate diesters, six primary metabolites (phthalate monoesters) and seven different cytokines were investigated. Though all studies varied greatly in study design and species sources, four out of five studies that investigated di-2-ethylhexyl phthalate found an increased tumour necrosis factor...

  1. Cytokines in bipolar disorder vs. healthy control subjects

    DEFF Research Database (Denmark)

    Munkholm, Klaus; Braüner, Julie Vestergaard; Kessing, Lars Vedel

    2013-01-01

    Bipolar disorder may be associated with peripheral immune system dysfunction; however, results in individual studies are conflicting. Our aim was to systematically review evidence of peripheral cytokine alterations in bipolar disorder integrating findings from various affective states....

  2. Serum Cytokine Profile in a Patient Diagnosed with Dysferlinopathy

    Directory of Open Access Journals (Sweden)

    Svetlana F. Khaiboullina

    2017-01-01

    Full Text Available Limb-girdle muscular dystrophy type 2 (LGMD2B is a mild form of dysferlinopathy, characterized by limb weakness and wasting. It is an autosomal recessive disease, with currently 140 mutations in the LGMD2B gene identified. Lack of functional dysferlin inhibits muscle fiber regeneration in voluntary muscles, the main pathological finding in LGMD2B patients. However, the immune system has been suggested to contribute to muscle cell death and tissue regeneration. Serum levels of 27 cytokines were evaluated in a dysferlinopathy patient. Levels of 8 cytokines differed in patient serum compared to controls. Five cytokines (IL-10, IL-17, CCL2, CXCL10, and G-CSF were higher while 3 were lower in the patient than in controls (IL-2, IL-8, and CCL11. Together, these data on serum cytokine profile of this dysferlinopathy patient suggest immune response activation, which could explain leukocyte infiltration in the muscle tissue.

  3. The Immune System, Cytokines, and Biomarkers in Autism Spectrum Disorder.

    Science.gov (United States)

    Masi, Anne; Glozier, Nicholas; Dale, Russell; Guastella, Adam J

    2017-04-01

    Autism Spectrum Disorder (ASD) is a pervasive neurodevelopmental condition characterized by variable impairments in communication and social interaction as well as restricted interests and repetitive behaviors. Heterogeneity of presentation is a hallmark. Investigations of immune system problems in ASD, including aberrations in cytokine profiles and signaling, have been increasing in recent times and are the subject of ongoing interest. With the aim of establishing whether cytokines have utility as potential biomarkers that may define a subgroup of ASD, or function as an objective measure of response to treatment, this review summarizes the role of the immune system, discusses the relationship between the immune system, the brain, and behavior, and presents previously-identified immune system abnormalities in ASD, specifically addressing the role of cytokines in these aberrations. The roles and identification of biomarkers are also addressed, particularly with respect to cytokine profiles in ASD.

  4. High efficiency cell-specific targeting of cytokine activity

    Science.gov (United States)

    Garcin, Geneviève; Paul, Franciane; Staufenbiel, Markus; Bordat, Yann; van der Heyden, José; Wilmes, Stephan; Cartron, Guillaume; Apparailly, Florence; de Koker, Stefaan; Piehler, Jacob; Tavernier, Jan; Uzé, Gilles

    2014-01-01

    Systemic toxicity currently prevents exploiting the huge potential of many cytokines for medical applications. Here we present a novel strategy to engineer immunocytokines with very high targeting efficacies. The method lies in the use of mutants of toxic cytokines that markedly reduce their receptor-binding affinities, and that are thus rendered essentially inactive. Upon fusion to nanobodies specifically binding to marker proteins, activity of these cytokines is selectively restored for cell populations expressing this marker. This ‘activity-by-targeting’ concept was validated for type I interferons and leptin. In the case of interferon, activity can be directed to target cells in vitro and to selected cell populations in mice, with up to 1,000-fold increased specific activity. This targeting strategy holds promise to revitalize the clinical potential of many cytokines.

  5. Influence of accompanying immunocorrecting therapy on the quality of life of breast cancer patients at post-operative radiation therapy

    International Nuclear Information System (INIS)

    Prokhach, N.E.

    2013-01-01

    To investigate the influence of accompanying immunotherapy on the parameters of the quality of life of the patients with breast cancer with various profiles of cytokines at post-operative radiation therapy. The study was performed on 30 breast cancer patients at stages of combination therapy

  6. Role of cytokines in Trypanosoma brucei-induced anaemia: A ...

    African Journals Online (AJOL)

    Publications on the cytokines studied in trypanosomiasis-associated anaemia ordered by year. Publication. Infecting trypanosome. Clinical sample. Cytokines. Other factors associated with anaemia. Magez et al. 1999. T.b.b AnTat1.1E. Blood from TNF-α -/-. TNF-α. -. Namangala et al. 2001. T.b.b AnTat1.1E. T.b.b PLC-/-.

  7. Systemic Cytokines in Type 2 Diabetes Mellitus and Chronic Periodontitis.

    Science.gov (United States)

    Acharya, Anirudh B; Thakur, Srinath; Muddapur, M V; Kulkarni, Raghavendra D

    2018-01-01

    Cytokine dysregulation plays an important role in Type 2 Diabetes Mellitus (T2DM) and Chronic Periodontitis (CP) with a commonality in pathogenic mechanisms. CP is considered the sixth complication of diabetes and may have an increased influence on systemic levels of cytokines in individuals with T2DM. This study investigated two pro-, and two presumed anti-inflammatory cytokines and their ratios in the serum of healthy individuals, in chronic periodontitis with and without T2DM with, and without CP and in CP alone aimed at evaluating the systemic inflammatory burden of a local oral infection. Eighty participants were divided equally into four groups as healthy volunteers (H) and patients having T2DM with, and without CP (T2DM+CP, and T2DM) and only CP (CP). Serum samples were collected to measure glycated hemoglobin (HbA1c), Random Blood Sugar (RBS) and also Tumor Necrosis Factor (TNF)-α, Interleukin (IL)-4, -6 - 10 were assessed using commercially available ELISA kits. The cytokines were detected in all groups. Significant differences were observed between groups for all the clinical, biochemical parameters and cytokines. Cytokine levels and the ratios showed significant correlations. The ratios of the cytokines differed significantly amongst groups, were highest in T2DM+CP. In this study, the cytokine ratios provided a qualitative profile along with the absolute levels in T2DM with periodontitis, indicative of an intensified systemic inflammatory state. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  8. Relationship between cytokines and running economy in marathon runners

    Directory of Open Access Journals (Sweden)

    Luna Junior Luiz Antonio

    2016-01-01

    Full Text Available Running economy (RE, expresses the relationship between the energy cost of running (Cr and the work performed by a runner and is an predictor of performance. Given the intense effort of marathon runners during training and competition and the dearth of studies that address performance and cytokines in this population, the objective of the current study was to investigate the relationship between RE and cytokines in marathon runners.

  9. Cytokine profile associated with human chronic schistosomiasis mansoni

    OpenAIRE

    Magalhães, Andréa; Miranda, Delfin Gonzalez; Miranda, Roberval Gonzalez; Araujo, Maria Ilma Andrade Santos; Jesus, Adriana Almeida de

    2004-01-01

    p. 21-26 This study objective was to evaluate the cytokines associated with early events of hepatic fibrosis in schistosomiasis mansoni. Hepatic fibrosis was classified by ultrasonography in 94 patients.Immunological evaluation was performed by measurement of secreted cytokines (interleukin IL-5, IL-10, IL-13, interferon-g, tumor necrosis factor-a and transforming growth factors-b) in peripherl blood mononuclear cells stimulated by Schistosoma mansoni antigens. Significantly, higher levels...

  10. Human astrocytes: secretome profiles of cytokines and chemokines.

    Directory of Open Access Journals (Sweden)

    Sung S Choi

    Full Text Available Astrocytes play a key role in maintenance of neuronal functions in the central nervous system by producing various cytokines, chemokines, and growth factors, which act as a molecular coordinator of neuron-glia communication. At the site of neuroinflammation, astrocyte-derived cytokines and chemokines play both neuroprotective and neurotoxic roles in brain lesions of human neurological diseases. At present, the comprehensive profile of human astrocyte-derived cytokines and chemokines during inflammation remains to be fully characterized. We investigated the cytokine secretome profile of highly purified human astrocytes by using a protein microarray. Non-stimulated human astrocytes in culture expressed eight cytokines, including G-CSF, GM-CSF, GROα (CXCL1, IL-6, IL-8 (CXCL8, MCP-1 (CCL2, MIF and Serpin E1. Following stimulation with IL-1β and TNF-α, activated astrocytes newly produced IL-1β, IL-1ra, TNF-α, IP-10 (CXCL10, MIP-1α (CCL3 and RANTES (CCL5, in addition to the induction of sICAM-1 and complement component 5. Database search indicated that most of cytokines and chemokines produced by non-stimulated and activated astrocytes are direct targets of the transcription factor NF-kB. These results indicated that cultured human astrocytes express a distinct set of NF-kB-target cytokines and chemokines in resting and activated conditions, suggesting that the NF-kB signaling pathway differentially regulates gene expression of cytokines and chemokines in human astrocytes under physiological and inflammatory conditions.

  11. Pro-inflammatory cytokines in cryptoglandular anal fistulas.

    Science.gov (United States)

    van Onkelen, R S; Gosselink, M P; van Meurs, M; Melief, M J; Schouten, W R; Laman, J D

    2016-09-01

    Sphincter-preserving procedures for the treatment of transsphincteric fistulas fail in at least one out of every three patients. It has been suggested that failure is due to ongoing disease in the remaining fistula tract. Cytokines play an important role in inflammation. At present, biologicals targeting cytokines are available. Therefore, detection and identification of cytokines in anal fistulas might have implications for future treatment modalities. The objective of the present study was to assess local production of a selected panel of cytokines in anal fistulas, including pro-inflammatory interleukin (IL)-1β and tumor necrosis factor α (TNF-α). Fistula tract tissue was obtained from 27 patients with a transsphincteric fistula of cryptoglandular origin who underwent flap repair, ligation of the intersphincteric fistula tract or a combination of both procedures. Patients with a rectovaginal fistula or a fistula due to Crohn's disease were excluded. Frozen tissue samples were sectioned and stained using advanced immuno-enzyme staining methods for detection of selected cytokines, IL-1β, IL-8, IL-10, IL-12p40, IL-17A, IL-18, IL-36 and TNF-α. The presence and frequencies of cytokine-producing cells in samples were quantitated. The key finding was abundant expression of IL-1β in 93 % of the anal fistulas. Frequencies of IL-1β-producing cells were highest (>50 positive stained cells) in 7 % of the anal fistulas. Also, cytokines IL-8, IL-12p40 and TNF-α were present in respectively 70, 33 and 30 % of the anal fistulas. IL-1β is expressed in the large majority of cryptoglandular anal fistulas, as well as several other pro-inflammatory cytokines.

  12. Analysis of the physical activity effects and measurement of pro-inflammatory cytokines in irradiated lungs in rats

    Energy Technology Data Exchange (ETDEWEB)

    Bianchi, Renata Cristiane Gennari; Katashima, Carlos Kiyoshi [Faculty of Medical Sciences, UNICAMP, Campinas, SP (Brazil); Ropelle, Eduardo Rochete [School of Applied Sciences, University of Campinas, UNICAMP, Limeira, SP (Brazil); Carvalheira, Jose Barreto Campello [Department of Internal Medicine, UNICAMP, Campinas, SP (Brazil); Lopes, Luiz Roberto; Andreollo, Nelson Adami [Department of Surgery, UNICAMP, Campinas, SP (Brazil)

    2012-03-15

    Purpose: To study if the pre-radiotherapy physical activity has radio-protective elements, by measuring the radio-induced activation of pro-inflammatory cytokines as interleukin-6 (il-6), transforming growth factor -{beta} (tgf -{beta}), tumor necrosis factor -a (tnf-a) and protein beta kinase {beta} (ikk{beta}), through western blotting analysis. Methods: A randomized study with 28 Wistar Hannover rats, males, with a mean age of 90 days and weighing about 200 grams. The animals were divided into three groups: (GI, GII and GIII). GIII group were submitted to swimming for eight weeks (zero load, three times a week, about 30 minutes). Then, the groups (except the control group) were submitted to irradiation by cobalt therapy, single dose of 3.5 gray in the whole body. All animals were sacrificed by overdose of pentobarbital, according to the time for analysis of cytokines, and then a fragment of the lower lobe of the right lung went to western blotting analysis. Results: The cytokines IKK{beta}, TNF-{alpha} and IL-6 induced by radiation in the lung were lower in the exercised animals. However, exercise did not alter the radiation-induced increase in tgf-{beta}. Conclusion: The results show a lower response in relation to inflammatory cytokines in the group that practiced the exercise preradiotherapy, showing that exercise can protect tissues from tissue damage due to irradiation. (author)

  13. Learning from the Messengers: Innate Sensing of Viruses and Cytokine Regulation of Immunity — Clues for Treatments and Vaccines

    Directory of Open Access Journals (Sweden)

    Jesper Melchjorsen

    2013-01-01

    Full Text Available Virus infections are a major global public health concern, and only via substantial knowledge of virus pathogenesis and antiviral immune responses can we develop and improve medical treatments, and preventive and therapeutic vaccines. Innate immunity and the shaping of efficient early immune responses are essential for control of viral infections. In order to trigger an efficient antiviral defense, the host senses the invading microbe via pattern recognition receptors (PRRs, recognizing distinct conserved pathogen-associated molecular patterns (PAMPs. The innate sensing of the invading virus results in intracellular signal transduction and subsequent production of interferons (IFNs and proinflammatory cytokines. Cytokines, including IFNs and chemokines, are vital molecules of antiviral defense regulating cell activation, differentiation of cells, and, not least, exerting direct antiviral effects. Cytokines shape and modulate the immune response and IFNs are principle antiviral mediators initiating antiviral response through induction of antiviral proteins. In the present review, I describe and discuss the current knowledge on early virus–host interactions, focusing on early recognition of virus infection and the resulting expression of type I and type III IFNs, proinflammatory cytokines, and intracellular antiviral mediators. In addition, the review elucidates how targeted stimulation of innate sensors, such as toll-like receptors (TLRs and intracellular RNA and DNA sensors, may be used therapeutically. Moreover, I present and discuss data showing how current antimicrobial therapies, including antibiotics and antiviral medication, may interfere with, or improve, immune response.

  14. Altered Circulating Inflammatory Cytokines Are Associated with Anovulatory Polycystic Ovary Syndrome (PCOS) Women Resistant to Clomiphene Citrate Treatment.

    Science.gov (United States)

    Wang, LianLian; Qi, HongBo; Baker, Philip N; Zhen, QianNa; Zeng, Qing; Shi, Rui; Tong, Chao; Ge, Qian

    2017-03-01

    BACKGROUND Polycystic ovary syndrome (PCOS) is a common gynecological disease characterized by chronic oligoanovulation, clinical/biochemical hyperandrogenism, polycystic ovaries, and insulin resistance. Accumulating evidence has shown that PCOS-related ovarian dysfunction is the main cause of anovulatory infertility. Clomiphene citrate (CC) is the first-line therapy for PCOS patients; however, approximately 15-40% PCOS patients are resistant to CC treatment. It has been demonstrated that PCOS is a chronic pro-inflammatory state, as some pro-inflammatory cytokines were elevated in the peripheral circulation of PCOS patients, but whether altered inflammatory cytokines expression in PCOS patients is associated with blunted response to CC remains unknown. MATERIAL AND METHODS We recruited 44 CC-resistant PCOS patients, along with 55 age and body mass index (BMI)-matched CC-sensitive PCOS patients. Ovulation was induced by administrating 50-100 mg/day CC on days 5 to 9 of each menstrual cycle. The cytokine profiles were detected by cytokine antibody microarrays and further validated by ELISAs. RESULTS CC-resistant patients had higher levels of high-sensitivity C-reactive protein (hsCRP) than the CC-sensitive individuals. A growth factor, angiopoietin-2, was significantly reduced [1.64 (0.93-1.95) vs. 1.08 (0.85-1.34), pPCOS patients. Altered angiopoietin-2 and CXCL-16 levels might compromise the responsiveness of the ovary to CC through up-regulating angiogenesis and inflammation.

  15. Impaired Expression of Cytokines as a Result of Viral Infections with an Emphasis on Small Ruminant Lentivirus Infection in Goats

    Directory of Open Access Journals (Sweden)

    Justyna Jarczak

    2016-07-01

    Full Text Available Knowing about the genes involved in immunity, and being able to identify the factors influencing their expressions, helps in gaining awareness of the immune processes. The qPCR method is a useful gene expression analysis tool, but studies on immune system genes are still limited, especially on the caprine immune system. Caprine arthritis encephalitis, a disease caused by small ruminant lentivirus (SRLV, causes economic losses in goat breeding, and there is no therapy against SRLV. The results of studies on vaccines against other viruses are promising. Moreover, the Marker-Assisted Selection strategy against SRLV is possible, as has been shown in sheep breeding. However, there are still many gaps in our knowledge on the caprine immune response to infection. All types of cytokines play pivotal roles in immunity, and SRLV infection influences the expression of many cytokines in different types of cells. This information encouraged the authors to examine the results of studies conducted on SRLV and other viral infections, with an emphasis on the expression of cytokine genes. This review attempts to summarize the results of studies on the expression of cytokines in the context of the SRLV infection.

  16. Biological therapy of psoriasis

    Directory of Open Access Journals (Sweden)

    Sivamani Raja

    2010-01-01

    Full Text Available The treatment of psoriasis has undergone a revolution with the advent of biologic therapies, including infliximab, etanercept, adalimumab, efalizumab, and alefacept. These medications are designed to target specific components of the immune system and are a major technological advancement over traditional immunosuppressive medications. These usually being well tolerated are being found useful in a growing number of immune-mediated diseases, psoriasis being just one example. The newest biologic, ustekinumab, is directed against the p40 subunit of the IL-12 and IL-23 cytokines. It has provided a new avenue of therapy for an array of T-cell-mediated diseases. Biologics are generally safe; however, there has been concern over the risk of lymphoma with use of these agents. All anti-TNF-α agents have been associated with a variety of serious and "routine" opportunistic infections.

  17. Anti-parasite effects of cytokines in malaria.

    Science.gov (United States)

    Mendis, K N; Naotunne, T D; Karunaweera, N D; Del Giudice, G; Grau, G E; Carter, R

    1990-08-01

    Cytokines induced during natural malaria infections, e.g., at crisis of a blood infection of Plasmodium cynomolgi, and during clinical paroxysms in human Plasmodium vivax infections, mediate killing of intra-erythrocytic blood stage malaria parasites. These cytokines, TNF and IFN-gamma, require additional, yet unidentified complementary factors that are present in "crisis" and "paroxysm" serum to kill intra-erythrocytic blood stage parasites. In contrast, cytokines, (mainly IFN-gamma) are able to effect killing of intra-hepatic stages of the parasite by themselves independent of serum complementary factors, suggesting that the mechanisms of killing may be different with respect to the two parasite stages. Cytokines also appear to be critical intermediates in mechanisms of clinical disease in malaria. Serum cytokine (TNF) levels and killing effects on blood stage malaria parasites were lower in patients who were exposed to endemic P. vivax malaria who had partial clinical immunity, than in non-immune patients. Evidence suggest that individuals acquire natural immunity to the disease by avoiding the induction of high levels of cytokines and complementary factors.

  18. INVESTIGATION OF CYTOKINE PROFILE IN PATIENTS WITH REACTIVE ARTHRITIS

    Directory of Open Access Journals (Sweden)

    T. V. Gaponova

    2008-01-01

    Full Text Available Abstract. Pathogenesis of reactive arthritis (ReA is not clear yet. Several trials suggest that increased production of proinflammatory cytokines is responsible for development of arthritis in ReA, while other studies report that Th1 cytokine response in ReA is impaired in favor of Th2 response. The aim of our study was to investigate serum levels of cytokines IL-1β, IL-4, IL-6, TNFα, IFNγ and IL-1Ra in the patients with ReA of different etiology, as compared with infection-related arthritis. The results of our study had demonstrated that serum levels of IL-1β and TNFα in the patients with ReA were significantly higher, whereas IL-1Ra, IL-4, IL-6 proved to be significantly lower than in healthy controls. Serum levels of IL-6 were significantly higher in patients with chronic ReA, as compared to the cases of acute and recurrent ReA. No significant differences in cytokine profiles were found between the patients with ReA, and the persons with infection-related arthritis. The data obtained are, generally, suggestive for proinflammatory Th1 cytokine profile in ReA patients studied, this confirming the mostly assumed pathogenetic hypothesis for reactive arthritis where an underlying cytokine imbalance is suggested. (Med. Immunol., 2008, vol. 10, N 2-3, pp 167-172.

  19. Temporal Regulation of Cytokines by the Circadian Clock

    Directory of Open Access Journals (Sweden)

    Atsuhito Nakao

    2014-01-01

    Full Text Available Several parameters of the immune system exhibit oscillations with a period of approximately 24 hours that refers to “circadian rhythms.” Such daily variations in host immune system status might evolve to maximize immune reactions at times when encounters with pathogens are most likely to occur. However, the mechanisms behind circadian immunity have not been fully understood. Recent studies reveal that the internal time keeping system “circadian clock” plays a key role in driving the daily rhythms evident in the immune system. Importantly, several studies unveil molecular mechanisms of how certain clock proteins (e.g., BMAL1 and CLOCK temporally regulate expression of cytokines. Since cytokines are crucial mediators for shaping immune responses, this review mainly summarizes the new knowledge that highlights an emerging role of the circadian clock as a novel regulator of cytokines. A greater understanding of circadian regulation of cytokines will be important to exploit new strategies to protect host against infection by efficient cytokine induction or to treat autoimmunity and allergy by ameliorating excessive activity of cytokines.

  20. FEATURES OF CYTOKINE PRODUCTION IN PATIENTS WITH RECURRENT HERPETIC INFECTION

    Directory of Open Access Journals (Sweden)

    I. A. Novikovа

    2013-01-01

    Full Text Available Abstract. Cytokines play an important role in resistance to herpesvirus infections. Therefore, studies of cytokine profile are necessary in recurrent herpetic infection. However, functional studies of cytokine network upon remission of the disease yielded controversial results. In this paper, we provide some results concerning comprehensive evaluation of ex vivo cytokine production by whole blood leukocytes drawn from 15 patients observed during clinical remission of recurrent Herpes Simplex virus infection. We have found a decrease of IL-1β, IL-8 and IL-10 production, as well as imbalance of cytokine profile, with predominance of IFNγ and IL-8 synthesis over IL-10 production, along with increased IL-4 and IL-13 levels to IL-1β contents. Differently directed correlations between the content of activated lymphocytes (CD3+HLA-DR+ and CD3+CD4+CD25+, natural killers (СD3-СD16/56+, NKT-cells and cytokine production levels were found in the groups of patients and healthy individuals. These differences may be due to shifts in major cytokineproducing populations in herpesvirus infections.

  1. A small-molecule/cytokine combination enhances hematopoietic stem cell proliferation via inhibition of cell differentiation.

    Science.gov (United States)

    Wang, Lan; Guan, Xin; Wang, Huihui; Shen, Bin; Zhang, Yu; Ren, Zhihua; Ma, Yupo; Ding, Xinxin; Jiang, Yongping

    2017-07-18

    Accumulated evidence supports the potent stimulating effects of multiple small molecules on the expansion of hematopoietic stem cells (HSCs) which are important for the therapy of various hematological disorders. Here, we report a novel, optimized formula, named the SC cocktail, which contains a combination of three such small molecules and four cytokines. Small-molecule candidates were individually screened and then combined at their optimal concentration with the presence of cytokines to achieve maximum capacity for stimulating the human CD34 + cell expansion ex vivo. The extent of cell expansion and the immunophenotype of expanded cells were assessed through flow cytometry. The functional preservation of HSC stemness was confirmed by additional cell and molecular assays in vitro. Subsequently, the expanded cells were transplanted into sublethally irradiated NOD/SCID mice for the assessment of human cell viability and engraftment potential in vivo. Furthermore, the expression of several genes in the cell proliferation and differentiation pathways was analyzed through quantitative polymerase chain reaction (qPCR) during the process of CD34 + cell expansion. The SC cocktail supported the retention of the immunophenotype of hematopoietic stem/progenitor cells remarkably well, by yielding purities of 86.6 ± 11.2% for CD34 + cells and 76.2 ± 10.5% for CD34 + CD38 - cells, respectively, for a 7-day culture. On day 7, the enhancement of expansion of CD34 + cells and CD34 + CD38 - cells reached a maxima of 28.0 ± 5.5-fold and 27.9 ± 4.3-fold, respectively. The SC cocktail-expanded CD34 + cells preserved the characteristics of HSCs by effectively inhibiting their differentiation in vitro and retained the multilineage differentiation potential in primary and secondary in vivo murine xenotransplantation trials. Further gene expression analysis suggested that the small-molecule combination strengthened the ability of the cytokines to enhance the Notch

  2. Aggressive Periodontitis and Chronic Arthritis: Blood Mononuclear Cell Gene Expression and Plasma Protein Levels of Cytokines and Cytokine Inhibitors

    DEFF Research Database (Denmark)

    Sørensen, Lars Korsbæk Connor; Poulsen, Anne Havemose; Bendtzen, Klaus

    2009-01-01

    -inflammatory cytokines and cytokine receptors in patients with periodontitis and patients with arthritis representing two examples of chronic inflammatory diseases, such as periodontitis and arthritis. To identify possible disease-specific characteristics of subjects with periodontitis relative to subjects with chronic...... inflammation in general, patients with arthritis (juvenile idiopathic arthritis [JIA] and rheumatoid arthritis [RA]) were included. METHODS: The study population consisted of white adults aggressive periodontitis (LAgP; n = 18), generalized aggressive periodontitis......TNF-RI plasma levels in patients with LAgP and RA. CONCLUSIONS: The study demonstrated only a few changes in the PBMC expression of various cytokine and cytokine inhibitor genes in aggressive periodontitis and chronic arthritis compared to controls. There were a few similarities among disease groups...

  3. Platelet-rich plasma preparation for regenerative medicine: optimization and quantification of cytokines and growth factors.

    Science.gov (United States)

    Amable, Paola Romina; Carias, Rosana Bizon Vieira; Teixeira, Marcus Vinicius Telles; da Cruz Pacheco, Italo; Corrêa do Amaral, Ronaldo José Farias; Granjeiro, José Mauro; Borojevic, Radovan

    2013-06-07

    Platelet-rich plasma (PRP) is nowadays widely applied in different clinical scenarios, such as orthopedics, ophthalmology and healing therapies, as a growth factor pool for improving tissue regeneration. Studies into its clinical efficiency are not conclusive and one of the main reasons for this is that different PRP preparations are used, eliciting different responses that cannot be compared. Platelet quantification and the growth factor content definition must be defined in order to understand molecular mechanisms behind PRP regenerative strength. Standardization of PRP preparations is thus urgently needed. PRP was prepared by centrifugation varying the relative centrifugal force, temperature, and time. Having quantified platelet recovery and yield, the two-step procedure that rendered the highest output was chosen and further analyzed. Cytokine content was determined in different fractions obtained throughout the whole centrifugation procedure. Our method showed reproducibility when applied to different blood donors. We recovered 46.9 to 69.5% of total initial platelets and the procedure resulted in a 5.4-fold to 7.3-fold increase in platelet concentration (1.4 × 10(6) to 1.9 × 10(6) platelets/μl). Platelets were highly purified, because only platelets after activation with calcium and calcium/thrombin. High concentrations of platelet-derived growth factor, endothelial growth factor and transforming growth factor (TGF) were secreted, together with the anti-inflammatory and proinflammatory cytokines interleukin (IL)-4, IL-8, IL-13, IL-17, tumor necrosis factor (TNF)-α and interferon (IFN)-α. No cytokines were secreted before platelet activation. TGF-β3 and IFNγ were not detected in any studied fraction. Clots obtained after platelet coagulation retained a high concentration of several growth factors, including platelet-derived growth factor and TGF. Our study resulted in a consistent PRP preparation method that yielded a cytokine and growth factor pool

  4. Chemokine/cytokine profiling after rituximab: reciprocal expression of BCA-1/CXCL13 and BAFF in childhood OMS.

    Science.gov (United States)

    Pranzatelli, Michael R; Tate, Elizabeth D; Travelstead, Anna L; Verhulst, Steven J

    2011-03-01

    The aim of the study was to test the hypothesis that B-cell repopulation following rituximab (anti-CD20) therapy is orchestrated by chemokines and non-chemokine cytokines. Twenty-five children with opsoclonus-myoclonus syndrome (OMS) received rituximab with or without conventional agents. A comprehensive panel of 40 chemokines and other cytokines were measured in serum by ELISA and multiplexed fluorescent bead-based immunoassay. Serum BAFF concentration changed dramatically (even after first infusion) and inversely with B-cell depletion/repopulation and CXCL13 concentration at 1, 3, and 6 months. Negative correlations were found for BAFF concentration vs blood B cell percentage and serum CXCL13 concentration; positive correlations with serum rituximab concentrations. Six months after initiation of therapy, no significant difference in the levels of APRIL, CXCL10, IL-6, or 17 other cytokines/chemokines were detected. These data reveal a major role for BAFF in peripheral B cell repopulation following rituximab-induced B-cell depletion, and novel changes in CXCL13. ClinicalTrials.gov NCT0024436. Copyright © 2010 Elsevier Ltd. All rights reserved.

  5. Collection of Aerosolized Human Cytokines Using Teflon® Filters

    Science.gov (United States)

    McKenzie, Jennifer H.; McDevitt, James J.; Fabian, M. Patricia; Hwang, Grace M.; Milton, Donald K.

    2012-01-01

    Background Collection of exhaled breath samples for the analysis of inflammatory biomarkers is an important area of research aimed at improving our ability to diagnose, treat and understand the mechanisms of chronic pulmonary disease. Current collection methods based on condensation of water vapor from exhaled breath yield biomarker levels at or near the detection limits of immunoassays contributing to problems with reproducibility and validity of biomarker measurements. In this study, we compare the collection efficiency of two aerosol-to-liquid sampling devices to a filter-based collection method for recovery of dilute laboratory generated aerosols of human cytokines so as to identify potential alternatives to exhaled breath condensate collection. Methodology/Principal Findings Two aerosol-to-liquid sampling devices, the SKC® Biosampler and Omni 3000™, as well as Teflon® filters were used to collect aerosols of human cytokines generated using a HEART nebulizer and single-pass aerosol chamber setup in order to compare the collection efficiencies of these sampling methods. Additionally, methods for the use of Teflon® filters to collect and measure cytokines recovered from aerosols were developed and evaluated through use of a high-sensitivity multiplex immunoassay. Our results show successful collection of cytokines from pg/m3 aerosol concentrations using Teflon® filters and measurement of cytokine levels in the sub-picogram/mL concentration range using a multiplex immunoassay with sampling times less than 30 minutes. Significant degradation of cytokines was observed due to storage of cytokines in concentrated filter extract solutions as compared to storage of dry filters. Conclusions Use of filter collection methods resulted in significantly higher efficiency of collection than the two aerosol-to-liquid samplers evaluated in our study. The results of this study provide the foundation for a potential new technique to evaluate biomarkers of inflammation in

  6. Plasma cytokine levels predict response to corticosteroids in septic shock.

    Science.gov (United States)

    Bentzer, Peter; Fjell, Chris; Walley, Keith R; Boyd, John; Russell, James A

    2016-12-01

    To investigate if plasma cytokine concentrations predict a beneficial response to corticosteroid treatment in septic shock patients. A cohort of septic shock patients in whom a panel of 39 cytokines had been measured at baseline (n = 363) was included. Patients who received corticosteroids were propensity score matched to non-corticosteroid-treated patients. An optimal threshold to identify responders to corticosteroid treatment for each cytokine was defined as the concentration above which the odds ratio for 28-day survival between corticosteroid- and non-corticosteroid-treated patients was highest. Propensity score matching partitioned 165 patients into 61 sets; each set contained matched corticosteroid- and non-corticosteroid-treated patients. For 13 plasma cytokines threshold concentrations were found where the odds ratio for survival between corticosteroid- and non-corticosteroid-treated patients was significant (P highest odds ratio and identified 21 % of the patients in the propensity score matched cohort as responders to corticosteroid treatment. Combinations of triplets of cytokines with a significant odds ratio, using the thresholds identified above, were tested to find a higher proportion of responders. IL3, IL6, and CCL4 identified 50 % of the patients in the propensity score matched cohort as responders to corticosteroid treatment. The odds ratio for 28-day survival was 19 (95 % CI 3.5-140, P = 0.02) with a concentration above threshold for a least one of these cytokines. Plasma concentration of selected cytokines is a potential predictive biomarker to identify septic shock patients that may benefit from treatment with corticosteroids.

  7. Systemic nickel allergy: oral desensitization and possible role of cytokines interleukins 2 and 10.

    Science.gov (United States)

    Ricciardi, L; Carni, A; Loschiavo, G; Gangemi, S; Tigano, V; Arena, E; Mannucci, C; Calapai, G

    2013-01-01

    Nickel ingested with food can elicit either systemic cutaneous or gastrointestinal symptoms causing a systemic nickel allergy syndrome (SNAS) that can be treated with tolerance by oral ingestion of the metal. It has been suggested that interleukins 2 (IL-2) and 10 (IL-10) are involved in the mechanisms underlying oral tolerance. We evaluated the clinical efficacy of oral desensitization therapy in SNAS consisting in the administration of nickel sulphate. Because nickel allergy prevalently affects women, only female subjects (N = 22) were recruited. Oral nickel desensitizing therapy was associated with low-nickel diet for three months. Before and after therapy, clinical conditions were evaluated, and circulating cytokines IL-2 and IL-10 were measured. After the two-year treatment, visual analogue scale (VAS) scores for symptoms were significantly reduced (P less than 0.001). Patients were released by either cutaneous or gastrointestinal symptoms and by tolerating nickel-containing food. At the end of the treatment, nickel oral challenge test was negative in 18 patients, and IL-2 level in the serum was significantly reduced while IL-10 was increased, although this datum was not statistically significant. Our study confirms the clinical efficacy of nickel oral immunotherapy and focuses on the mechanisms triggered by oral tolerance indicating that reduction of IL-2 can be associated with success of oral nickel desensitizing therapy.

  8. Cellular sources of dysregulated cytokines in relapsing-remitting multiple sclerosis

    DEFF Research Database (Denmark)

    Romme Christensen, Jeppe; Börnsen, Lars; Hesse, Dan

    2012-01-01

    Numerous cytokines are implicated in the immunopathogenesis of multiple sclerosis (MS), but studies are often limited to whole blood (WB) or peripheral blood mononuclear cells (PBMCs), thereby omitting important information about the cellular origin of the cytokines. Knowledge about the relation...... between blood and cerebrospinal fluid (CSF) cell expression of cytokines and the cellular source of CSF cytokines is even more scarce....

  9. Th17 plasticity and transition toward a pathogenic cytokine signature are regulated by cyclosporine after allogeneic SCT.

    Science.gov (United States)

    Gartlan, Kate H; Varelias, Antiopi; Koyama, Motoko; Robb, Renee J; Markey, Kate A; Chang, Karshing; Wilkinson, Andrew N; Smith, David; Ullah, Md Ashik; Kuns, Rachel D; Raffelt, Neil C; Olver, Stuart D; Lineburg, Katie E; Teal, Bianca E; Cheong, Melody; Teng, Michele W L; Smyth, Mark J; Tey, Siok-Keen; MacDonald, Kelli P A; Hill, Geoffrey R

    2017-02-14

    T-helper 17 (Th17) cells have been widely implicated as drivers of autoimmune disease. In particular, Th17 cytokine plasticity and acquisition of an interleukin-17A + (IL-17A + )interferon γ(IFNγ) + cytokine profile is associated with increased pathogenic capacity. Donor Th17 polarization is known to exacerbate graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (allo-SCT); however, donor Th17 cytokine coexpression and plasticity have not been fully characterized. Using IL-17 "fate-mapping" mice, we identified IL-6-dependent Th17 cells early after allo-SCT, characterized by elevated expression of proinflammatory cytokines, IL-17A, IL-22, granulocyte-macrophage colony-stimulating factor, and tumor necrosis factor. This population did not maintain lineage fidelity, with a marked loss of IL-17A and IL-22 expression late posttransplant. Th17 cells were further segregated based on IFNγ coexpression, and IL-17A + IFNγ + Th17 displayed an enhanced proinflammatory phenotype. Th17 cytokine plasticity and IFNγ production were critically dependent upon donor-derived IL-12p40, and cyclosporine (CsA) treatment regulated this differentiation pathway. This observation was highly concordant with clinical samples from allo-SCT recipients receiving CsA-based immune suppression where although the IFNγ-negative-Th17 subset predominated, IFNγ + -Th17 cells were also present. In sum, Th17 polarization and ensuing differentiation are mediated by sequential inflammatory signals, which are modulated by immunosuppressive therapy, leading to distinct phenotypes within this lineage.

  10. Cytokine networks in animal models of colitis-associated cancer.

    Science.gov (United States)

    Antoniou, Efstathios; Margonis, Georgios Antonios; Angelou, Anastasios; Zografos, George C; Pikoulis, Emmanouil

    2015-01-01

    It is well-known that inflammatory bowel disease (IBD) poses an increased, yet not definitely estimated, risk of colitis-associated colon cancer (CAC), which is considered a more aggressive and distinct in both genetic and molecular levels clinical entity compared to sporadic colorectal cancer (CRC). The present review discusses the cytokine networks involved in CAC-based translational findings from suitable animal models of the disease. Moreover, we summarize the most prominent data concerning the role of Th1, Th2, Th17 and anti-inflammatory cytokines in the pathogenesis of CAC. Last, we briefly address the controversies between basic science findings in IBD and CAC and suggest further directions regarding research on cytokines. This review should serve as a primer for clinicians and surgeons to understand the rapidly evolving field of cytokines in the context of CAC. The MEDLINE database was thoroughly searched using the keywords: cytokines, colitis-associated cancer, animal models, carcinogenesis. Additional articles were gathered and evaluated. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  11. Zinc and Regulation of Inflammatory Cytokines: Implications for Cardiometabolic Disease

    Science.gov (United States)

    Foster, Meika; Samman, Samir

    2012-01-01

    In atherosclerosis and diabetes mellitus, the concomitant presence of low-grade systemic inflammation and mild zinc deficiency highlights a role for zinc nutrition in the management of chronic disease. This review aims to evaluate the literature that reports on the interactions of zinc and cytokines. In humans, inflammatory cytokines have been shown both to up- and down-regulate the expression of specific cellular zinc transporters in response to an increased demand for zinc in inflammatory conditions. The acute phase response includes a rapid decline in the plasma zinc concentration as a result of the redistribution of zinc into cellular compartments. Zinc deficiency influences the generation of cytokines, including IL-1β, IL-2, IL-6, and TNF-α, and in response to zinc supplementation plasma cytokines exhibit a dose-dependent response. The mechanism of action may reflect the ability of zinc to either induce or inhibit the activation of NF-κB. Confounders in understanding the zinc-cytokine relationship on the basis of in vitro experimentation include methodological issues such as the cell type and the means of activating cells in culture. Impaired zinc homeostasis and chronic inflammation feature prominently in a number of cardiometabolic diseases. Given the high prevalence of zinc deficiency and chronic disease globally, the interplay of zinc and inflammation warrants further examination. PMID:22852057

  12. Instruction of hematopoietic lineage choice by cytokine signaling

    Energy Technology Data Exchange (ETDEWEB)

    Endele, Max; Etzrodt, Martin; Schroeder, Timm, E-mail: timm.schroeder@bsse.ethz.ch

    2014-12-10

    Hematopoiesis is the cumulative consequence of finely tuned signaling pathways activated through extrinsic factors, such as local niche signals and systemic hematopoietic cytokines. Whether extrinsic factors actively instruct the lineage choice of hematopoietic stem and progenitor cells or are only selectively allowing survival and proliferation of already intrinsically lineage-committed cells has been debated over decades. Recent results demonstrated that cytokines can instruct lineage choice. However, the precise function of individual cytokine-triggered signaling molecules in inducing cellular events like proliferation, lineage choice, and differentiation remains largely elusive. Signal transduction pathways activated by different cytokine receptors are highly overlapping, but support the production of distinct hematopoietic lineages. Cellular context, signaling dynamics, and the crosstalk of different signaling pathways determine the cellular response of a given extrinsic signal. New tools to manipulate and continuously quantify signaling events at the single cell level are therefore required to thoroughly interrogate how dynamic signaling networks yield a specific cellular response. - Highlights: • Recent studies provided definite proof for lineage-instructive action of cytokines. • Signaling pathways involved in hematopoietic lineage instruction remain elusive. • New tools are emerging to quantitatively study dynamic signaling networks over time.

  13. A Review: Inflammatory Process in Alzheimer's Disease, Role of Cytokines

    Directory of Open Access Journals (Sweden)

    Jose Miguel Rubio-Perez

    2012-01-01

    Full Text Available Alzheimer's disease (AD is the most common neurodegenerative disorder to date. Neuropathological hallmarks are β-amyloid (Aβ plaques and neurofibrillary tangles, but the inflammatory process has a fundamental role in the pathogenesis of AD. Inflammatory components related to AD neuroinflammation include brain cells such as microglia and astrocytes, the complement system, as well as cytokines and chemokines. Cytokines play a key role in inflammatory and anti-inflammatory processes in AD. An important factor in the onset of inflammatory process is the overexpression of interleukin (IL-1, which produces many reactions in a vicious circle that cause dysfunction and neuronal death. Other important cytokines in neuroinflammation are IL-6 and tumor necrosis factor (TNF-α. By contrast, other cytokines such as IL-1 receptor antagonist (IL-1ra, IL-4, IL-10, and transforming growth factor (TGF-β can suppress both proinflammatory cytokine production and their action, subsequently protecting the brain. It has been observed in epidemiological studies that treatment with nonsteroidal anti-inflammatory drugs (NSAIDs decreases the risk for developing AD. Unfortunately, clinical trials of NSAIDs in AD patients have not been very fruitful. Proinflammatory responses may be countered through polyphenols. Supplementation of these natural compounds may provide a new therapeutic line of approach to this brain disorder.

  14. Th1/Th2 cytokine expression in diabetic retinopathy.

    Science.gov (United States)

    Cao, Y L; Zhang, F Q; Hao, F Q

    2016-07-15

    Diabetic retinopathy (DR), an important complication of diabetes mellitus (DM), is not well understood. T helper cell balance (Th1/Th2) is involved in various autoimmune diseases; however, its role in DR is not understood. This study explores changes in Th1 and Th2 cytokine expression during DR. Blood samples were collected from 25 healthy volunteers (normal control group), 35 patients with type 2 DM (T2DM group) without DR, and 30 cases of T2DM patients with DR (DR group). Real-time PCR was used to measure mRNA expression of IL-2 and TNF-α, secreted from Th1 cells, and of IL-4 and IL-10, secreted from Th2 cells. We used ELISA to detect cytokine expression in serum to analyze the correlation between Th1 and Th2 cytokines. IL-2 and TNF-αmRNA and protein expression levels in the T2DM and DR groups were significantly higher than in the normal control group (P 0.05). IL-2 and TNF-αwere negatively correlated with IL-4 and IL-10 in the DR group, respectively. We found that Th1 cytokine secretion was higher and Th2 cytokines secretion was lower during DR, leading to a Th1/ Th2 imbalance, suggesting that Th1/Th2 imbalance is a side effect for DR occurrence and development.

  15. Modulation of Conjunctival Goblet Cell Function by Inflammatory Cytokines

    Directory of Open Access Journals (Sweden)

    L. Contreras-Ruiz

    2013-01-01

    Full Text Available Ocular surface inflammation associated with Sjögren’s syndrome is characterized by a loss of secretory function and alteration in numbers of mucin secreting goblet cells. Such changes are a prominent feature of ocular surface inflammatory diseases and are attributed to inflammation; however, the exact effect of the inflammatory cytokines on conjunctival goblet cell function remains largely unknown. In this study, we developed a primary culture of mouse goblet cells from conjunctival tissue and evaluated the effects on their function by inflammatory cytokines detected in the conjunctiva of mouse model of Sjögren’s syndrome (Thrombospondin-1 deficient mice. We found that apoptosis of goblet cells was primarily induced by TNF-α and IFN-γ. These two cytokines also inhibited mucin secretion by goblet cells in response to cholinergic stimulation, whereas IL-6 enhanced such secretion. No changes in secretory response were detected in the presence of IL-13 or IL-17. Goblet cells proliferated to varying degrees in response to all the tested cytokines with the greatest response to IL-13 followed by IL-6. Our results therefore reveal that inflammatory cytokines expressed in the conjunctiva during an ocular surface disease directly disrupt conjunctival goblet cell functions, compromising the protective function of tears, thereby contributing to ocular surface damage.

  16. Butyrate regulates the expression of inflammatory and chemotactic cytokines in human acute leukemic cells during apoptosis.

    Science.gov (United States)

    Pulliam, Stephanie R; Pellom, Samuel T; Shanker, Anil; Adunyah, Samuel E

    2016-08-01

    Butyrate is a histone deacetylase inhibitor implicated in many studies as a potential therapy for various forms of cancer. High concentrations of butyrate (>1.5mM) have been shown to activate apoptosis in several cancer cell lines including prostate, breast, and leukemia. Butyrate is also known to influence multiple signaling pathways that are mediators of cytokine production. The purpose of this study was to evaluate the impact of high concentrations of butyrate on the cancer microenvironment vis-à-vis apoptosis, cellular migration, and capacity to modulate cytokine expression in cancer cells. The results indicate that high concentrations of butyrate induced a 2-fold activation of caspase-3 and reduced cell viability by 60% in U937 leukemia cells. Within 24h, butyrate significantly decreased the levels of chemokines CCL2 and CCL5 in HL-60 and U937 cells, and decreased CCL5 in THP-1 leukemia cells. Differential effects were observed in treatments with valproic acid for CCL2 and CCL5 indicating butyrate-specificity. Many of the biological effects examined in this study are linked to activation of the AKT and MAPK signaling pathways; therefore, we investigated whether butyrate alters the levels of phosphorylated forms of these signaling proteins and how it correlated with the expression of chemokines. The results show that butyrate may partially regulate CCL5 production via p38 MAPK. The decrease in p-ERK1/2 and p-AKT levels correlated with the decrease in CCL2 production. These data suggest that while promoting apoptosis, butyrate has the potential to influence the cancer microenvironment by inducing differential expression of cytokines. Copyright © 2016 Elsevier Ltd. All rights reserved.

  17. The cytokines and micro-environment of fracture haematoma: Current evidence.

    Science.gov (United States)

    Walters, Gavin; Pountos, Ippokratis; Giannoudis, Peter V

    2018-03-01

    Fracture haematoma formation is the first and foremost important stage of fracture healing. It orchestrates the inflammatory and cellular processes leading to the formation of callus and the restoration of the continuity of the bone. Evidence suggests that blocking this initial stage could lead to an impairment of the overall bone healing process. This review aims to analyse the existing evidence of molecular contributions to bone healing within fracture haematoma and to determine the potential to modify the molecular response to fracture in the haematoma with the aim of improving union times. A comprehensive search of literature documenting fracture haematoma cytokine content was performed. Suitable papers according to prespecified criteria were identified and analysed according to Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. A total of 89 manuscripts formed the basis of this analysis. Low oxygen tension, high acidity, and high calcium characterised initially the fracture haematoma micro-environment. In addition, a number of cytokines have been measured with concentrations significantly higher than those found in peripheral circulation. Growth factors have also been isolated, with an observed increase in bone morphogenetic proteins, platelet-derived growth factor, and transforming growth factor. Although molecular modification of fracture haematoma has been attempted, more research is required to determine a suitable biological response modifier leading to therapeutic effects. The cytokine content of fracture haematoma gives insight into processes occurring in the initial stages of fracture healing. Manipulation of signalling molecules represents a promising pathway to target future therapies aiming to upregulate the osteogenesis. Copyright © 2017 John Wiley & Sons, Ltd.

  18. Interleukin-30 (IL27p28) alleviates experimental sepsis by modulating cytokine profile in NKT cells.

    Science.gov (United States)

    Yan, Jun; Mitra, Abhisek; Hu, Jiemiao; Cutrera, Jeffery J; Xia, Xueqing; Doetschman, Thomas; Gagea, Mihai; Mishra, Lopa; Li, Shulin

    2016-05-01

    Sepsis is an acute systemic inflammatory response to infection associated with high patient mortality (28-40%). We hypothesized that interleukin (IL)-30, a novel cytokine protecting mice against liver injury resulting from inflammation, would generate a protective effect against systemic inflammation and sepsis-induced death. Sepsis was induced by lipopolysaccharide (LPS) or cecal ligation and puncture (CLP). The inhibitory effects of IL-30 on septic inflammation and associated therapeutic effects were determined in wild-type, IL30 (p28)(-/-), IL10(-/-), and CD1d(-/-) mice. Mice treated with pIL30 gene therapy or recombinant IL-30 protein (rIL30) were protected from LPS-induced septic shock or CLP-induced polymicrobial sepsis and showed markedly less liver damage and lymphocyte apoptosis than control septic mice. The resulting reduction in mortality was mediated through attenuation of the systemic pro-inflammatory response and augmentation of bacterial clearance. Mice lacking IL-30 were more sensitive to LPS-induced sepsis. Natural killer-like T cells (NKT) produced much higher levels of IL-10 and lower levels of interferon-gamma and tumor necrosis factor-alpha in IL-30-treated septic mice than in control septic mice. Likewise, deficiency in IL-10 or NKT cells abolished the protective role of IL-30 against sepsis. Furthermore, IL-30 induced IL-10 production in purified and LPS-stimulated NKT cells. Blocking IL-6R or gp130 inhibited IL-30 mediated IL-10 production. IL-30 is important in modulating production of NKT cytokines and subsequent NKT cell-mediated immune regulation of other cells. Therefore, IL-30 has a role in prevention and treatment of sepsis via modulation of cytokine production by NKT. Copyright © 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  19. Country report: Germany. Preclinical evaluation of Y-90 labelled Rituximab and ERIC-1, two antibodies for tumor therapy

    International Nuclear Information System (INIS)

    Schomäcker, Klaus; Fischer, Thomas

    2010-01-01

    This project focuses on harnessing the great potential of radionuclide therapy, using various different vehicles to transport radionuclides into tumor tissues. A central aim of the project will be to manufacture specific vehicle molecules whose tumor affinity and suitability for radioactive coupling have already been proven through laboratory trials on animals and cell cultures at the Department of Nuclear Medicine, University of Cologne and to label it with Y- 90. The vectors to be used to transport radionuclides into tumor tissue for treatment are antibodies against lymphomas and neuroblastomas. The technology applied for coupling Y-90 to various antibodies has been developed to a high level in Cologne and is now ready to be transferred and adapted to GMP (Good Manufacturing Practice) conditions. The antibody against NHL can be acquired commercially and must then be modified for binding to the therapeutically active nuclide Y-90. Similarly, the antibody against neuroblastoma must also be modified to bind to Y-90 but is produced in Cologne. To improve the therapeutic value of antibodies we tried to introduce the pretargeting method

  20. Expression of IL-23/Th17-related cytokines in basal cell carcinoma and in the response to medical treatments.

    Directory of Open Access Journals (Sweden)

    Cristina Pellegrini

    Full Text Available Several immune-related markers have been implicated in basal cell carcinoma (BCC pathogenesis. The BCC inflammatory infiltrate is dominated by Th2 cytokines, suggesting a specific state of immunosuppression. In contrast, regressing BCC are characterized by a Th1 immune response with IFN-γ promoting a tumor suppressive activity. IL-23/Th17-related cytokines, as interleukin (IL-17, IL-23 and IL-22, play a significant role in cutaneous inflammatory diseases, but their involvement in skin carcinogenesis is controversial and is poorly investigated in BCC. In this study we investigated the expression of IFN-γ, IL-17, IL-23 and IL-22 cytokines in BCC at the protein and mRNA level and their modulation during imiquimod (IMQ treatment or photodynamic therapy (PDT. IFN-γ, IL-17, IL-23 and IL-22 levels were evaluated by immunohistochemistry and quantitative Real Time PCR in 41 histopathologically-proven BCCs (28 superficial and 13 nodular from 39 patients. All BCC samples were analyzed at baseline and 19 of 41 also during medical treatment (9 with IMQ 5% cream and 10 with MAL-PDT. Association between cytokines expression and clinico-pathological variables was evaluated. Higher levels of IFN-γ, IL-17, IL-23 and IL-22 were found in BCCs, mainly in the peritumoral infiltrate, compared to normal skin, with the expression being correlated to the severity of the inflammatory infiltrate. IFN-γ production was higher in superficial BCCs compared to nodular BCCs, while IL-17 was increased in nodular BCCs. A significant correlation was found between IFN-γ and IL-17 expression with both cytokines expressed by CD4+ and CD8+ T-cells. An increase of all cytokines occurred during the inflammatory phase induced by IMQ and at the early time point of PDT treatment, with significant evidence for IFN-γ, IL-23, and IL-22. Our results confirm the role of IFN-γ and support the involvement of IL-23/Th17-related cytokines in BCC pathogenesis and in the inflammatory response

  1. Expression of IL-23/Th17-related cytokines in basal cell carcinoma and in the response to medical treatments.

    Science.gov (United States)

    Pellegrini, Cristina; Orlandi, Augusto; Costanza, Gaetana; Di Stefani, Alessandro; Piccioni, Antonella; Di Cesare, Antonella; Chiricozzi, Andrea; Ferlosio, Amedeo; Peris, Ketty; Fargnoli, Maria Concetta

    2017-01-01

    Several immune-related markers have been implicated in basal cell carcinoma (BCC) pathogenesis. The BCC inflammatory infiltrate is dominated by Th2 cytokines, suggesting a specific state of immunosuppression. In contrast, regressing BCC are characterized by a Th1 immune response with IFN-γ promoting a tumor suppressive activity. IL-23/Th17-related cytokines, as interleukin (IL)-17, IL-23 and IL-22, play a significant role in cutaneous inflammatory diseases, but their involvement in skin carcinogenesis is controversial and is poorly investigated in BCC. In this study we investigated the expression of IFN-γ, IL-17, IL-23 and IL-22 cytokines in BCC at the protein and mRNA level and their modulation during imiquimod (IMQ) treatment or photodynamic therapy (PDT). IFN-γ, IL-17, IL-23 and IL-22 levels were evaluated by immunohistochemistry and quantitative Real Time PCR in 41 histopathologically-proven BCCs (28 superficial and 13 nodular) from 39 patients. All BCC samples were analyzed at baseline and 19 of 41 also during medical treatment (9 with IMQ 5% cream and 10 with MAL-PDT). Association between cytokines expression and clinico-pathological variables was evaluated. Higher levels of IFN-γ, IL-17, IL-23 and IL-22 were found in BCCs, mainly in the peritumoral infiltrate, compared to normal skin, with the expression being correlated to the severity of the inflammatory infiltrate. IFN-γ production was higher in superficial BCCs compared to nodular BCCs, while IL-17 was increased in nodular BCCs. A significant correlation was found between IFN-γ and IL-17 expression with both cytokines expressed by CD4+ and CD8+ T-cells. An increase of all cytokines occurred during the inflammatory phase induced by IMQ and at the early time point of PDT treatment, with significant evidence for IFN-γ, IL-23, and IL-22. Our results confirm the role of IFN-γ and support the involvement of IL-23/Th17-related cytokines in BCC pathogenesis and in the inflammatory response during IMQ and

  2. Suppressor of cytokine signalling-3 expression inhibits cytokine-mediated destruction of primary mouse and rat pancreatic islets and delays allograft rejection

    DEFF Research Database (Denmark)

    Rønn, S G; Börjesson, A; Bruun, C

    2008-01-01

    The pro-inflammatory cytokines IL-1 and IFNgamma are critical molecules in immune-mediated beta cell destruction leading to type 1 diabetes mellitus. Suppressor of cytokine signalling (SOCS)-3 inhibits the cytokine-mediated destruction of insulinoma-1 cells. Here we investigate the effect of SOCS...... in primary rodent beta cells and diabetic animal models....

  3. Cytokine networks in the establishment and maintenance of pregnancy.

    Science.gov (United States)

    Orsi, Nicolas Michel

    2008-12-01

    Pregnancy is an immunological compromise geared towards inducing maternal immunopermissiveness that promotes tolerance of the foetal allograft. This process is mediated by an extensive array of cytokines, which operate in a highly coordinated and complex network system at both local (compartmentalized) and systemic levels. These glycoproteins also play an active role in gametogenesis and act as embryotrophins in the maternal tract. In addition to being involved in the seminal plasma-induced priming of the uterus for the establishment of pregnancy, they mediate the embryo-maternal paracrine dialogue and thus orchestrate various facets of embryo implantation and trophoblast invasion. Cytokines are recognized regulators of embryogenesis and foetal development, and participate in the inflammatory triggering of the onset of labour in late pregnancy. Given their central role in gestation, deregulations in cytokine networks are correspondingly associated with a host of human pregnancy complications, including miscarriage, pre-eclampsia and preterm labour.

  4. Proinflammatory cytokine levels in patients with conversion disorder.

    Science.gov (United States)

    Tiyekli, Utkan; Calıyurt, Okan; Tiyekli, Nimet Dilek

    2013-06-01

    It was aimed to evaluate the relationship between proinflammatory cytokine levels and conversion disorder both commonly known as stress regulated. Baseline proinflammatory cytokine levels-[Tumour necrosis factor alpha (TNF-α), Interleukin-1 beta (IL-1β), Interleukin-6 (IL-6)]-were evaluated with enzyme-linked immunosorbent assay in 35 conversion disorder patients and 30 healthy controls. Possible changes in proinflammatory cytokine levels were evaluated again, after their acute phase in conversion disorder patients. Statistically significant decreased serum TNF-α levels were obtained in acute phase of conversion disorder. Those levels increased after acute conversion phase. There were no statistically significant difference observed between groups in serum IL-1β and (IL-6) levels. Stress associated with conversion disorder may suppress immune function in acute conversion phase and may have diagnostic and therapeutic value.

  5. Cytokine-producing T cell subsets in human leishmaniasis

    DEFF Research Database (Denmark)

    Kemp, Kåre

    2000-01-01

    Leishmania specific Th1/Th2 cells have been identified in humans as well as in mice. There is a correlation between the clinical outcome of the infection and the cytokine response profile. Generally, the production of Th2 cytokines leads to severe infection, whereas the production of Th1 cytokines...... leads to subclinical or mild infections. In mice, an infection leads to a polarisation of either Th1 or Th2 Leishmania antigen specific cells. In contrast, both Th1 and Th2 Leishmania antigen specific cells can be identified in humans cured from L. donovani infections. Theoretically, Th1 cells and Th2...... cells mutually down-regulate each other. However, the presence of antigen specific regulatory T cell subsets may provide an environment that allows the presence of both Th1 and Th2 cells....

  6. Dysregulation of suppressor of cytokine signaling 3 in keratinocytes causes skin inflammation mediated by interleukin-20 receptor-related cytokines.

    Directory of Open Access Journals (Sweden)

    Ayako Uto-Konomi

    Full Text Available Homeostatic regulation of epidermal keratinocytes is controlled by the local cytokine milieu. However, a role for suppressor of cytokine signaling (SOCS, a negative feedback regulator of cytokine networks, in skin homeostasis remains unclear. Keratinocyte specific deletion of Socs3 (Socs3 cKO caused severe skin inflammation with hyper-production of IgE, epidermal hyperplasia, and S100A8/9 expression, although Socs1 deletion caused no inflammation. The inflamed skin showed constitutive STAT3 activation and up-regulation of IL-6 and IL-20 receptor (IL-20R related cytokines, IL-19, IL-20 and IL-24. Disease development was rescued by deletion of the Il6 gene, but not by the deletion of Il23, Il4r, or Rag1 genes. The expression of IL-6 in Socs3 cKO keratinocytes increased expression of IL-20R-related cytokines that further facilitated STAT3 hyperactivation, epidermal hyperplasia and neutrophilia. These results demonstrate that skin homeostasis is strictly regulated by the IL-6-STAT3-SOCS3 axis. Moreover, the SOCS3-mediated negative feedback loop in keratinocytes has a critical mechanistic role in the prevention of skin inflammation caused by hyperactivation of STAT3.

  7. CHARACTERISTIC INFLUENCE OF PULSE ELECTROTHERAPY (ELECTRICAL SLEEP AT A NEUROPEPTIDE-CYTOKINE LINKS IN ARTERIAL HYPERTENSION ACCOMPANIED BY A ASTHENONEUROTIC DISTURBANCES IN YOUNG MEN EMPLOYED IN STRESSFUL PROFESSIONS

    Directory of Open Access Journals (Sweden)

    A. V. Gertsev

    2018-01-01

    Full Text Available Disorders in functioning of major regulatory systems in patients with somatic diseases required development of new and effective integrated approaches to their treatment and prevention. Effective electrotherapy (electrical sleep is among these methods. Despite existence of studies proving high efficiency of electrical sleep results in therapeutic practice, some open questions remain concerning impact of this treatment upon neuropeptide-cytokine links of immune system, which is one of the most important effector of pathogenesis in cardiovascular diseases in young persons with hypertension from the group occupied with stressful jobs. In this connection, the aim of our study was to investigate the influence on electrical sleep upon neuropeptide-cytokine profile in arterial hypertension conditions accomplished by asthenic-neurotic disorders in young men from the group of stressful activities. The following treatment groups were formed: 1st (n = 12, antihypertensive therapy; 2nd (n = 10, complex therapeutic measures added to antihypertensive therapy plus minor tranquilizers; in the 3rd group (n = 12, electric sleep was performed. Neuropeptide-cytokine profile was investigated as serum contents of β-endorphin, proinflammatory (TNFα, IL-1β, IL-6 and anti-inflammatory (IL-4, IL-10 cytokines. In the course of the clinical and laboratory examination, the authors have found that electric sleep applied in a complex primary schedule, with antihypertensive drug treatment in patients with hypertension and asthenic-neurotic disorders proved to exert optimizing effect upon functioning of neuropeptide-cytokine pool of immune system, which manifested by stimulation of beta-endorphin production, a decrease via regulation of proinflammatory effectors (TNFα, IL-1β, IL-6, and increased anti-inflammatory cytokines (IL-4, IL-10. 

  8. Plasma levels of cytokines and chemokines and the risk of mortality in HIV-infected individuals: a case-control analysis nested in a large clinical trial.

    Science.gov (United States)

    French, Martyn A; Cozzi-Lepri, Alessandro; Arduino, Roberto C; Johnson, Margaret; Achhra, Amit C; Landay, Alan

    2015-04-24

    All-cause mortality and serious non-AIDS events (SNAEs) in individuals with HIV-1 infection receiving antiretroviral therapy are associated with increased production of interleukin-6 which appears to be driven by monocyte/macrophage activation. Plasma levels of other cytokines or chemokines associated with immune activation might also be biomarkers of an increased risk of mortality and/or SNAEs. Baseline plasma samples from 142 participants enrolled into the Strategies for Management of Antiretroviral Therapy study, who subsequently died, and 284 matched controls, were assayed for levels of 15 cytokines and chemokines. Cytokine and chemokine levels were analysed individually and when grouped according to function (innate/proinflammatory response, cell trafficking and cell activation/proliferation) for their association with the risk of subsequent death. Higher plasma levels of proinflammatory cytokines (interleukin-6 and tumour necrosis factor-α) were associated with an increased risk of all-cause mortality but in analyses adjusted for potential confounders, only the association with interleukin-6 persisted. Increased plasma levels of the chemokine CXCL8 were also associated with all-cause mortality independently of hepatitis C virus status but not when analyses were adjusted for all confounders. In contrast, higher plasma levels of cytokines mediating cell activation/proliferation were not associated with a higher mortality risk and exhibited a weak protective effect when analysed as a group. Whereas plasma levels of interleukin-6 are the most informative biomarker of cytokine dysregulation associated with all-cause mortality in individuals with HIV-1 infection, assessment of plasma levels of CXCL8 might provide information about causes of mortality and possibly SNAEs.

  9. The influence of inflammatory cytokines in physiopathology of suicidal behavior.

    Science.gov (United States)

    Miná, V A L; Lacerda-Pinheiro, S F; Maia, L C; Pinheiro, R F F; Meireles, C B; de Souza, S I R; Reis, A O A; Bianco, B; Rolim, M L N

    2015-02-01

    Based on the urgent need for reliable biomarkers in relation to suicide risk both for more accurate prediction as well as for new therapeutic opportunities, several researchers have been studied evidences of the potential participation of inflammatory processes in the brain, in particular cytokines, in suicide. The purpose of this review was to analyze the associations between inflammation markers and suicide. To achieve this goal, a systematic review of literature was conducted via electronic database Scopus using the Medical Subject Headings (MeSH) terms: "cytokines", "suicide" and "inflammation". Through this search it was found 54 articles. After analyzing them 15 met the eligibility criteria and were included in the final sample. One of the most mentioned inflammatory markers was Interferon-α (IFN-α), a pro-inflammatory cytokine which has been shown to increase serum concentrations of pro-inflammatory cytokines such as interleukin (IL)-1, IL-6, tumor necrosis factor-a (TNF- α) and IFN-ϒ, which are factors increased suicide victims and attempters. In this line, IL-6 is not only found to be elevated in the cerebrospinal fluid of suicide attempters, even its levels in the peripheral blood have been proposed as a biological suicide marker. Another study stated that increased levels of IL-4 and IL-13 transcription in the orbitofrontal cortex of suicides suggest that these cytokines may affect neurobehavioral processes relevant to suicide. A lack of studies and great amount of cross-sectional studies. Inflammation may play an important role in the pathophysiology of suicide, especially, levels of some specific inflammatory cytokines. Copyright © 2014 Elsevier B.V. All rights reserved.

  10. Effect of Probiotic Supplement on Cytokine Levels in HIV-Infected Individuals: A Preliminary Study

    Directory of Open Access Journals (Sweden)

    Katia Falasca

    2015-09-01

    Full Text Available Inflammation persists in patients infected with HIV. Reduction of inflammatory cytokines and microbial translocation might be one way that this could be managed. Purpose: The anti-inflammatory properties of certain probiotic strains prompted us to investigate whether a probiotic could reduce the inflammatory index of HIV-infected patients. Methods: The study involved 30 HIV+ males on antiretroviral therapy, who were given one bottle of fermented milk Yakult Light® containing Lactobacillus casei Shirota (LcS twice a day for four weeks. Results: The probiotic LcS was associated with an increase of T lymphocytes and a significant increase of CD56+ cells (p = 0.04. There was also a significant decrease of mRNA levels of TGFβ, IL-10 and IL-12 (p < 0.001 and IL-1β expression (p < 0.001 and an increase of serum IL-23 (p = 0.03. In addition, decreased inflammation and cardiovascular risk were observed, as shown by a reduction of cystatin C (p < 0.001. Conclusions: These data provide preliminary evidence that probiotic supplementation may modulate certain immunological parameters and some of the cytokines that were analyzed. Thus, we propose that LcS may be an inexpensive and practical strategy to support the immune function of HIV+ patients.

  11. MIF family cytokines in cardiovascular diseases and prospects for precision-based therapeutics.

    Science.gov (United States)

    Tilstam, Pathricia V; Qi, Dake; Leng, Lin; Young, Lawrence; Bucala, Richard

    2017-07-01

    Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine with chemokine-like functions that increasingly is being studied in different aspects of cardiovascular disease. MIF was first identified as a proinflammatory and pro-survival mediator within the immune system, and a second structurally related MIF family member, D-dopachrome tautomerase (a.k.a. MIF-2), was reported recently. Both MIF family members are released by myocardium and modulate the manifestations of cardiovascular disease, specifically in myocardial ischemia. Areas covered: A scientific overview is provided for the involvement of MIF family cytokines in the inflammatory pathogenesis of atherosclerosis, myocardial infarction, and ischemia-reperfusion injury. We summarize findings of experimental, human genetic and clinical studies, and suggest therapeutic opportunities for modulating the activity of MIF family proteins that potentially may be applied in a MIF allele specific manner. Expert opinion: Knowledge of MIF, MIF-2 and their receptor pathways are under active investigation in different types of cardiovascular diseases, and novel therapeutic opportunities are being identified. Clinical translation may be accelerated by accruing experience with MIF-directed therapies currently in human testing in cancer and autoimmunity.

  12. Cytokine Secreting Microparticles Engineer the Fate and the Effector Functions of T-Cells.

    Science.gov (United States)

    Majedi, Fatemeh S; Hasani-Sadrabadi, Mohammad Mahdi; Kidani, Yoko; Thauland, Timothy J; Moshaverinia, Alireza; Butte, Manish J; Bensinger, Steven J; Bouchard, Louis-S

    2018-02-01

    T-cell immunotherapy is a promising approach for cancer, infection, and autoimmune diseases. However, significant challenges hamper its therapeutic potential, including insufficient activation, delivery, and clonal expansion of T-cells into the tumor environment. To facilitate T-cell activation and differentiation in vitro, core-shell microparticles are developed for sustained delivery of cytokines. These particles are enriched by heparin to enable a steady release of interleukin-2 (IL-2), the major T-cell growth factor, over 10+ d. The controlled delivery of cytokines is used to steer lineage specification of cultured T-cells. This approach enables differentiation of T-cells into central memory and effector memory subsets. It is shown that the sustained release of stromal cell-derived factor 1α could accelerate T-cell migration. It is demonstrated that CD4+ T-cells could be induced to high concentrations of regulatory T-cells through controlled release of IL-2 and transforming growth factor beta. It is found that CD8+ T-cells that received IL-2 from microparticles are more likely to gain effector functions as compared with traditional administration of IL-2. Culture of T-cells within 3D scaffolds that contain IL-2-secreting microparticles enhances proliferation as compared with traditional, 2D approaches. This yield a new method to control the fate of T-cells and ultimately to new strategies for immune therapy. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  13. Multiple effects of TRAIL in human carcinoma cells: Induction of apoptosis, senescence, proliferation, and cytokine production

    International Nuclear Information System (INIS)

    Levina, Vera; Marrangoni, Adele M.; DeMarco, Richard; Gorelik, Elieser; Lokshin, Anna E.

    2008-01-01

    TRAIL is a death ligand that induces apoptosis in malignant but not normal cells. Recently the ability of TRAIL to induce proliferation in apoptosis-resistant normal and malignant cells was reported. In this study, we analyzed TRAIL effects in apoptosis sensitive MCF7, OVCAR3 and H460 human tumor cell lines. TRAIL at low concentrations preferentially induced cell proliferation. At 100 ng/ml, apoptotic death was readily observed, however surviving cells acquired higher proliferative capacity. TRAIL-stimulated production of several cytokines, IL-8, RANTES, MCP-1 and bFGF, and activation of caspases 1 and 8 was essential for this effect. Antibodies to IL-8, RANTES, and bFGF blocked TRAIL-induced cell proliferation and further stimulated apoptosis. For the first time, we report that high TRAIL concentrations induced cell senescence as determined by the altered morphology and expression of several senescence markers: SA-β-gal, p21 Waf1/Cip1 , p16 INK4a , and HMGA. Caspase 9 inhibition protected TRAIL-treated cells from senescence, whereas inhibition of caspases 1 and 8 increased the yield of SLP cells. In conclusion, in cultured human carcinoma cells, TRAIL therapy results in three functional outcomes, apoptosis, proliferation and senescence. TRAIL-induced proapoptotic and prosurvival responses correlate with the strength of signaling. TRAIL-induced cytokine production is responsible for its proliferative and prosurvival effects

  14. Cytokine vaccination: neutralising IL-1alpha autoantibodies induced by immunisation with homologous IL-1alpha

    DEFF Research Database (Denmark)

    Svenson, M; Hansen, M B; Thomsen, Allan Randrup

    2000-01-01

    High-affinity IgG autoantibodies (aAb) to IL-1alpha are among the most frequently found aAb to cytokines in humans. To establish an animal model with aAb to IL-1alpha, we immunised mice with recombinant murine IL-1alpha. Unprimed and Bacille Calmette-Guérin (BCG)-primed BALB/cA mice were vaccinated...... in mice by vaccination with recombinant murine IL-1alpha conjugated to PPD. Studies of the effects of IL-1alpha aAb in such animals may help clarify the importance of naturally occurring IL-1alpha aAb in humans and permit the evaluation of future therapies with cytokine aAb in patients...... with IL-1alpha coupled to purified protein derivative of tuberculin (PPD). Both unprimed and primed animals developed IgG aAb to IL-1alpha. These aAb persisted at high levels more than 100 days after vaccination and did not cross-react with murine IL-1beta. The induced anti-IL-1alpha aAb inhibited binding...

  15. Relationship between Severity of Aseptic Meningitis and Cerebrospinal Fluid Cytokine Levels.

    Science.gov (United States)

    Hikita, Norikatsu; Seto, Toshiyuki; Yamashita, Kanako; Iritani, Nobuhiro; Aata, Minoru; Ogura, Hisashi; Shintaku, Haruo

    2015-12-01

    Pediatricians sometimes see patients with severe aseptic meningitis and prolonged fever or severe headache, or both. This condition generally has a good prognosis and is usually treated with supportive therapy. However, there is neither guideline nor consensus for the treatment of patients with severe aseptic meningitis. Here, we investigated the relationship between disease severity and biomarkers. The subjects were 32 children aged 0 to 14 years, 23 of whom had aseptic meningitis and 9 of whom were meningitis-free controls. Aseptic meningitis was retrospectively categorized into two subgroups, namely mumps meningitis (MM) and viral meningitis excluding that caused by mumps (EM). We defined a novel aseptic meningitis severity score (AMSS) from the signs and symptoms of aseptic meningitis and thus evaluated disease severity. We analyzed the profiles of cytokines in the patients' cerebrospinal fluid (CSF). The AMSS in MM was significantly higher than that in EM. IL-4, IL-6, IL-8, IL-10, and G-CSF levels in MM and EM CSF were higher than those in control CSF. IFN-γ levels were higher in MM than in controls (p<0.01). IL-10 and IFN-γ levels in MM were higher than those in EM. MM was more severe than EM. One likely reason is the higher CSF cytokine levels in MM. IFN-γ may be a potentially strong biomarker of MM severity. Our findings would help further understanding

  16. Distinctive cytokines as biomarkers predicting fatal outcome of severe Staphylococcus aureus bacteremia in mice.

    Science.gov (United States)

    van den Berg, Sanne; Laman, Jon D; Boon, Louis; ten Kate, Marian T; de Knegt, Gerjo J; Verdijk, Rob M; Verbrugh, Henri A; Nouwen, Jan L; Bakker-Woudenberg, Irma A J M

    2013-01-01

    Invasive Staphylococcus aureus infections are frequently associated with bacteraemia. To support clinical decisions on antibiotic therapy, there is an urgent need for reliable markers as predictors of infection outcome. In the present study in mice, bacteraemia was established by intravenous inoculation of a clinical S. aureus isolate at the LD50 inoculum. As potential biomarkers for fatal outcome, blood culture (qualitative and quantitative), serum levels of C-reactive protein (CRP), as well as 31 selected cytokines and chemokines were assessed during the first three days of infection. A positive S. aureus blood culture, the quantitative blood culture, CRP levels, and levels of eight cytokines were indicative for the presence of S. aureus bacteraemia. However, only tumor necrosis factor (TNF) α, interleukin (IL) 1α, and keratinocyte chemoattractant (KC; a functional homologue of human IL-8) were each significantly elevated in eventually non-surviving infected mice versus eventually surviving infected mice. In severe S. aureus bacteraemia in mice, TNF-α, IL-1α, and KC are biomarkers predicting fatal outcome of infection. KC was a biomarker elevated irrespective the progression of infection, which is very interesting regarding clinical application in view of the heterogeneity of patients experiencing bacteraemia in this respect.

  17. Evaluation of Inflammatory Cytokine Secretion by Human Alveolar Macrophages

    Directory of Open Access Journals (Sweden)

    J. E. Losa García

    1999-01-01

    Full Text Available The alveolar macrophage (AM secretes interleukin 1β (IL-1β, tumour necrosis factor-α (TNF-α, interleukin-6 (IL-6 and interleukin-8 (IL-8, all of them inflammatory cytokines involved in the pathogenesis of many lung diseases. The aim of the present work was to evaluate the basal and stimulated secretion of these cytokines by human AMs. Human AMs were collected by bronchoalveolar lavage (BAL from four healthy controls and 13 patients with diffuse interstitial lung disease (five cases of sarcoidosis, three of hypersensitivity pneumonitis and five of idiopathic pulmonary fibrosis. AMs were cultured in the presence or absence of different concentrations of lipopolysaccharide (LPS, phorbolmyristate and gammainterferon. IL-1β, TNF-α, IL-6 and IL-8 levels were measured in BAL fluid and culture supernatant using specific enzyme-linked immunosorbent assays. The substance found to stimulate the secretion of inflammatory cytokines to the greatest extent was LPS at a concentration of 10 μg/ml. Regarding the secretion of IL-1β, four observations were of interest: basal secretion was very low; LPS exerted a potent stimulatory effect; considerable within-group variability was observed; and there were no significant differences in the comparisons among groups. With respect to TNF-α secretion, the results were similar. The only striking finding was the higher basal secretion of this cytokine with respect to that of IL-1β. Regarding the secretion of IL-6, the same pattern followed by TNF-α was found. However, it should be stressed that the increase induced by LPS was smaller than in the two previous cytokines. Regarding the secretion of IL-8, three findings were patent: the strong basal secretion of this cytokine; the moderate increase induced by LPS; and the existence of significant differences among the different groups with respect to the stimulated secretion of this cytokine, which reached maximum values in patients with idiopathic pulmonary

  18. Serum levels of the pro-inflammatory cytokine interleukin-12 and the anti-inflammatory cytokine interleukin-10 in patients with psoriasis treated by the Goeckerman regimen

    Energy Technology Data Exchange (ETDEWEB)

    Borska, L.; Andrys, C.; Krejsek, J.; Hamakova, K.; Kremlacek, J.; Ettler, K.; Fiala, Z. [Charles University Prague, Hradec Kralove (Czech Republic)

    2008-08-15

    The Goeckerman regimen (GR) involves the dermal application of a crude coal tar (polycyclic aromatic hydrocarbon, PAH) and exposure to ultraviolet (UV) radiation. Both PAH and UV radiation exhibit immunosuppressive activity. This study describes the changes in the serum levels of the pro-inflammatory cytokine interleukin-12 (IL-12) and the anti-inflammatory cytokine IL-10 in patients with psoriasis (n = 55) treated with GR. The serum levels of IL-12 and IL-10 were compared before and after GR. In addition, the IL-12 and IL-10 levels in psoriatic patients were compared with those in a control group of healthy blood donors (n = 47). The Psoriasis Area and Severity Index (PASI) was used to evaluate the efficacy of GR. When compared with the control group, both IL-12 and IL-10 were significantly higher in psoriatic patients in all cases (P < 0.001). When compared before and after GR, the IL-12 and IL-10 levels (P < 0.01) and PASI value (P < 0.001) were significantly lower after GR. The decrease in the serum level of IL-12 and IL-10 after GR was related to the entry value before GR (IL-12, r = 0.60, P < 0.001; IL-10, r = 0.36, P < 0.01). There was a significant correlation between the IL-10 level before GR and the PASI value after GR = -0.39; P < 0.01). The results indicate a strong pro-inflammatory effect of IL-12 in the immunopathogenesis of psoriasis, and confirm the immunosuppressive and anti-inflammatory effect of GR. IL-10 seems to be a promising individual marker for a positive effect of GR therapy.

  19. Cytokine and Phenotypic Cell Profiles of Leishmania infantum Infection in the Dog

    Directory of Open Access Journals (Sweden)

    Carla Maia

    2012-01-01

    Full Text Available Leishmaniasis has reemerged in recent years showing a wider geographic distribution and increased global incidence of human and canine disease than previously known. Dogs are the main domestic/peridomestic reservoir hosts of zoonotic visceral leishmaniasis caused by Leishmania infantum. Since the evolution of leishmaniasis and clinical appearance is a consequence of complex interactions between the parasite and host immune response, a profound knowledge about the immune profile developed in dog's infection is crucial for vaccine and immunomodulatory therapy design. The main goal of this paper is to compile the recent advances made on cytokine and phenotypic cell profiles in different tissues and organs of dogs infected with L. infantum. This paper also stressed that the knowledge of the immune responses developed, namely, in liver, lymph node, and spleen is very limited. All data emphasizes that more research on canine leishmaniasis is necessary for the development of new and efficacious tools to control zoonotic leishmaniasis.

  20. Pro-Inflammatory Cytokine Levels in HIV Infected and Uninfected Pregnant Women with and without Preeclampsia.

    Directory of Open Access Journals (Sweden)

    Niren Ray Maharaj

    Full Text Available Preeclampsia and HIV/AIDS are inflammatory conditions that contribute significantly to adverse maternal and foetal outcomes. The immune reconstitution effects of HAART on inflammatory mediators has not been adequately studied in pregnancy and may impact on the inflammatory cytokine network in women with co-morbid preeclampsia. Our study evaluated changes in pro-inflammatory cytokines IL-2, TNF-α, IFN-γ and IL-6 in HIV infected preeclamptic women on HAART.A prospective experimental study was conducted at Prince Mshiyeni Memorial Hospital between July 2013 and September 2014. One hundred and ninety three pregnant women were recruited into 4 groups: uninfected normotensive (50; 26%, infected normotensive (45; 23%, uninfected preeclamptic (53; 28% and infected preeclamptic women (45; 23%. Serum levels of cytokines TNF-α, IFN- γ, IL-2 and IL-6 were determined using commercially available kits and a Cytometric Bead Array (CBA. Comparative data was recorded and analysed descriptively.In the control groups (normotensive, significantly lower values were found in IL-2 (p = 0.010, TNF-α (p = 0.045, and IL-6 (p = 0.005; and a non-significant decrease was observed in IFN-γ (p = 0.345 in HIV infected women on HAART compared to uninfected controls. In the experimental group (preeclamptic women, significantly reduced levels were observed in IL-2 and TNF-α (p = 0.001; p = 0.000 and non-significant decreases were observed in IFN-γ and IL-6 (p = 0.023; p = 0.086 in HIV infected women on HAART compared with uninfected preeclamptic women. Non-significant differences were observed between uninfected preeclamptic and normotensive women.In uncomplicated/normotensive pregnancies, HIV/HAART is associated with significant decreases in IL-2, TNF-α and IL-6, and in preeclamptic women significant decreases in IL-2 and TNF-α were observed. These findings suggest that HIV/HAART impacts on pro-inflammatory cytokines in women with co-morbid preeclampsia. This provides

  1. Rheumatoid arthritis: Recent advances on its etiology, role of cytokines and pharmacotherapy.

    Science.gov (United States)

    Alam, Javaid; Jantan, Ibrahim; Bukhari, Syed Nasir Abbas

    2017-08-01

    An autoimmune disease is defined as a clinical syndrome resulted from an instigation of both T cell and B cell or individually, in the absence of any present infection or any sort of distinguishable cause. Clonal deletion of auto reactive cells remains the central canon of immunology for decades, keeping the role of T cell and B cell aside, which are actually the guards to recognize the entry of foreign body. According to NIH, 23.5 million Americans are all together affected by these diseases. They are rare, but with the exception of RA. Rheumatoid arthritis is chronic and systemic autoimmune response to the multiple joints with unknown ethology, progressive disability, systemic complications, early death and high socioeconomic costs. Its ancient disease with an old history found in North American tribes since 1500 BCE, but its etiology is yet to be explored. Current conventional and biological therapies used for RA are not fulfilling the need of the patients but give only partial responses. There is a lack of consistent and liable biomarkers of prognosis therapeutic response, and toxicity. Rheumatoid arthritis is characterized by hyperplasic synovium, production of cytokines, chemokines, autoantibodies like rheumatoid factor (RF) and anticitrullinated protein antibody (ACPA), osteoclastogensis, angiogenesis and systemic consequences like cardiovascular, pulmonary, psychological, and skeletal disorders. Cytokines, a diverse group of polypeptides, play critical role in the pathogenesis of RA. Their involvement in autoimmune diseases is a rapidly growing area of biological and clinical research. Among the proinflammatory cytokines, IL-1α/β and TNF-α trigger the intracellular molecular signalling pathway responsible for the pathogenesis of RA that leads to the activation of mesenchymal cell, recruitment of innate and adaptive immune system cells, activation of synoviocytes which in term activates various mediators including tumour necrosis factor-alpha (TNF

  2. Pro-Inflammatory Cytokine Levels in HIV Infected and Uninfected Pregnant Women with and without Preeclampsia.

    Science.gov (United States)

    Maharaj, Niren Ray; Phulukdaree, Alisa; Nagiah, Savania; Ramkaran, Prithiksha; Tiloke, Charlette; Chuturgoon, Anil Amichund

    2017-01-01

    Preeclampsia and HIV/AIDS are inflammatory conditions that contribute significantly to adverse maternal and foetal outcomes. The immune reconstitution effects of HAART on inflammatory mediators has not been adequately studied in pregnancy and may impact on the inflammatory cytokine network in women with co-morbid preeclampsia. Our study evaluated changes in pro-inflammatory cytokines IL-2, TNF-α, IFN-γ and IL-6 in HIV infected preeclamptic women on HAART. A prospective experimental study was conducted at Prince Mshiyeni Memorial Hospital between July 2013 and September 2014. One hundred and ninety three pregnant women were recruited into 4 groups: uninfected normotensive (50; 26%), infected normotensive (45; 23%), uninfected preeclamptic (53; 28%) and infected preeclamptic women (45; 23%). Serum levels of cytokines TNF-α, IFN- γ, IL-2 and IL-6 were determined using commercially available kits and a Cytometric Bead Array (CBA). Comparative data was recorded and analysed descriptively. In the control groups (normotensive), significantly lower values were found in IL-2 (p = 0.010), TNF-α (p = 0.045), and IL-6 (p = 0.005); and a non-significant decrease was observed in IFN-γ (p = 0.345) in HIV infected women on HAART compared to uninfected controls. In the experimental group (preeclamptic) women, significantly reduced levels were observed in IL-2 and TNF-α (p = 0.001; p = 0.000) and non-significant decreases were observed in IFN-γ and IL-6 (p = 0.023; p = 0.086) in HIV infected women on HAART compared with uninfected preeclamptic women. Non-significant differences were observed between uninfected preeclamptic and normotensive women. In uncomplicated/normotensive pregnancies, HIV/HAART is associated with significant decreases in IL-2, TNF-α and IL-6, and in preeclamptic women significant decreases in IL-2 and TNF-α were observed. These findings suggest that HIV/HAART impacts on pro-inflammatory cytokines in women with co-morbid preeclampsia. This provides a

  3. Th1 Cytokine-Secreting Recombinant Mycobacterium bovis Bacillus Calmette-Guérin and Prospective Use in Immunotherapy of Bladder Cancer

    Directory of Open Access Journals (Sweden)

    Yi Luo

    2011-01-01

    Full Text Available Intravesical instillation of Mycobacterium bovis bacillus Calmette-Guérin (BCG has been used for treating bladder cancer for 3 decades. However, BCG therapy is ineffective in approximately 30–40% of cases. Since evidence supports the T helper type 1 (Th1 response to be essential in BCG-induced tumor destruction, studies have focused on enhancing BCG induction of Th1 immune responses. Although BCG in combination with Th1 cytokines (e.g., interferon-α has demonstrated improved efficacy, combination therapy requires multiple applications and a large quantity of cytokines. On the other hand, genetic manipulation of BCG to secrete Th1 cytokines continues to be pursued with considerable interest. To date, a number of recombinant BCG (rBCG strains capable of secreting functional Th1 cytokines have been developed and demonstrated to be superior to BCG. This paper discusses current rBCG research, concerns, and future directions with an intention to inspire the development of this very promising immunotherapeutic modality for bladder cancer.

  4. Anti-Inflammatory Effect of Crocus sativus on Serum Cytokine Levels in Subjects with Metabolic Syndrome: A Randomized, Double-Blind, Placebo- Controlled Trial.

    Science.gov (United States)

    Kermani, Tayebe; Zebarjadi, Maedeh; Mehrad-Majd, Hassan; Mirhafez, Seyed-Reza; Shemshian, Maryam; Ghasemi, Faezeh; Mohammadzadeh, Elham; Mousavi, Seyed Hadi; Norouzy, Abdolreza; Moghiman, Toktam; Sadeghi, Akram; Ferns, Gordon; Avan, Amir; Mahdipour, Elaheh; Ghayour-Mobarhan, Majid

    2017-01-01

    A growing body of evidence supports an important role of inflammatory cytokines in the development and progression of the Metabolic Syndrome (MetS), which explains, at least in part, its relationship with an increased cardiovascular-risk. Several studies have reported the therapeutic-impact of crocus-sativus in a preclinical/clinical setting. Here we have explored the effects of crocus-sativus, on the serum concentrations of twelve serum cytokines in subjects with MetS in a randomized control trial. Forty four adult volunteers, who met the diagnostic-criteria of MetS, were enrolled and randomly divided into 2 groups, to receive 100 mg/day crocus-sativus for 12 weeks. 12 cytokines, including IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, TNF-α, MCP-1, IFN-γ, EGF, and VEGF were measured using sandwich chemi-luminescence assays before/after therapy. Individuals with MetS who received crocus-sativus had significantly (Ptherapeutic effects of this therapy in MetS patients via perturbation of serum cytokines and reducing the levels of triglyceride and LDL/TC, but further studies are required in larger populations. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  5. Th17- and Treg-related cytokine and mRNA expression are associated with acute and resolving Kawasaki disease.

    Science.gov (United States)

    Guo, M M-H; Tseng, W-N; Ko, C-H; Pan, H-M; Hsieh, K-S; Kuo, H-C

    2015-03-01

    Kawasaki disease is a vasculitis most commonly afflicting children Kawasaki disease. Blood samples were obtained from 186 children with Kawasaki disease at 24 h before IVIG therapy, followed by 3 days and 21 days after IVIG therapy. Thirty children with an acute febrile infectious disease and 30 healthy children were obtained as control. Plasma levels of Th17- and Treg-related cytokines including IL-6, IL-17A, IL-10, TGF-β, and mRNA expression levels of RORγt and Foxp3 were tested. Patients with Kawasaki disease had higher levels of plasma IL-17A (25.35 ± 3.21 vs 7.78 ± 1.78 pg/ml, P Kawasaki disease was associated with higher IL-17A and IL-6, a cytokine profile similar to other autoimmune diseases. IVIG therapy resulted in increased expression of Treg-related FoxP3. IVIG resistance was associated with higher levels of IL-10 and IL-17A. Our findings provide further evidence that Kawasaki disease is an autoimmune-like disease. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  6. Sex Therapy

    Science.gov (United States)

    Sex therapy Overview Sex therapy is a type of psychotherapy — a general term for treating mental health problems by talking with a mental health professional. Through sex therapy, you can address concerns about sexual function, ...

  7. The presence of cytokines in Langerhans' cell histiocytosis

    NARCIS (Netherlands)

    deGraaf, JH; Tamminga, RYJ; DamMeiring, A; Kamps, WA; Timens, W

    1996-01-01

    Langerhans' cell histiocytosis (LCH) is characterized by an accumulation and/or proliferation of cells with a Langerhans' cell (LC) phenotype. The aetiology and pathogenesis of LCH are unknown; it is suggested that LCH is caused by an immunological dysregulation. Production of cytokines is a central

  8. Oral warfarin intake affects skin inflammatory cytokine responses in rats.

    Science.gov (United States)

    Aleksandrov, Aleksandra Popov; Mirkov, Ivana; Zolotarevski, Lidija; Ninkov, Marina; Mileusnic, Dina; Kataranovski, Dragan; Kataranovski, Milena

    2017-09-01

    Warfarin is an anticoagulant used in prevention/prophylaxis of thromboembolism. Besides the effects on coagulation, non-hemorrhagic reactions have also been documented. Although cutaneous reactions were reported in some patients, the impact on skin immunity was not explored. In the present paper, the effect of 30-day oral warfarin intake on skin cytokine responses in rats was analyzed. Increased release of inflammatory cytokines (TNF, IL-1β and IL-10) was noted by skin explants from rats which received warfarin, but without effect on IL-6. No impact on epidermal cell cytokine secretion was seen, except a tendency of an increase of IL-6 response to stimulation with microbial product lipopolysaccharide (LPS). Topical application of contact allergen dinitrochlorobenzene (DNCB) resulted in slight (numerical solely) increase of TNF release by skin explants of warfarin-treated animals, while epidermal cells responded by increased secretion of all four cytokines examined. The data presented provide new information on the potential of oral warfarin to modulate skin innate immune activity. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Role of a Th2 cytokine inhibitor in asthma treatment

    Directory of Open Access Journals (Sweden)

    Jun Tamaoki

    2004-01-01

    Full Text Available The airway wall of asthmatic patients is infiltrated with inflammatory cells, consisting chiefly of eosinophils and T lymphocytes. Among these T lymphocytes, Th2 cells are involved in the regulation of the IgE immune response and local allergic inflammation, which underlie allergic diseases. Various cytokines produced and released by Th2 cells play important roles in the development of many allergic diseases, including asthma, and the exacerbations of their disease states. Therefore, targeting of Th2 cell-derived cytokines is a rational therapeutic strategy for the treatment of asthma. Corticosteroids and immunosuppressive agents can potently inhibit Th2 cytokine-mediated responses, but have no selectivity for Th2 cells: they also exert pharmacological activity against cells other than inflammatory cells, thereby potentially causing adverse side-effects. However, suplatast tosilate is the only specific Th2 cytokine inhibitor that can be used clinically and it has been used widely in Japan as a maintenance drug in the treatment of asthma, atopic dermatitis and allergic rhinitis. There is considerable evidence of the effectiveness of suplatast tosilate in patients with mild asthma or moderate persistent asthma. Furthermore, an effect on cough variant asthma and a steroid-sparing effect have also been reported for suplatast tosilate.

  10. A BACTERIAL CYTOKINE Mukamolova et al (1998) PNAS, 95, 8916 ...

    Indian Academy of Sciences (India)

    First page Back Continue Last page Overview Graphics. A BACTERIAL CYTOKINE Mukamolova et al (1998) PNAS, 95, 8916-8921. To grow or not to grow is a social decision. A resuscitation promoting factor (rpf) identified. The rpf protein shares similarity with M. tuberculosis and M. leprae ...

  11. Identification of overexpressed cytokines as serum biomarkers of ...

    African Journals Online (AJOL)

    Yomi

    assess the severity of fibrosis according to METAVIR classification. Afterward, 15 samples from healthy controls were .... liver fibrosis animal model as compared to healthy controls (Liu et al., 2011). Moreover, the levels .... ethanol abuse, viral infection, cholestasis or metabolic syndrome; these four cytokines were confirmed ...

  12. EVALUATION OF CYTOKINE GENE POLYMORPHISM IN B CELL LYMPHOID MALIGNANCIES

    Directory of Open Access Journals (Sweden)

    E. L. Nazarova

    2014-01-01

    Full Text Available Previous studies with some solid tumors has shown that polymorphisms of certain cytokine genes may be used as predictors of clinical outcome in the patients. It seemed important to evaluate potential correlations between production of certain pro- and anti-inflammatory cytokines and co-receptor molecules, and promoter polymorphism of the cytokine genes involved into regulation of cell proliferation, differentiation, apoptosis, lipid metabolism and blood clotting in the patients with hematological malignancies. The article contains our results concerning associations between of IL-1β, -2, -4, -10, -17, TNFα, and allelic polymorphisms of their genes in 62 patients with B cell lymphoid malignancies in an ethnically homogenous group (self-identified as Russians. We have shown that the GА and AA genotypes of the G-308A polymorphism in TNFα gene are significantly associated with increased production of this cytokine, being more common in aggressive non-Hodgkin lymphomas, more rare in multiple myeloma and in indolent non-Hodgkin lymphomas.

  13. Neonatal levels of cytokines and risk of autism spectrum disorders

    DEFF Research Database (Denmark)

    Abdallah, Morsi; Larsen, Nanna; Mortensen, Erik Lykke

    2012-01-01

    The aim of the study was to analyze cytokine profiles in neonatal dried blood samples (n-DBSS) retrieved from The Danish Newborn Screening Biobank of children developing Autism Spectrum Disorders (ASD) later in life and controls. Samples of 359 ASD cases and 741 controls were analyzed using Luminex...

  14. Etanercept Inhibits Pro-inflammatory Cytokines Expression in ...

    African Journals Online (AJOL)

    Purpose: To investigate the inhibitory role of Etanercept in pro-inflammatory cytokines such as TNF-α, IL-1β and IL-6 production in titanium (Ti) particle stimulated macrophages. Methods: Peritoneal macrophages were stimulated with 1 × 109 Ti particles and treated simultaneously with or without 10, 100, or 1000 ng/mL ...

  15. Etanercept Inhibits Pro-inflammatory Cytokines Expression in ...

    African Journals Online (AJOL)

    Purpose: To investigate the inhibitory role of Etanercept in pro-inflammatory cytokines such as TNF-α,. IL-1β and IL-6 production in titanium (Ti) particle stimulated macrophages. Methods: Peritoneal macrophages were stimulated with 1 × 109 Ti particles and treated simultaneously with or without 10, 100, or 1000 ng/mL ...

  16. Development of chronic colitis is dependent on the cytokine MIF

    NARCIS (Netherlands)

    de Jong, Y. P.; Abadia-Molina, A. C.; Satoskar, A. R.; Clarke, K.; Rietdijk, S. T.; Faubion, W. A.; Mizoguchi, E.; Metz, C. N.; Alsahli, M.; ten Hove, T.; Keates, A. C.; Lubetsky, J. B.; Farrell, R. J.; Michetti, P.; van Deventer, S. J.; Lolis, E.; David, J. R.; Bhan, A. K.; Terhorst, C.; Sahli, M. A.

    2001-01-01

    The cytokine macrophage-migration inhibitory factor (MIF) is secreted by a number of cell types upon induction by lipopolysaccharide (LPS). Because colitis is dependent on interplay between the mucosal immune system and intestinal bacteria, we investigated the role of MIF in experimental colitis.

  17. Significance of expression of suppressor of cytokine signaling proteins: Suppressor of cytokine signaling-1, suppressor of cytokine signaling-2, and suppressor of cytokine signaling-3 in papillary thyroid cancer

    Directory of Open Access Journals (Sweden)

    Toral Pundrik Kobawala

    2017-01-01

    Conclusion: Expression of the studied SOCS proteins may be a consequence of activation of Janus kinase-signal transducers and activators of transcription and other pathways supporting growth and survival of cancer cells that are sustained by several cytokines. Thus, SOCS-1, SOCS-2, and SOCS-3 proteins may directly or indirectly, have important roles in development and pathogenesis of papillary thyroid cancer.

  18. Cytokine production by porcine mononuclear leukocytes stimulated by mitogens

    Czech Academy of Sciences Publication Activity Database

    Rašková, G.; Kovářů, František; Bártová, J.

    2005-01-01

    Roč. 74, - (2005), s. 521-525 ISSN 0001-7213 R&D Projects: GA ČR GA524/05/0267 Institutional research plan: CEZ:AV0Z50450515 Keywords : cytokine * ELISpot * mitogen Subject RIV: ED - Physiology Impact factor: 0.353, year: 2005

  19. Cytokine response to Escherichia coli in gnotobiotic pigs

    Czech Academy of Sciences Publication Activity Database

    Šplíchal, Igor; Šplíchalová, Alla; Trebichavský, Ilja

    2008-01-01

    Roč. 53, č. 2 (2008), s. 161-164 ISSN 0015-5632 R&D Projects: GA ČR GA523/05/0249 Institutional research plan: CEZ:AV0Z50200510 Keywords : germ-free pigs * escherichia coli * cytokine response Subject RIV: EE - Microbiology, Virology Impact factor: 1.172, year: 2008

  20. Proinflammatory cytokines, aging, and age-related diseases.

    Science.gov (United States)

    Michaud, Martin; Balardy, Laurent; Moulis, Guillaume; Gaudin, Clement; Peyrot, Caroline; Vellas, Bruno; Cesari, Matteo; Nourhashemi, Fati

    2013-12-01

    Inflammation is a physiological process that repairs tissues in response to endogenous or exogenous aggressions. Nevertheless, a chronic state of inflammation may have detrimental consequences. Aging is associated with increased levels of circulating cytokines and proinflammatory markers. Aged-related changes in the immune system, known as immunosenescence, and increased secretion of cytokines by adipose tissue, represent the major causes of chronic inflammation. This phenomenon is known as "inflamm-aging." High levels of interleukin (IL)-6, IL-1, tumor necrosis factor-α, and C-reactive protein are associated in the older subject with increased risk of morbidity and mortality. In particular, cohort studies have indicated TNF-α and IL-6 levels as markers of frailty. The low-grade inflammation characterizing the aging process notably concurs at the pathophysiological mechanisms underlying sarcopenia. In addition, proinflammatory cytokines (through a variety of mechanisms, such as platelet activation and endothelial activation) may play a major role in the risk of cardiovascular events. Dysregulation of the inflammatory pathway may also affect the central nervous system and be involved in the pathophysiological mechanisms of neurodegenerative disorders (eg, Alzheimer disease).The aim of the present review was to summarize different targets of the activity of proinflammatory cytokines implicated in the risk of pathological aging. Copyright © 2013 American Medical Directors Association, Inc. Published by Elsevier Inc. All rights reserved.

  1. Plasma cytokines levels in aggressive and chronic periodontitis.

    Science.gov (United States)

    Mattuella, Letícia Grando; Campagnaro, Milene Borges; Vargas, Andréia Escosteguy; Xavier, Léder Leal; Oppermann, Rui Vicente; Chies, José Artur Bogo; Miranda, Letícia Algarves

    2013-01-01

    The present study evaluated the Th1/Th2 cytokine profile in plasma from healthy controls and different types of periodontitis patients. The concentration of IL-2, IL-4, IL-5, IL-10, TNF-α and IFN-γ was determined in healthy controls (n = 18) and patients with chronic (n = 19) and aggressive periodontitis (n = 19) using a flow cytometric multiplex immunoassay. Means and standard deviations were calculated and compared using Kruskal-Wallis test. Spearman rho coefficient was used to correlate cytokines in the studied groups. Although there was no significant difference in the concentration of cytokines between groups, there was a tendency to lower levels of IL-5 and IL-10 in the aggressive periodontitis group. Stronger correlations were observed between IL-2/IL-4 and IL-2/IL-10 in healthy controls (0.938 and 0.669, respectively) compared with chronic (0.746 and 0.532) and aggressive periodontitis groups (0.395 and 0.266). When compared to healthy (0.812) and chronic periodontitis (0.845) groups, the correlation of IL-4/IL-5 was weaker in the aggressive group (0.459). No difference between systemic levels of Th1/Th2 was observed. In aggressive periodontitis patients, nevertheless, a trend towards low levels of Th2 cytokines could suggest a contribution to the development of such an exacerbated manifestation of this disease.

  2. The response of pre-inflammatory cytokines factors to different ...

    African Journals Online (AJOL)

    Khalid Mohamadzadeh Salamat

    2016-01-23

    Jan 23, 2016 ... Abstract Applying several energy systems and concurrent performing of various training models have a more effective ... concurrent (endurance–resistance) training on pre-inflammatory cytokines in overweight men. Accordingly, 43 healthy ... in pathology of many chronic diseases such as cardiovascular.

  3. Cytokines in Male Fertility and Reproductive Pathologies: Immunoregulation and Beyond

    Directory of Open Access Journals (Sweden)

    Kate L. Loveland

    2017-11-01

    Full Text Available Germline development in vivo is dependent on the environment formed by somatic cells and the differentiation cues they provide; hence, the impact of local factors is highly relevant to the production of sperm. Knowledge of how somatic and germline cells interact is central to achieving biomedical goals relating to restoring, preserving or restricting fertility in humans. This review discusses the growing understanding of how cytokines contribute to testicular function and maintenance of male reproductive health, and to the pathologies associated with their abnormal activity in this organ. Here we consider both cytokines that signal through JAKs and are regulated by SOCS, and those utilizing other pathways, such as the MAP kinases and SMADs. The importance of cytokines in the establishment and maintenance of the testis as an immune-privilege site are described. Current research relating to the involvement of immune cells in testis development and disease is highlighted. This includes new data relating to testicular cancer which reinforce the understanding that tumorigenic cells shape their microenvironment through cytokine actions. Clinical implications in pathologies relating to local inflammation and to immunotherapies are discussed.

  4. Differences in innate cytokine responses between European and African children.

    Science.gov (United States)

    Labuda, Lucja A; de Jong, Sanne E; Meurs, Lynn; Amoah, Abena S; Mbow, Moustapha; Ateba-Ngoa, Ulysse; van der Ham, Alwin J; Knulst, André C; Yazdanbakhsh, Maria; Adegnika, Ayola A

    2014-01-01

    Although differences in immunological responses between populations have been found in terms of vaccine efficacy, immune responses to infections and prevalence of chronic inflammatory diseases, the mechanisms responsible for these differences are not well understood. Therefore, innate cytokine responses mediated by various classes of pattern-recognition receptors including Toll-like receptors (TLR), C-type lectin receptors (CLRs) and nucleotide-binding oligomerisation domain-like receptors (NLRs) were compared between Dutch (European), semi-urban and rural Gabonese (African) children. Whole blood was stimulated for 24 hours and the pro-inflammatory tumor necrosis factor (TNF) and the anti-inflammatory/regulatory interleukin-10 (IL-10) cytokines in culture supernatant were measured by enzyme-linked immunosorbent assay (ELISA). Gabonese children had a lower pro-inflammatory response to poly(I:C) (TLR3 ligand), but a higher pro-inflammatory response to FSL-1 (TLR2/6 ligand), Pam3 (TLR2/1 ligand) and LPS (TLR4 ligand) compared to Dutch children. Anti-inflammatory responses to Pam3 were also higher in Gabonese children. Non-TLR ligands did not induce substantial cytokine production on their own. Interaction between various TLR and non-TLR receptors was further assessed, but no differences were found between the three populations. In conclusion, using a field applicable assay, significant differences were observed in cytokine responses between European and African children to TLR ligands, but not to non-TLR ligands.

  5. Differences in innate cytokine responses between European and African children.

    Directory of Open Access Journals (Sweden)

    Lucja A Labuda

    Full Text Available Although differences in immunological responses between populations have been found in terms of vaccine efficacy, immune responses to infections and prevalence of chronic inflammatory diseases, the mechanisms responsible for these differences are not well understood. Therefore, innate cytokine responses mediated by various classes of pattern-recognition receptors including Toll-like receptors (TLR, C-type lectin receptors (CLRs and nucleotide-binding oligomerisation domain-like receptors (NLRs were compared between Dutch (European, semi-urban and rural Gabonese (African children. Whole blood was stimulated for 24 hours and the pro-inflammatory tumor necrosis factor (TNF and the anti-inflammatory/regulatory interleukin-10 (IL-10 cytokines in culture supernatant were measured by enzyme-linked immunosorbent assay (ELISA. Gabonese children had a lower pro-inflammatory response to poly(I:C (TLR3 ligand, but a higher pro-inflammatory response to FSL-1 (TLR2/6 ligand, Pam3 (TLR2/1 ligand and LPS (TLR4 ligand compared to Dutch children. Anti-inflammatory responses to Pam3 were also higher in Gabonese children. Non-TLR ligands did not induce substantial cytokine production on their own. Interaction between various TLR and non-TLR receptors was further assessed, but no differences were found between the three populations. In conclusion, using a field applicable assay, significant differences were observed in cytokine responses between European and African children to TLR ligands, but not to non-TLR ligands.

  6. Impact of Cytokines and Chemokines on Alzheimer's Disease Neuropathological Hallmarks.

    Science.gov (United States)

    Domingues, Catarina; da Cruz E Silva, Odete A B; Henriques, Ana Gabriela

    2017-01-01

    Alzheimer's disease (AD) is the most common neurodegenerative disorder, neuropathologically characterized by aggregates of β-amyloid peptides, which deposit as senile plaques, and of TAU protein, which forms neurofibrillary tangles. It is now widely accepted that neuroinflammation is implicated in AD pathogenesis. Indeed, inflammatory mediators, such as cytokines and chemokines (chemotactic cytokines) can impact on the Alzheimer´s amyloid precursor protein by affecting its expression levels and amyloidogenic processing and/or β -amyloid aggregation. Additionally, cytokines and chemokines can influence kinases' activities, leading to abnormal TAU phosphorylation. To date there is no cure for AD, but several therapeutic strategies have been directed to prevent neuroinflammation. Anti-inflammatory, but also anti-amyloidogenic compounds, such as flavonoids were shown to favourably modulate some pathological events associated with neurodegeneration. This review focuses on the role of cytokines and chemokines in AD-associated pathologies, and summarizes the potential anti-inflammatory therapeutic approaches aimed at preventing or slowing down disease progression. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  7. Mouse cytokine profile skewed towards Th2 in pregnancy during ...

    African Journals Online (AJOL)

    The two classes of cytokines Th1 and Th2 determine the type of immune response elicited. The Th2 immune response is associated with successful pregnancy. Brucellosis is an intracellular bacterium that elicits the Th1 response and is known to cause spontaneous abortion in mammalian species. This study sought to ...

  8. Role of Cytokines in Trypanosoma brucei -Induced Anaemia: A ...

    African Journals Online (AJOL)

    A number of studies have implicated inflammatory cytokines, but these data are limited and inconsistent. In this article, we reviewed the published literature on ... The mechanism of anaemia is multifactorial and therefore requires further, more elaborate research. Data from human subjects would also shed more light.

  9. Development of specific cytokine and Chemokine ELISAs for Bottlenose Dolphins

    Science.gov (United States)

    Earlier detection of changes in the health status of bottlenose dolphins (Tursiops truncatus) is expected to further improve their medical care. Cytokines and chemokines are critical mediators of the cellular immune response, and studies have suggested that these molecules may serve as important bio...

  10. Review: Cytokines in Gaucher disease: Role in the pathogenesis of ...

    African Journals Online (AJOL)

    Review: Cytokines in Gaucher disease: Role in the pathogenesis of bone and pulmonary disease. AAG Tantawy. Abstract. Gaucher disease (GD) is the most frequently encountered lysosomal storage disease caused by inborn defects of themembrane-bound lysosomal enzyme, acid b-glucosidase or glucocerebrosidase.

  11. Aspergillus fumigatus conidial melanin modulates host cytokine response.

    NARCIS (Netherlands)

    Chai, L.; Netea, M.G.; Sugui, J.; Vonk, A.G.; Sande, W.W. van de; Warris, A.; Kwon-Chung, K.J.; Kullberg, B.J.

    2010-01-01

    Melanin biopigments have been linked to fungal virulence. Aspergillus fumigatus conidia are melanised and are weakly immunogenic. We show that melanin pigments on the surface of resting Aspergillus fumigatus conidia may serve to mask pathogen-associated molecular patterns (PAMPs)-induced cytokine

  12. Spontaneous and cytokine induced basophil adhesion evaluated by microtiter assay

    DEFF Research Database (Denmark)

    Quan, Sha; Poulsen, Lars K; Reimert, Claus Michael

    2002-01-01

    We have developed a microtiter assay for evaluating basophil spontaneous adhesion to extracellular matrix (ECM) proteins exemplified by fibronectin and cytokine induced basophil adhesion to bovine serum albumin (BSA). The percentage of basophils adhering to either ECM or BSA was quantified by the...

  13. Linking the Human Gut Microbiome to Inflammatory Cytokine Production Capacity

    NARCIS (Netherlands)

    Schirmer, M.; Smeekens, S.P.; Vlamakis, H.; Jaeger, M.; Oosting, M.; Franzosa, E.A.; Jansen, T.; Jacobs, L.; Bonder, M.J.; Kurilshikov, A.; Fu, J.; Joosten, L.A.; Zhernakova, A.; Huttenhower, C.; Wijmenga, C.; Netea, M.G.; Xavier, R.J.

    2016-01-01

    Gut microbial dysbioses are linked to aberrant immune responses, which are often accompanied by abnormal production of inflammatory cytokines. As part of the Human Functional Genomics Project (HFGP), we investigate how differences in composition and function of gut microbial communities may

  14. FUNDAMENTAL IMMUNOBIOLOGY OF PRO-INFLAMMATORY CYTOKINES AND MIF

    Directory of Open Access Journals (Sweden)

    A. P. Suslov

    2006-01-01

    Full Text Available Fundamental immunobiology of proinflammatory cytokines and MIFThere are a lot of similarity as well as differences when we compare cytokines with MIF according their biological properties. MIF characteristics are unique structure, organs and tissues ubiquity, extremely wide variety of functions (proinflammatory cytokine, enzyme, hormone, ability to be induced by glucocorticoid hormones and affects as their immunosuppressive effects antagonist. MIF exists in preformed condition in lymphocytes, macrophages and endothelium cells. It secrets by these cells and operates as a mobilizing defense system factor in the first minutes of foreign invasion. MIF exhibits the properties of super-ligand binding with many biologically important molecules. This factor carries out the functions that are important for cell activation, proliferation and death, using a variety of intracellular signaling pathways. Some of MIF homologues exists in plants and bacteria earlier than innate and adaptive immune systems appears in evolution. In ontogenesis MIF appears at the stage of firsts cell divisions. MIF has a lot of functions, variety of ligand bindings, many effector pathways, it appears early in ontogeny and phylogeny. MIF takes part into protective reactions at any levels – from cell up to whole organism. All these MIF features taking together into account make it possible to possess it as a particular type of cytokine – eocytokine (from Greek word “eo” – early. It is assumed that MIF may function as some kind of cells and organisms "natural stability" key factor.

  15. The role of cytokines as inflammatory mediators in preeclampsia ...

    African Journals Online (AJOL)

    The role of cytokines as inflammatory mediators in preeclampsia. ... Introduction: this study is to determine the concentrations of IL-6, TNF 5, and C reactive protein (CRP) in women with severe preeclampsia, and compare with ... A role may exist for anti inflammatory agents in the management of women with preeclampsia.

  16. Prognosis Relevance of Serum Cytokines in Pancreatic Cancer

    Science.gov (United States)

    Alejandre, Maria José; Palomino-Morales, Rogelio J.; Prados, Jose; Aránega, Antonia; Delgado, Juan R.; Irigoyen, Antonio; Martínez-Galán, Joaquina; Ortuño, Francisco M.

    2015-01-01

    The overall survival of patients with pancreatic ductal adenocarcinoma is extremely low. Although gemcitabine is the standard used chemotherapy for this disease, clinical outcomes do not reflect significant improvements, not even when combined with adjuvant treatments. There is an urgent need for prognosis markers to be found. The aim of this study was to analyze the potential value of serum cytokines to find a profile that can predict the clinical outcome in patients with pancreatic cancer and to establish a practical prognosis index that significantly predicts patients' outcomes. We have conducted an extensive analysis of serum prognosis biomarkers using an antibody array comprising 507 human cytokines. Overall survival was estimated using the Kaplan-Meier method. Univariate and multivariate Cox's proportional hazard models were used to analyze prognosis factors. To determine the extent that survival could be predicted based on this index, we used the leave-one-out cross-validation model. The multivariate model showed a better performance and it could represent a novel panel of serum cytokines that correlates to poor prognosis in pancreatic cancer. B7-1/CD80, EG-VEGF/PK1, IL-29, NRG1-beta1/HRG1-beta1, and PD-ECGF expressions portend a poor prognosis for patients with pancreatic cancer and these cytokines could represent novel therapeutic targets for this disease. PMID:26346854

  17. Prognosis Relevance of Serum Cytokines in Pancreatic Cancer

    Directory of Open Access Journals (Sweden)

    Carolina Torres

    2015-01-01

    Full Text Available The overall survival of patients with pancreatic ductal adenocarcinoma is extremely low. Although gemcitabine is the standard used chemotherapy for this disease, clinical outcomes do not reflect significant improvements, not even when combined with adjuvant treatments. There is an urgent need for prognosis markers to be found. The aim of this study was to analyze the potential value of serum cytokines to find a profile that can predict the clinical outcome in patients with pancreatic cancer and to establish a practical prognosis index that significantly predicts patients’ outcomes. We have conducted an extensive analysis of serum prognosis biomarkers using an antibody array comprising 507 human cytokines. Overall survival was estimated using the Kaplan-Meier method. Univariate and multivariate Cox’s proportional hazard models were used to analyze prognosis factors. To determine the extent that survival could be predicted based on this index, we used the leave-one-out cross-validation model. The multivariate model showed a better performance and it could represent a novel panel of serum cytokines that correlates to poor prognosis in pancreatic cancer. B7-1/CD80, EG-VEGF/PK1, IL-29, NRG1-beta1/HRG1-beta1, and PD-ECGF expressions portend a poor prognosis for patients with pancreatic cancer and these cytokines could represent novel therapeutic targets for this disease.

  18. Impact of weight loss on oxidative stress and inflammatory cytokines ...

    African Journals Online (AJOL)

    Background: Type 2 diabetes mellitus is associated with abnormal markers of inflammatory cytokines and oxidative stress markers. Although, these abnormalities could be modulated with weight reduction; there is limitation in clinical studies that have addressed the beneficial effects of weight reduction in modulating ...

  19. Cytokines in Gaucher disease: Role in the pathogenesis of bone ...

    African Journals Online (AJOL)

    Azza A.G. Tantawy

    2015-03-03

    Mar 3, 2015 ... Cytokines in Gaucher disease: Role in the pathogenesis of bone and pulmonary ... Studies are increasingly recognizing the role of immune dysregulation and inflammation in the pathogenesis of Gaucher disease. ..... by various other cells of the immune system [11]. Recent work in a murine model of ...

  20. Circulating cytokines as biomarkers of alcohol abuse and alcoholism.

    Science.gov (United States)

    Achur, Rajeshwara N; Freeman, Willard M; Vrana, Kent E

    2010-03-01

    There are currently no consistent objective biochemical markers of alcohol abuse and alcoholism. Development of reliable diagnostic biomarkers that permit accurate assessment of alcohol intake and patterns of drinking is of prime importance to treatment and research fields. Diagnostic biomarker development in other diseases has demonstrated the utility of both open, systems biology, screening for biomarkers and more rational focused efforts on specific biomolecules or families of biomolecules. Long-term alcohol consumption leads to altered inflammatory cell and adaptive immune responses with associated pathologies and increased incidence of infections. This has led researchers to focus attention on identifying cytokine biomarkers in models of alcohol abuse. Alcohol is known to alter cytokine levels in plasma and a variety of tissues including lung, liver, and very importantly brain. A number of cytokine biomarker candidates have been identified, including: tumor necrosis factor-alpha, interleukin (IL)-1-alpha, IL-1-beta, IL-6, IL-8, IL-12, and monocyte chemoattractant protein-1. This is an emerging and potentially exciting avenue of research in that circulating cytokines may contribute to diagnostic biomarker panels, and a combination of multiple biomarkers may significantly increase the sensitivity and specificity of the biochemical tests aiding reliable and accurate detection of excessive alcohol intake.

  1. Mouse cytokine profile skewed towards Th2 in pregnancy during ...

    African Journals Online (AJOL)

    responses in pregnancy (Moraes- Pinto et al., 1998). By examining the cytokine profile in pregnancy, the objective of this study was to establish if ..... Terrestrial Manual 624-659. Paludan, S.R. (1998) Interleukin 4 and Interferon γ: The essence of a mutually antagonistic relationship. Scandnavian Journal of Immunology 48, ...

  2. Inflammatory Cytokines and Sleep Disturbance in Patients with Temporomandibular Disorders.

    Science.gov (United States)

    Park, Ji Woon; Chung, Jin Woo

    2016-01-01

    To assess the degree and interrelationship of sleep disturbance and plasma cytokine levels in temporomandibular disorder (TMD) pain patients. Forty female TMD patients and 20 age-, sex-, and body mass index (BMI)-matched healthy subjects were enrolled. TMD was diagnosed using the Research Diagnostic Criteria for TMD. The TMD patients were classified as having low or high disability according to Graded Chronic Pain Scale findings. The Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS) were used to measure sleep quality. Plasma concentrations of interleukin (IL)-1β, IL-6, IL-10, tumor necrosis factor-α (TNF-α), and C-reactive protein (CRP) were measured from blood samples collected between 9 am and noon. Statistical analyses included Kruskal-Wallis and one-way analysis of variance tests to compare results between different groups and multivariate general linear models to evaluate the effect of sleep status on cytokine levels. The high-disability group had the highest PSQI and ESS scores (P disability group exhibiting the highest values (P ≤ .001). The plasma cytokine levels were significantly correlated with PSQI scores (P disability level after adjusting for both sleep indices (both P disability, had elevated plasma cytokine levels and increased ESS and PSQI scores suggestive of sleep disturbance.

  3. Cytokines as Key Players in the Pathophysiology of Preeclampsia

    Science.gov (United States)

    Raghupathy, Raj

    2013-01-01

    Preeclampsia (PE) is an important, common, and dangerous complication of pregnancy; it causes maternal and perinatal illness and is responsible for a high proportion of maternal and infant deaths. PE is associated with increased blood pressure and proteinuria, with a whole host of other potentially serious complications in the mother and fetus. The maternal syndrome in PE is primarily that of generalized dysfunction of the maternal endothelium, and this generalized endothelial dysfunction appears to be part of an exaggerated systemic inflammatory response that involves maternal leukocytes and proinflammatory cytokines. This review examines evidence that points to a significant role for the maternal immune system; inadequate trophoblast invasion of spiral arteries initiates ischemia and hypoxia in the placenta, resulting in an increased release of proinflammatory cytokines in the placenta. Placental ischemia and hypoxia also cause the enhanced release of trophoblast microparticles into the maternal circulation which stimulates increased induction of proinflammatory cytokines and the activation of maternal endothelial cells. This activation results in a systemic, diffuse endothelial cell dysfunction which is the fundamental pathophysiological feature of this syndrome. Recent evidence also supports important roles for proinflammatory cytokines in hypertension, proteinuria, and edema which are characteristic features of PE. PMID:23949305

  4. Cytokines and anticytokines in the pathogenesis of sepsis

    NARCIS (Netherlands)

    van der Poll, T.; van Deventer, S. J.

    1999-01-01

    Clinical trials with anti-inflammatory agents in patients with sepsis are based on the assumption that excessive proinflammatory activity of the cytokine network negatively influences the outcome of severe bacterial infections. The failure of these trials to show clinical benefit, in conjunction

  5. Effects of coagulation factors and inflammatory cytokines on ...

    African Journals Online (AJOL)

    Purpose: To investigate the effects of coagulation factors and inflammatory cytokines on acute myocardial infarction (AMI) development in patients younger than 60 years. Methods: In this study, 60 patients admitted to The First Affiliated Hospital of Dalian Medical University (Dalian, China) with AMI and 30 other subjects ...

  6. Cytokine Network Involvement in Subjects Exposed to Benzene

    Science.gov (United States)

    Gangemi, Sebastiano

    2014-01-01

    Benzene represents an ubiquitous pollutant both in the workplace and in the general environment. Health risk and stress posed by benzene have long been a concern because of the carcinogenic effects of the compound which was classified as a Group 1 carcinogen to humans and animals. There is a close correlation between leukemia, especially acute myeloid leukemia, and benzene exposure. In addition, exposure to benzene can cause harmful effects on immunological, neurological, and reproductive systems. Benzene can directly damage hematopoietic progenitor cells, which in turn could lead to apoptosis or may decrease responsiveness to cytokines and cellular adhesion molecules. Alternatively, benzene toxicity to stromal cells or mature blood cells could disrupt the regulation of hematopoiesis, including hematopoietic commitment, maturation, or mobilization, through the network of cytokines, chemokines, and adhesion molecules. Today there is mounting evidence that benzene may alter the gene expression, production, or processing of several cytokines in vitro and in vivo. The purpose of this review was to systematically analyze the published cases of cytokine effects on human benzene exposure, particularly hematotoxicity, and atopy, and on lungs. PMID:25202711

  7. Cytokines, Type 2 DM and the Metabolic Syndrome | Ogbera ...

    African Journals Online (AJOL)

    comparable in the DM subjects with and without the Mets and also comparable in obese DM and non obese DM subjects. Of the Mets defining criteria, waist circumference (WC) and Triglyceride (TG) were found to be significantly associated with only two of the studied cytokines. The correlation coefficient and p values of ...

  8. Pro-inflammatory cytokines: Useful markers for the diagnosis of canine mammary tumours?

    Science.gov (United States)

    Andaluz, Ana; Yeste, Marc; Rodríguez-Gil, Joan E; Rigau, Teresa; García, Félix; Rivera del Álamo, Maria Montserrat

    2016-04-01

    The aim of the present study was to analyse the expression of 60 pro-inflammatory cytokines as possible markers of malignancy in canine mammary tumours using a human cytokine antibody array. The cytokines were grouped into two different categories: (1) cytokines in which expression indicated the presence of a mammary tumour and (2) cytokines in which expression differentiated between simple mammary adenoma, tubulopapillary carcinoma or complex carcinoma. These data suggest that specific pro-inflammatory cytokines could be useful as tools for the diagnosis of canine mammary tumours. Copyright © 2016 Elsevier Ltd. All rights reserved.

  9. Development of silicon photonic microring resonator biosensors for multiplexed cytokine assays and in vitro diagnostics

    Science.gov (United States)

    Luchansky, Matthew Sam

    In order to guide critical care therapies that are personalized to a patient's unique disease state, a diagnostic or theranostic medical device must quickly provide a detailed biomolecular understanding of disease onset and progression. This detailed molecular understanding of cellular processes and pathways requires the ability to measure multiple analytes in parallel. Though many traditional sensing technologies for biomarker analysis and fundamental biological studies (i.e. enzyme-linked immunosorbent assays, real-time polymerase chain reaction, etc.) rely on single-parameter measurements, it has become increasingly clear that the inherent complexity of many human illnesses and pathways necessitates quantitative and multiparameter analysis of biological samples. Currently used analytical methods are deficient in that they often provide either highly quantitative data for a single biomarker or qualitative data for many targets, but methods that simultaneously provide highly quantitative analysis of many targets have yet to be adequately developed. Fields such as medical diagnostics and cellular biology would benefit greatly from a technology that enables rapid, quantitative and reproducible assays for many targets within a single sample. In an effort to fill this unmet need, this doctoral dissertation describes the development of a clinically translational biosensing technology based on silicon photonics and developed in the chemistry research laboratory of Ryan C. Bailey. Silicon photonic microring resonators, a class of high-Q optical sensors, represent a promising platform for rapid, multiparameter in vitro measurements. The original device design utilizes 32-ring arrays for real-time biomolecular sensing without fluorescent labels, and these optical biosensors display great potential for more highly multiplexed (100s-1000s) measurements based on the impressive scalability of silicon device fabrication. Though this technology can be used to detect a variety of

  10. CLINICO-PATHOGENETIC VALUE OF SOME CYTOKINES IN PERIODONTITIS

    Directory of Open Access Journals (Sweden)

    L. G. Polushina

    2017-01-01

    Full Text Available Most authors ascribe pathogenesis of parodontitis to alterations of oral microbiota and mechanisms of local immunity. One may therefore assume that of the concepts of pathogenesis, diagnosis and treatment of the disease may be successfully developed when implementing immunological studies of oral fluid. The aim of present study was to characterize cytokine status of the oral fluid in patients with chronic periodontitis. The study included 101 subjects who were divided into two groups, according to results of retrospective analysis, i.e., study group (69 patients with moderate or severe periodontitis, and control group (32 virtually healthy volunteers.In control group of patients, cytokine levels corresponded to normal values. In the patients with periodontitis, we have revealed increased IL-2, IL-4 levels. This finding suggests that the cytokine balance in periodontitis is characterized by predominance of Th2 produced factors, i.e., activation of “anti-inflammatory” immunemediated mechanisms. We have also determined VEGF levels in oral fluid, since disturbances of microcirculatory bed seem to be important in evolving periodontitis, along with immune shifts. The VEGF content in oral fluid also tended to increase in the patients. We have found that the IL-4 level in the oral fluid is of high diagnostic value in periodontitis, with diagnostic sensitivity of 88%, and diagnostic specificity of 99% (AUC = 0.95.In our study, we have obtained data corresponding to general view on altered local immune mechanisms in developing chronic periodontitis. This shift manifests as imbalance in cytokine production, especially, by activated IL-4 production. One may assume that this cytokine exerts both pathogenetic effect (immunomediated destruction of tissues and protective action (stimulation of antimicrobial immunity in periodontitis.Prevalence and ratio of these effects seems to determine progression rates and development of complications in the disease

  11. Cytokine profile of rats fed a diet containing shrimp

    Directory of Open Access Journals (Sweden)

    Elizabeth Lage Borges

    2013-02-01

    Full Text Available OBJECTIVE: Studies have shown that shrimps reduced the tensile strength of scars in rat skin. The aim of the present study was to assess the cytokine profile of rats fed shrimp. METHODS: Group 1 (control received a regular diet and Group 2 (experimental received a diet containing 33% shrimp for nine days. The two diets contained the same amounts of proteins, fats and carbohydrates. Serum cytokine levels were determined by ELISA and a segment of the jejunum was taken to investigate its histological morphology and eosinophil infiltrate. RESULTS: The experimental group had lower serum levels of interleukin-4 (IL-4 (14.4±1.9 versus 18.11±2.6pg/mL; p<0.05 and IL-10 (5.0±0.98 versus 7.5±1.2pg/mL; p<0.05 and higher levels of IL-6 (17.8±2.3 versus 3.2±0.4pg/mL, p<0.001 than controls. Morphologically, the shrimp-based diet caused an architectural disorganization of the intestinal mucosa and a greater amount of eosinophils in the jejunal villus. CONCLUSION: Our data suggests that shrimp consumption leads to a significant increase in the cytokine IL-6, a decrease in the immunomodulatory cytokine IL-10 in the serum of rats, and high eosinophil infiltration in the jejunum. The cytokine profile typical of inflammation and the histological aspect of the jejunum are compatible with food allergy.

  12. Aptamers Against Pro- and Anti-Inflammatory Cytokines: A Review.

    Science.gov (United States)

    Boshtam, Maryam; Asgary, Seddigheh; Kouhpayeh, Shirin; Shariati, Laleh; Khanahmad, Hossein

    2017-02-01

    Inflammatory disorders result from continuous inflammation in injured sites. Many molecules are involved in this process; the inhibition of which could prevent the inflammation. Chemokines are a group of these biological mediators which are categorized into pro-, anti-, and pro-/anti-inflammatory. Thus, targeting these essential molecules can be an effective way for prevention and control of inflammatory diseases. Various therapeutic agents have been developed for primary and secondary prevention of these disorders, but each of them has its own limitations. Aptamers, as novel therapeutic agents, are a new generation of drugs which could replace other medications even antibodies. Aptamer can bind to its target molecule to trap it and prohibit its function. Among large group of inflammatory cytokines, only 11 aptamers have been selected either against cytokines or their related receptors. These cytokines include interleukin (IL)-2, IL-6, IL-10, IL-11, IL-17, IL-32, TGF-β, TNF-α, IFN-γ, CCL2, and IP-10. Most of the isolated aptamers are against pro-inflammatory or dual function cytokines, and it seems that they could be used for diagnosis, prevention, and treatment of the related inflammatory diseases. Most of the aptamers have been tested in vitro, but so far, none of them has been approved for in vivo use. Given a vast number of inflammatory cytokines, more aptamers against this group of biological molecules will be selected in the near future. The available aptamers will also be tested in clinical trials. Therefore, a significant improvement is expected for the prevention and control of inflammatory disorders.

  13. Non-invasive monitoring of cytokine-based regenerative treatment of cartilage by hyperspectral unmixing (Conference Presentation)

    Science.gov (United States)

    Mahbub, Saabah B.; Succer, Peter; Gosnell, Martin E.; Anwaer, Ayad G.; Herbert, Benjamin; Vesey, Graham; Goldys, Ewa M.

    2016-03-01

    Extracting biochemical information from tissue autofluorescence is a promising approach to non-invasively monitor disease treatments at a cellular level, without using any external biomarkers. Our recently developed unsupervised hyperspectral unmixing by Dependent Component Analysis (DECA) provides robust and detailed metabolic information with proper account of intrinsic cellular heterogeneity. Moreover this method is compatible with established methods of fluorescent biomarker labelling. Recently adipose-derived stem cell (ADSC) - based therapies have been introduced for treating different diseases in animals and humans. ADSC have been shown promise in regenerative treatments for osteoarthritis and other bone and joint disorders. One of the mechanism of their action is their anti-inflammatory effects within osteoarthritic joints which aid the regeneration of cartilage. These therapeutic effects are known to be driven by secretions of different cytokines from the ADSCs. We have been using the hyperspectral unmixing techniques to study in-vitro the effects of ADSC-derived cytokine-rich secretions with the cartilage chip in both human and bovine samples. The study of metabolic effects of different cytokine treatment on different cartilage layers makes it possible to compare the merits of those treatments for repairing cartilage.

  14. Lactobacillus Acidophilus Strain L-92 Regulates the Production of Th1 Cytokine as well as Th2 Cytokines

    Directory of Open Access Journals (Sweden)

    Akiko Torii

    2007-01-01

    Conclusions: Oral L-92 administration regulated both Th1 and Th2 cytokine responses, suppressed serum OVA-specific IgE, and induced TGF-β production in PPs. TGF-β is known to be associated with activation of regulatory T (Treg cells. These data suggest that LAB may have immunomodulative effect by Treg cells via TGF-β activity.

  15. INTEGRAL EVALUATION OF THE CYTOKINE SYSTEM IN VIRAL MYOCARDITIS

    Directory of Open Access Journals (Sweden)

    Peremot S. D.

    2017-10-01

    Full Text Available The need for an individual approach in the choice of means for the prevention of complications in inflammatory processes in cardiomyocytes, the course of which unfolds against a persistent viral infection, dictates the need to determine the general mechanisms for maintaining and progressing of the pathological process and an objective evaluation of immunological changes. The aim of the study was to determine changes in the system of inflammatory mediators in patients with subacute and chronic herpesviral infectious myocarditis on the basis of an integral assessment of the levels of opposing groups of cytokines. Materials & methods. To achieve this goal, we conducted a determination and analysis of changes in the cytokine profile in 87 patients with subacute (from 2 to 6 months and chronic (more than 6 months myocarditis due to an integral assessment of the mediator levels of inflammation of opposing groups in patients with herpesviral myocarditis on treatment in medical institutions of the Kharkov city. The average age of the patients was (27 ± 7.4 years. The control group was attracted to 40 people without clinical manifestations of cardiovascular diseases and in whose anamnesis there were no data on the transferred inflammatory diseases of the myocardium. Both groups of subjects were comparable in age and gender. The main group of subjects was divided into two subgroups. The first was 44 patients with subacute flow, the second - 43 patients with chronic infectious myocarditis. The diagnosis was established in accordance with the recommendations of the Association of Cardiologists of Ukraine and experts of the European Society of Cardiology, according to the formation of definitions of diseases in the International Classification of Diseases (ICD-10 of the tenth revision. The removal of material from patients was carried out according to the rules for the collection of infectious material. The concentration of cytokines: IL-2, IL-4, IL-6, IL

  16. Heterogeneity of the cytokinome in undifferentiated arthritis progressing to rheumatoid arthritis and its change in the course of therapy. Move toward personalized medicine.

    Science.gov (United States)

    Brzustewicz, Edyta; Bzoma, Izabella; Daca, Agnieszka; Szarecka, Maria; Bykowska, Malgorzata Sochocka; Witkowski, Jacek M; Bryl, Ewa

    2017-09-01

    To conduct a comprehensive analysis of cytokine concentrations in sera and mononuclear cell supernatants in order to examine inter- and intra-individual cytokine variations in undifferentiated arthritis progressing to rheumatoid arthritis and healthy control groups. Patients with UA (undifferentiated arthritis) developing RA (rheumatoid arthritis) (UA→RA) (n=16) and healthy controls (n=16) were enrolled into the study. UA→RA patients were followed up for six months since the final RA diagnosis. Cytokines IFN-γ, IL-10, TNF, IL-17A, IL-6, IL-1β, IL-2 in sera and mononuclear cell supernatants in 72h and 120h culture variants with- and without anti-CD3 stimulations were assayed using flow cytometric bead array. The cytokine profile of UA→RA differs from the healthy individual cytokine profile. It is possible to observe specific cytokine pattern characterizing each patient, which alters during course of disease. Specifically, we can distinguish three UA→RA cohorts: the group of patients susceptible to the therapy, characterized by the drop of cytokine levels between 1st and 3rd visit with visible decrease of cytokines in 2nd visit and then secondary slighter increase in 3rd visit; the group of patients refractory or clinically worsening on the therapy, characterized by the highest cytokine levels at 2nd visit with secondary decrease in 3rd visit; and the group of patients with variable responses to the therapy without any specific common cytokine pattern. The cytokine patterns in supernatants of PBMC stimulated anti-CD3 for 72h and 120h are very similar. The personal profile including multiplexed cytokine patterns in serum and supernatant may be potentially used for optimization of therapy introduction and monitoring. Copyright © 2017 Elsevier Ltd. All rights reserved.

  17. Taxonomic applicability of inflammatory cytokines in adverse outcome pathway (AOP) development

    Science.gov (United States)

    Cytokines, low-molecular-weight messenger proteins that act as intercellular immunomodulatory signals, have become a mainstream preclinical marker for assessing the systemic inflammatory response to external stressors. The challenge is to quantitate from healthy subjects cytokine...

  18. Consumption of soy isoflavone enriched bread in men with prostate cancer is associated with reduced proinflammatory cytokines and immunosuppressive cells.

    Science.gov (United States)

    Lesinski, Gregory B; Reville, Patrick K; Mace, Thomas A; Young, Gregory S; Ahn-Jarvis, Jennifer; Thomas-Ahner, Jennifer; Vodovotz, Yael; Ameen, Zeenath; Grainger, Elizabeth; Riedl, Kenneth; Schwartz, Steven; Clinton, Steven K

    2015-11-01

    We hypothesized that soy phytochemicals may have immunomodulatory properties that may affect prostate carcinogenesis and progression. A randomized, phase II trial was conducted in 32 patients with prostate cancer with asymptomatic biochemical recurrence but no measurable disease on standard staging studies. Patients were randomized to two slices of soy bread (34 mg isoflavones/slice) or soy bread containing almond powder daily as a source of β-glucosidase. Flow cytometry and bioplex assays were used to measure cytokines or immune cell phenotype in blood at baseline (day 0) and following intervention (day 56). Adequate blood samples were available at enrollment and day 56 and evaluated. Multiple plasma cytokines and chemokines were significantly decreased on day 56 versus baseline. Subgroup analysis indicated reduced TH1 (P = 0.028) and myeloid-derived suppressor cell (MDSC)-associated cytokines (P = 0.035). TH2 and TH17 cytokines were not significantly altered. Phenotypic analysis revealed no change in CD8(+) or CD4(+) T cells but showed increased CD56(+) natural killer (NK) cells (P = 0.038). The percentage of cells with a T regulatory cell phenotype (CD4(+)CD25(+)FoxP3(+)) was significantly decreased after 56 days of soy bread (P = 0.0136). Significantly decreased monocytic (CD33(+)HLADR(neg)CD14(+)) MDSC were observed in patients consuming soy bread (P = 0.0056). These data suggest that soy bread modulates systemic soluble and cellular biomarkers consistent with limiting inflammation and suppression of MDSCs. Additional studies to elucidate impact on the carcinogenic process or as a complement to immune-based therapy are required. ©2015 American Association for Cancer Research.

  19. Influence of tanshinone combined with antiallergic drugs on serum cytokine levels and immune function in children with Henoch- Schonlein purpura

    Directory of Open Access Journals (Sweden)

    Li-Hong Jian

    2017-05-01

    Full Text Available Objective: To study the influence of tanshinone combined with antiallergic drugs on serum cytokine levels and immune function in children with Henoch-Schonlein purpura (HSP. Methods: A total of 52 cases of HSP children treated in Maternal and Child Health Hospital of Guangyuan between April 2013 and July 2016 were collected and divided into control group (n=26 and observation group (n=26 according to random number table. Patients in control group were treated with anti-allergic drugs, and those in observation group were treated with tanshinone combined with anti-allergic drugs. Before treatment and 2 weeks after treatment, the serum cytokines and immune function were compared between two groups of children. Results: Before treatment, differences in serum levels of Th17/IL-23 inflammatory axis, renal function indexes, Th1/Th2 immunity, immunoglobulin and complement were not statistically significant between two groups of children. After treatment, serum IL-23 and IL-17 levels of observation group were lower than those of control group, renal function indexes Scr, BUN and CysC levels were lower than those of control group, Th1 cytokines IL-2 and IFN-γ levels were higher than those of control group, Th2 cytokines IL-10, IL-4 and IL-13 levels were lower than those of control group, and IgA, C3 and C4 levels were lower than those of control group. Conclusion: Tanshinone combined with anti-allergic drug therapy can help to further inhibit the systemic inflammatory response, reduce renal damage and correct immune dysfunction in children with HSP.

  20. Nonsteroidal anti-inflammatory drugs may affect cytokine response and benefit healing of combat-related extremity wounds.

    Science.gov (United States)

    Lisboa, Felipe A; Bradley, Matthew J; Hueman, Matthew T; Schobel, Seth A; Gaucher, Beverly J; Styrmisdottir, Edda L; Potter, Benjamin K; Forsberg, Jonathan A; Elster, Eric A

    2017-04-01

    After adequate operative debridement and antimicrobial therapies, combat-related extremity wounds that either heal or fail are both associated with a distinct inflammatory response. Short-term use of nonsteroidal anti-inflammatory drugs in postoperative pain management may affect this response and, by consequence, the healing potential of these wounds. We investigated whether patients treated with nonsteroidal anti-inflammatory drugs had a distinct inflammatory response; different rates of critical colonization, defined as >10 5 colony forming units on quantitative bacteriology; and healing potential. We retrospectively reviewed the records of 73 patients with combat-related extremity wounds. Patients were separated into 2 groups: those who received nonsteroidal anti-inflammatory drugs during the debridement period (nonsteroidal anti-inflammatory drugs group, N = 17) and those who did not (control group; N = 56). Serum and wound tissue samples collected during each operative debridement were measured for 32 known cytokines and tested for quantitative bacteriology, respectively. We compared cytokine concentrations between groups and then designed a logistic regression model to identify variables associated with successful wound healing, while controlling for known confounders. Despite similar demographics and wound characteristics, the nonsteroidal anti-inflammatory drugs group had significant lesser concentrations of inflammatory cytokines, interleukin-2, interleukin-6, interleukin-8, and monocyte chemoattractant protein-1. On multivariate analysis, nonsteroidal anti-inflammatory drug treatment emerged as a predictor of successful wound healing after controlling for known confounders such as wound size, tobacco use, Acute Physiology and Chronic Health Evaluation II score, and critical colonization. Treatment with nonsteroidal anti-inflammatory drugs for postoperative pain management after major combat-related extremity trauma is associated with lesser

  1. Molecular Targets for Targeted Radionuclide Therapy

    International Nuclear Information System (INIS)

    Mather, S.J.

    2009-01-01

    Molecular targeted radionuclide cancer therapy is becoming of increasing importance, especially for disseminated diseases. Systemic chemotherapies often lack selectivity while targeted radionuclide therapy has important advantages as the radioactive cytotoxic unit of the targeting vector is specifically directed to the cancer, sparing normal tissues. The principle strategy to improve cancer selectivity is to couple therapeutic agents to tumour-targeting vectors. In targeted radionuclide therapy (TRT), the cytotoxic portion of the conjugates normally contains a therapeutic radiometal immobilised by a bifunctional chelator. The aim is therefore to use as ligand-targeted therapeutics vectors coupled to Auger-, alpha- and/or beta-emitting radionuclides. An advantage of using radiation instead of chemotherapeutics as the cytotoxic agent is the so called 'crossfire effect'. This allows sterilisation of tumour cells that are not directly targeted due to heterogeneity in target molecule expression or inhomogeneous vector delivery. However, before the targeting ligands can be selected, the target molecule on the tumour has to be selected. It should be uniquely expressed, or at least highly overexpressed, on or in the target cells relative to normal tissues. The target should be easily accessible for ligand delivery and should not be shed or down- regulated after ligand binding. An important property of a receptor (or antigen) is its potential to be internalized upon binding of the ligand. This provides an active uptake mechanism and allows the therapeutic agent to be trapped within the tumour cells. Molecular targets of current interest include: Receptors: G-protein coupled receptors are overexpressed on many major human tumours. The prototype of these receptors are somatostatin receptors which show very high density in neuroendocrine tumours, but there are many other most interesting receptors to be applied for TRT. The targeting ligands for these receptors are

  2. Calcium Contributes to the Cytotoxic Interaction Between Diclofenac and Cytokines.

    Science.gov (United States)

    Maiuri, Ashley R; Breier, Anna B; Turkus, Jonathan D; Ganey, Patricia E; Roth, Robert A

    2016-02-01

    Diclofenac (DCLF) is a widely used non-steroidal anti-inflammatory drug that is associated with idiosyncratic, drug-induced liver injury (IDILI) in humans. The mechanisms of DCLF-induced liver injury are unknown; however, patients with certain inflammatory diseases have an increased risk of developing IDILI, which raises the possibility that immune mediators play a role in the pathogenesis. DCLF synergizes with the cytokines tumor necrosis factor-alpha (TNF) and interferon-gamma (IFN) to cause hepatocellular apoptosis in vitro by a mechanism that involves activation of the endoplasmic reticulum (ER) stress response pathway and of the mitogen-activated protein kinases, c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK). DCLF also causes an increase in intracellular calcium (Ca(++)) in hepatocytes, but the role of this in the cytotoxic synergy between DCLF and cytokines is unknown. We tested the hypothesis that Ca(++) contributes to DCLF/cytokine-induced cytotoxic synergy. Treatment of HepG2 cells with DCLF led to an increase in intracellular Ca(++) at 6 and 12 h, and this response was augmented in the presence of TNF and IFN at 12 h. The intracellular Ca(++) chelator BAPTA/AM reduced cytotoxicity and caspase-3 activation caused by DCLF/cytokine cotreatment. BAPTA/AM also significantly reduced DCLF-induced activation of the ER stress sensor, protein kinase RNA-like ER kinase (PERK), as well as activation of JNK and ERK. Treatment of cells with an inositol trisphosphate receptor antagonist almost completely eliminated DCLF/cytokine-induced cytotoxicity and decreased DCLF-induced activation of PERK, JNK, and ERK. These findings indicate that Ca(++) contributes to DCLF/cytokine-induced cytotoxic synergy by promoting activation of the ER stress-response pathway and JNK and ERK. © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  3. Cytokines in Machado Joseph Disease/Spinocerebellar Ataxia 3.

    Science.gov (United States)

    da Silva Carvalho, Gerson; Saute, Jonas Alex Morales; Haas, Clarissa Branco; Torrez, Vitor Rocco; Brochier, Andressa Wigner; Souza, Gabriele Nunes; Furtado, Gabriel Vasata; Gheno, Tailise; Russo, Aline; Monte, Thais Lampert; Schumacher-Schuh, Artur; D'Avila, Rui; Donis, Karina Carvalho; Castilhos, Raphael Machado; Souza, Diogo Onofre; Saraiva-Pereira, Maria Luiza; Torman, Vanessa Leotti; Camey, Suzi; Portela, Luis Valmor; Jardim, Laura Bannach

    2016-08-01

    The aim of the present study is to describe the serum concentrations of a broad spectrum of cytokines in symptomatic and asymptomatic carriers of Machado Joseph disease (SCA3/MJD) CAG expansions. Molecularly confirmed carriers and controls were studied. Age at onset, disease duration, and clinical scales Scale for the Assessment and Rating of Ataxia (SARA), Neurological Examination Score for Spinocerebellar Ataxias (NESSCA), SCA Functional Index (SCAFI), and Composite Cerebellar Functional Score (CCFS) were obtained from the symptomatic carriers. Serum was obtained from all individuals and a cytokine panel "consisted of" eotaxin, granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon (IFN)-α, IFN-γ, interleukin (IL)-1β, IL-1RA, IL-2, IL-2R, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-15, IL-17, interferon gamma-induced protein (IP)-10, monocyte chemoattractant protein (MCP)-1, monokine induced by gamma interferon (MIG), macrophage inflammatory protein (MIP)-a, MIP-b, regulated on activation, normal T cell expressed and secreted (RANTES) and tumor necrosis factor (TNF)-α was analyzed. In a subgroup of symptomatic carriers, the cytokine panel was repeated after 360 days. Cytokine distribution among groups was studied by discriminant analysis; changes in serum levels after 360 days were studied by generalized estimation equation. Sixty-six symptomatic carriers, 13 asymptomatic carriers, and 43 controls were studied. No differences in cytokine patterns were found between controls and carriers of the CAG expansions or between controls and symptomatic carriers only. In contrast, eotaxin concentrations were significantly higher in asymptomatic than in symptomatic carriers or in controls (p = 0.001, ANCOVA). Eotaxin did not correlate with age, disease duration, CAG expansion, NESSCA score, and SARA score. Among symptomatic carriers, eotaxin dropped after 360 days (p = 0.039, GEE). SCA3/MJD patients presented a benign pattern of

  4. Immunomodulatory therapies for acute pancreatitis

    Science.gov (United States)

    Li, Jing; Yang, Wen-Juan; Huang, Lu-Ming; Tang, Cheng-Wei

    2014-01-01

    It is currently difficult for conventional treatments of acute pancreatitis (AP), which primarily consist of anti-inflammatory therapies, to prevent the progression of AP or to improve its outcome. This may be because the occurrence and progression of AP, which involves various inflammatory cells and cytokines, includes a series of complex immune events. Considering the complex immune system alterations during the course of AP, it is necessary to monitor the indicators related to immune cells and inflammatory mediators and to develop more individualized interventions for AP patients using immunomodulatory therapy. This review discusses the recent advances in immunomodulatory therapies. It has been suggested that overactive inflammatory responses should be inhibited and excessive immunosuppression should be avoided in the early stages of AP. The optimal duration of anti-inflammatory therapy may be shorter than previously expected (< 24 h), and appropriate immunostimulatory therapies should be administered during the period from the 3rd d to the 14th d in the course of AP. A combination therapy of anti-inflammatory and immune-stimulating drugs would hopefully constitute an alternative to anti-inflammatory drug monotherapy. Additionally, the detection of the genotypes of critical inflammatory mediators may be useful for screening populations of AP patients at high risk of severe infections to enable the administration of early interventions to improve their prognosis. PMID:25493006

  5. Changes of plasma cytokines and chemokines expression level in nasopharyngeal carcinoma patients after treatment with definitive intensity-modulated radiotherapy (IMRT.

    Directory of Open Access Journals (Sweden)

    Ya-Bin Jin

    Full Text Available Potential clinical application values of certain cytokines and chemokines that participate in the process of tumor growth, invasion, and metastasis have been reported. However, there still lack of biomarkers for a great many of malignancy. This study identified cytokines or chemokines involved in the occurrence and development of nasopharyngeal carcinoma (NPC, which might be a biomarker for noninvasive early diagnosis.The plasma levels of 19 cytokines and chemokines were detected by the luminex liquid array-based multiplexed immunoassays in 39 NPC patients before and after treatment by definitive intensity-modulated radiotherapy (IMRT.Plasma levels of almost all of the 19 cytokines and chemokines in NPC patients were higher than healthy controls, while only IFN-γ, IL-1b IL-6, MCP-1, TNF-α, FKN, IL-12P70, IL-2, IL-5 and IP-10 showed significant differences. However, expression levels of most of the 19 cytokines and chemokines decreased after therapy, especially IFN-γ, IL-10, IL-1b, IL-6, IL-8, MCP-1, TNF-α, VEGF, IL-17A, IL-2, IL-5 and MIP-1b, have a dramatic decline. Taking together, plasma levels of IFN-γ, IL-1b, IL-6, MCP-1, TNF-α, IL-2 and IL-5 are significantly increased in NPC patients and dramatically decreased after treatment, suggesting these cytokines and chemokines might play important roles in the progress of NPC. More interestingly, the expression level of MPC-1 is significantly associated with clinical stage.MCP-1 might involve in the genesis and development process of NPC, which might serve as a noninvasive biomarker for early diagnosis.

  6. Effects of Curcuma comosa on the expression of atherosclerosis-related cytokine genes in rabbits fed a high-cholesterol diet.

    Science.gov (United States)

    Charoenwanthanang, Puttavee; Lawanprasert, Somsong; Phivthong-Ngam, Laddawal; Piyachaturawat, Pawinee; Sanvarinda, Yupin; Porntadavity, Sureerut

    2011-04-12

    Curcuma comosa has been known to have potential use in cardiovascular diseases, but its immunoregulatory role in atherosclerosis development and liver toxicity has not been well studied. We therefore investigated the effects of Curcuma comosa on the expression of atherosclerosis-related cytokine genes in rabbits fed a high-cholesterol diet. Twelve male New Zealand White rabbits were treated with 1.0% cholesterol for one month and were subsequently treated with 0.5% cholesterol either alone, or in combination with 5mg/kg/day of simvastatin or with 400mg/kg/day of Curcuma comosa powder for three months. The expression of IL-1, MCP-1, TNF-α, IL-10, and TGF-β in the isolated abdominal aorta and liver were determined by real-time RT-PCR. Liver toxicity was determined by hepatic enzyme activity. Curcuma comosa significantly decreased the expression of pro-inflammatory cytokines, leading to a stronger reduction in IL-1, MCP-1, and TNF-α expression compared to that was suppressed by simvastatin treatment. However, neither Curcuma comosa nor simvastatin affected the expression of anti-inflammation cytokines. In the liver, Curcuma comosa insignificantly decreased the expression of pro-inflammatory cytokines and significantly increased the expression of the anti-inflammatory cytokine IL-10 without altering the activity of hepatic enzymes. In contrast, simvastatin significantly increased the MCP-1 and TNF-α expressions and serum ALT level, without affecting the expression of anti-inflammatory cytokines. In this study, we demonstrated that Curcuma comosa exerts anti-inflammatory activity in the aorta and liver without causing liver toxicity, indicating that Curcuma comosa is a potential candidate as an alternative agent in cardiovascular disease therapy. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  7. Plasma levels of cytokines and chemokines and the risk of mortality in HIV-infected individuals: a case-control analysis nested in a large clinical trial

    Science.gov (United States)

    French, MA; Cozzi-Lepri, A; Arduino, RC; Johnson, M; Achhra, AC; Landay, A

    2015-01-01

    Background All-cause mortality and serious non-AIDS events (SNAEs) in individuals with HIV-1 infection receiving antiretroviral therapy are associated with increased production of interleukin (IL)-6, which appears to be driven by monocyte/macrophage activation. Plasma levels of other cytokines or chemokines associated with immune activation might also be biomarkers of an increased risk of mortality and/or SNAEs. Methods Baseline plasma samples from 142 participants enrolled into the SMART study who subsequently died, and 284 matched controls, were assayedfor levels of 15 cytokines and chemokines. Cytokine and chemokine levels were analysed individually and when grouped according to function (innate/pro-inflammatory response, cell trafficking and cell activation/proliferation) for their association with the risk of subsequent death. Results Higher plasma levels of pro-inflammatory cytokines (IL-6 and tumour necrosis factor-alpha) were associated with an increased risk of all-cause mortality but in analyses adjusted for potential confounders, only the association with IL-6 persisted. Increased plasma levels of the chemokine CXCL8 were also associated with all-cause mortality independently of HCV status but not when analyses were adjusted for all confounders. In contrast, higher plasma levels of cytokines mediating cell activation/proliferation were not associated with a higher mortality risk and exhibited a weak protective effect when analysed as a group. Conclusions While plasma levels of IL-6 are the most informative biomarker of cytokine dysregulation associated with all-cause mortality in individuals with HIV-1 infection, assessment of plasma levels of CXCL8 might provide information about causes of mortality and possibly SNAEs. PMID:25695873

  8. Changes of plasma cytokines and chemokines expression level in nasopharyngeal carcinoma patients after treatment with definitive intensity-modulated radiotherapy (IMRT).

    Science.gov (United States)

    Jin, Ya-Bin; Zhang, Guo-Yi; Lin, Kai-Rong; Chen, Xiang-Ping; Cui, Jin-Huan; Wang, Yue-Jian; Luo, Wei

    2017-01-01

    Potential clinical application values of certain cytokines and chemokines that participate in the process of tumor growth, invasion, and metastasis have been reported. However, there still lack of biomarkers for a great many of malignancy. This study identified cytokines or chemokines involved in the occurrence and development of nasopharyngeal carcinoma (NPC), which might be a biomarker for noninvasive early diagnosis. The plasma levels of 19 cytokines and chemokines were detected by the luminex liquid array-based multiplexed immunoassays in 39 NPC patients before and after treatment by definitive intensity-modulated radiotherapy (IMRT). Plasma levels of almost all of the 19 cytokines and chemokines in NPC patients were higher than healthy controls, while only IFN-γ, IL-1b IL-6, MCP-1, TNF-α, FKN, IL-12P70, IL-2, IL-5 and IP-10 showed significant differences. However, expression levels of most of the 19 cytokines and chemokines decreased after therapy, especially IFN-γ, IL-10, IL-1b, IL-6, IL-8, MCP-1, TNF-α, VEGF, IL-17A, IL-2, IL-5 and MIP-1b, have a dramatic decline. Taking together, plasma levels of IFN-γ, IL-1b, IL-6, MCP-1, TNF-α, IL-2 and IL-5 are significantly increased in NPC patients and dramatically decreased after treatment, suggesting these cytokines and chemokines might play important roles in the progress of NPC. More interestingly, the expression level of MPC-1 is significantly associated with clinical stage. MCP-1 might involve in the genesis and development process of NPC, which might serve as a noninvasive biomarker for early diagnosis.

  9. Role of Cytokines and Neurotrophins in the Central Nervous System in Venezuelan Equine Encephalitis Pathogenesis

    Science.gov (United States)

    2001-03-21

    Professor, Department of Microbiology and Immunology Venezuelan equine encephalitis virus (VEE) is a mosquito -borne alphavirus capable of causing...the role of cytokines in CNS pathologies, researchers have utilized transgenic mice with targeted expression of specific cytokines in their astrocytes...These mice exhib neurological disorders that can be correlated with the level of cytokine expression. Specifically, IL-6-expressing transgenic mice

  10. Research Review: The Role of Cytokines in Depression in Adolescents: A Systematic Review

    Science.gov (United States)

    Mills, Natalie T.; Scott, James G.; Wray, Naomi R.; Cohen-Woods, Sarah; Baune, Bernhard T.

    2013-01-01

    Background: While cytokines have been implicated in the pathophysiology of depression in adults, the potential role in younger age groups such as adolescents is less clear. This article therefore reviews the literature (a) to explore the relationship between cytokines and depression in adolescents, and (b) to examine how cytokines may be related…

  11. DMPD: Cytokine signaling modules in inflammatory responses. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 18400190 Cytokine<