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Sample records for human immune reconstituted

  1. Immune reconstitution syndrome in a human immunodeficiency virus infected child due to giardiasis leading to shock

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    Sneha Nandy

    2015-01-01

    Full Text Available Human immunodeficiency virus (HIV-associated immune reconstitution inflammatory syndrome has been reported in association with tuberculosis, herpes zoster (shingles, Cryptococcus neoformans, Kaposi′s sarcoma, Pneumocystis pneumonia, hepatitis B virus, hepatitis C virus, herpes simplex virus, Histoplasma capsulatum, human papillomavirus, and Cytomegalovirus. However, it has never been documented with giardiasis. We present a 7-year-old HIV infected girl who developed diarrhea and shock following the initiation of antiretroviral therapy, and her stool showed the presence of giardiasis.

  2. Borderline tuberculoid leprosy: A manifestation of immune reconstitution inflammatory syndrome in a human immunodeficiency virus infected person

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    Mukhopadhyay Partha

    2006-01-01

    Full Text Available Immune reconstitution inflammatory syndrome describes a collection of inflammatory disorders associated with paradoxical deterioration of various pre-existing processes following start of highly active antiretroviral therapy (HAART in human immunodeficiency virus (HIV-infected patients. Leprosy as an opportunistic infection in immune reconstitution syndrome has been rarely reported in literature. A case of a 30-year-old HIV positive man with extrapulmonary tuberculosis of left foot on HAART having developed borderline tuberculoid leprosy as opportunistic infection in immune reconstitution syndrome has been reported.

  3. Hashimoto's Thyroiditis Presenting as Acute Painful Thyroiditis and as a Manifestation of an Immune Reconstitution Inflammatory Syndrome in a Human Immunodeficiency Virus-Seropositive Patient.

    NARCIS (Netherlands)

    Visser, R.; Mast, Q. de; Netea-Maier, R.T.; Ven, A.J.A.M. van der

    2012-01-01

    Background: An immune reconstitution inflammatory syndrome (IRIS) may complicate immune restoration following start of antiretroviral therapy (ART) in human immunodeficiency virus (HIV)-infected patients. The occurrence of Graves' disease in the setting of an IRIS is well recognized. We hereby

  4. Immune Reconstitution Inflammatory Syndrome and Shingles ...

    African Journals Online (AJOL)

    Immune Reconstitution Inflammatory Syndrome and Shingles Associated with a Combined Paralysis of Three Oculomotor Nerves: A Case Report. ... CASE DETAILS: A 40 years old patient was seen for a pain of the right side of the face and a complete immobility of the eyeball. The diagnosis of V1 shingles with a pan uveitis ...

  5. Human innate responses and adjuvant activity of TLR ligands in vivo in mice reconstituted with a human immune system.

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    Cheng, Liang; Zhang, Zheng; Li, Guangming; Li, Feng; Wang, Li; Zhang, Liguo; Zurawski, Sandra M; Zurawski, Gerard; Levy, Yves; Su, Lishan

    2017-10-27

    TLR ligands (TLR-Ls) represent a class of novel vaccine adjuvants. However, their immunologic effects in humans remain poorly defined in vivo. Using a humanized mouse model with a functional human immune system, we investigated how different TLR-Ls stimulated human innate immune response in vivo and their applications as vaccine adjuvants for enhancing human cellular immune response. We found that splenocytes from humanized mice showed identical responses to various TLR-Ls as human PBMCs in vitro. To our surprise, various TLR-Ls stimulated human cytokines and chemokines differently in vivo compared to that in vitro. For example, CpG-A was most efficient to induce IFN-α production in vitro. In contrast, CpG-B, R848 and Poly I:C stimulated much more IFN-α than CpG-A in vivo. Importantly, the human innate immune response to specific TLR-Ls in humanized mice was different from that reported in C57BL/6 mice, but similar to that reported in nonhuman primates. Furthermore, we found that different TLR-Ls distinctively activated and mobilized human plasmacytoid dendritic cells (pDCs), myeloid DCs (mDCs) and monocytes in different organs. Finally, we showed that, as adjuvants, CpG-B, R848 and Poly I:C can all enhance antigen specific CD4 + T cell response, while only R848 and Poly I:C induced CD8 + cytotoxic T cells response to a CD40-targeting HIV vaccine in humanized mice, correlated with their ability to activate human mDCs but not pDCs. We conclude that humanized mice serve as a highly relevant model to evaluate and rank the human immunologic effects of novel adjuvants in vivo prior to testing in humans. Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. Matrix Degradation in Human Immunodeficiency Virus Type 1-Associated Tuberculosis and Tuberculosis Immune Reconstitution Inflammatory Syndrome: A Prospective Observational Study.

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    Walker, Naomi F; Wilkinson, Katalin A; Meintjes, Graeme; Tezera, Liku B; Goliath, Rene; Peyper, Janique M; Tadokera, Rebecca; Opondo, Charles; Coussens, Anna K; Wilkinson, Robert J; Friedland, Jon S; Elkington, Paul T

    2017-07-01

    Extensive immunopathology occurs in human immunodeficiency virus (HIV)/tuberculosis (TB) coinfection, but the underlying molecular mechanisms are not well-defined. Excessive matrix metalloproteinase (MMP) activity is emerging as a key process but has not been systematically studied in HIV-associated TB. We performed a cross-sectional study of matrix turnover in HIV type 1 (HIV-1)-infected and -uninfected TB patients and controls, and a prospective cohort study of HIV-1-infected TB patients at risk of TB immune reconstitution inflammatory syndrome (TB-IRIS), in Cape Town, South Africa. Sputum and plasma MMP concentrations were quantified by Luminex, plasma procollagen III N-terminal propeptide (PIIINP) by enzyme-linked immunosorbent assay, and urinary lipoarabinomannan (LAM) by Alere Determine TB LAM assay. Peripheral blood mononuclear cells from healthy donors were cultured with Mycobacterium tuberculosis and extracellular matrix in a 3D model of TB granuloma formation. MMP activity differed between HIV-1-infected and -uninfected TB patients and corresponded with specific TB clinical phenotypes. HIV-1-infected TB patients had reduced pulmonary MMP concentrations, associated with reduced cavitation, but increased plasma PIIINP, compared to HIV-1-uninfected TB patients. Elevated extrapulmonary extracellular matrix turnover was associated with TB-IRIS, both before and during TB-IRIS onset. The predominant collagenase was MMP-8, which was likely neutrophil derived and M. tuberculosis-antigen driven. Mycobacterium tuberculosis-induced matrix degradation was suppressed by the MMP inhibitor doxycycline in vitro. MMP activity in TB differs by HIV-1 status and compartment, and releases matrix degradation products. Matrix turnover in HIV-1-infected patients is increased before and during TB-IRIS, informing novel diagnostic strategies. MMP inhibition is a potential host-directed therapy strategy for prevention and treatment of TB-IRIS. © The Author 2017. Published by Oxford

  7. Immune Reconstitution after Allogeneic Hematopoietic Stem Cell Transplantation

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    Ogonek, Justyna; Kralj Juric, Mateja; Ghimire, Sakhila; Varanasi, Pavankumar Reddy; Holler, Ernst; Greinix, Hildegard; Weissinger, Eva

    2016-01-01

    The timely reconstitution and regain of function of a donor-derived immune system is of utmost importance for the recovery and long-term survival of patients after allogeneic hematopoietic stem cell transplantation (HSCT). Of note, new developments such as umbilical cord blood or haploidentical grafts were associated with prolonged immunodeficiency due to delayed immune reconstitution, raising the need for better understanding and enhancing the process of immune reconstitution and finding strategies to further optimize these transplant procedures. Immune reconstitution post-HSCT occurs in several phases, innate immunity being the first to regain function. The slow T cell reconstitution is regarded as primarily responsible for deleterious infections with latent viruses or fungi, occurrence of graft-versus-host disease, and relapse. Here we aim to summarize the major steps of the adaptive immune reconstitution and will discuss the importance of immune balance in patients after HSCT. PMID:27909435

  8. Immune Reconstitution Inflammatory Syndrome in children

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    Nasreen Mahomed

    2017-11-01

    Full Text Available Immune Reconstitution Inflammatory Syndrome (IRIS refers to a collection of inflammatorydisorders, predominantly related to infectious processes that manifest after the initiation ofantiretroviral therapy (ART and can be classified as unmasking or paradoxical. The prevalenceof IRIS in children in sub-Saharan Africa is low. Approximately half of all cases are associatedwith Mycobacterium tuberculosis. It may be difficult to distinguish IRIS from tuberculosis andother opportunistic infections radiologically; therefore, radiological findings must be interpretedwith clinical and laboratory findings. In this review article, we describe the clinical andradiological manifestations of IRIS in children and provide illustrative radiological examples.

  9. Increasing Stem Cell Dose Promotes Posttransplant Immune Reconstitution.

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    Xu, Ning; Shen, Sylvie; Dolnikov, Alla

    2017-04-01

    Umbilical cord blood (UCB) transplantation can provide a successful therapeutic option for patients that have no suitable related donor. UCB transplantation is often limited by the relatively small hematopoietic stem cell (HSC) numbers in UCB especially for adult recipients. Early neutrophil and platelet engraftment correlates with the stem cell numbers in UCB transplant. Compared to other HSC sources, immune reconstitution following UCB transplant is slower and complicated by increased frequency of opportunistic infections. The effect of HSC numbers in UCB transplant on immune reconstitution was not thoroughly examined. Using immunocompromised mice transplanted with purified UCB CD34+ stem cells, we have demonstrated that increasing the numbers of CD34+ cells in the transplant promotes hematopoietic and immune reconstitution. At early stages posttransplant, high stem cell dose generated relatively more B cells, while lower dose generated more myeloid and T cells. Thus, the size of the stem cell graft appears to modulate the differentiation potential of infused stem cells. In addition, increasing stem cell dose in the transplant improved CD8+ T cell development and delayed late memory T cell skewing in expense of naive T cells highlighting the importance of HSC dose to maintain the pool of naive T cells able to develop strong immune responses. Transplantation of ex vivo expanded CD34+ cells did not promote, but rather delayed immune reconstitution suggesting the loss of primitive lymphoid precursor cells during ex vivo expansion.

  10. Immune Reconstitution Inflammatory Syndrome (IRIS): What pathologists should know.

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    Nelson, Ann Marie; Manabe, Yukari C; Lucas, Sebastian B

    2017-07-01

    Antiretroviral therapy has significantly improved the quality and length of life for those patients able to access effective and sustained treatment. The resulting restoration of the immune response is associated with a change in the clinical presentation of opportunistic infections, and the histologic reaction to pathogens. A complex combination of alterations in host response across the stages of HIV infection has been documented over the past 3 decades. The defects are seen in both acute and chronic phases of inflammation and involve innate and adaptive immunity. In advanced stages of HIV infection, the marked disruption of lymphoid tissue and loss of follicular dendritic cells limits the host's ability to process antigen and mount specific responses to pathogens. There are qualitative and quantitative defects in CD4 T cells due to HIV infection. The resulting indirect effects include loss of cytokine production, dysregulation of B-cell function, loss of cellular mediated immunity and "holes" in the immunologic repertoire that may not be restored with the use of antiretroviral therapy. Immune reconstitution allows the host to respond to and control infection, but a significant number of patients will have atypical inflammatory syndromes during the recovery period. We briefly discuss the impact of HIV infection on the immune system and give an overview of the spectrum of conditions attributed to the Immune Reconstitution Inflammatory syndrome (IRIS). Copyright © 2017 Elsevier Inc. All rights reserved.

  11. Improving engraftment and immune reconstitution in umbilical cord blood transplantation

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    Robert eDanby

    2014-02-01

    Full Text Available Umbilical cord blood (UCB is an important source of haematopoietic stem cells (HSC for allogeneic transplantation when HLA-matched sibling and unrelated donors (MUD are unavailable. Although the overall survival rates of UCB transplantation are comparable to the results with MUD, UCB transplants are associated with slow engraftment, delayed immune reconstitution, and increased opportunistic infections. While this may be a consequence of the lower cell dose in UCB grafts, it also reflects the relative immaturity of cellular immunity within cord blood. Furthermore, the limited number of cells and the non-availability of donor lymphocyte infusions (DLI currently prevent the use of post-transplant cellular immunotherapy to boost donor-derived immunity to treat infection, mixed chimerism and disease relapse. Therefore, to further develop UCB transplantation, many strategies to enhance engraftment and immune reconstitution are currently under investigation. This review summarises our current understanding of engraftment and immune recovery following UCB transplantation and why this differs from allogeneic transplants using other sources of HSC. It also provides an comprehensive overview of the promising techniques being used to improve myeloid and lymphoid recovery, including expansion, homing, and delivery of UCB HSC; combined use of UCB with third party donors; isolation and expansion of NK cells, pathogen specific T cells, and regulatory T cells; methods to protect and/or improve thymopoiesis. As many of these strategies are now in clinical trials, it is anticipated that UCB transplantation will continue to advance, further expanding our understanding of UCB biology and HSC transplantation.

  12. Long-term human immune system reconstitution in non-obese diabetic (NOD)-Rag (-)-γ chain (-) (NRG) mice is similar but not identical to the original stem cell donor.

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    Harris, D T; Badowski, M; Balamurugan, A; Yang, O O

    2013-12-01

    The murine immune system is not necessarily identical to it human counterpart, which has led to the construction of humanized mice. The current study analysed whether or not a human immune system contained within the non-obese diabetic (NOD)-Rag1(null) -γ chain(null) (NRG) mouse model was an accurate representation of the original stem cell donor and if multiple mice constructed from the same donor were similar to one another. To that end, lightly irradiated NRG mice were injected intrahepatically on day 1 of life with purified cord blood-derived CD34(+) stem and progenitor cells. Multiple mice were constructed from each cord blood donor. Mice were analysed quarterly for changes in the immune system, and followed for periods up to 12 months post-transplant. Mice from the same donor were compared directly with each other as well as with the original donor. Analyses were performed for immune reconstitution, including flow cytometry, T cell receptor (TCR) and B cell receptor (BCR) spectratyping. It was observed that NRG mice could be 'humanized' long-term using cord blood stem cells, and that animals constructed from the same cord blood donor were nearly identical to one another, but quite different from the original stem cell donor immune system. © 2013 British Society for Immunology.

  13. Immunopathology of immune reconstitution inflammatory syndrome in Whipple's disease.

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    Moos, Verena; Feurle, Gerhard E; Schinnerling, Katina; Geelhaar, Anika; Friebel, Julian; Allers, Kristina; Moter, Annette; Kikhney, Judith; Loddenkemper, Christoph; Kühl, Anja A; Erben, Ulrike; Fenollar, Florence; Raoult, Didier; Schneider, Thomas

    2013-03-01

    During antimicrobial treatment of classic Whipple's disease (CWD), the chronic systemic infection with Tropheryma whipplei, immune reconstitution inflammatory syndrome (IRIS), is a serious complication. The aim of our study was to characterize the immunological processes underlying IRIS in CWD. Following the definition of IRIS, we describe histological features of IRIS and immunological parameters of 24 CWD IRIS patients, 189 CWD patients without IRIS, and 89 healthy individuals. T cell reconstitution, Th1 reactivity, and the phenotype of T cells were described in the peripheral blood, and infiltration of CD4(+) T cells and regulatory T cells in the duodenal mucosa was determined. During IRIS, tissues were heavily infiltrated by CD3(+), predominantly CD45RO(+)CD4(+) T cells. In the periphery, initial reduction of CD4(+) cell counts and their reconstitution on treatment was more pronounced in CWD patients with IRIS than in those without IRIS. The ratio of activated and regulatory CD4(+) T cells, nonspecific Th1 reactivity, and the proportion of naive among CD4(+) T cells was high, whereas serum IL-10 was low during IRIS. T. whipplei-specific Th1 reactivity remained suppressed before and after emergence of IRIS. The findings that IRIS in CWD mainly are mediated by nonspecific activation of CD4(+) T cells and that it is not sufficiently counterbalanced by regulatory T cells indicate that flare-up of pathogen-specific immunoreactivity is not instrumental in the pathogenesis of IRIS in CWD.

  14. Confusion in the Study of Immune Reconstitution Inflammatory Syndrome

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    Claudia Alvarado-de la Barrera

    2017-05-01

    Full Text Available As a consequence of late presentation for HIV care, a significant proportion of individuals develop immune reconstitution inflammatory syndrome (IRIS soon after initiation of antiretroviral therapy. Incidence, predictors, and models of pathogenesis of IRIS vary in the literature. Here we discuss factors that may contribute to this lack of consensus. We propose that different pathogens drive different types of IRIS and suggest that these clinical conditions should be studied individually and not grouped under the general heading of “IRIS.”

  15. The effects of IL-20 subfamily cytokines on reconstituted human epidermis suggest potential roles in cutaneous innate defense and pathogenic adaptive immunity in psoriasis.

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    Sa, Susan M; Valdez, Patricia A; Wu, Jianfeng; Jung, Kenneth; Zhong, Fiona; Hall, Linda; Kasman, Ian; Winer, Jane; Modrusan, Zora; Danilenko, Dimitry M; Ouyang, Wenjun

    2007-02-15

    IL-19, IL-20, IL-22, IL-24, and IL-26 are members of the IL-10 family of cytokines that have been shown to be up-regulated in psoriatic skin. Contrary to IL-10, these cytokines signal using receptor complex R1 subunits that are preferentially expressed on cells of epithelial origin; thus, we henceforth refer to them as the IL-20 subfamily cytokines. In this study, we show that primary human keratinocytes (KCs) express receptors for these cytokines and that IL-19, IL-20, IL-22, and IL-24 induce acanthosis in reconstituted human epidermis (RHE) in a dose-dependent manner. These cytokines also induce expression of the psoriasis-associated protein S100A7 and keratin 16 in RHE and cause persistent activation of Stat3 with nuclear localization. IL-22 had the most pronounced effects on KC proliferation and on the differentiation of KCs in RHE, inducing a decrease in the granular cell layer (hypogranulosis). Furthermore, gene expression analysis performed on cultured RHE treated with these cytokines showed that IL-19, IL-20, IL-22, and IL-24 regulate many of these same genes to variable degrees, inducing a gene expression profile consistent with inflammatory responses, wound healing re-epithelialization, and altered differentiation. Many of these genes have also been found to be up-regulated in psoriatic skin, including several chemokines, beta-defensins, S100 family proteins, and kallikreins. These results confirm that IL-20 subfamily cytokines are important regulators of epidermal KC biology with potentially pivotal roles in the immunopathology of psoriasis.

  16. Human hepatocyte depletion in the presence of HIV-1 infection in dual reconstituted humanized mice

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    Wang, Weimin; Cheng, Yan; Makarov, Edward; Ganesan, Murali; Gebhart, Catherine L.; Gorantla, Santhi; Osna, Natalia

    2018-01-01

    ABSTRACT Human immunodeficiency virus type 1 (HIV-1) infection impairs liver function, and liver diseases have become a leading cause of morbidity in infected patients. The immunopathology of liver damage caused by HIV-1 remains unclear. We used chimeric mice dually reconstituted with a human immune system and hepatocytes to address the relevance of the model to pathobiology questions related to human hepatocyte survival in the presence of systemic infection. TK-NOG males were transplanted with mismatched human hematopoietic stem/progenitor cells and hepatocytes, human albumin concentration and the presence of human immune cells in blood were monitored for hepatocytes and immune reconstitution, and mice were infected with HIV-1. HIV-1-infected animals showed a decline in human albumin concentration with a significant reduction in percentage of human hepatocytes compared to uninfected mice. The decrease in human albumin levels correlated with a decline in CD4+ cells in the liver and with an increase in HIV-1 viral load. HIV-1 infection elicited proinflammatory response in the immunological milieu of the liver in HIV-infected mice compared to uninfected animals, as determined by upregulation of IL23, CXCL10 and multiple toll-like receptor expression. The inflammatory reaction associated with HIV-1 infection in vivo could contribute to the depletion and dysfunction of hepatocytes. The dual reconstituted TK-NOG mouse model is a feasible platform to investigate hepatocyte-related HIV-1 immunopathogenesis. This article has an associated First Person interview with the first author of the paper. PMID:29361613

  17. Human hepatocyte depletion in the presence of HIV-1 infection in dual reconstituted humanized mice

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    Raghubendra Singh Dagur

    2018-02-01

    Full Text Available Human immunodeficiency virus type 1 (HIV-1 infection impairs liver function, and liver diseases have become a leading cause of morbidity in infected patients. The immunopathology of liver damage caused by HIV-1 remains unclear. We used chimeric mice dually reconstituted with a human immune system and hepatocytes to address the relevance of the model to pathobiology questions related to human hepatocyte survival in the presence of systemic infection. TK-NOG males were transplanted with mismatched human hematopoietic stem/progenitor cells and hepatocytes, human albumin concentration and the presence of human immune cells in blood were monitored for hepatocytes and immune reconstitution, and mice were infected with HIV-1. HIV-1-infected animals showed a decline in human albumin concentration with a significant reduction in percentage of human hepatocytes compared to uninfected mice. The decrease in human albumin levels correlated with a decline in CD4+ cells in the liver and with an increase in HIV-1 viral load. HIV-1 infection elicited proinflammatory response in the immunological milieu of the liver in HIV-infected mice compared to uninfected animals, as determined by upregulation of IL23, CXCL10 and multiple toll-like receptor expression. The inflammatory reaction associated with HIV-1 infection in vivo could contribute to the depletion and dysfunction of hepatocytes. The dual reconstituted TK-NOG mouse model is a feasible platform to investigate hepatocyte-related HIV-1 immunopathogenesis. This article has an associated First Person interview with the first author of the paper.

  18. Insights into pathogenic events of HIV-associated Kaposi sarcoma and immune reconstitution syndrome related Kaposi sarcoma

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    Lemmer Johan

    2008-01-01

    Full Text Available Abstract A decrease in the incidence of human immune deficiency virus-associated Kaposi sarcoma (HIV-KS and regression of some established HIV-KS lesions is evident after the introduction of highly active anti-retroviral treatment (HAART, and is attributed to generalized immune restoration, to the reconstitution of human herpesvirus (HHV-8 specific cellular immune responses, and to the decrease in HIV Tat protein and HHV-8 loads following HAART. However, a small subset of HIV-seropositive subjects with a low CD4+ T cell count at the time of introduction of HAART, may develop HIV-KS as immune reconstitution inflammatory syndrome (IRIS within 8 weeks thereafter.

  19. Comparison of immune reconstitution after allogeneic vs. autologous stem cell transplantation in 182 pediatric recipients

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    V. Wiegering

    2017-03-01

    Conclusion: Children undergoing a HSCT show a different pattern of immune reconstitution in the allogeneic and autologous setting. This might influence the outcome and should affect the clinical handling of infectious prophylaxis and re-vaccinations.

  20. Mutual Interference between Cytomegalovirus and Reconstitution of Protective Immunity after Hematopoietic Cell Transplantation

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    Matthias J. Reddehase

    2016-08-01

    Full Text Available Hematopoietic cell transplantation (HCT is a therapy option for aggressive forms of hematopoietic malignancies that are resistant to standard antitumoral therapies. Hematoablative treatment preceding HCT, however, opens a ‘window of opportunity’ for latent cytomegalovirus (CMV by releasing it from immune control with the consequence of reactivation of productive viral gene expression and recurrence of infectious virus. A ‘window of opportunity’ for the virus represents a ‘window of risk’ for the patient. In the interim between HCT and reconstitution of antiviral immunity, primarily mediated by CD8+ T cells, initially low amounts of reactivated virus can expand exponentially, disseminate to essentially all organs, and cause multiple organ CMV disease, with interstitial pneumonia (CMV-IP representing the most severe clinical manifestation. Here I will review predictions originally made in the mouse model of experimental HCT and murine CMV infection, some of which have already paved the way to translational preclinical research and promising clinical trials of a pre-emptive cytoimmunotherapy of human CMV disease. Specifically, the mouse model has been pivotal in providing ‘proof of concept’ for preventing CMV disease after HCT by adoptive transfer of preselected, virus epitope-specific effector and memory CD8+ T cells bridging the critical interim. CMV, however, is not a ‘passive antigen’ but is a pathogen that actively interferes with the reconstitution of protective immunity by infecting bone marrow stromal cells that otherwise form niches for hematopoiesis by providing the structural microenvironment and by producing hematopoietically active cytokines, the hemopoietins. Depending on the precise conditions of HCT, reduced homing of transplanted hematopoietic stem- and progenitor cells to infected bone marrow stroma and impaired colony growth and lineage differentiation can lead to ‘graft failure’. In consequence

  1. In vitro reconstitution of chaperone-mediated human RISC assembly.

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    Naruse, Ken; Matsuura-Suzuki, Eriko; Watanabe, Mariko; Iwasaki, Shintaro; Tomari, Yukihide

    2018-01-01

    To silence target mRNAs, small RNAs and Argonaute (Ago) proteins need to be assembled into RNA-induced silencing complexes (RISCs). Although the assembly of Drosophila melanogaster RISC was recently reconstituted by Ago2, the Dicer-2/R2D2 heterodimer, and five chaperone proteins, the absence of a reconstitution system for mammalian RISC assembly has posed analytical challenges. Here we describe reconstitution of human RISC assembly using Ago2 and five recombinant chaperone proteins: Hsp90β, Hsc70, Hop, Dnaja2, and p23. Our data show that ATP hydrolysis by both Hsp90β and Hsc70 is required for RISC assembly of small RNA duplexes but not for that of single-stranded RNAs. The reconstitution system lays the groundwork for further studies of small RNA-mediated gene silencing in mammals. © 2018 Naruse et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society.

  2. Evolutionary biology and anthropology suggest biome reconstitution as a necessary approach toward dealing with immune disorders.

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    Parker, William; Ollerton, Jeff

    2013-01-01

    Industrialized society currently faces a wide range of non-infectious, immune-related pandemics. These pandemics include a variety of autoimmune, inflammatory and allergic diseases that are often associated with common environmental triggers and with genetic predisposition, but that do not occur in developing societies. In this review, we briefly present the idea that these pandemics are due to a limited number of evolutionary mismatches, the most damaging being 'biome depletion'. This particular mismatch involves the loss of species from the ecosystem of the human body, the human biome, many of which have traditionally been classified as parasites, although some may actually be commensal or even mutualistic. This view, evolved from the 'hygiene hypothesis', encompasses a broad ecological and evolutionary perspective that considers host-symbiont relations as plastic, changing through ecological space and evolutionary time. Fortunately, this perspective provides a blueprint, termed 'biome reconstitution', for disease treatment and especially for disease prevention. Biome reconstitution includes the controlled and population-wide reintroduction (i.e. domestication) of selected species that have been all but eradicated from the human biome in industrialized society and holds great promise for the elimination of pandemics of allergic, inflammatory and autoimmune diseases.

  3. Cryptococcal Meningoencephalitis Relapse after an 8 Year Delay: An Interplay of Infection and Immune Reconstitution?

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    Katchanov, Juri; Blechschmidt, Cristiane; Nielsen, Kirsten; Branding, Gordian; Arastéh, Keikawus; Tintelnot, Kathrin; Meintjes, Graeme; Boulware, David R.; Stocker, Hartmut

    2016-01-01

    We report a case of a symptomatic relapse of HIV-related cryptococcal meningoencephalitis 8 years after the first diagnosis on the background of immune reconstitution. The findings as well as the clinical course suggests a combination of smouldering localized infection and enhanced inflammatory reaction related to immune restoration due to antiretroviral therapy. A combination of antifungal and anti-inflammatory therapy resulted in clinical and radiological improvement. Our case challenges the concept that immune reconstitution inflammatory syndrome and microbiological relapse are dichotomous entities. PMID:25505049

  4. Cryptococcal meningoencephalitis relapse after an eight-year delay: an interplay of infection and immune reconstitution.

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    Katchanov, Juri; Blechschmidt, Cristiane; Nielsen, Kirsten; Branding, Gordian; Arastéh, Keikawus; Tintelnot, Kathrin; Meintjes, Graeme; Boulware, David R; Stocker, Hartmut

    2015-10-01

    We report a case of a symptomatic relapse of HIV-related cryptococcal meningoencephalitis eight years after the first diagnosis on the background of immune reconstitution. The findings as well as the clinical course suggests a combination of smouldering localised infection and enhanced inflammatory reaction related to immune restoration due to antiretroviral therapy. A combination of antifungal and anti-inflammatory therapy resulted in clinical and radiological improvement. Our case challenges the concept that immune reconstitution inflammatory syndrome and microbiological relapse are dichotomous entities. © The Author(s) 2015.

  5. Epigenetic programming of T cells impacts immune reconstitution in hematopoietic stem cell transplant recipients.

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    Hardy, Kristine; Smith, Corey; Tu, Wen Juan; McCuaig, Robert; Panikkar, Archana; Dasari, Vijayendra; Wu, Fan; Tey, Siok-Keen; Hill, Geoffrey R; Khanna, Rajiv; Rao, Sudha

    2018-03-27

    Immune reconstitution following hematopoietic stem cell transplantation (HSCT) is critical in preventing harmful sequelae in recipients with cytomegalovirus (CMV) infection. To understand the molecular mechanisms underlying immune reconstitution kinetics, we profiled the transcriptome-chromatin accessibility landscape of CMV-specific CD8 + T cells from HCST recipients with different immune reconstitution efficiencies. CMV-specific T cells from HSCT recipients with stable antiviral immunity expressed higher levels of interferon/defense response and cell cycle genes in an interconnected network involving PI3KCG , STAT5B , NFAT , RBPJ , and lower HDAC6 , increasing chromatin accessibility at the enhancer regions of immune and T-cell receptor signaling pathway genes. By contrast, the transcriptional and epigenomic signatures of CMV-specific T cells from HSCT recipients with unstable immune reconstitution showed commonalities with T-cell responses in other nonresolving chronic infections. These signatures included higher levels of EGR and KLF factors that, along with lower JARID2 expression, maintained higher accessibility at promoter and CpG-rich regions of genes associated with apoptosis. Furthermore, epigenetic targeting via inhibition of HDAC6 or JARID2 enhanced the transcription of genes associated with differential responses, suggesting that drugs targeting epigenomic modifiers may have therapeutic potential for enhancing immune reconstitution in HSCT recipients. Taken together, these analyses demonstrate that transcription factors and chromatin modulators create different chromatin accessibility landscapes in T cells of HSCT recipients that not only affect immediate gene expression but also differentially prime cells for responses to additional signals. Epigenetic therapy may be a promising strategy to promote immune reconstitution in HSCT recipients. © 2018 by The American Society of Hematology.

  6. Pathology in euthermic bats with white nose syndrome suggests a natural manifestation of immune reconstitution inflammatory syndrome.

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    Meteyer, Carol U; Barber, Daniel; Mandl, Judith N

    2012-11-15

    White nose syndrome, caused by Geomyces destructans, has killed more than 5 million cave hibernating bats in eastern North America. During hibernation, the lack of inflammatory cell recruitment at the site of fungal infection and erosion is consistent with a temperature-induced inhibition of immune cell trafficking. This immune suppression allows G. destructans to colonize and erode the skin of wings, ears and muzzle of bat hosts unchecked. Yet, paradoxically, within weeks of emergence from hibernation an intense neutrophilic inflammatory response to G. destructans is generated, causing severe pathology that can contribute to death. We hypothesize that the sudden reversal of immune suppression in bats upon the return to euthermia leads to a form of immune reconstitution inflammatory syndrome (IRIS). IRIS was first described in HIV-infected humans with low helper T lymphocyte counts and bacterial or fungal opportunistic infections. IRIS is a paradoxical and rapid worsening of symptoms in immune compromised humans upon restoration of immunity in the face of an ongoing infectious process. In humans with HIV, the restoration of adaptive immunity following suppression of HIV replication with anti-retroviral therapy (ART) can trigger severe immune-mediated tissue damage that can result in death. We propose that the sudden restoration of immune responses in bats infected with G. destructans results in an IRIS-like dysregulated immune response that causes the post-emergent pathology.

  7. Pathology in euthermic bats with white nose syndrome suggests a natural manifestation of immune reconstitution inflammatory syndrome

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    Meteyer, Carol U.; Barber, Daniel; Mandl, Judith N.

    2012-01-01

    White nose syndrome, caused by Geomyces destructans, has killed more than 5 million cave hibernating bats in eastern North America. During hibernation, the lack of inflammatory cell recruitment at the site of fungal infection and erosion is consistent with a temperature-induced inhibition of immune cell trafficking. This immune suppression allows G. destructans to colonize and erode the skin of wings, ears and muzzle of bat hosts unchecked. Yet, paradoxically, within weeks of emergence from hibernation an intense neutrophilic inflammatory response to G. destructans is generated, causing severe pathology that can contribute to death. We hypothesize that the sudden reversal of immune suppression in bats upon the return to euthermia leads to a form of immune reconstitution inflammatory syndrome (IRIS), which was first described in HIV-infected humans with low helper T lymphocyte counts and bacterial or fungal opportunistic infections. IRIS is a paradoxical and rapid worsening of symptoms in immune compromised humans upon restoration of immunity in the face of an ongoing infectious process. In humans with HIV, the restoration of adaptive immunity following suppression of HIV replication with anti-retroviral therapy (ART) can trigger severe immune-mediated tissue damage that can result in death. We propose that the sudden restoration of immune responses in bats infected with G. destructans results in an IRIS-like dysregulated immune response that causes the post-emergent pathology.

  8. Reconstitution of immunodeficient SCID/beige mice with human cells: Applications in preclinical studies

    International Nuclear Information System (INIS)

    Thomsen, Mogens; Galvani, Sylvain; Canivet, Cindy; Kamar, Nassim; Boehler, Torsten

    2008-01-01

    Experimental studies of the in vivo behaviour of human cells and tissues have become possible with the development of immunodeficient mice strains. Such mice accept readily allogeneic or xenogeneic grafts, including grafts of human cells or tissues, without rejection. In this review we describe different immunodeficient mouse strains that have been used for reconstitution by human immune cells. We subsequently go through the experience that we and others have had with reconstitution, and mention the adverse effects, in particular xenogeneic graft versus host reactions. The use of haematopoietic stem cells avoids such reactions but the immunological reconstitution may take several months. We then report the use of immunodeficient mice for the study of chronic vascular rejection of human mesenteric arteries due to cellular or humoral alloreaction. We have shown that SCID/beige mice grafted with a human artery at the place of the aorta developed a thickening of the intima of the human artery after 5-6 weeks, when they were reconstituted with spleen cells from another human donor. The thickening is mainly due to a proliferation of smooth muscle cells. The same type of lesion developed if they received injection of antibodies towards HLA class I antigens. The arteries of the mouse did not develop any lesion. The arterial lesions closely resembled those seen after clinical organ transplantation. Mice that received spleen cells from the same human donor developed little or no lesions. An important aspect of this experimental transplantation model is the possibility to test drugs that may be used in clinical transplantation. In recent experiments we have shown that novel immunosuppressive drugs can inhibit the hyperproliferation of smooth muscle cells in vitro. Preclinical testing in reconstituted SCID/beige mice grafted with human arteries will permit the evaluation of the potential use of these drugs to prevent chronic vascular rejection. The model also allows

  9. HIV-positive patient with herpes zoster: a manifestation of the immune reconstitution inflammatory syndrome.

    Science.gov (United States)

    Lutwak, Nancy; Dill, Curt

    2012-01-01

    Herpes zoster is a common illness that can lead to serious morbidity. There is now evidence that HIV-infected patients who have been treated with antiretroviral therapy are at greater risk of developing herpes zoster not when they are severely immunocompromised but, paradoxically, when their immune system is recovering. This is a manifestation of the immune reconstitution inflammatory syndrome. The objectives of this report are to (1) inform health care providers that HIV-infected patients may develop multiple infectious, autoimmune, and oncological manifestations after treatment with antiretroviral medication, as they have immune system reconstitution, and (2) discuss herpes zoster, one of the possible manifestations. The patient is a 68-year-old HIV-positive man who presented with herpes zoster after being treated with highly active antiretroviral therapy (HAART) when his immune system was recovering, not when he was most immunosuppressed. Emergency department physicians should be aware that HIV-infected patients treated with HAART may have clinical deterioration despite immune system strengthening. This immune reconstitution inflammatory syndrome can present with infectious, autoimmune, or oncological manifestations. Our case patient, an HIV-positive man with immune system recovery after treatment with HAART, presented with an infectious manifestation, herpes zoster.

  10. Leprosy reversal reaction as immune reconstitution inflammatory syndrome in patients with AIDS

    OpenAIRE

    Batista, Mariana Dias [UNIFESP; Porro, Adriana Maria [UNIFESP; Maeda, Solange Miki [UNIFESP; Gomes, Elimar Elias [UNIFESP; Yoshioka, Marcia Cristina Naomi [UNIFESP; Enokihara, Mílvia Maria Simões e Silva [UNIFESP; Tomimori, Jane [UNIFESP

    2008-01-01

    We report 2 instances in which reactional borderline leprosy manifested itself as an immune reconstitution phenomenon in patients with acquired immunodeficiency syndrome. We discuss the clinical, laboratory-based, histopathologic, and immunohistochemical characteristics of both patients. Furthermore, we review similar reports from the literature.

  11. Leprosy reversal reaction as immune reconstitution inflammatory syndrome in patients with AIDS.

    Science.gov (United States)

    Batista, Mariana D; Porro, Adriana M; Maeda, Solange M; Gomes, Elimar E; Yoshioka, Márcia C N; Enokihara, Mílvia M S S; Tomimori, Jane

    2008-03-15

    We report 2 instances in which reactional borderline leprosy manifested itself as an immune reconstitution phenomenon in patients with acquired immunodeficiency syndrome. We discuss the clinical, laboratory-based, histopathologic, and immunohistochemical characteristics of both patients. Furthermore, we review similar reports from the literature.

  12. Immune reconstitution syndrome presenting as probable AIDS-related lymphoma: a case report

    DEFF Research Database (Denmark)

    Mortensen, Bo K; Nielsen, Susanne D; Christensen, Charlotte

    2011-01-01

    ABSTRACT: We report an unusual case of HIV-related immune reconstitution inflammatory syndrome, presenting as suspected AIDS-related lymphoma. Symptoms, initial investigations including fine-needle biopsy and 18F-FDG PET/CT scan were highly compatible with high grade AIDS-related lymphoma, however...

  13. The role of monocytes in the development of Tuberculosis-associated Immune Reconstitution Inflammatory Syndrome

    NARCIS (Netherlands)

    Tran, Huyen Thi Thanh; van den Bergh, Rafael; Vu, Trung Nghia; Laukens, Kris; Worodria, William; Loembé, Marguerite Massinga; Colebunders, Robert; Kestens, Luc; de Baetselier, Patrick; Raes, Geert; Mayanja-Kizza, Harriet; Mascart, Françoise; den Bergh, Rafaelvan; Locht, Camille; Reiss, Peter; Cobelens, Frank; Ondoa, Pascale; Pakker, Nadine; Mugerwa, Roy

    2014-01-01

    Tuberculosis-associated Immune Reconstitution Inflammatory Syndrome (TB-IRIS) is a common complication of combined antiretroviral therapy (cART) in HIV-TB co-infected patients. However, the disease mechanism is poorly understood, prognosis of TB-IRIS is currently impossible, and diagnosis is highly

  14. Immune reconstitution inflammatory syndrome unmasking erythema nodosum leprosum: A rare case report

    Directory of Open Access Journals (Sweden)

    Geeta Kiran Arakkal

    2015-01-01

    Full Text Available Immune reconstitution inflammatory syndrome (IRIS occurs as an acute symptomatic expression of a latent infection during the recovery of immune system in response to antiretroviral therapy in HIV patients. IRIS triggers both opportunistic and non-opportunistic infections. We report a case of IRIS in a patient with HIV, presenting as erythema nodosum leprosum (ENL, which led to unmasking of lepromatous leprosy following anti-retroviral therapy (ART.

  15. Immune reconstitution inflammatory syndrome due to Mycobacterium avium complex successfully followed up using 18 F-fluorodeoxyglucose positron emission tomography-computed tomography in a patient with human immunodeficiency virus infection: A case report

    International Nuclear Information System (INIS)

    Namkoong, Ho; Fujiwara, Hiroshi; Ishii, Makoto; Yagi, Kazuma; Haraguchi, Mizuha; Matsusaka, Masako; Suzuki, Shoji; Asakura, Takanori; Asami, Takahiro; Saito, Fumitake; Fukunaga, Koichi; Tasaka, Sadatomo; Betsuyaku, Tomoko; Hasegawa, Naoki

    2015-01-01

    In human immunodeficiency virus (HIV)-infected patients, immune reconstitution inflammatory syndrome (IRIS) due to nontuberculous mycobacteria (NTM) infection is one of the most difficult types of IRIS to manage. 18 F-fluorodeoxyglucose positron emission tomography/computed tomography ( 18 F-FDG PET/CT) has been suggested as a useful tool for evaluating the inflammatory status of HIV-infected patients. We present the first case of Mycobacterium avium complex (MAC)-associated IRIS (MAC-IRIS) that was successfully followed up using 18 F-FDG PET/CT. A 44-year-old homosexual Japanese man was referred to our hospital with fever and dyspnea. He was diagnosed with Pneumocystis jiroveci pneumonia and found to be HIV positive. After the initiation of combined antiretroviral therapy (cART), the patient’s mediastinal and bilateral hilar lymphadenopathy gradually enlarged, and bilateral infiltrates appeared in the upper lung fields. 18 F-FDG PET/CT was performed five months after the initiation of cART and showed intense accumulation of fluorodeoxyglucose (FDG) corresponding to the lesions of infiltration as well as the mediastinal and bilateral hilar lymphadenopathy. A bronchial wash culture and pathology findings led to a diagnosis of MAC-IRIS. Anti-mycobacterial chemotherapy with rifampicin, ethambutol, clarithromycin, and levofloxacin was started. One year after the chemotherapy was initiated, there was a significant reduction in FDG uptake in the area of the lesions except in the mediastinal lymph node. This implied incomplete resolution of the MAC-IRIS-related inflammation. Anti-mycobacterial chemotherapy was continued because of the residual lesion. To date, the patient has not experienced a recurrence of MAC-IRIS, a period of nine months. We present a case of MAC-IRIS in an HIV-infected patient whose disease activity was successfully followed up using 18 F-FDG PET/CT. Our data suggest that 18 F-FDG PET/CT is useful for evaluating the disease activity of NTM-IRIS and

  16. Multiphasic and multifocal cryptococcal immune reconstitution inflammatory syndrome in an HIV-infected patient: interplay of infection and immunity.

    Science.gov (United States)

    Katchanov, Juri; Zimmermann, Ulrike; Branding, Gordian; Tintelnot, Kathrin; Müller, Markus; Arastéh, Keikawus; Stocker, Hartmut

    2014-01-01

    We report a case of cryptococcal immune reconstitution inflammatory syndrome affecting the lungs, and 10 months later the cervical lymph nodes, in the absence of cryptococcal meningitis, in advanced HIV infection. Our report demonstrates the organ-specificity of the timing of the inflammatory response and illustrates the organ-specific interplay of immunity and infection in cryptococcal disease. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

  17. Innate immune reconstitution with suppression of HIV-1.

    Science.gov (United States)

    Scully, Eileen P; Lockhart, Ainsley; Garcia-Beltran, Wilfredo; Palmer, Christine D; Musante, Chelsey; Rosenberg, Eric; Allen, Todd M; Chang, J Judy; Bosch, Ronald J; Altfeld, Marcus

    2016-03-17

    Progressive HIV-1 infection leads to both profound immune suppression and pathologic inflammation in the majority of infected individuals. While adaptive immune dysfunction, as evidenced by CD4 + T cell depletion and exhaustion, has been extensively studied, less is known about the functional capacity of innate immune cell populations in the context of HIV-1 infection. Given the broad susceptibility to opportunistic infections and the dysregulated inflammation observed in progressive disease, we hypothesized that there would be significant changes in the innate cellular responses. Using a cohort of patients with multiple samplings before and after antiretroviral therapy (ART) initiation, we demonstrated increased responses to innate immune stimuli following viral suppression, as measured by the production of inflammatory cytokines. Plasma viral load itself had the strongest association with this change in innate functional capacity. We further identified epigenetic modifications in the TNFA promoter locus in monocytes that are associated with viremia, suggesting a molecular mechanism for the observed changes in innate immune function following initiation of ART. These data indicate that suppression of HIV-1 viremia is associated with changes in innate cellular function that may in part determine the restoration of protective immune responses.

  18. Immune reconstitution inflammatory syndrome after initiating highly active antiretroviral therapy in HIV-infected children

    International Nuclear Information System (INIS)

    Kilborn, Tracy; Zampoli, Marco

    2009-01-01

    The outcome of HIV infection has improved since the widespread availability of highly active antiretroviral therapy (HAART). Some patients, however, develop a clinical and radiological deterioration following initiation of HAART due to either the unmasking of occult subclinical infection or an enhanced inflammatory response to a treated infection. This phenomenon is believed to result from the restored ability to mount an immune response and is termed immune reconstitution inflammatory syndrome (IRIS) or immune reconstitution disease. IRIS is widely reported in the literature in adult patients, most commonly associated with mycobacterial infections. There is, however, a paucity of data documenting the radiological findings of IRIS in children. Radiologists need to be aware of this entity. As a diagnosis of exclusion it is essential that the radiological findings be assessed in the context of the clinical presentation. This article reviews the common clinical and radiological manifestations of IRIS in HIV-infected children. (orig.)

  19. Acute gouty arthritis as a manifestation of immune reconstitution inflammatory syndrome after initiation of antiretroviral therapy

    Directory of Open Access Journals (Sweden)

    Walter de Araujo Eyer-Silva

    2012-08-01

    Full Text Available Immune reconstitution inflammatory syndrome (IRIS in HIV-infected subjects initiating antiretroviral therapy most commonly involves new or worsening manifestations of previously subclinical or overt infectious diseases. Reports of non-infectious IRIS are much less common but represent important diagnostic and treatment challenges. We report on a 34-year-old HIV-infected male patient with no history of gout who developed acute gouty arthritis in a single joint one month after initiating highly active antiretroviral therapy.

  20. Immune reconstitution syndrome presenting as probable AIDS-related lymphoma: a case report

    OpenAIRE

    Christensen Charlotte B; Nielsen Susanne D; Mortensen Bo K; Helweg-Larsen Jannik

    2011-01-01

    Abstract We report an unusual case of HIV-related immune reconstitution inflammatory syndrome, presenting as suspected AIDS-related lymphoma. Symptoms, initial investigations including fine-needle biopsy and 18F-FDG PET/CT scan were highly compatible with high grade AIDS-related lymphoma, however subsequently IRIS was diagnosed. We discuss pitfalls in the interpretation of diagnostic results in ARL versus IRIS.

  1. The Immune Pathogenesis of Immune Reconstitution Inflammatory Syndrome Associated with Highly Active Antiretroviral Therapy in AIDS

    Science.gov (United States)

    Zhou, Huaying; He, Yan; Chen, Zi; He, Bo; He, Mei

    2014-01-01

    Abstract The present study investigated the immunological pathogenesis of immune reconstitution inflammatory syndrome (IRIS) in acquired immunodeficiency syndrome (AIDS) patients undergoing highly active antiretroviral therapy (HAART). A total of 238 patients with AIDS who received initial HAART were included in this prospective cohort study. Blood samples were collected immediately, at baseline, at week 12, and at week 24 after initial HAART and at the onset of IRIS. Lymphocyte subsets, Th1 and Th2 cytokines, and interleukin (IL)-7 levels were measured by flow cytometry or ELISA. Among the 238 patients with AIDS who received HAART, 47 patients developed IRIS. The percentages of CD4+ and CD8+ naive, memory, and activated cells exhibited no significant differences between AIDS patients with and without IRIS 24 weeks after initial HAART. The percentage of CD4+CD25+Foxp3+ regulatory T cells was lower in IRIS patients than in non-IRIS patients before HAART, 12 weeks after HAART, 24 weeks after HAART, and at the onset of IRIS. IL-2 and interferon (IFN)-γ levels were significantly higher at week 4 and at the onset of IRIS in IRIS patients than in non-IRIS patients. In contrast, IL-4 and IL-10 levels were significantly lower at week 4 and at the onset of IRIS in IRIS patients than in non-IRIS patients. Plasma IL-7 decreased gradually with the progression of HAART. The level of IL-7 was higher in IRIS patients than in non-IRIS patients at all follow-up time points. An imbalance of Th1/Th2 cytokines, a consistently low CD+CD25+Fox3+ percentage, and a high IL-7 level may be crucial in the pathogenesis of IRIS in AIDS patients who had received HAART. PMID:25131160

  2. B-lymphocyte differentiation in lethally irradiated and reconstituted mice. II. Recovery of humoral immune responsiveness

    International Nuclear Information System (INIS)

    Rozing, J.; Brons, N.H.C.; Benner, R.

    1977-01-01

    The recovery of humoral immune responsiveness was studied in lethally irradiated, fetal liver-reconstituted mice. By means of both membrane fluorescence and antibody formation to sheep red blood cells (SRBC) as a functional assay, the rate of recovery of the compartments of B and T lymphocytes was determined in various lymphoid organs. The recovery of the immunoglobulin-positive (B) cell compartment after irradiation and reconstitution started in the spleen. This organ was also found to be the first in which the recovery of the B-cell population was completed. The interval between the recovery of the B-cell population in the spleen and that in the other organs tested was found to increase when the irradiated mice were reconstituted with spleen colony cells instead of fetal liver cells. This proved to be caused by the number and nature of the reconstituting hemopoietic stem cells. The immunoglobulin-positive (B) cells were found to appear before SRBC-reactive B cells could be demonstrated in spleen, lymph nodes, and Peyer's patches. The appearance of T lymphocytes in the various lymphoid organs required even more time. By means of cell transfer experiments, a sequential appearance of the precursors of anti-SRBC IgM-, IgG-, and IgA-plaque-forming cells could be demonstrated in spleen, bone marrow, lymph nodes, and Peyer's patches

  3. Lack of mucosal immune reconstitution during prolonged treatment of acute and early HIV-1 infection.

    Directory of Open Access Journals (Sweden)

    Saurabh Mehandru

    2006-12-01

    Full Text Available During acute and early HIV-1 infection (AEI, up to 60% of CD4(+ T cells in the lamina propria of the lower gastrointestinal (GI tract are lost as early as 2-4 wk after infection. Reconstitution in the peripheral blood during therapy with highly active antiretroviral therapy (HAART is well established. However, the extent of immune reconstitution in the GI tract is unknown.Fifty-four AEI patients and 18 uninfected control participants underwent colonic biopsy. Forty of the 54 AEI patients were followed after initiation of antiretroviral therapy (18 were studied longitudinally with sequential biopsies over a 3-y period after beginning HAART, and 22 were studied cross sectionally after 1-7 y of uninterrupted therapy. Lymphocyte subsets, markers of immune activation and memory in the peripheral blood and GI tract were determined by flow cytometry and immunohistochemistry. In situ hybridization was performed in order to identify persistent HIV-1 RNA expression. Of the patients studied, 70% maintained, on average, a 50%-60% depletion of lamina propria lymphocytes despite 1-7 y of HAART. Lymphocytes expressing CCR5 and both CCR5 and CXCR4 were persistently and preferentially depleted. Levels of immune activation in the memory cell population, CD45RO+ HLA-DR+, returned to levels seen in the uninfected control participants in the peripheral blood, but were elevated in the GI tract of patients with persistent CD4+ T cell depletion despite therapy. Rare HIV-1 RNA-expressing cells were detected by in situ hybridization.Apparently suppressive treatment with HAART during acute and early infection does not lead to complete immune reconstitution in the GI mucosa in the majority of patients studied, despite immune reconstitution in the peripheral blood. Though the mechanism remains obscure, the data suggest that there is either viral or immune-mediated accelerated T cell destruction or, possibly, alterations in T cell homing to the GI tract. Although clinically

  4. Neuroimaging of HIV-associated cryptococcal meningitis: comparison of magnetic resonance imaging findings in patients with and without immune reconstitution.

    Science.gov (United States)

    Katchanov, Juri; Branding, Gordian; Jefferys, Laura; Arastéh, Keikawus; Stocker, Hartmut; Siebert, Eberhard

    2016-02-01

    To determine the frequency, imaging characteristics, neuroanatomical distribution and dynamics of magnetic resonance imaging findings in HIV-associated cryptococcal meningitis in immunocompromised patients we compared patients without antiretroviral therapy with patients undergoing immune reconstitution. Neuroimaging and clinical data of 21 consecutive patients presenting to a German HIV centre in a 10-year period between 2005 and 2014 were reviewed. We identified eight patients with magnetic resonance imaging findings related to cryptococcal disease: five patients without antiretroviral therapy and three patients receiving effective antiretroviral therapy resulting in immune reconstitution. The pattern of magnetic resonance imaging manifestations was different in the two groups. In patients not on antiretroviral therapy, pseudocysts (n = 3) and lacunar ischaemic lesions (n = 2) were detected. Contrast-enhancing focal leptomeningeal and/or parenchymal lesions were found in all patients under immune reconstitution (n = 3). Magnetic resonance imaging lesions suggestive of leptomeningitis or meningoencephalitis were detected in all patients with a recurrence of cryptococcal meningitis under immune reconstitution, which differs from the classical magnetic resonance imaging findings in patients without antiretroviral therapy. In antiretroviral therapy-treated patients with past medical history of cryptococcal meningitis, detection of contrast-enhancing focal meningeal and/or parenchymal lesions should prompt further investigations for a recurrence of cryptococcal meningitis under immune reconstitution. © The Author(s) 2015.

  5. Bone marrow reconstitution of immune responses following irradiation in the leopard frog, Rana pipiens

    International Nuclear Information System (INIS)

    Ramirez, J.A.; Wright, R.K.; Cooper, E.L.

    1983-01-01

    The bone marrow of Rana is an important source of cells capable of maintaining individual viability, responding to Concanavalin A (Con A) and producing PFC against sheep erythrocyte (SRBC) antigens. Frog marrow is more effective than the spleen in maintaining life. Radiation destroys the ability of frogs to respond to SRBC immunization (lack of bone marrow and spleen PFC, serum antibody) and bone marrow/spleen cells to respond to Con A, i.e., bone marrow and spleen contain radiation-sensitive cells. Shielding one hind leg during irradiation leads to reconstitution of bone marrow/spleen PFC responses, antibody synthesis and individual viability. Our results suggest that bone marrow is: a) the source of stem cells, and b) the source of mature T- and B- lymphocytes that can recirculate within the immune system

  6. Immune reconstitution inflammatory syndrome in HIV and sporotrichosis coinfection: report of two cases and review of the literature

    Directory of Open Access Journals (Sweden)

    Marcelo Rosandiski Lyra

    2014-12-01

    Full Text Available We report 2 cases of patients with immune reconstitution inflammatory syndrome (IRIS associated with cutaneous disseminated sporotrichosis and human immunodeficiency virus (HIV coinfection. The patients received specific treatment for sporotrichosis. However, after 4 and 5 weeks from the beginning of antiretroviral therapy, both patients experienced clinical exacerbation of skin lesions despite increased T CD4+ cells (T cells cluster of differentiation 4 positive count and decreased viral load. Despite this exacerbation, subsequent mycological examination after systemic corticosteroid administration did not reveal fungal growth. Accordingly, they were diagnosed with IRIS. However, the sudden withdrawal of the corticosteroids resulted in the recurrence of IRIS symptoms. No serious adverse effects could be attributed to prednisone. We recommend corticosteroid treatment for mild-to-moderate cases of IRIS in sporotrichosis and HIV coinfection with close follow-up.

  7. Immune reconstitution inflammatory syndrome in HIV and sporotrichosis coinfection: report of two cases and review of the literature.

    Science.gov (United States)

    Lyra, Marcelo Rosandiski; Nascimento, Maria Letícia Fernandes Oliveira; Varon, Andréa Gina; Pimentel, Maria Inês Fernandes; Antonio, Liliane de Fátima; Saheki, Maurício Naoto; Bedoya-Pacheco, Sandro Javier; Valle, Antonio Carlos Francesconi do

    2014-01-01

    We report 2 cases of patients with immune reconstitution inflammatory syndrome (IRIS) associated with cutaneous disseminated sporotrichosis and human immunodeficiency virus (HIV) coinfection. The patients received specific treatment for sporotrichosis. However, after 4 and 5 weeks from the beginning of antiretroviral therapy, both patients experienced clinical exacerbation of skin lesions despite increased T CD4+ cells (T cells cluster of differentiation 4 positive) count and decreased viral load. Despite this exacerbation, subsequent mycological examination after systemic corticosteroid administration did not reveal fungal growth. Accordingly, they were diagnosed with IRIS. However, the sudden withdrawal of the corticosteroids resulted in the recurrence of IRIS symptoms. No serious adverse effects could be attributed to prednisone. We recommend corticosteroid treatment for mild-to-moderate cases of IRIS in sporotrichosis and HIV coinfection with close follow-up.

  8. Chronic Disseminated Candidiasis Complicated by Immune Reconstitution Inflammatory Syndrome in Child with Acute Lymphoblastic Leukemia

    Directory of Open Access Journals (Sweden)

    Olga Zając-Spychała

    2016-01-01

    Full Text Available Hepatosplenic candidiasis also known as chronic disseminated candidiasis is a rare manifestation of invasive fungal infection typically observed in patients with acute leukemia in prolonged, deep neutropenia. Immune reconstitution inflammatory syndrome (IRIS is an inflammatory disorder triggered by rapid resolution of neutropenia. Diagnosis and treatment of IRIS are still challenging due to a variety of clinical symptoms, lack of certain diagnostic criteria, and no standards of treatment. The diagnosis of IRIS is even more difficult in patients with hematological malignancies complicated by “probable” invasive fungal infection, when fungal pathogen is still uncertain. We report a case of probable hepatic candidiasis in 4-year-old boy with acute lymphoblastic leukemia. Despite proper antifungal therapy, there was no clinical and radiological improvement, so diagnosis of Candida-related IRIS was made and corticosteroid therapy was added to antifungal treatment achieving prompt resolution of infection symptoms.

  9. Immune Reconstitution Kinetics following Intentionally Induced Mixed Chimerism by Nonmyeloablative Transplantation.

    Directory of Open Access Journals (Sweden)

    Nayoun Kim

    Full Text Available Establishing mixed chimerism is a promising approach for inducing donor-specific transplant tolerance. The establishment and maintenance of mixed chimerism may enable long-term engraftment of organ transplants while minimizing the use of immunosuppressants. Several protocols for inducing mixed chimerism have been reported; however, the exact mechanism underlying the development of immune tolerance remains to be elucidated. Therefore, understanding the kinetics of engraftment during early post-transplant period may provide insight into establishing long-term mixed chimerism and permanent transplant tolerance. In this study, we intentionally induced allogeneic mixed chimerism using a nonmyeloablative regimen by host natural killer (NK cell depletion and T cell-depleted bone marrow (BM grafts in a major histocompatibility complex (MHC-mismatched murine model and analyzed the kinetics of donor (C57BL/6 and recipient (BALB/c engraftment in the weeks following transplantation. Donor BM cells were well engrafted and stabilized without graft-versus-host disease (GVHD as early as one week post-bone marrow transplantation (BMT. Donor-derived thymic T cells were reconstituted four weeks after BMT; however, the emergence of newly developed T cells was more obvious at the periphery as early as two weeks after BMT. Also, the emergence and changes in ratio of recipient- and donor-derived NKT cells and antigen presenting cells (APCs including dendritic cells (DCs and B cells were noted after BMT. Here, we report a longitudinal analysis of the development of donor- and recipient-originated hematopoietic cells in various lymphatic tissues of intentionally induced mixed chimerism mouse model during early post-transplant period. Through the understanding of immune reconstitution at early time points after nonmyeloablative BMT, we suggest guidelines on intentionally inducing durable mixed chimerism.

  10. Unmasking cryptococcal meningitis immune reconstitution inflammatory syndrome in pregnancy induced by HIV antiretroviral therapy with postpartum paradoxical exacerbation

    Directory of Open Access Journals (Sweden)

    Reuben Kiggundu

    2014-07-01

    Full Text Available Cryptococcosis is the most common cause of meningitis in Africa due to the high burden of HIV. Immune reconstitution inflammatory syndrome (IRIS is a frequent and deadly complication of cryptococcal meningitis. We report a fatal case of cryptococcal-IRIS in a pregnant woman that began after starting antiretroviral therapy (unmasking IRIS and markedly worsened postpartum after delivery (paradoxical IRIS.

  11. Immune reconstitution and risk of Kaposi sarcoma and non-Hodgkin lymphoma in HIV-infected adults

    NARCIS (Netherlands)

    Jaffe, Harold W.; de Stavola, Bianca L.; Carpenter, Lucy M.; Porter, Kholoud; Cox, David R.; del Amo, Julia; Meyer, Laurence; Bucher, Heiner C.; Chêne, Geneviève; Hamouda, Osamah; Pillay, Deenan; Prins, Maria; Rosinska, Magda; Sabin, Caroline; Touloumi, Giota; Lodi, Sara; Coughlin, Kate; Walker, Sarah; Babiker, Abdel; de Luca, Andrea; Fisher, Martin; Muga, Roberto; Zangerle, Robert; Kelleher, A. D.; Cooper, D. A.; Grey, Pat; Finlayson, Robert; Bloch, Mark; Kelleher, Tony; Ramacciotti, Tim; Gelgor, Linda; Cooper, David; Gill, John; Jørgensen, Louise B.; Tartu, U.; Lutsar, Irja; Dabis, Francois; Thiebaut, Rodolphe; Masquelier, Bernard; Costagliola, Dominique; Guiguet, Marguerite; Vanhems, Philippe; Chaix, Marie-Laure; Ghosn, Jade; Boufassa, Faroudy; Kücherer, Claudia; Bartmeyer, Barbara; Geskus, Ronald; van der Helm, Jannie; Schuitemaker, Hanneke

    2011-01-01

    Given the well documented occurrence of immune reconstitution inflammatory syndrome (IRIS) in HIV-infected patients who recently started combination antiretroviral therapy (cART), we examined whether cART initiation increased the risk of Kaposi sarcoma and non-Hodgkin lymphoma (NHL) using data from

  12. Engineered Murine HSCs Reconstitute Multi-lineage Hematopoiesis and Adaptive Immunity

    Directory of Open Access Journals (Sweden)

    Yi-Fen Lu

    2016-12-01

    Full Text Available Hematopoietic stem cell (HSC transplantation is curative for malignant and genetic blood disorders, but is limited by donor availability and immune-mismatch. Deriving HSCs from patient-matched embryonic/induced-pluripotent stem cells (ESCs/iPSCs could address these limitations. Prior efforts in murine models exploited ectopic HoxB4 expression to drive self-renewal and enable multi-lineage reconstitution, yet fell short in delivering robust lymphoid engraftment. Here, by titrating exposure of HoxB4-ESC-HSC to Notch ligands, we report derivation of engineered HSCs that self-renew, repopulate multi-lineage hematopoiesis in primary and secondary engrafted mice, and endow adaptive immunity in immune-deficient recipients. Single-cell analysis shows that following engraftment in the bone marrow niche, these engineered HSCs further specify to a hybrid cell type, in which distinct gene regulatory networks of hematopoietic stem/progenitors and differentiated hematopoietic lineages are co-expressed. Our work demonstrates engineering of fully functional HSCs via modulation of genetic programs that govern self-renewal and lineage priming.

  13. Antifibrotic Therapy in Simian Immunodeficiency Virus Infection Preserves CD4+ T-Cell Populations and Improves Immune Reconstitution With Antiretroviral Therapy

    Science.gov (United States)

    Estes, Jacob D.; Reilly, Cavan; Trubey, Charles M.; Fletcher, Courtney V.; Cory, Theodore J.; Piatak, Michael; Russ, Samuel; Anderson, Jodi; Reimann, Thomas G.; Star, Robert; Smith, Anthony; Tracy, Russell P.; Berglund, Anna; Schmidt, Thomas; Coalter, Vicky; Chertova, Elena; Smedley, Jeremy; Haase, Ashley T.; Lifson, Jeffrey D.; Schacker, Timothy W.

    2015-01-01

    Even with prolonged antiretroviral therapy (ART), many human immunodeficiency virus-infected individuals have <500 CD4+ T cells/µL, and CD4+ T cells in lymphoid tissues remain severely depleted, due in part to fibrosis of the paracortical T-cell zone (TZ) that impairs homeostatic mechanisms required for T-cell survival. We therefore used antifibrotic therapy in simian immunodeficiency virus-infected rhesus macaques to determine whether decreased TZ fibrosis would improve reconstitution of peripheral and lymphoid CD4+ T cells. Treatment with the antifibrotic drug pirfenidone preserved TZ architecture and was associated with significantly larger populations of CD4+ T cells in peripheral blood and lymphoid tissues. Combining pirfenidone with an ART regimen was associated with greater preservation of CD4+ T cells than ART alone and was also associated with higher pirfenidone concentrations. These data support a potential role for antifibrotic drug treatment as adjunctive therapy with ART to improve immune reconstitution. PMID:25246534

  14. Neurotuberculosis immune reconstitution inflammatory syndrome in the setting of HIV infection: A case report and review of literature

    Directory of Open Access Journals (Sweden)

    Deepasree Jaganmohan

    2016-01-01

    Full Text Available Immune reconstitution inflammatory syndrome (IRIS is an exaggerated immune response which can occur with various coinfections in human immunodeficiency virus (HIV infected patients, of which the most commonly implicated in central nervous system (CNS-IRIS are progressive multifocal leukoencephalopathy (PML, cryptococcosis, and tuberculosis (TB. TB-IRIS is a known complication of pulmonary TB or TB lymphadenitis coinfection in HIV infected patients who are on antituberculosis treatment (ATT after the initiation of antiretroviral therapy (ART. However, development of IRIS in extrapulmonary TB such as CNS TB is very rare. Our case is that of an isolated CNS-TB-IRIS, presenting as increase in the size and perilesional edema of the ring enhancing lesions in the brain, which was observed in two sequential magnetic resonance imaging done over a period of 2 months in a retropositive patient who presented with clinical deterioration after commencement of ART. As prompt diagnosis was made and specific management aimed at IRIS was started without delay, the patient improved symptomatically.

  15. Immune reconstitution with two different rabbit polyclonal anti-thymocytes globulins.

    Science.gov (United States)

    Bamoulid, Jamal; Crepin, Thomas; Gaiffe, Emilie; Laheurte, Caroline; Moulin, Bruno; Frimat, Luc; Rieu, Philippe; Mousson, Christiane; Durrbach, Antoine; Heng, Anne-Elisabeth; Rebibou, Jean-Michel; Saas, Philippe; Courivaud, Cécile; Ducloux, Didier

    2017-12-01

    Broad T cell depletion by polyclonal anti-thymocyte globulins (ATG) has been used for many years as a part of immunosuppressive treatment in transplantation. Currently, two different ATG are used in clinical practice, Thymoglobulin and Grafalon. Due to differences in the immunization source, these products contain different specificities and quantity of antibodies. These differences may have clinical consequences. We conducted a nested study in a large prospective multicentric cohort of kidney transplant to determine whether Grafalon-treated and Thymoglobulin-treated patients experience different lymphocyte reconstitution and clinical outcomes. 182 patients matched for age, gender, CMV status, CMV prophylaxis, number of previous transplantation, and maintenance immunosuppressive treatment were included (Thymoglobulin, [n=91]; Grafalon®, [n=91]). One-year post-transplant, recent thymic emigrants were significantly decreased (12±10% vs 21±12%; p<0.001) in Grafalon-treated patients. By contrast, T cell activation (CD38+DR+Ki67+) and senescence (CD8+CD57+CD28-) was increased in Thymoglobulin-treated patients. Compared to Grafalon, Thymoglobulin was not associated with a significantly different rate of acute rejection. CMV disease (p=0.013) was more frequent in Thymoglobulin-treated patients. Grafalon and Thymoglobulin seem to be equivalent to prevent acute rejection. CMV disease is more frequent in Thymoglobulin-treated patients. One year post-transplant immune profile profoundly differs according to the type of ATG. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Central nervous system immune reconstitution inflammatory syndrome in AIDS: experience of a Mexican neurological centre.

    Science.gov (United States)

    Guevara-Silva, Erik A; Ramírez-Crescencio, María A; Soto-Hernández, José Luís; Cárdenas, Graciela

    2012-09-01

    Highly active antiretroviral therapy (HAART) restores the inflammatory immune response in AIDS patients and it may unmask previous subclinical infections or paradoxically exacerbate symptoms of opportunistic infections. Up to 25% of patients receiving HAART develop immune reconstitution inflammatory syndrome (IRIS). We describe six patients with IRIS central nervous system (CNSIRIS) manifestations emphasizing the relevance of CSF cultures and neuroimaging in early diagnosis and management. Patients with CNSIRIS were identified among hospitalized HIV-infected patients that started HAART from January 2002 through December 2007 at a referral neurological center in Mexico. One-hundred and forty-two HIV-infected patients with neurological signs were hospitalized, 64 of which had received HAART, and six (9.3%) developed CNSIRIS. Five patients were male. Two cases of tuberculosis, two of cryptococcosis, one of brain toxoplasmosis, and one possible PML case were found. IRIS onset occurred within 12 weeks of HAART in five patients. Anti-infective therapy was continued. In one case, HAART was temporarily suspended. In long-term follow-up the clinical condition improved in all patients. CNSIRIS associated to opportunistic infections appeared in 9% of patients receiving HAART. Interestingly, no cases of malignancy or neoplasm IRIS-related were found. Frequent clinical assessment and neuroimaging studies supported diagnosis and treatment. Risk factors were similar to those found in other series. Copyright © 2012 Elsevier B.V. All rights reserved.

  17. Successful immune reconstitution in severe combined immunodeficiency despite Epstein-Barr virus and cytomegalovirus infections.

    Science.gov (United States)

    DeVoe, P W; Buckley, R H; Shirley, L R; Darby, C P; Ward, F E; Mickey, G H; Raab-Traub, N; Vandenbark, G R

    1985-01-01

    Cytomegalovirus (CMV) and Epstein-Barr virus (EBV), frequently found in the acquired immune deficiency syndrome (AIDS), have been suspected of contributing to the latter immunodeficiency. The ability of normal HLA-identical sibling bone marrow to reconstitute an 8-month-old infant with severe combined immunodeficiency infected with these two viral agents is of interest. After presentation with severe mucocutaneous candidiasis, cavitary pulmonary disease, nodular cutaneous lesions, and hepatic abscesses containing acid-fast organisms, immunologic studies revealed lymphopenia, 1-3% T cells, and no lymphocyte responses to mitogens. Prior to transplantation, the infant's blood B lymphocytes grew spontaneously in culture, suggesting they were infected with EBV. Indeed, an appropriate antibody response to EBV was detected at 2 months post-transplantation. At 3 weeks postgrafting, neutropenia and cholestatic jaundice developed without other signs of graft versus host disease. Liver biopsy demonstrated CMV but no EBV by DNA hybridization. There was evidence of T- and B-cell function by 2 weeks postgrafting, including vigorous in vivo and in vitro responses to candida. Although the blood lymphocyte T4:T8 ratio was inverted at 2 weeks, it reverted to normal by 6 weeks post-transplantation. All clinical disease resolved by 8 months and karotyping revealed all T and B lymphocytes to be XX. Thus, despite infections with both CMV and EBV, complete immunologic reconstitution was achieved in this, the most severe of all genetically determined immunodeficiency conditions, arguing against these viruses having a major role in the failure of bone marrow transplantation in AIDS.

  18. Maintenance of host leukocytes in peripheral immune compartments following lethal irradiation and bone marrow reconstitution: implications for graft versus host disease.

    Science.gov (United States)

    Staley, Elizabeth M; Tanner, Scott M; Daft, Joseph G; Stanus, Andrea L; Martin, Steven M; Lorenz, Robin G

    2013-03-01

    Bone marrow reconstitution is utilized as a tool for disease treatment and as a research technique to elucidate the function of bone marrow derived cells. Clinically successful engraftment is indicated by the development of a functioning immune repertoire. In research, reconstitution is considered successful if >85% of splenic leukocytes are of donor origins. Previous work suggests that splenic reconstitution may not be indicative of reconstitution in the mucosa. We sought to evaluate mucosal reconstitution in animals following a standard bone marrow eradication and reconstitution technique. Bone marrow was harvested from adult B6.SJL donor mice (CD45.1) and injected via either the retro-orbital or intraperitoneal route into lethally irradiated B6 (CD45.2) adult or neonatal recipients respectively. The expression of CD45 by flow cytometry was used to calculate reconstitution with respect to immune compartment and cell type. In reconstituted adult animals 93.2±1.5% of splenic leukocytes expressed the donor CD45.1 antigen thus meeting the standard definition of reconstitution, however only 58.6±13.6% of intestinal lamina propria lymphocytes and 52.4±16.0% of intestinal intraepithelial lymphocytes were of donor origin, confirming splenic reconstitution fails to represent peripheral immune reconstitution. T-cells in the gastrointestinal tract are the most poorly reconstituted, while B-cells appear to be almost universally replaced by donor cells. The inadequate mucosal reconstitution was not corrected by evaluating later time points or by performing the bone marrow transfer during the neonatal period. This demonstration that substantial host T-cells remain in the intestinal mucosa after a "successful" bone marrow transplantation should cause a re-evaluation of data from research bone marrow chimera experiments, as well as the mechanisms for complications after clinical bone marrow transplantation. Copyright © 2013 Elsevier B.V. All rights reserved.

  19. An HIV-positive Case of Obstructive Jaundice Caused by Immune Reconstitution Inflammatory Syndrome of Tuberculous Lymphadenitis Successfully Treated with Corticosteroids.

    Science.gov (United States)

    Watanabe, Naoaki; Sato, Ryota; Nagai, Hideaki; Matsui, Hirotoshi; Yamane, Akira; Kawashima, Masahiro; Suzuki, Junko; Tashimo, Hiroyuki; Ohshima, Nobuharu; Masuda, Kimihiko; Tamura, Atsuhisa; Akagawa, Shinobu; Hebisawa, Akira; Ohta, Ken

    2017-10-01

    A 60-year-old man was admitted to our hospital because of a persistent fever with enlargement of multiple lymph nodes in the mediastinum and around the pancreatic head. He was diagnosed with tuberculosis and human immunodeficiency virus infection. We started antiretroviral therapy three weeks after the initiation of anti-tuberculous therapy. Two weeks later, jaundice appeared with dilatation of the biliary tract due to further enlargement of the lymph nodes, which seemed to be immune reconstitution inflammatory syndrome (IRIS). The administration of corticosteroids resolved the obstructive jaundice without surgical treatment or endoscopic drainage. Obstructive jaundice caused by IRIS should first be treated with corticosteroids before invasive treatment.

  20. Late onset of cryptococcal cervical lymphadenitis following immune reconstitution inflammatory syndrome in a patient with AIDS.

    Science.gov (United States)

    Sethupathi, Meenakshi; Yoganathan, Kathir

    2015-01-06

    A 32-year-old woman was diagnosed HIV positive with disseminated cryptococcal infection in May 2006. Her initial CD4 was 7 cells/µL and she had a right supraclavicular nodal mass, which was biopsied and shown to be consistent with cryptococcal lymphadenitis. She was treated for disseminated cryptococcal infection and was started on antiretroviral medications subsequently. Two years later, she developed a left supraclavicular mass. Her CD4 count was 320 cells/µL and HIV RNA level was undetectable. Investigations and biopsy results were consistent with a late presentation of cryptococcal immune reconstitution inflammatory syndrome (IRIS). She was treated with oral corticosteroids and her symptoms resolved completely. IRIS is a recognised complication of HIV treatment and occurs in a significant percentage of patients within the first 3 months of starting antiretroviral therapy. This case report illustrates the importance of recognising late presentations of IRIS. It is vital to differentiate true cryptococcal lymphadenitis from IRIS-induced cryptococcal lymphadenitis. 2015 BMJ Publishing Group Ltd.

  1. Is vitamin D deficiency involved in the immune reconstitution inflammatory syndrome?

    Directory of Open Access Journals (Sweden)

    Moreno-Reyes Rodrigo

    2009-04-01

    Full Text Available Abstract Background About 20–30% of persons with HIV infection, especially those living in countries with limited resources, experience an immune reconstitution inflammatory syndrome (IRIS after starting antiretroviral treatment. The active form of vitamin D, 1,25-dihydroxyvitamin D, is a key player in the clearance of pathogens and influences the level of inflammation and macrophage activation. Presentation of the hypothesis We hypothesize that low availability of 1,25-dihydroxyvitamin D, either due to vitamin D deficiency or due to polymorphisms in the vitamin D receptor or in its activating/inactivating enzymes, contributes to the appearance of IRIS. Furthermore, drug interactions with the enzymatic pathways of vitamin D could favour the development of IRIS. Testing the hypothesis Our hypothesis could be explored by a case-control study to assess the prevalence of vitamin D deficiency in HIV-infected patients on antiretroviral treatment who develop and do not develop IRIS. Implications of the hypothesis If the role of vitamin D in IRIS is confirmed, we would be able to screen patients at risk for IRIS by screening for vitamin D deficiency. After confirmation by means of a clinical trial, vitamin D supplementation could be a cheap and safe way to reduce the incidence of IRIS.

  2. Different profiles of immune reconstitution in children and adults with HIV-infection after highly active antiretroviral therapy

    Directory of Open Access Journals (Sweden)

    Leal Manuel

    2006-07-01

    Full Text Available Abstract Background Recent advances in characterizing the immune recovery of HIV-1-infected people have highlighted the importance of the thymus for peripheral T-cell diversity and function. The aim of this study was to investigate differences in immune reconstitution profiles after highly active antiretroviral therapy (HAART between HIV-children and adults. Methods HIV patients were grouped according to their previous clinical and immunological status: 9 HIV-Reconstituting-adults (HIV-Rec-adults and 10 HIV-Reconstituting-children (HIV-Rec-children on HAART with viral load (VL ≤400 copies/ml and CD4+ ≥500 cells/μL at least during 6 months before the study and CD4+ ≤300 cells/μL anytime before. Fifteen healthy-adults and 20 healthy-children (control subjects were used to calculate Z-score values to unify value scales between children and adults to make them comparable. Results HIV-Rec-children had higher T-cell receptor excision circles (TREC and lower interleukin (IL-7 levels than HIV-Rec-adults (p + (CD4+CD45RA hi+CD27+, naïve CD8+ (CD8+CD45RA hi+CD27+, and memory CD8+ (CD8+CD45RO+ cells/μl than HIV-Rec-adults, but similar memory CD4+ (CD4+CD45RO+ counts. HIV-Rec-children had lower naïve CD8+ Z-score values than HIV-Rec-adults (p = 0.05. Conclusion Our data suggest that HIV-Rec-children had better thymic function than HIV-Rec-adults and this fact affects the peripheral T-cell subsets. Thus, T-cell recovery after HAART in HIV-Rec-adults could be the consequence of antigen-independent peripheral T-cell expansion while in HIV-Rec-children thymic output could play a predominant role in immune reconstitution.

  3. Immune reconstitution in patients with Fanconi anemia after allogeneic bone marrow transplantation.

    Science.gov (United States)

    Perlingeiro Beltrame, Miriam; Malvezzi, Mariester; Bonfim, Carmem; Covas, Dimas Tadeu; Orfao, Alberto; Pasquini, Ricardo

    2014-07-01

    Fanconi anemia is an autosomal recessive or X-linked genetic disorder characterized by bone marrow (BM) failure/aplasia. Failure of hematopoiesis results in depletion of the BM stem cell reservoir, which leads to severe anemia, neutropenia and thrombocytopenia, frequently requiring therapeutic interventions, including hematopoietic stem cell transplantation (HSCT). Successful BM transplantation (BMT) requires reconstitution of normal immunity. In the present study, we performed a detailed analysis of the distribution of peripheral blood subsets of T, B and natural killer (NK) lymphocytes in 23 patients with Fanconi anemia before and after BMT on days +30, +60, +100, +180, +270 and +360. In parallel, we evaluated the effect of related versus unrelated donor marrow as well as the presence of graft-versus-host disease (GVHD). After transplantation, we found different kinetics of recovery for the distinct major subsets of lymphocytes. NK cells were the first to recover, followed by cytotoxic CD8(+) T cells and B cells, and finally CD4(+) helper T cells. Early lymphocyte recovery was at the expense of memory cells, potentially derived from the graft, whereas recent thymic emigrant (CD31(+) CD45RA(+)) and naive CD4(+) or CD8(+) T cells rose only at 6 months after HSCT, in the presence of immunosuppressive GVHD prophylactic agents. Only slight differences were observed in the early recovery of cytotoxic CD8(+) T cells among those cases receiving a graft from a related donor versus an unrelated donor. Patients with GVHD displayed a markedly delayed recovery of NK cells and B cells as well as of regulatory T cells and both early thymic emigrant and total CD4(+) T cells. Our results support the utility of post-transplant monitoring of a peripheral blood lymphocyte subset for improved follow-up of patients with Fanconi anemia undergoing BMT. Copyright © 2014 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  4. Validation of a published case definition for tuberculosis-associated immune reconstitution inflammatory syndrome.

    Science.gov (United States)

    Haddow, Lewis J; Moosa, Mahomed-Yunus S; Easterbrook, Philippa J

    2010-01-02

    To evaluate the International Network for the Study of HIV-associated IRIS (INSHI) case definitions for tuberculosis (TB)-associated immune reconstitution inflammatory syndrome (IRIS) in a South African cohort. Prospective cohort of 498 adult HIV-infected patients initiating antiretroviral therapy. Patients were followed up for 24 weeks and all clinical events were recorded. Events with TB-IRIS as possible cause were assessed by consensus expert opinion and INSHI case definition. Positive, negative, and chance-corrected agreement (kappa) were calculated, and reasons for disagreement were assessed. One hundred and two (20%) patients were receiving TB therapy at antiretroviral therapy initiation. Three hundred and thirty-three events were evaluated (74 potential paradoxical IRIS, 259 potential unmasking IRIS). Based on expert opinion, there were 18 cases of paradoxical IRIS associated with TB and/or other opportunistic disease. The INSHI criteria for TB-IRIS agreed in 13 paradoxical cases, giving positive agreement of 72.2%, negative agreement in 52/56 non-TB-IRIS events (92.9%), and kappa of 0.66. There were 19 unmasking TB-IRIS cases based on expert opinion, of which 12 were considered IRIS using the INSHI definition (positive agreement 63.2%). There was agreement in all 240 non-TB-IRIS events (negative agreement 100%) and kappa was 0.76. There was good agreement between the INSHI case definition for both paradoxical and unmasking TB-IRIS and consensus expert opinion. These results support the use of this definition in clinical and research practice, with minor caveats in its application.

  5. Immune reconstitution inflammatory syndrome in HIV-infected patients with Pneumocystis jirovecii pneumonia.

    Science.gov (United States)

    Roade Tato, Luisa; Burgos Cibrian, Joaquín; Curran Fábregas, Adrià; Navarro Mercadé, Jordi; Willekens, Rein; Martín Gómez, María Teresa; Ribera Pascuet, Esteban; Falcó Ferrer, Vicenç

    2017-11-26

    The incidence of immune reconstitution inflammatory syndrome (IRIS) in HIV-infected patients after an episode of Pneumocystis jirovecii pneumonia (PJP) seems to be lower than with other opportunistic infections. We conducted an observational study in order to determine the incidence, clinical characteristics and outcome of patients diagnosed with PJP-related IRIS. We conducted an observational study of HIV patients diagnosed with PJP-related IRIS from January 2000 to November 2015. We analyzed epidemiological and clinical characteristics as well as laboratory findings. We also carried out a systematic review of published cases. Six cases of IRIS out of 123 (4.9%) HIV-infected patients with PJP who started ART were diagnosed. All six cases were men with a median age of 34 (IQR: 8) years. The six patients developed paradoxical IRIS. Subjects younger than 40 years old (p=0.084) and with an HIV-RNA viral load >100000 copies/ml (p=0.081) at diagnosis showed a tendency to develop IRIS. Thirty-seven published cases of PJP-related IRIS were identified. Although 51% of cases involved respiratory failure, no deaths were reported. PJP-related IRIS is rare condition compared to other opportunistic infections. It can lead to a severe respiratory failure in a significant proportion of cases, although no deaths have been reported. Copyright © 2017 Elsevier España, S.L.U. and Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.

  6. Reconstituting development of pancreatic intraepithelial neoplasia from primary human pancreas duct cells

    OpenAIRE

    Lee, Jonghyeob; Snyder, Emily R.; Liu, Yinghua; Gu, Xueying; Wang, Jing; Flowers, Brittany M.; Kim, Yoo Jung; Park, Sangbin; Szot, Gregory L.; Hruban, Ralph H.; Longacre, Teri A.; Kim, Seung K.

    2017-01-01

    Development of systems that reconstitute hallmark features of human pancreatic intraepithelial neoplasia (PanINs), the precursor to pancreatic ductal adenocarcinoma, could generate new strategies for early diagnosis and intervention. However, human cell-based PanIN models with defined mutations are unavailable. Here, we report that genetic modification of primary human pancreatic cells leads to development of lesions resembling native human PanINs. Primary human pancreas duct cells harbouring...

  7. Dynamical System Modeling of Immune Reconstitution after Allogeneic Stem Cell Transplantation Identifies Patients at Risk for Adverse Outcomes.

    Science.gov (United States)

    Toor, Amir A; Sabo, Roy T; Roberts, Catherine H; Moore, Bonny L; Salman, Salman R; Scalora, Allison F; Aziz, May T; Shubar Ali, Ali S; Hall, Charles E; Meier, Jeremy; Thorn, Radhika M; Wang, Elaine; Song, Shiyu; Miller, Kristin; Rizzo, Kathryn; Clark, William B; McCarty, John M; Chung, Harold M; Manjili, Masoud H; Neale, Michael C

    2015-07-01

    Systems that evolve over time and follow mathematical laws as they evolve are called dynamical systems. Lymphocyte recovery and clinical outcomes in 41 allograft recipients conditioned using antithymocyte globulin (ATG) and 4.5-Gy total body irradiation were studied to determine if immune reconstitution could be described as a dynamical system. Survival, relapse, and graft-versus-host disease (GVHD) were not significantly different in 2 cohorts of patients receiving different doses of ATG. However, donor-derived CD3(+) cell reconstitution was superior in the lower ATG dose cohort, and there were fewer instances of donor lymphocyte infusion (DLI). Lymphoid recovery was plotted in each individual over time and demonstrated 1 of 3 sigmoid growth patterns: Pattern A (n = 15) had rapid growth with high lymphocyte counts, pattern B (n = 14) had slower growth with intermediate recovery, and pattern C (n = 10) had poor lymphocyte reconstitution. There was a significant association between lymphocyte recovery patterns and both the rate of change of donor-derived CD3(+) at day 30 after stem cell transplantation (SCT) and clinical outcomes. GVHD was observed more frequently with pattern A, relapse and DLI more so with pattern C, with a consequent survival advantage in patients with patterns A and B. We conclude that evaluating immune reconstitution after SCT as a dynamical system may differentiate patients at risk of adverse outcomes and allow early intervention to modulate that risk. Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  8. Clinical case definition and manifestations of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome.

    Science.gov (United States)

    Manosuthi, Weerawat; Van Tieu, Hong; Mankatitham, Wiroj; Lueangniyomkul, Aroon; Ananworanich, Jintanat; Avihingsanon, Anchalee; Siangphoe, Umaporn; Klongugkara, Sukonsri; Likanonsakul, Sirirat; Thawornwan, Unchana; Suntisuklappon, Bussakorn; Sungkanuparph, Somnuek

    2009-11-27

    The International Network for the Study of HIV-associated IRIS (INSHI) recently published criteria for tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) diagnosis. The performance of this definition and clinical manifestations of TB-IRIS were studied. Antiretroviral therapy-naive HIV/TB Thai patients receiving antituberculous therapy were enrolled during 2006-2007 and prospectively followed through 24 weeks of antiretroviral therapy. Patients were defined as having paradoxical TB-IRIS if they fulfilled the 'study definition' by French 2004 and were confirmed by an external reviewer. All were later compared by the classification according to 'INSHI-2008'. For the 126 patients, median baseline CD4 cell count was 43 cells/microl and HIV-1 RNA was 5.9 log(10) Y copies/ml. Seventy-three (58%) had extrapulmonary/disseminated TB. Twenty-two (18%) and 21 (17%) fulfilled TB-IRIS criteria according to the study definition and INSHI-2008 definition, respectively. Two (2%) were diagnosed by study definition only and one (1%) by INSHI-2008 definition only. Twenty (16%) were concordantly diagnosed by both definitions and 103 (82%) were consistently negative. Eighteen (82%) had worsening of a preexisting site, whereas four (18%) had TB-IRIS in a new location. Lymph node enlargement (73%) and fever (59%) were common in TB-IRIS. Sensitivity and specificity of INSHI-2008 was 91% (95% confidence interval, 72-98%) and 99% (95% confidence interval, 95-99.8%), respectively. Positive predictive value was 95% and negative predictive value was 98%. By multivariate analysis, factors predicting TB-IRIS were extrapulmonary TB (odds ratio, 8.63) and disseminated TB (odds ratio, 4.17). There was high concordance between the INSHI-2008 and French 2004 definition for TB-IRIS diagnosis in HIV/TB patients with relatively high rate of paradoxical TB-IRIS. This suggests that lack of HIV-1 RNA and CD4 cell count monitoring does not impede the ability to diagnose TB-IRIS.

  9. Immune Reconstitution Inflammatory Syndrome Unmasking or Worsening AIDS-Related Progressive Multifocal Leukoencephalopathy: A Literature Review

    Directory of Open Access Journals (Sweden)

    Anna Fournier

    2017-05-01

    Full Text Available Incidence of progressive multifocal leukoencephalopathy (PML in HIV-infected patients has declined in the combined antiretroviral therapy (cART era although a growing number of acquired immunodeficiency syndrome (AIDS-related PML-immune reconstitution inflammatory syndromes (PML-IRIS have been published during the same period. Therapeutic management of PML-IRIS is not consensual and mainly relies on corticosteroids. Our main aim was, in addition to provide a thoughtful analysis of published PML-IRIS cases, to assess the benefit of corticosteroids in the management of PML-IRIS, focusing on confirmed cases. We performed a literature review of the 46 confirmed cases of PML-IRIS cases occurring in HIV-infected patients from 1998 to September 2016 (21 unmasking and 25 paradoxical PML-IRIS. AIDS-related PML-IRIS patients were mostly men (sex ratio 4/1 with a median age of 40.5 years (range 12–66. Median CD4 T cell count before cART and at PML-IRIS onset was 45/μl (0–301 and 101/μl (20–610, respectively. After cART initiation, PML-IRIS occurred within a median timescale of 38 days (18–120. Clinical signs were motor deficits (69%, speech disorders (36%, cognitive disorders (33%, cerebellar ataxia (28%, and visual disturbances (23%. Brain MRI revealed hyperintense areas on T2-weighted sequences and FLAIR images (76% and suggestive contrast enhancement (87%. PCR for John Cunningham virus (JCV in cerebrospinal fluid (CSF was positive in only 84% of cases; however, when performed, brain biopsy confirmed diagnosis of PML in 90% of cases and demonstrated histological signs of IRIS in 95% of cases. Clinical worsening related to PML-IRIS and leading to death was observed in 28% of cases. Corticosteroids were prescribed in 63% of cases and maraviroc in one case. Statistical analysis failed to demonstrate significant benefit from steroid treatment, despite spectacular improvement in certain cases. Diagnosis of PML-IRIS should be considered in HIV

  10. Immune Reconstitution Inflammatory Syndrome Unmasking or Worsening AIDS-Related Progressive Multifocal Leukoencephalopathy: A Literature Review.

    Science.gov (United States)

    Fournier, Anna; Martin-Blondel, Guillaume; Lechapt-Zalcman, Emmanuèle; Dina, Julia; Kazemi, Apolline; Verdon, Renaud; Mortier, Emmanuel; de La Blanchardière, Arnaud

    2017-01-01

    Incidence of progressive multifocal leukoencephalopathy (PML) in HIV-infected patients has declined in the combined antiretroviral therapy (cART) era although a growing number of acquired immunodeficiency syndrome (AIDS)-related PML-immune reconstitution inflammatory syndromes (PML-IRIS) have been published during the same period. Therapeutic management of PML-IRIS is not consensual and mainly relies on corticosteroids. Our main aim was, in addition to provide a thoughtful analysis of published PML-IRIS cases, to assess the benefit of corticosteroids in the management of PML-IRIS, focusing on confirmed cases. We performed a literature review of the 46 confirmed cases of PML-IRIS cases occurring in HIV-infected patients from 1998 to September 2016 (21 unmasking and 25 paradoxical PML-IRIS). AIDS-related PML-IRIS patients were mostly men (sex ratio 4/1) with a median age of 40.5 years (range 12-66). Median CD4 T cell count before cART and at PML-IRIS onset was 45/μl (0-301) and 101/μl (20-610), respectively. After cART initiation, PML-IRIS occurred within a median timescale of 38 days (18-120). Clinical signs were motor deficits (69%), speech disorders (36%), cognitive disorders (33%), cerebellar ataxia (28%), and visual disturbances (23%). Brain MRI revealed hyperintense areas on T2-weighted sequences and FLAIR images (76%) and suggestive contrast enhancement (87%). PCR for John Cunningham virus (JCV) in cerebrospinal fluid (CSF) was positive in only 84% of cases; however, when performed, brain biopsy confirmed diagnosis of PML in 90% of cases and demonstrated histological signs of IRIS in 95% of cases. Clinical worsening related to PML-IRIS and leading to death was observed in 28% of cases. Corticosteroids were prescribed in 63% of cases and maraviroc in one case. Statistical analysis failed to demonstrate significant benefit from steroid treatment, despite spectacular improvement in certain cases. Diagnosis of PML-IRIS should be considered in HIV

  11. Paradoxical immune reconstitution inflammatory syndrome associated with previous Cryptococcus neoformans infection in an HIV-positive patient requiring neurosurgical intervention.

    Science.gov (United States)

    Biagetti, Carlo; Nicola, Monica; Borderi, Marco; Pavoni, Michele; Tampellini, Livia; Verucchi, Gabriella; Chiodo, Francesco

    2009-04-01

    Immune reconstitution inflammatory syndrome (IRIS) in HIV-1-infected patients is associated with an exaggerated inflammatory response against an opportunistic infection during highly active antiretroviral therapy. The only review on IRIS associated with Criptococcus neoformans reported 21 episodes including lymphadenitis, necrotizing pneumonitis, breast and cutaneous abscess, and cryptococcomas. To our knowledge this is the first report of IRIS associated with previous meningeal criptococcal infection which required neurosurgical intervention with placement of a ventriculo-peritoneal shunt to drain a CSF cyst formed by exclusion of the temporal horn of the right lateral ventricle. We demonstrate that this procedure is possible without complications such as cryptococcal dissemination into the peritoneum.

  12. Cryptococcal breast abscess in an HIV-positive patient: arguments for reviewing the definition of immune reconstitution inflammatory syndrome.

    Science.gov (United States)

    Haddow, Lewis J; Sahid, Faieza; Moosa, Mahomed-Yunus S

    2008-07-01

    Atypical manifestations of Cryptococcus neoformans disease have been reported in patients with HIV-1 infection as part of the spectrum of the immune reconstitution inflammatory syndrome (IRIS). We describe a cryptococcal breast abscess in a patient presenting after 11 months of highly active antiretroviral therapy (HAART). The arguments for and against the case being a novel manifestation of IRIS are discussed. The potential hazards of using CD4 count as a surrogate marker of IRIS and the danger of misdiagnosing IRIS as failure of HAART are highlighted.

  13. CD8 apoptosis may be a predictor of T cell number normalization after immune reconstitution in HIV

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    Martinez Maria L

    2007-01-01

    Full Text Available Abstract Background As part of the Houston Vanguard study, a subset of 10 patients randomized to receive IL-2 therapy were compared to 4 patients randomized to not receive IL-2, for markers of T cell activation and death during the first three cycles of IL-2. All patients were treated with combination antiretroviral therapy (ART and were virally suppressed. The purpose of the study was to examine the role of CD8+ T cell death in responses to ART and IL-2 therapy. Methods Lymphocytes were examined at Day 0, 5 and 30 days during three cycles of IL-2 therapy. CD25, CD38, HLA-DR expression and annexin (cell death were examined on CD4 and CD8 subpopulations. Follow up studies examined CD4 levels and CD4:CD8 reconstitution after 6 years using both univariant and multivariate analyses. Results Human lymphocytes responded to IL-2 therapy by upregulation of CD25 on CD4+ T cells, leading to an increase in CD4 cell counts. CD8+ T cells did not increase CD25 expression, but upregulated activation antigens (CD38 and DR and had increased death. At baseline, 7 of the 14 patients had high CD8+ T cell apoptosis (mean 17.0% ± 6.0. We did an exploratory analysis of immune status after six years, and found that baseline CD8+ T cell apoptosis was correlated with CD4 cell count gain beginning two years post enrollment. Patients with low levels of CD8+ T cell apoptosis at baseline (mean 2.2% ± 2.1 had significantly higher CD4 cell counts and more normalized CD4:CD8 ratios than patients with high CD8+ T cell apoptosis (mean CD4 cell counts 1,209 ± 164 vs 754 ± 320 cells/mm3; CD4:CD8 ratios 1.55 vs. 0.70, respectively. Conclusion We postulate that CD8+ T cell apoptosis may reflect inherent activation status, which continues in some patients even though viral replication is suppressed which influences the ability of CD4+ T cells to rebound. Levels of CD8+ T cell apoptosis may therefore be an independent predictor of immune status, which should be shown in a

  14. CD8 apoptosis may be a predictor of T cell number normalization after immune reconstitution in HIV

    Science.gov (United States)

    Lewis, Dorothy E; Gross, Kimber L; Diez, Martine M; Martinez, Maria L; Lukefahr, Helen N; Kozinetz, Claudia A; Arduino, Roberto C

    2007-01-01

    Background As part of the Houston Vanguard study, a subset of 10 patients randomized to receive IL-2 therapy were compared to 4 patients randomized to not receive IL-2, for markers of T cell activation and death during the first three cycles of IL-2. All patients were treated with combination antiretroviral therapy (ART) and were virally suppressed. The purpose of the study was to examine the role of CD8+ T cell death in responses to ART and IL-2 therapy. Methods Lymphocytes were examined at Day 0, 5 and 30 days during three cycles of IL-2 therapy. CD25, CD38, HLA-DR expression and annexin (cell death) were examined on CD4 and CD8 subpopulations. Follow up studies examined CD4 levels and CD4:CD8 reconstitution after 6 years using both univariant and multivariate analyses. Results Human lymphocytes responded to IL-2 therapy by upregulation of CD25 on CD4+ T cells, leading to an increase in CD4 cell counts. CD8+ T cells did not increase CD25 expression, but upregulated activation antigens (CD38 and DR) and had increased death. At baseline, 7 of the 14 patients had high CD8+ T cell apoptosis (mean 17.0% ± 6.0). We did an exploratory analysis of immune status after six years, and found that baseline CD8+ T cell apoptosis was correlated with CD4 cell count gain beginning two years post enrollment. Patients with low levels of CD8+ T cell apoptosis at baseline (mean 2.2% ± 2.1) had significantly higher CD4 cell counts and more normalized CD4:CD8 ratios than patients with high CD8+ T cell apoptosis (mean CD4 cell counts 1,209 ± 164 vs 754 ± 320 cells/mm3; CD4:CD8 ratios 1.55 vs. 0.70, respectively). Conclusion We postulate that CD8+ T cell apoptosis may reflect inherent activation status, which continues in some patients even though viral replication is suppressed which influences the ability of CD4+ T cells to rebound. Levels of CD8+ T cell apoptosis may therefore be an independent predictor of immune status, which should be shown in a prospective study. PMID:17263884

  15. Cerebrospinal fluid cytokine profiles predict risk of early mortality and immune reconstitution inflammatory syndrome in HIV-associated cryptococcal meningitis.

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    Joseph N Jarvis

    2015-04-01

    Full Text Available Understanding the host immune response during cryptococcal meningitis (CM is of critical importance for the development of immunomodulatory therapies. We profiled the cerebrospinal fluid (CSF immune-response in ninety patients with HIV-associated CM, and examined associations between immune phenotype and clinical outcome. CSF cytokine, chemokine, and macrophage activation marker concentrations were assayed at disease presentation, and associations between these parameters and microbiological and clinical outcomes were examined using principal component analysis (PCA. PCA demonstrated a co-correlated CSF cytokine and chemokine response consisting primarily of Th1, Th2, and Th17-type cytokines. The presence of this CSF cytokine response was associated with evidence of increased macrophage activation, more rapid clearance of Cryptococci from CSF, and survival at 2 weeks. The key components of this protective immune-response were interleukin (IL-6 and interferon-γ, IL-4, IL-10 and IL-17 levels also made a modest positive contribution to the PC1 score. A second component of co-correlated chemokines was identified by PCA, consisting primarily of monocyte chemotactic protein-1 (MCP-1 and macrophage inflammatory protein-1α (MIP-1α. High CSF chemokine concentrations were associated with low peripheral CD4 cell counts and CSF lymphocyte counts and were predictive of immune reconstitution inflammatory syndrome (IRIS. In conclusion CSF cytokine and chemokine profiles predict risk of early mortality and IRIS in HIV-associated CM. We speculate that the presence of even minimal Cryptococcus-specific Th1-type CD4+ T-cell responses lead to increased recruitment of circulating lymphocytes and monocytes into the central nervous system (CNS, more effective activation of CNS macrophages and microglial cells, and faster organism clearance; while high CNS chemokine levels may predispose to over recruitment or inappropriate recruitment of immune cells to the CNS and

  16. Reconstitution of the NF1 GAP-related domain in NF1-deficient human Schwann cells

    International Nuclear Information System (INIS)

    Thomas, Stacey L.; Deadwyler, Gail D.; Tang, Jun; Stubbs, Evan B.; Muir, David; Hiatt, Kelly K.; Clapp, D. Wade; De Vries, George H.

    2006-01-01

    Schwann cells derived from peripheral nerve sheath tumors from individuals with Neurofibromatosis Type 1 (NF1) are deficient for the protein neurofibromin, which contains a GAP-related domain (NF1-GRD). Neurofibromin-deficient Schwann cells have increased Ras activation, increased proliferation in response to certain growth stimuli, increased angiogenic potential, and altered cell morphology. This study examined whether expression of functional NF1-GRD can reverse the transformed phenotype of neurofibromin-deficient Schwann cells from both benign and malignant peripheral nerve sheath tumors. We reconstituted the NF1-GRD using retroviral transduction and examined the effects on cell morphology, growth potential, and angiogenic potential. NF1-GRD reconstitution resulted in morphologic changes, a 16-33% reduction in Ras activation, and a 53% decrease in proliferation in neurofibromin-deficient Schwann cells. However, NF1-GRD reconstitution was not sufficient to decrease the in vitro angiogenic potential of the cells. This study demonstrates that reconstitution of the NF1-GRD can at least partially reverse the transformation of human NF1 tumor-derived Schwann cells

  17. Chylous Ascites in a Patient with HIV/AIDS: A Late Complication of Mycobacterium avium Complex-Immune Reconstitution Inflammatory Syndrome

    Directory of Open Access Journals (Sweden)

    Imam H. Shaik

    2014-01-01

    Full Text Available Chylous ascites is very rare in HIV/AIDS and its association with Mycobacterium avium complex-immune reconstitution inflammatory syndrome (MAC-IRIS has been rarely reported. Here, we report a case of a young African-American male who developed chylous ascites as a late sequela to immune reconstitution inflammatory syndrome while on treatment for MAC. Antiretroviral drug-naive patients who start HAART in close proximity to the diagnosis of an opportunistic infection and have a rapid decline in HIV RNA level should be monitored for development of IRIS. Although the long term prognosis is poor, early diagnosis and treatment help to improve quality of life.

  18. Critical role of CD4 T cells in maintaining lymphoid tissue structure for immune cell homeostasis and reconstitution.

    Science.gov (United States)

    Zeng, Ming; Paiardini, Mirko; Engram, Jessica C; Beilman, Greg J; Chipman, Jeffrey G; Schacker, Timothy W; Silvestri, Guido; Haase, Ashley T

    2012-08-30

    Loss of the fibroblastic reticular cell (FRC) network in lymphoid tissues during HIV-1 infection has been shown to impair the survival of naive T cells and limit immune reconstitution after antiretroviral therapy. What causes this FRC loss is unknown. Because FRC loss correlates with loss of both naive CD4 and CD8 T-cell subsets and decreased lymphotoxin-β, a key factor for maintenance of FRC network, we hypothesized that loss of naive T cells is responsible for loss of the FRC network. To test this hypothesis, we assessed the consequences of antibody-mediated depletion of CD4 and CD8 T cells in rhesus macaques and sooty mangabeys. We found that only CD4 T-cell depletion resulted in FRC loss in both species and that this loss was caused by decreased lymphotoxin-β mainly produced by the CD4 T cells. We further found the same dependence of the FRC network on CD4 T cells in HIV-1-infected patients before and after antiretroviral therapy and in other immunodeficiency conditions, such as CD4 depletion in cancer patients induced by chemotherapy and irradiation. CD4 T cells thus play a central role in the maintenance of lymphoid tissue structure necessary for their own homeostasis and reconstitution.

  19. IL-2 receptor γ-chain molecule is critical for intestinal T-cell reconstitution in humanized mice.

    Science.gov (United States)

    Denton, P W; Nochi, T; Lim, A; Krisko, J F; Martinez-Torres, F; Choudhary, S K; Wahl, A; Olesen, R; Zou, W; Di Santo, J P; Margolis, D M; Garcia, J V

    2012-09-01

    Intestinal immune cells are important in host defense, yet the determinants for human lymphoid homeostasis in the intestines are poorly understood. In contrast, lymphoid homeostasis has been studied extensively in mice, where the requirement for a functional common γ-chain molecule has been established. We hypothesized that humanized mice could offer insights into human intestinal lymphoid homeostasis if generated in a strain with an intact mouse common γ-chain molecule. To address this hypothesis, we used three mouse strains (non-obese diabetic (NOD)/severe-combined immunodeficient (SCID) (N/S); NOD/SCID γ-chain(-/-) (NSG); and Rag2(-/-) γ-chain(-/-) (DKO)) and two humanization techniques (bone marrow liver thymus (BLT) and human CD34(+) cell bone marrow transplant of newborn mice (hu)) to generate four common types of humanized mice: N/S-BLT, NSG-BLT, NSG-hu, and DKO-hu mice. The highest levels of intestinal human T cells throughout the small and large intestines were observed in N/S-BLT mice, which have an intact common γ-chain molecule. Furthermore, the small intestine lamina propria T-cell populations of N/S-BLT mice exhibit a human intestine-specific surface phenotype. Thus, the extensive intestinal immune reconstitution of N/S-BLT mice was both quantitatively and qualitatively better when compared with the other models tested such that N/S-BLT mice are well suited for the analysis of human intestinal lymphocyte trafficking and human-specific diseases affecting the intestines.

  20. Reconstitution of active human core Mediator complex reveals a pivotal role of the MED14 subunit

    Science.gov (United States)

    Cevher, Murat A.; Shi, Yi; Li, Dan; Chait, Brian T.; Malik, Sohail; Roeder, Robert G.

    2014-01-01

    The evolutionarily conserved Mediator complex is a critical coactivator for RNA polymerase II (Pol II)-mediated transcription. Here, we report the reconstitution of a functional 15-subunit human core Mediator complex and its characterization by functional assays and chemical cross-linking coupled to mass spectrometry (CX-MS). Whereas the reconstituted head and middle modules can stably associate, only with incorporation of MED14 into the bi-modular complex does it acquire basal and coactivator functions. This results from a dramatically enhanced ability of MED14-containing complexes to associate with Pol II. Altogether, our analyses identify MED14 as both an architectural and a functional backbone of the Mediator complex. We further establish a conditional requirement for metazoan-specific MED26 that becomes evident in the presence of heterologous nuclear factors. This general approach paves the way for systematically dissecting the multiple layers of functionalities associated with the Mediator complex. PMID:25383669

  1. Reconstitution of active human core Mediator complex reveals a critical role of the MED14 subunit.

    Science.gov (United States)

    Cevher, Murat A; Shi, Yi; Li, Dan; Chait, Brian T; Malik, Sohail; Roeder, Robert G

    2014-12-01

    The evolutionarily conserved Mediator complex is a critical coactivator for RNA polymerase II (Pol II)-mediated transcription. Here we report the reconstitution of a functional 15-subunit human core Mediator complex and its characterization by functional assays and chemical cross-linking coupled to MS (CX-MS). Whereas the reconstituted head and middle modules can stably associate, basal and coactivator functions are acquired only after incorporation of MED14 into the bimodular complex. This results from a dramatically enhanced ability of MED14-containing complexes to associate with Pol II. Altogether, our analyses identify MED14 as both an architectural and a functional backbone of the Mediator complex. We further establish a conditional requirement for metazoan-specific MED26 that becomes evident in the presence of heterologous nuclear factors. This general approach paves the way for systematic dissection of the multiple layers of functionality associated with the Mediator complex.

  2. Graves' Disease as a Manifestation of Immune Reconstitution in HIV-Infected Individuals after Initiation of Highly Active Antiretroviral Therapy

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    Samad Rasul

    2011-01-01

    Full Text Available Graves' disease after the initiation of highly active antiretroviral therapy (HAART in certain HIV-1-infected individuals has been described as an immune reconstitution inflammatory syndrome (IRIS. This phenomenon should be suspected in individuals who present with clinical deterioration and a presentation suggestive of hyperthyroidism despite good virological and immunological response to HAART. Signs and symptoms of hyperthyroidism may be discrete or overt and typically develop 8–33 months after initiating therapy. One to two percent of HIV-infected patients can present with overt thyroid disease. Relatively few cases of Graves' IRIS have been reported in the literature to date. We describe four cases of Graves' IRIS in HIV-infected patients who were started on HAART therapy.

  3. Expression of human adenosine deaminase in mice reconstituted with retrovirus-transduced hematopoietic stem cells

    International Nuclear Information System (INIS)

    Wilson, J.M.; Danos, O.; Grossman, M.; Raulet, D.H.; Mulligan, R.C.

    1990-01-01

    Recombinant retroviruses encoding human adenosine deaminase have been used to infect murine hematopoietic stem cells. In bone marrow transplant recipients reconstituted with the genetically modified cells, human ADA was detected in peripheral blood mononuclear cells of the recipients for at least 6 months after transplantation. In animals analyzed in detail 4 months after transplantation, human ADA and proviral sequences were detected in all hematopoietic lineages; in several cases, human ADA activity exceeded the endogenous activity. These studies demonstrate the feasibility of introducing a functional human ADA gene into hematopoietic stem cells and obtaining expression in multiple hematopoietic lineages long after transplantation. This approach should be helpful in designing effective gene therapies for severe combined immunodeficiency syndromes in humans

  4. Enhanced Reconstitution of Human Erythropoiesis and Thrombopoiesis in an Immunodeficient Mouse Model with KitWv Mutations

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    Ayano Yurino

    2016-09-01

    Full Text Available In human-to-mouse xenograft models, reconstitution of human hematopoiesis is usually B-lymphoid dominant. Here we show that the introduction of homozygous KitWv mutations into C57BL/6.Rag2nullIl2rgnull mice with NOD-Sirpa (BRGS strongly promoted human multi-lineage reconstitution. After xenotransplantation of human CD34+CD38− cord blood cells, these newly generated C57BL/6.Rag2nullIl2rgnullNOD-Sirpa KitWv/Wv (BRGSKWv/Wv mice showed significantly higher levels of human cell chimerism and long-term multi-lineage reconstitution compared with BRGS mice. Strikingly, this mouse displayed a robust reconstitution of human erythropoiesis and thrombopoiesis with terminal maturation in the bone marrow. Furthermore, depletion of host macrophages by clodronate administration resulted in the presence of human erythrocytes and platelets in the circulation. Thus, attenuation of mouse KIT signaling greatly enhances the multi-lineage differentiation of human hematopoietic stem and progenitor cells (HSPCs in mouse bone marrow, presumably by outcompeting mouse HSPCs to occupy suitable microenvironments. The BRGSKWv/Wv mouse model is a useful tool to study human multi-lineage hematopoiesis.

  5. Immune Reconstitution Inflammatory Syndrome and Shingles Associated with a Combined Paralysis of Three Oculomotor Nerves: A Case Report.

    Science.gov (United States)

    Atipo-Tsiba, P W; Kombo Bayonne, E S

    2016-05-01

    In countries with high prevalence of HIV/AIDS infection, particularly in black Africa, shingles is one of the main opportunistic infections during immunosuppression due to AIDS in young patients. If immunological weakness is important, usually when the CD4 cell count is less than 100 cells/mm(3), the risk of inflammatory reactions in the first three months after initiating of antiretroviral treatment (ART) is very high. This inflammatory reaction is called immune reconstitution inflammatory syndrome (IRIS). This observation reports the first documented case of IRIS with V1 shingles in a young HIV patient at University Hospital of Brazzaville. A 40 years old patient was seen for a pain of the right side of the face and a complete immobility of the eyeball. The diagnosis of V1 shingles with a pan uveitis, and a paralysis of III, IV and VI nerves was made. The patiants HIV status was positive and CD4 cell count was 150 cells/mm(3). After two months of evolution under ART with a CD4 count of 850 cells /mm(3), the symptomatology was quickly complicated by significant inflammation causing a phtisis bulbi. CD4 cells count is an important indicator in the HIV/AIDS therapy. In some major forms of IRIS, momentary pause of anti retroviral treatment is sometimes necessary.

  6. Evaluation of Cellular Phenotypes Implicated in Immunopathogenesis and Monitoring Immune Reconstitution Inflammatory Syndrome in HIV/Leprosy Cases

    Science.gov (United States)

    Giacoia-Gripp, Carmem Beatriz Wagner; Sales, Anna Maria; Nery, José Augusto da Costa; Santos-Oliveira, Joanna Reis; de Oliveira, Ariane Leite; Sarno, Euzenir Nunes; Morgado, Mariza Gonçalves

    2011-01-01

    Background It is now evident that HAART-associated immunological improvement often leads to a variety of new clinical manifestations, collectively termed immune reconstitution inflammatory syndrome, or IRIS. This phenomenon has already been described in cases of HIV coinfection with Mycobacterium leprae, most of them belonging to the tuberculoid spectrum of leprosy disease, as observed in leprosy reversal reaction (RR). However, the events related to the pathogenesis of this association need to be clarified. This study investigated the immunological profile of HIV/leprosy patients, with special attention to the cellular activation status, to better understand the mechanisms related to IRIS/RR immunopathogenesis, identifying any potential biomarkers for IRIS/RR intercurrence. Methods/Principal Findings Eighty-five individuals were assessed in this study: HIV/leprosy and HIV-monoinfected patients, grouped according to HIV-viral load levels, leprosy patients without HIV coinfection, and healthy controls. Phenotypes were evaluated by flow cytometry for T cell subsets and immune differentiation/activation markers. As expected, absolute counts of the CD4+ and CD8+ T cells from the HIV-infected individuals changed in relation to those of the leprosy patients and controls. However, there were no significant differences among the groups, whether in the expression of cellular differentiation phenotypes or cellular activation, as reflected by the expression of CD38 and HLA-DR. Six HIV/leprosy patients identified as IRIS/RR were analyzed during IRIS/RR episodes and after prednisone treatment. These patients presented high cellular activation levels regarding the expression of CD38 in CD8+ cells T during IRIS/RR (median: 77,15%), dropping significantly (pleprosy individuals at risk for IRIS/RR. So, a comparative investigation to leprosy patients at RR should be conducted. PMID:22205964

  7. Secreted aspartic proteases are not required for invasion of reconstituted human epithelia by Candida albicans.

    Science.gov (United States)

    Lermann, Ulrich; Morschhäuser, Joachim

    2008-11-01

    A well-known virulence attribute of the human-pathogenic yeast Candida albicans is the secretion of aspartic proteases (Saps), which may contribute to colonization and infection of different host niches by degrading tissue barriers, destroying host defence molecules, or digesting proteins for nutrient supply. The role of individual Sap isoenzymes, which are encoded by a large gene family, for the pathogenicity of C. albicans has been investigated by assessing the virulence of mutants lacking specific SAP genes and by studying the expression pattern of the SAP genes in various models of superficial and systemic infections. We used a recombination-based genetic reporter system to detect the induction of the SAP1-SAP6 genes during infection of reconstituted human vaginal epithelium. Only SAP5, but none of the other tested SAP genes, was detectably activated in this in vitro infection model. To directly address the importance of the SAP1-SAP6 genes for invasion of reconstituted human epithelia (RHE), we constructed a set of mutants of the wild-type C. albicans model strain SC5314 in which either single or multiple SAP genes were specifically deleted. Even mutants lacking all of the SAP1-SAP3 or the SAP4-SAP6 genes displayed the same capacity to invade and damage both oral and vaginal RHE as their wild-type parental strain, in contrast to a nonfilamentous efg1Delta mutant that was avirulent under these conditions. We therefore conclude from these results that the secreted aspartic proteases Sap1p-Sap6p are not required for invasion of RHE by C. albicans.

  8. Immune reconstitution after allogeneic hematopoietic stem cell transplantation in children: a single institution study of 59 patients

    Directory of Open Access Journals (Sweden)

    Hyun O Kim

    2013-01-01

    Full Text Available &lt;b&gt;Purpose:&lt;/b&gt; Lymphocyte subset recovery is an important factor that determines the success of hematopoietic stem cell transplantation (HSCT. Temporal differences in the recovery of lymphocyte subsets and the factors influencing this recovery are important variables that affect a patient's posttransplant immune reconstitution, and therefore require investigation. &lt;b&gt;Methods:&lt;/b&gt; The time taken to achieve lymphocyte subset recovery and the factors influencing this recovery were investigated in 59 children who had undergone HSCT at the Department of Pediatrics, The Catholic University of Korea Seoul St. Mary's Hospital, and who had an uneventful follow-up period of at least 1 year. Analyses were carried out at 3 and 12 months post-transplant. An additional study was performed 1 month post-transplant to evaluate natural killer (NK cell recovery. The impact of preand post-transplant variables, including diagnosis of Epstein-Barr virus (EBV DNAemia posttransplant,on lymphocyte recovery was evaluated. &lt;b&gt;Results:&lt;/b&gt; The lymphocyte subsets recovered in the following order: NK cells, cytotoxic T cells, B cells,and helper T cells. At 1 month post-transplant, acute graft-versus-host disease was found to contribute significantly to the delay of CD16+/56+ cell recovery. Younger patients showed delayed recovery of both CD3+/CD8+ and CD19+ cells. EBV DNAemia had a deleterious impact on the recovery of both CD3+ and CD3+/CD4+ lymphocytes at 1 year post-transplant. &lt;b&gt;Conclusion:&lt;/b&gt; In our pediatric allogeneic HSCT cohort, helper T cells were the last subset to recover. Younger age and EBV DNAemia had a negative impact on the post-transplant recovery of T cells and B cells.

  9. Growth and characterization of different human rhinovirus C types in three-dimensional human airway epithelia reconstituted in vitro

    International Nuclear Information System (INIS)

    Tapparel, Caroline; Sobo, Komla; Constant, Samuel; Huang, Song; Van Belle, Sandra; Kaiser, Laurent

    2013-01-01

    New molecular diagnostic tools have recently allowed the discovery of human rhinovirus species C (HRV-C) that may be overrepresented in children with lower respiratory tract complications. Unlike HRV-A and HRV-B, HRV-C cannot be propagated in conventional immortalized cell lines and their biological properties have been difficult to study. Recent studies have described the successful amplification of HRV-C15, HRV-C11, and HRV-C41 in sinus mucosal organ cultures and in fully differentiated human airway epithelial cells. Consistent with these studies, we report that a panel of clinical HRV-C specimens including HRV-C2, HRV-C7, HRV-C12, HRV-C15, and HRV-C29 types were all capable of mediating productive infection in reconstituted 3D human primary upper airway epithelial tissues and that the virions enter and exit preferentially through the apical surface. Similar to HRV-A and HRV-B, our data support the acid sensitivity of HRV-C. We observed also that the optimum temperature requirement during HRV-C growth may be type-dependent. - Highlights: • A 3D human upper airway epithelia reconstituted in vitro supports HRV-C growth. • HRV-Cs enter and exit preferentially at the apical side of this ALI culture system. • HRV-Cs are acid sensitive. • Temperature sensitivity may be type-dependent for HRV-Cs

  10. Growth and characterization of different human rhinovirus C types in three-dimensional human airway epithelia reconstituted in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Tapparel, Caroline, E-mail: Caroline.Tapparel@hcuge.ch [Laboratory of Virology, Division of Infectious Diseases and Division of Laboratory Medicine, University of Geneva Hospitals, 4 Rue Gabrielle-Perret-Gentil, 1211 Geneva 14 (Switzerland); Sobo, Komla [Laboratory of Virology, Division of Infectious Diseases and Division of Laboratory Medicine, University of Geneva Hospitals, 4 Rue Gabrielle-Perret-Gentil, 1211 Geneva 14 (Switzerland); Constant, Samuel; Huang, Song [Epithelix sárl, 14 Chemin des Aulx, 1228 Plan les Ouates, Geneva (Switzerland); Van Belle, Sandra; Kaiser, Laurent [Laboratory of Virology, Division of Infectious Diseases and Division of Laboratory Medicine, University of Geneva Hospitals, 4 Rue Gabrielle-Perret-Gentil, 1211 Geneva 14 (Switzerland)

    2013-11-15

    New molecular diagnostic tools have recently allowed the discovery of human rhinovirus species C (HRV-C) that may be overrepresented in children with lower respiratory tract complications. Unlike HRV-A and HRV-B, HRV-C cannot be propagated in conventional immortalized cell lines and their biological properties have been difficult to study. Recent studies have described the successful amplification of HRV-C15, HRV-C11, and HRV-C41 in sinus mucosal organ cultures and in fully differentiated human airway epithelial cells. Consistent with these studies, we report that a panel of clinical HRV-C specimens including HRV-C2, HRV-C7, HRV-C12, HRV-C15, and HRV-C29 types were all capable of mediating productive infection in reconstituted 3D human primary upper airway epithelial tissues and that the virions enter and exit preferentially through the apical surface. Similar to HRV-A and HRV-B, our data support the acid sensitivity of HRV-C. We observed also that the optimum temperature requirement during HRV-C growth may be type-dependent. - Highlights: • A 3D human upper airway epithelia reconstituted in vitro supports HRV-C growth. • HRV-Cs enter and exit preferentially at the apical side of this ALI culture system. • HRV-Cs are acid sensitive. • Temperature sensitivity may be type-dependent for HRV-Cs.

  11. Heme orientational disorder in human adult hemoglobin reconstituted with a ring fluorinated heme and its functional consequences

    International Nuclear Information System (INIS)

    Nagao, Satoshi; Hirai, Yueki; Kawano, Shin; Imai, Kiyohiro; Suzuki, Akihiro; Yamamoto, Yasuhiko

    2007-01-01

    A ring fluorinated heme, 13,17-bis(2-carboxylatoethyl)-3,8-diethyl-2-fluoro-7,12, 18-trimethyl-porphyrin-atoiron(III), has been incorporated into human adult hemoglobin (Hb A). The heme orientational disorder in the individual subunits of the protein has been readily characterized using 19 F NMR and the O 2 binding properties of the protein have been evaluated through the oxygen equilibrium analysis. The equilibrated orientations of hemes in α- and β- subunits of the reconstituted protein were found to be almost completely opposite to each other, and hence were largely different from those of the native and the previously reported reconstituted proteins [T. Jue, G.N. La Mar, Heme orientational heterogeneity in deuterohemin-reconstituted horse and human hemoglobin characterized by proton nuclear magnetic resonance spectroscopy, Biochem. Biophys. Res. Commun. 119 (1984) 640-645]. Despite the large difference in the degree of the heme orientational disorder in the subunits of the proteins, the O 2 affinity and the cooperativity of the protein reconstituted with 2-MF were similar to those of the proteins reconstituted with a series of hemes chemically modified at the heme 3- and 8-positions [K. Kawabe, K. Imaizumi, Z. Yoshida, K. Imai, I. Tyuma, Studies on reconstituted myoglobins and hemoglobins II. Role of the heme side chains in the oxygenation of hemoglobin, J. Biochem. 92 (1982) 1713-1722], whose O 2 affinity and cooperativity were higher and lower, respectively, relative to those of native protein. These results indicated that the heme orientational disorder could exert little effect, if any, on the O 2 affinity properties of Hb A. This finding provides new insights into structure-function relationship of Hb A

  12. Evaluation of cellular phenotypes implicated in immunopathogenesis and monitoring immune reconstitution inflammatory syndrome in HIV/leprosy cases.

    Science.gov (United States)

    Giacoia-Gripp, Carmem Beatriz Wagner; Sales, Anna Maria; Nery, José Augusto da Costa; Santos-Oliveira, Joanna Reis; de Oliveira, Ariane Leite; Sarno, Euzenir Nunes; Morgado, Mariza Gonçalves

    2011-01-01

    It is now evident that HAART-associated immunological improvement often leads to a variety of new clinical manifestations, collectively termed immune reconstitution inflammatory syndrome, or IRIS. This phenomenon has already been described in cases of HIV coinfection with Mycobacterium leprae, most of them belonging to the tuberculoid spectrum of leprosy disease, as observed in leprosy reversal reaction (RR). However, the events related to the pathogenesis of this association need to be clarified. This study investigated the immunological profile of HIV/leprosy patients, with special attention to the cellular activation status, to better understand the mechanisms related to IRIS/RR immunopathogenesis, identifying any potential biomarkers for IRIS/RR intercurrence. Eighty-five individuals were assessed in this study: HIV/leprosy and HIV-monoinfected patients, grouped according to HIV-viral load levels, leprosy patients without HIV coinfection, and healthy controls. Phenotypes were evaluated by flow cytometry for T cell subsets and immune differentiation/activation markers. As expected, absolute counts of the CD4+ and CD8+ T cells from the HIV-infected individuals changed in relation to those of the leprosy patients and controls. However, there were no significant differences among the groups, whether in the expression of cellular differentiation phenotypes or cellular activation, as reflected by the expression of CD38 and HLA-DR. Six HIV/leprosy patients identified as IRIS/RR were analyzed during IRIS/RR episodes and after prednisone treatment. These patients presented high cellular activation levels regarding the expression of CD38 in CD8+ cells T during IRIS/RR (median: 77,15%), dropping significantly (p<0,05) during post-IRIS/RR moments (median: 29,7%). Furthermore, an increase of cellular activation seems to occur prior to IRIS/RR. These data suggest CD38 expression in CD8+ T cells interesting tool identifying HIV/leprosy individuals at risk for IRIS/RR. So, a

  13. Evaluation of cellular phenotypes implicated in immunopathogenesis and monitoring immune reconstitution inflammatory syndrome in HIV/leprosy cases.

    Directory of Open Access Journals (Sweden)

    Carmem Beatriz Wagner Giacoia-Gripp

    Full Text Available BACKGROUND: It is now evident that HAART-associated immunological improvement often leads to a variety of new clinical manifestations, collectively termed immune reconstitution inflammatory syndrome, or IRIS. This phenomenon has already been described in cases of HIV coinfection with Mycobacterium leprae, most of them belonging to the tuberculoid spectrum of leprosy disease, as observed in leprosy reversal reaction (RR. However, the events related to the pathogenesis of this association need to be clarified. This study investigated the immunological profile of HIV/leprosy patients, with special attention to the cellular activation status, to better understand the mechanisms related to IRIS/RR immunopathogenesis, identifying any potential biomarkers for IRIS/RR intercurrence. METHODS/PRINCIPAL FINDINGS: Eighty-five individuals were assessed in this study: HIV/leprosy and HIV-monoinfected patients, grouped according to HIV-viral load levels, leprosy patients without HIV coinfection, and healthy controls. Phenotypes were evaluated by flow cytometry for T cell subsets and immune differentiation/activation markers. As expected, absolute counts of the CD4+ and CD8+ T cells from the HIV-infected individuals changed in relation to those of the leprosy patients and controls. However, there were no significant differences among the groups, whether in the expression of cellular differentiation phenotypes or cellular activation, as reflected by the expression of CD38 and HLA-DR. Six HIV/leprosy patients identified as IRIS/RR were analyzed during IRIS/RR episodes and after prednisone treatment. These patients presented high cellular activation levels regarding the expression of CD38 in CD8+ cells T during IRIS/RR (median: 77,15%, dropping significantly (p<0,05 during post-IRIS/RR moments (median: 29,7%. Furthermore, an increase of cellular activation seems to occur prior to IRIS/RR. CONCLUSION/SIGNIFICANCE: These data suggest CD38 expression in CD8+ T cells

  14. Risk factors for increased immune reconstitution in response to Mycobacterium tuberculosis antigens in tuberculosis HIV-infected, antiretroviral-naïve patients.

    Science.gov (United States)

    da Silva, Tatiana Pereira; Giacoia-Gripp, Carmem Beatriz Wagner; Schmaltz, Carolina A; Sant'Anna, Flavia Marinho; Saad, Maria Helena; Matos, Juliana Arruda de; de Lima E Silva, Julio Castro Alves; Rolla, Valeria Cavalcanti; Morgado, Mariza Gonçalves

    2017-09-06

    Little is known regarding the restoration of the specific immune response after combined antiretroviral therapy (cART) and anti-tuberculosis (TB) therapy introduction among TB-HIV patients. In this study, we examined the immune response of TB-HIV patients to Mycobacterium tuberculosis (Mtb) antigens to evaluate the response dynamics to different antigens over time. Moreover, we also evaluated the influence of two different doses of efavirenz and the factors associated with immune reconstitution. This is a longitudinal study nested in a clinical trial, where cART was initiated during the baseline visit (D0), which occurred 30 ± 10 days after the introduction of anti-TB therapy. Follow-up visits were performed at 30, 60, 90 and 180 days after cART initiation. The production of IFN-γ upon in vitro stimulation with Mtb antigens purified protein derivative (PPD), ESAT-6 and 38 kDa/CFP-10 using ELISpot was examined at baseline and follow-up visits. Sixty-one patients, all ART-naïve, were selected and included in the immune reconstitution analysis; seven (11.5%) developed Immune Reconstitution Inflammatory Syndrome (IRIS). The Mtb specific immune response was higher for the PPD antigen followed by 38 kDa/CFP-10 and increased in the first 60 days after cART initiation. In multivariate analysis, the variables independently associated with increased IFN-γ production in response to PPD antigen were CD4 + T cell counts tuberculosis, 800 mg efavirenz dose and follow-up CD4 + T cell counts. Moreover, the factors associated with the production of IFN-γ in response to 38 kDa/CFP-10 were detectable HIV viral load (VL) and CD4 + T cell counts at follow-up visits of ≥200 cells/mm 3 . These findings highlight the differences in immune response according to the specificity of the Mtb antigen, which contributes to a better understanding of TB-HIV immunopathogenesis. IFN-γ production elicited by PPD and 38 kDa/CFP-10 antigens have a greater magnitude compared to ESAT-6

  15. Functional reconstitution into liposomes of purified human RhCG ammonia channel.

    Directory of Open Access Journals (Sweden)

    Isabelle Mouro-Chanteloup

    Full Text Available BACKGROUND: Rh glycoproteins (RhAG, RhBG, RhCG are members of the Amt/Mep/Rh family which facilitate movement of ammonium across plasma membranes. Changes in ammonium transport activity following expression of Rh glycoproteins have been described in different heterologous systems such as yeasts, oocytes and eukaryotic cell lines. However, in these complex systems, a potential contribution of endogenous proteins to this function cannot be excluded. To demonstrate that Rh glycoproteins by themselves transport NH(3, human RhCG was purified to homogeneity and reconstituted into liposomes, giving new insights into its channel functional properties. METHODOLOGY/PRINCIPAL FINDINGS: An HA-tag introduced in the second extracellular loop of RhCG was used to purify to homogeneity the HA-tagged RhCG glycoprotein from detergent-solubilized recombinant HEK293E cells. Electron microscopy analysis of negatively stained purified RhCG-HA revealed, after image processing, homogeneous particles of 9 nm diameter with a trimeric protein structure. Reconstitution was performed with sphingomyelin, phosphatidylcholine and phosphatidic acid lipids in the presence of the C(12E(8 detergent which was subsequently removed by Biobeads. Control of protein incorporation was carried out by freeze-fracture electron microscopy. Particle density in liposomes was a function of the Lipid/Protein ratio. When compared to empty liposomes, ammonium permeability was increased two and three fold in RhCG-proteoliposomes, depending on the Lipid/Protein ratio (1/300 and 1/150, respectively. This strong NH(3 transport was reversibly inhibited by mercuric and copper salts and exhibited a low Arrhenius activation energy. CONCLUSIONS/SIGNIFICANCE: This study allowed the determination of ammonia permeability per RhCG monomer, showing that the apparent Punit(NH3 (around 1x10(-3 microm(3xs(-1 is close to the permeability measured in HEK293E cells expressing a recombinant human RhCG (1.60x10

  16. Role of LTA4H Polymorphism in Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome Occurrence and Clinical Severity in Patients Infected with HIV.

    Science.gov (United States)

    Narendran, Gopalan; Kavitha, Dhanasekaran; Karunaianantham, Ramesh; Gil-Santana, Leonardo; Almeida-Junior, Jilson L; Reddy, Sirasanambatti Devarajulu; Kumar, Marimuthu Makesh; Hemalatha, Haribabu; Jayanthi, Nagesh Nalini; Ravichandran, Narayanan; Krishnaraja, Raja; Prabhakar, Angamuthu; Manoharan, Tamizhselvan; Nithyananthan, Lokeswaran; Arjunan, Gunasundari; Natrajan, Mohan; Swaminathan, Soumya; Andrade, Bruno B

    2016-01-01

    Paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is an inflammatory phenomenon complicating HIV management in coincidental tuberculosis (TB) infection, upon immune reconstitution driven by antiretroviral therapy (ART). Leukotriene A4 hydroxylase (LTA4H), an enzyme which converts LTA4 to LTB4, regulates the balance between the anti-inflammatory lipoxins and pro-inflammatory LTB4, with direct implications in TB-driven inflammation. In humans, a single nucleotide polymorphism (SNP) in the LTA4H promoter which regulates its transcriptional activity (rs17525495) has been identified and described to impact clinical severity of TB presentation and response to corticosteroid therapy. Notably, the role of LTA4H on TB-IRIS has not been previously evaluated. Here, we performed an exploratory investigation testing the association of LTA4H polymorphism with respect to frequency of TB-IRIS occurrence and severity of TB-IRIS presentation in HIV-TB co-infected individuals. Genotypic evaluation of the LTA4H enzyme from available samples was retrospectively correlated with clinical data captured in case sheets including IRIS details. The cohort included patients recruited from a prospective cohort study nested within a randomized clinical trial (NCT0933790) of ART-naïve HIV+ patients with newly diagnosed rifampicin sensitive pulmonary TB in South India. Frequency of the wild type genotype (CC), as well as of the mutant genotypes (CT or TT) in the IRIS and non-IRIS patients was estimated. Comparative analyses were performed between wild genotype (CC) and the mutant genotypes (CT or TT) and tested for association between the LTA4H polymorphisms and IRIS incidence and clinical severity. A total of 142 eligible ART-naïve patients were included in the analyses. Eighty-six individuals exhibited the wild genotype (CC) while 56 had mutant genotypes (43-CT and only 13-TT). Variant allele frequency was 0.23 and 0.26 in non-IRIS group and in IRIS

  17. Immune Reconstitution Syndrome

    Indian Academy of Sciences (India)

    First page Back Continue Last page Graphics. Occurs in 20-30% of patients starting ART. Occurs in 20-30% of patients starting ART. Two forms – unmasking type and paradoxical. TB commonest form of IRIS. Risk factors: ARV within 6 wks, disseminated disease, low baseline CD4, rapid rise in CD4%, fall in VL, high ...

  18. Biochemical reconstitution and phylogenetic comparison of human SET1 family core complexes involved in histone methylation.

    Science.gov (United States)

    Shinsky, Stephen A; Monteith, Kelsey E; Viggiano, Susan; Cosgrove, Michael S

    2015-03-06

    Mixed lineage leukemia protein-1 (MLL1) is a member of the SET1 family of histone H3 lysine 4 (H3K4) methyltransferases that are required for metazoan development. MLL1 is the best characterized human SET1 family member, which includes MLL1-4 and SETd1A/B. MLL1 assembles with WDR5, RBBP5, ASH2L, DPY-30 (WRAD) to form the MLL1 core complex, which is required for H3K4 dimethylation and transcriptional activation. Because all SET1 family proteins interact with WRAD in vivo, it is hypothesized they are regulated by similar mechanisms. However, recent evidence suggests differences among family members that may reflect unique regulatory inputs in the cell. Missing is an understanding of the intrinsic enzymatic activities of different SET1 family complexes under standard conditions. In this investigation, we reconstituted each human SET1 family core complex and compared subunit assembly and enzymatic activities. We found that in the absence of WRAD, all but one SET domain catalyzes at least weak H3K4 monomethylation. In the presence of WRAD, all SET1 family members showed stimulated monomethyltransferase activity but differed in their di- and trimethylation activities. We found that these differences are correlated with evolutionary lineage, suggesting these enzyme complexes have evolved to accomplish unique tasks within metazoan genomes. To understand the structural basis for these differences, we employed a "phylogenetic scanning mutagenesis" assay and identified a cluster of amino acid substitutions that confer a WRAD-dependent gain-of-function dimethylation activity on complexes assembled with the MLL3 or Drosophila trithorax proteins. These results form the basis for understanding how WRAD differentially regulates SET1 family complexes in vivo. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  19. Induction of immune resistance against L1210 lymphatic leukemia in mice after chemoradiotherapy of the leukemia and reconstitution with bone marrow purged from the leukemia with mafosfamide

    International Nuclear Information System (INIS)

    Skorski, T.; Kawalec, M.

    1988-01-01

    Lymphatic leukemia L1210-bearing semisyngeneic Balb/c x DBA/2Wf F1 (CD2F1) mice were subjected to chemoradiotherapy (2 x 100 mg/kg of cyclophosphamide i.p. and 1000 cGy of total body irradiation) and reconstitution with 10(7) syngeneic bone marrow cells i.v. The bone marrow obtained from leukemic mice was previously ex vivo purged of the leukemia cells with mafosfamide (ASTA Z7654) and stored in liquid nitrogen. Eight weeks after cytoreductive therapy and bone marrow transplantation we tried to immunize the mice against the lethal dose of the leukemia by i.p. injections of L1210-Maf cells (L1210 cells treated in vitro with mafosfamide for inhibition of their growth). About 75% of such mice were able to reject the subsequent 10(3) L1210 leukemia cell challenge, as compared with 70% of normal immunized mice and 55% of mice reconstituted with bone marrow cells not treated with mafosfamide

  20. Effects of X-rays and γ-rays on reconstitution of hematopoiesis and immunity after allogeneic bone marrow transplantation

    International Nuclear Information System (INIS)

    Pan Bin; Zeng Lingyu; Cheng Hai; Song Guoliang; Jia Lu; Yan Zhiling; Chen Chong; Xu Kailin

    2011-01-01

    those of the X-ray + transplantation group (t=3.624, 6.695, P<0.05). The chimeric rats of the peripheral lymphocytes 10 and 20 days after transplantation of the γ-ray + transplantation group were both significantly higher than those of the X-ray + transplantation group (t=12.317, 8.295, P<0.05). The homogeneity rate of transplantation of the γ-ray + transplantation group was better than that of the X-ray + transplantation group. Conclusions: As a conditioning regimen in allogeneic hematopoietic stem cell transplantation γ-ray irradiation causes milder injury and accelerated reconstitution of hematopoiesis and immunity, in comparison with X-ray irradiation. (authors)

  1. Long-term leukocyte reconstitution in NSG mice transplanted with human cord blood hematopoietic stem and progenitor cells.

    Science.gov (United States)

    Audigé, Annette; Rochat, Mary-Aude; Li, Duo; Ivic, Sandra; Fahrny, Audrey; Muller, Christina K S; Gers-Huber, Gustavo; Myburgh, Renier; Bredl, Simon; Schlaepfer, Erika; Scherrer, Alexandra U; Kuster, Stefan P; Speck, Roberto F

    2017-05-30

    Humanized mice (hu mice) are based on the transplantation of hematopoietic stem and progenitor cells into immunodeficient mice and have become important pre-clinical models for biomedical research. However, data about their hematopoiesis over time are scarce. We therefore characterized leukocyte reconstitution in NSG mice, which were sublethally irradiated and transplanted with human cord blood-derived CD34+ cells at newborn age, longitudinally in peripheral blood and, for more detailed analyses, cross-sectionally in peripheral blood, spleen and bone marrow at different time points. Human cell chimerism and absolute human cell count decreased between week 16 and 24 in the peripheral blood of hu mice, but were stable thereafter as assessed up to 32 weeks. Human cell chimerism in spleen and bone marrow was maintained over time. Notably, human cell chimerism in peripheral blood and spleen as well as bone marrow positively correlated with each other. Percentage of B cells decreased between week 16 and 24, whereas percentage of T cells increased; subsequently, they levelled off with T cells clearly predominating at week 32. Natural killer cells, monocytes and plasmacytoid dendritic cells (DCs) as well as CD1c + and CD141+ myeloid DCs were all present in hu mice. Proliferative responses of splenic T cells to stimulation were preserved over time. Importantly, the percentage of more primitive hematopoietic stem cells (HSCs) in bone marrow was maintained over time. Overall, leukocyte reconstitution was maintained up to 32 weeks post-transplantation in our hu NSG model, possibly explained by the maintenance of HSCs in the bone marrow. Notably, we observed great variation in multi-lineage hematopoietic reconstitution in hu mice that needs to be taken into account for the experimental design with hu mice.

  2. Impact of the New Generation Reconstituted Surfactant CHF5633 on Human CD4+ Lymphocytes.

    Directory of Open Access Journals (Sweden)

    Markus Fehrholz

    Full Text Available Natural surfactant preparations, commonly isolated from porcine or bovine lungs, are used to treat respiratory distress syndrome in preterm infants. Besides biophysical effectiveness, several studies have documented additional immunomodulatory properties. Within the near future, synthetic surfactant preparations may be a promising alternative. CHF5633 is a new generation reconstituted synthetic surfactant preparation with defined composition, containing dipalmitoyl-phosphatidylcholine, palmitoyl-oleoyl-phosphatidylglycerol and synthetic analogs of surfactant protein (SP- B and SP-C. While its biophysical effectiveness has been demonstrated in vitro and in vivo, possible immunomodulatory abilities are currently unknown.The aim of the current study was to define a potential impact of CHF5633 and its single components on pro- and anti-inflammatory cytokine responses in human CD4+ lymphocytes.Purified human CD4+ T cells were activated using anti CD3/CD28 antibodies and exposed to CHF5633, its components, or to the well-known animal-derived surfactant Poractant alfa (Curosurf®. Proliferative response and cell viability were assessed using flow cytometry and a methylthiazolyldiphenyltetrazolium bromide colorimetric assay. The mRNA expression of IFNγ, IL-2, IL-17A, IL-22, IL-4, and IL-10 was measured by quantitative PCR, while intracellular protein expression was assessed by means of flow cytometry.Neither CHF5633 nor any of its phospholipid components with or without SP-B or SP-C analogs had any influence on proliferative ability and viability of CD4+ lymphocytes under the given conditions. IFNγ, IL-2, IL-17A, IL-22, IL-4, and IL-10 mRNA as well as IFNγ, IL-2, IL-4 and IL-10 protein levels were unaffected in both non-activated and activated CD4+ lymphocytes after exposure to CHF5633 or its constituents compared to non-exposed controls. However, in comparison to Curosurf®, expression levels of anti-inflammatory IL-4 and IL-10 mRNA were

  3. Ex vivo expanded human regulatory T cells delay islet allograft rejection via inhibiting islet-derived monocyte chemoattractant protein-1 production in CD34+ stem cells-reconstituted NOD-scid IL2rγnull mice.

    Science.gov (United States)

    Xiao, Fang; Ma, Liang; Zhao, Min; Huang, Guocai; Mirenda, Vincenzo; Dorling, Anthony; Lechler, Robert; Lombardi, Giovanna

    2014-01-01

    Type 1 diabetes mellitus (T1DM) is an autoimmune disease caused by immune-mediated destruction of insulin-secreting β cells of the pancreas. Near complete dependence on exogenous insulin makes T1DM very difficult to control, with the result that patients are exposed to high blood glucose and risk of diabetic complications and/or intermittent low blood glucose that can cause unconsciousness, fits and even death. Allograft transplantation of pancreatic islets restores normoglycemia with a low risk of surgical complications. However, although successful immediately after transplantation, islets are progressively lost, with most of the patients requiring exogenous insulin within 2 years post-transplant. Therefore, there is an urgent requirement for the development of new strategies to prevent islet rejection. In this study, we explored the importance of human regulatory T cells in the control of islets allograft rejection. We developed a pre-clinical model of human islet transplantation by reconstituting NOD-scid IL2rγnull mice with cord blood-derived human CD34+ stem cells and demonstrated that although the engrafted human immune system mediated the rejection of human islets, their survival was significantly prolonged following adoptive transfer of ex vivo expanded human Tregs. Mechanistically, Tregs inhibited the infiltration of innate immune cells and CD4+ T cells into the graft by down-regulating the islet graft-derived monocyte chemoattractant protein-1. Our findings might contribute to the development of clinical strategies for Treg therapy to control human islet rejection. We also show for the first time that CD34+ cells-reconstituted NOD-scid IL2rγnull mouse model could be beneficial for investigating human innate immunity in vivo.

  4. Ex Vivo Expanded Human Regulatory T Cells Delay Islet Allograft Rejection via Inhibiting Islet-Derived Monocyte Chemoattractant Protein-1 Production in CD34+ Stem Cells-Reconstituted NOD-scid IL2rγnull Mice

    Science.gov (United States)

    Xiao, Fang; Ma, Liang; Zhao, Min; Huang, Guocai; Mirenda, Vincenzo; Dorling, Anthony

    2014-01-01

    Type 1 diabetes mellitus (T1DM) is an autoimmune disease caused by immune-mediated destruction of insulin-secreting β cells of the pancreas. Near complete dependence on exogenous insulin makes T1DM very difficult to control, with the result that patients are exposed to high blood glucose and risk of diabetic complications and/or intermittent low blood glucose that can cause unconsciousness, fits and even death. Allograft transplantation of pancreatic islets restores normoglycemia with a low risk of surgical complications. However, although successful immediately after transplantation, islets are progressively lost, with most of the patients requiring exogenous insulin within 2 years post-transplant. Therefore, there is an urgent requirement for the development of new strategies to prevent islet rejection. In this study, we explored the importance of human regulatory T cells in the control of islets allograft rejection. We developed a pre-clinical model of human islet transplantation by reconstituting NOD-scid IL2rγnull mice with cord blood-derived human CD34+ stem cells and demonstrated that although the engrafted human immune system mediated the rejection of human islets, their survival was significantly prolonged following adoptive transfer of ex vivo expanded human Tregs. Mechanistically, Tregs inhibited the infiltration of innate immune cells and CD4+ T cells into the graft by down-regulating the islet graft-derived monocyte chemoattractant protein-1. Our findings might contribute to the development of clinical strategies for Treg therapy to control human islet rejection. We also show for the first time that CD34+ cells-reconstituted NOD-scid IL2rγnull mouse model could be beneficial for investigating human innate immunity in vivo. PMID:24594640

  5. Ex vivo expanded human regulatory T cells delay islet allograft rejection via inhibiting islet-derived monocyte chemoattractant protein-1 production in CD34+ stem cells-reconstituted NOD-scid IL2rγnull mice.

    Directory of Open Access Journals (Sweden)

    Fang Xiao

    Full Text Available Type 1 diabetes mellitus (T1DM is an autoimmune disease caused by immune-mediated destruction of insulin-secreting β cells of the pancreas. Near complete dependence on exogenous insulin makes T1DM very difficult to control, with the result that patients are exposed to high blood glucose and risk of diabetic complications and/or intermittent low blood glucose that can cause unconsciousness, fits and even death. Allograft transplantation of pancreatic islets restores normoglycemia with a low risk of surgical complications. However, although successful immediately after transplantation, islets are progressively lost, with most of the patients requiring exogenous insulin within 2 years post-transplant. Therefore, there is an urgent requirement for the development of new strategies to prevent islet rejection. In this study, we explored the importance of human regulatory T cells in the control of islets allograft rejection. We developed a pre-clinical model of human islet transplantation by reconstituting NOD-scid IL2rγnull mice with cord blood-derived human CD34+ stem cells and demonstrated that although the engrafted human immune system mediated the rejection of human islets, their survival was significantly prolonged following adoptive transfer of ex vivo expanded human Tregs. Mechanistically, Tregs inhibited the infiltration of innate immune cells and CD4+ T cells into the graft by down-regulating the islet graft-derived monocyte chemoattractant protein-1. Our findings might contribute to the development of clinical strategies for Treg therapy to control human islet rejection. We also show for the first time that CD34+ cells-reconstituted NOD-scid IL2rγnull mouse model could be beneficial for investigating human innate immunity in vivo.

  6. Mycobacterium shigaense Causes Lymph Node and Cutaneous Lesions as Immune Reconstitution Syndrome in an AIDS Patient: The Third Case Report of a Novel Strain Non-tuberculous Mycobacterium

    Science.gov (United States)

    Koizumi, Yusuke; Shimizu, Kaoru; Shigeta, Masayo; Minamiguchi, Hitoshi; Hodohara, Keiko; Andoh, Akira; Tanaka, Toshihide; Chikamatsu, Kinuyo; Mitarai, Satoshi; Mikamo, Hiroshige

    2016-01-01

    A 40-year-old man complaining of progressive body weight loss was diagnosed to have acquired immunodeficiency syndrome. Within 2 weeks after the initiation of combination antiretroviral therapy, he developed fever, massive cervical lymphadenopathy and a protruding subcutaneous abscess. A lymph node biopsy and abscess drainage revealed non-caseous granuloma and mycobacterium. The mycobacterium belonged to Runyon II group, but it showed no matches to any previously reported species. According to sequence analyses, the strain was identified as Mycobacterium shigaense. After six months of antimycobacterial treatment, the lesions were all successfully cured. This is the third case report of the novel mycobacterium, M. shigaense, presenting in associatioin with immune reconstitution syndrome. PMID:27853087

  7. Dynamics of immune reconstitution and activation markers in HIV+ treatment-naïve patients treated with raltegravir, tenofovir disoproxil fumarate and emtricitabine.

    Directory of Open Access Journals (Sweden)

    Nicholas T Funderburg

    Full Text Available The dynamics of CD4+ T cell reconstitution and changes in immune activation and inflammation in HIV-1 disease following initiation of antiretroviral therapy (ART are incompletely defined and their underlying mechanisms poorly understood.Thirty-nine treatment-naïve patients were treated with raltegravir, tenofovir DF and emtricitabine. Immunologic and inflammatory indices were examined in persons with sustained virologic control during 48 weeks of therapy.Initiation of ART increased CD4+ T cell numbers and decreased activation and cell cycle entry among CD4+ and CD8+ T cell subsets, and attenuated markers of coagulation (D-dimer levels and inflammation (IL-6 and TNFr1. These indices decayed at different rates and almost all remained elevated above levels measured in HIV-seronegatives through 48 weeks of viral control. Greater first and second phase CD4+ T cell restoration was related to lower T cell activation and cell cycling at baseline, to their decay with treatment, and to baseline levels of selected inflammatory indices, but less so to their changes on therapy.ART initiation results in dynamic changes in viral replication, T cell restoration, and indices of immune activation, inflammation, and coagulation. These findings suggest that determinants of T cell activation/cycling and inflammation/coagulation may have distinguishable impact on immune homeostasis.Clinicaltrials.gov NCT00660972.

  8. Adjuvant therapeutic vaccination in patients with non-small cell lung cancer made lymphopenic and reconstituted with autologous PBMC: first clinical experience and evidence of an immune response

    Directory of Open Access Journals (Sweden)

    Schendel Dolores J

    2007-09-01

    Full Text Available Abstract Background Given the considerable toxicity and modest benefit of adjuvant chemotherapy for non-small cell lung cancer (NSCLC, there is clearly a need for new treatment modalities in the adjuvant setting. Active specific immunotherapy may represent such an option. However, clinical responses have been rare so far. Manipulating the host by inducing lymphopenia before vaccination resulted in a magnification of the immune response in the preclinical setting. To evaluate feasibility and safety of an irradiated, autologous tumor cell vaccine given following induction of lymphopenia by chemotherapy and reinfusion of autologous peripheral blood mononuclear cells (PBMC, we are currently conducting a pilot-phase I clinical trial in patients with NSCLC following surgical resection. This paper reports on the first clinical experience and evidence of an immune response in patients suffering from NSCLC. Methods NSCLC patients stages I-IIIA are recruited. Vaccines are generated from their resected lung specimens. Patients undergo leukapheresis to harvest their PBMC prior to or following the surgical procedure. Furthermore, patients receive preparative chemotherapy (cyclophosphamide 350 mg/m2 and fludarabine 20 mg/m2 on 3 consecutive days for induction of lymphopenia followed by reconstitution with their autologous PBMC. Vaccines are administered intradermally on day 1 following reconstitution and every two weeks for a total of up to five vaccinations. Granulocyte-macrophage-colony-stimulating-factor (GM-CSF is given continuously (at a rate of 50 μg/24 h at the site of vaccination via minipump for six consecutive days after each vaccination. Results To date, vaccines were successfully manufactured for 4 of 4 patients. The most common toxicities were local injection-site reactions and mild constitutional symptoms. Immune responses to chemotherapy, reconstitution and vaccination are measured by vaccine site and delayed type hypersensitivity (DTH skin

  9. Early ART Results in Greater Immune Reconstitution Benefits in HIV-Infected Infants: Working with Data Missingness in a Longitudinal Dataset.

    Directory of Open Access Journals (Sweden)

    Livio Azzoni

    Full Text Available Early initiation of anti-retroviral treatment (ART decreases mortality as compared to deferred treatment, but whether it preserves immune cells from early loss or promotes their recovery remains undefined. Determination of complex immunological endpoints in infants is often marred by missing data due to missed visits and/or inadequate sampling. Specialized methods are required to address missingness and facilitate data analysis.We characterized the changes in cellular and humoral immune parameters over the first year of life in 66 HIV-infected infants (0-1 year of age enrolled in the CHER study starting therapy within 12 weeks of birth (n = 42 or upon disease progression (n = 24. A convenience cohort of 23 uninfected infants aged 0-6 months born to mothers with HIV-1 infection was used as controls. Flow cytometry and ELISA were used to evaluate changes in natural killer (NK cells, plasmacytoid dendritic cells (pDC, and CD4+ or CD8+ T-cell frequencies. Data missingness was assessed using Little's test. Complete datasets for analysis were created using Multiple Imputation (MI or Bayesian modeling and multivariate analysis was conducted on the imputed datasets.HIV-1-infected infants had greater frequency of CD4+ T cells with naïve phenotype, as well as higher serum IL-7 levels than HIV exposed/uninfected infants. The elevated data missingness was completely at random, allowing the use of both MI and Bayesian modeling. Both methods indicate that early ART initiation results in higher CD4+ T cell frequency, lower expression of CD95 in CD8+ T cell, and preservation of naïve T cell subsets. In contrast, innate immune effectors appeared to be similar independently of the timing of ART initiation.Early ART initiation in infants with perinatal HIV infection reduces immune activation and preserves an early expansion of naïve T-cells with undiminished innate cell numbers, giving greater immune reconstitution than achieved with deferred ART. Both

  10. Isoniazid-resistant Mycobacterium kansasii in an HIV-positive patient, and possible development of immune reconstitution inflammatory syndrome after initiation of highly active antiretroviral therapy: case report

    Directory of Open Access Journals (Sweden)

    A. Despotovic

    2016-01-01

    Full Text Available Non-tuberculous mycobacteria are rare but important causes of infection in HIV-positive individuals. A 28-year-old HIV-positive male presented with a high fever, non-productive cough, right subcostal pain, splenomegaly, a very low CD4 count, elevated C-reactive protein and erythrocyte sedimentation rate, and a normal white blood cell count. The suspicion of tuberculosis (TB was very high, and sputum samples were positive for acid-fast bacilli. Standard quadruple anti-TB therapy was initiated, but once culture of the sample revealed Mycobacterium kansasii, pyrazinamide was withdrawn. Highly active antiretroviral therapy (HAART was initiated soon after, consisting of abacavir/lamivudine and efavirenz. The patient's general condition deteriorated 2 weeks after HAART initiation, which could have been due to the development of immune reconstitution inflammatory syndrome (IRIS. The patient recovered and was discharged in good condition. However, the results of resistance testing of the isolated organism arrived after discharge, and showed isoniazid and streptomycin resistance. This is the first case report of M. kansasii infection from Serbia and shows the difficulties encountered during the course of treatment.

  11. Human neutrophils in auto-immunity.

    Science.gov (United States)

    Thieblemont, Nathalie; Wright, Helen L; Edwards, Steven W; Witko-Sarsat, Véronique

    2016-04-01

    Human neutrophils have great capacity to cause tissue damage in inflammatory diseases via their inappropriate activation to release reactive oxygen species (ROS), proteases and other tissue-damaging molecules. Furthermore, activated neutrophils can release a wide variety of cytokines and chemokines that can regulate almost every element of the immune system. In addition to these important immuno-regulatory processes, activated neutrophils can also release, expose or generate neoepitopes that have the potential to break immune tolerance and result in the generation of autoantibodies, that characterise a number of human auto-immune diseases. For example, in vasculitis, anti-neutrophil cytoplasmic antibodies (ANCA) that are directed against proteinase 3 or myeloperoxidase are neutrophil-derived autoantigens and activated neutrophils are the main effector cells of vascular damage. In other auto-immune diseases, these neutrophil-derived neoepitopes may arise from a number of processes that include release of granule enzymes and ROS, changes in the properties of components of their plasma membrane as a result of activation or apoptosis, and via the release of Neutrophil Extracellular Traps (NETs). NETs are extracellular structures that contain chromatin that is decorated with granule enzymes (including citrullinated proteins) that can act as neo-epitopes to generate auto-immunity. This review therefore describes the processes that can result in neutrophil-mediated auto-immunity, and the role of neutrophils in the molecular pathologies of auto-immune diseases such as vasculitis, rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). We discuss the potential role of NETs in these processes and some of the debate in the literature regarding the role of this phenomenon in microbial killing, cell death and auto-immunity. Copyright © 2016 Elsevier Ltd. All rights reserved.

  12. Partial reconstitution of humoral immunity and fewer infections in patients with chronic lymphocytic leukemia treated with ibrutinib.

    Science.gov (United States)

    Sun, Clare; Tian, Xin; Lee, Yuh Shan; Gunti, Sreenivasulu; Lipsky, Andrew; Herman, Sarah E M; Salem, Dalia; Stetler-Stevenson, Maryalice; Yuan, Constance; Kardava, Lela; Moir, Susan; Maric, Irina; Valdez, Janet; Soto, Susan; Marti, Gerald E; Farooqui, Mohammed Z; Notkins, Abner L; Wiestner, Adrian; Aue, Georg

    2015-11-05

    Chronic lymphocytic leukemia (CLL) is characterized by immune dysregulation, often including hypogammaglobulinemia, which contributes to a high rate of infections and morbidity. Ibrutinib, a covalent inhibitor of Bruton tyrosine kinase (BTK), inhibits B-cell receptor signaling and is an effective, US Food and Drug Administration (FDA)-approved treatment of CLL. Inactivating germline mutations in BTK cause a severe B-cell defect and agammaglobulinemia. Therefore, we assessed the impact of ibrutinib on immunoglobulin levels, normal B cells, and infection rate in patients with CLL treated with single-agent ibrutinib on a phase 2 investigator-initiated trial. Consistent with previous reports, immunoglobulin G (IgG) levels remained stable during the first 6 months on treatment, but decreased thereafter. In contrast, there were a transient increase in IgM and a sustained increase in IgA (median increase 45% at 12 months, P infections (P = .03). These data indicate that ibrutinib allows for a clinically meaningful recovery of humoral immune function in patients with CLL. This trial was registered at www.clinicaltrials.gov as #NCT015007330.

  13. Low-level viremia and proviral DNA impede immune reconstitution in HIV-1-infected patients receiving highly active antiretroviral therapy

    DEFF Research Database (Denmark)

    Ostrowski, Sisse R; Katzenstein, Terese L; Thim, Per T.

    2005-01-01

    Immunological and virological consequences of low-level viremia in human immunodeficiency virus (HIV) type 1-infected patients receiving highly active antiretroviral therapy (HAART) remain to be determined....

  14. 21 CFR 640.100 - Immune Globulin (Human).

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 7 2010-04-01 2010-04-01 false Immune Globulin (Human). 640.100 Section 640.100 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) BIOLOGICS ADDITIONAL STANDARDS FOR HUMAN BLOOD AND BLOOD PRODUCTS Immune Globulin (Human) § 640.100 Immune...

  15. Contribution of Human Lung Parenchyma and Leukocyte Influx to Oxidative Stress and Immune System-Mediated Pathology following Nipah Virus Infection.

    Science.gov (United States)

    Escaffre, Olivier; Saito, Tais B; Juelich, Terry L; Ikegami, Tetsuro; Smith, Jennifer K; Perez, David D; Atkins, Colm; Levine, Corri B; Huante, Matthew B; Nusbaum, Rebecca J; Endsley, Janice J; Freiberg, Alexander N; Rockx, Barry

    2017-08-01

    Nipah virus (NiV) is a zoonotic emerging paramyxovirus that can cause fatal respiratory illness or encephalitis in humans. Despite many efforts, the molecular mechanisms of NiV-induced acute lung injury (ALI) remain unclear. We previously showed that NiV replicates to high titers in human lung grafts in NOD-SCID/γ mice, resulting in a robust inflammatory response. Interestingly, these mice can undergo human immune system reconstitution by the bone marrow, liver, and thymus (BLT) reconstitution method, in addition to lung tissue engraftment, giving altogether a realistic model to study human respiratory viral infections. Here, we characterized NiV Bangladesh strain (NiV-B) infection of human lung grafts from human immune system-reconstituted mice in order to identify the overall effect of immune cells on NiV pathogenesis of the lung. We show that NiV-B replicated to high titers in human lung grafts and caused similar cytopathic effects irrespective of the presence of human leukocytes in mice. However, the human immune system interfered with virus spread across lung grafts, responded to infection by leukocyte migration to small airways and alveoli of the lung grafts, and accelerated oxidative stress in lung grafts. In addition, the presence of human leukocytes increased the expression of cytokines and chemokines that regulate inflammatory influx to sites of infection and tissue damage. These results advance our understanding of how the immune system limits NiV dissemination and contributes to ALI and inform efforts to identify therapeutic targets. IMPORTANCE Nipah virus (NiV) is an emerging paramyxovirus that can cause a lethal respiratory and neurological disease in humans. Only limited data are available on NiV pathogenesis in the human lung, and the relative contribution of the innate immune response and NiV to acute lung injury (ALI) is still unknown. Using human lung grafts in a human immune system-reconstituted mouse model, we showed that the NiV Bangladesh

  16. Síndrome inflamatória da reconstituição imunológica Immune reconstitution inflammatory syndrome

    Directory of Open Access Journals (Sweden)

    Sidney Roberto Nadal

    2009-03-01

    anogenitais, sarcoma de Kaposi, obstrução intestinal devida a histoplasmose disseminada e pancolite ulcerativa por CMV, levando a perfuração intestinal. A interação entre as equipes médicas deverá identificar a síndrome e definir o tratamento mais adequado para cada doente, evitando evoluções adversas.Highly active anti-retroviral therapy (HAART reduces HIV infection mortality and morbidity, modifying natural history of opportunistic and auto-immune diseases. However, in 10 to 25% of patients, the immune system restoration will provoke severe reaction against co-existent infections, causing diseases, by opportunistic agents, with atypical features, and intense tissue inflammation. All clinical and laboratorial changes resulting from this increased inflammatory response are called immune reconstitution inflammatory syndrome (IRIS. Paradoxical clinic worsening of a known disease or appearance of a new one, after beginning of HAART, characterize this syndrome. Potential mechanisms include partial immune reconstitution or host increased immune response to the antigenic stimulus. There are two main forms: an earlier that arises up to the third month after HAART, due to immune reaction against opportunistic agents that remained in a sub-clinic disease; and other later that emerges after months or years as an immune reaction evolution against opportunistic agents whose manifestations were unexpected. This syndrome occurs mainly in those with less than 50/mm³ T CD4 and very high HIV viral load before HAART, as so non-detected antigens from micro-organisms whose clinical manifestations were unexpected. Most diseases are dermatological, mainly, genital herpes and warts. However, among those infected with Mycobacterium tuberculosis, Mycobacterium avium complex or Cryptococcus neoformans, the syndrome affects up to 45% of patients. For the sake of the Proctologist, we could mention cases of herpes simplex, herpes zoster, contagious moluscus, condylomata acuminata, Kaposi

  17. The radiology of IRIS (immune reconstitution inflammatory syndrome) in patients with mycobacterial tuberculosis and HIV co-infection: appearances in 11 patients

    International Nuclear Information System (INIS)

    Rajeswaran, G.; Becker, J.L.; Michailidis, C.; Pozniak, A.L.; Padley, S.P.G.

    2006-01-01

    Aim: To determine the radiological manifestations of IRIS (immune reconstitution inflammatory syndrome) in patients with HIV and mycobacterium tuberculosis co-infection, in the context of their demographic and clinical data. Materials and methods: The radiological imaging, demographic and clinical data of 11 patients diagnosed with IRIS associated with HIV and mycobacterial tuberculosis co-infection were studied retrospectively. Where available, follow-up imaging studies were also reviewed. Results: The most common radiological feature of IRIS was lymph node enlargement (73%), with central low attenuation centres, in keeping with necrosis, present in most of these cases (88%). Most commonly affected were intra-abdominal nodes (70%), followed by axillary (40%) and mediastinal lymph nodes (36%). Within the lung parenchyma, diffuse, bilateral pulmonary nodules were seen in 55% of cases. Unilateral small volume pleural effusions were seen in two cases with associated parenchymal changes seen in only one. Small volume ascites was seen in two cases. Thirty-six percent of cases presented with new or worsening abscesses despite treatment. In this context, image-guided radiological drainage proved a useful adjunct to the conventional medical therapy for IRIS. The most common clinical signs of IRIS included fever (64%), abdominal pain (36%) and cough (27%). Conclusion: We have described the radiological features that are characteristic in IRIS and the importance of putting these into context with the clinical and pathological findings as part of a multidisciplinary approach in making the diagnosis. The role of the radiologist is central in diagnosis, monitoring of disease progression and management of complications in patients with IRIS

  18. The Effects of Low Dose Irradiation on Inflammatory Response Proteins in a 3D Reconstituted Human Skin Tissue Model

    Energy Technology Data Exchange (ETDEWEB)

    Varnum, Susan M.; Springer, David L.; Chaffee, Mary E.; Lien, Katie A.; Webb-Robertson, Bobbie-Jo M.; Waters, Katrina M.; Sacksteder, Colette A.

    2012-12-01

    Skin responses to moderate and high doses of ionizing radiation include the induction of DNA repair, apoptosis, and stress response pathways. Additionally, numerous studies indicate that radiation exposure leads to inflammatory responses in skin cells and tissue. However, the inflammatory response of skin tissue to low dose radiation (<10 cGy) is poorly understood. In order to address this, we have utilized a reconstituted human skin tissue model (MatTek EpiDerm FT) and assessed changes in 23 cytokines twenty-four and forty eight hours following treatment of skin with either 3 or 10 cGy low-dose of radiation. Three cytokines, IFN-γ, IL-2, MIP-1α, were significantly altered in response to low dose radiation. In contrast, seven cytokines were significantly altered in response to a high radiation dose of 200 cGy (IL-2, IL-10, IL-13, IFN-γ, MIP-1α, TNF α, and VEGF) or the tumor promoter 12-O-tetradecanoylphorbol 13-acetate (G-CSF, GM-CSF, IL-1α, IL-8, MIP-1α, MIP-1β, RANTES). Additionally, radiation induced inflammation appears to have a distinct cytokine response relative to the non-radiation induced stressor, TPA. Overall, these results indicate that there are subtle changes in the inflammatory protein levels following exposure to low dose radiation and this response is a sub-set of what is seen following a high dose in a human skin tissue model.

  19. Immune Defence Factors In Human Milk

    Directory of Open Access Journals (Sweden)

    Kumar Sanjeev

    1985-01-01

    Full Text Available Scientific evidence is accumulating to prove the nutritional, anti-infective, anti-fertility, psychosomal and economic advantages of breast-feeding. A number of studies have shown that breast milk protects against diarrheal, respiratory and other infections. Its value in protecting against allergy has also been established. This article reviews the studies on various immune defence factors present in the human milk. The available scientific knowledge makes a very strong case in favour of promoting breast-feeding.

  20. Aged Garlic Extract Modifies Human Immunity.

    Science.gov (United States)

    Percival, Susan S

    2016-02-01

    Garlic contains numerous compounds that have the potential to influence immunity. Immune cells, especially innate immune cells, are responsible for the inflammation necessary to kill pathogens. Two innate lymphocytes, γδ-T and natural killer (NK) cells, appear to be susceptible to diet modification. The purpose of this review was to summarize the influence of aged garlic extract (AGE) on the immune system. The author's laboratory is interested in AGE's effects on cell proliferation and activation and inflammation and to learn whether those changes might affect the occurrence and severity of colds and flu. Healthy human participants (n = 120), between 21 and 50 y of age, were recruited for a randomized, double-blind, placebo-controlled parallel-intervention study to consume 2.56 g AGE/d or placebo supplements for 90 d during the cold and flu season. Peripheral blood mononuclear cells were isolated before and after consumption, and γδ-T and NK cell function was assessed by flow cytometry. The effect on cold and flu symptoms was determined by using daily diary records of self-reported illnesses. After 45 d of AGE consumption, γδ-T and NK cells proliferated better and were more activated than cells from the placebo group. After 90 d, although the number of illnesses was not significantly different, the AGE group showed reduced cold and flu severity, with a reduction in the number of symptoms, the number of days participants functioned suboptimally, and the number of work/school days missed. These results suggest that AGE supplementation may enhance immune cell function and may be partly responsible for the reduced severity of colds and flu reported. The results also suggest that the immune system functions well with AGE supplementation, perhaps with less accompanying inflammation. This trial was registered at clinicaltrials.gov as NCT01390116. © 2016 American Society for Nutrition.

  1. Increasing Hematopoietic Stem Cell Yield to Develop Mice with Human Immune Systems

    Directory of Open Access Journals (Sweden)

    Juan-Carlos Biancotti

    2013-01-01

    Full Text Available Hematopoietic stem cells (HSCs are unique in their capacity to give rise to all mature cells of the immune system. For years, HSC transplantation has been used for treatment of genetic and neoplastic diseases of the hematopoietic and immune systems. The sourcing of HSCs from human umbilical cord blood has salient advantages over isolation from mobilized peripheral blood. However, poor sample yield has prompted development of methodologies to expand HSCs ex vivo. Cytokines, trophic factors, and small molecules have been variously used to promote survival and proliferation of HSCs in culture, whilst strategies to lower the concentration of inhibitors in the culture media have recently been applied to promote HSC expansion. In this paper, we outline strategies to expand HSCs in vitro, and to improve engraftment and reconstitution of human immune systems in immunocompromised mice. To the extent that these “humanized” mice are representative of the endogenous human immune system, they will be invaluable tools for both basic science and translational medicine.

  2. Immunoaffinity purification and reconstitution of the human bilirubin/phenol UDP-glucuronosyltransferase family

    NARCIS (Netherlands)

    Seppen, J.; Jansen, P. L.; Oude Elferink, R. P.

    1995-01-01

    When membrane proteins are solubilized and subjected to purification procedures, the loss of lipids surrounding the protein often results in irreversible inactivation. We describe a procedure for the immunoaffinity purification of the membrane protein UDP-glucuronosyltransferase from human liver.

  3. IMMUNOAFFINITY PURIFICATION AND RECONSTITUTION OF THE HUMAN BILIRUBIN PHENOL UDP-GLUCURONOSYLTRANSFERASE FAMILY

    NARCIS (Netherlands)

    SEPPEN, J; JANSEN, PLM; ELFERINK, RPJO

    When membrane proteins are solubilized and subjected to purification procedures, the loss of lipids surrounding the protein often results in irreversible inactivation. We describe a procedure for the immunoaffinity purification of the membrane protein UDP-glucuronosyltransferase from human liver.

  4. Production of Conjugated Linoleic and Conjugated α-Linolenic Acid in a Reconstituted Skim Milk-Based Medium by Bifidobacterial Strains Isolated from Human Breast Milk

    Directory of Open Access Journals (Sweden)

    María Antonia Villar-Tajadura

    2014-01-01

    Full Text Available Eight bifidobacterial strains isolated from human breast milk have been tested for their abilities to convert linoleic acid (LA and α-linolenic acid (LNA to conjugated linoleic acid (CLA and conjugated α-linolenic acid (CLNA, respectively. These bioactive lipids display important properties that may contribute to the maintenance and improvement human health. Three selected Bifidobacterium breve strains produced CLA from LA and CLNA from LNA in MRS (160–170 and 210–230 μg mL−1, resp. and, also, in reconstituted skim milk (75–95 and 210–244 μg mL−1, resp.. These bifidobacterial strains were also able to simultaneously produce both CLA (90–105 μg mL−1 and CLNA (290–320 μg mL−1 in reconstituted skim milk. Globally, our findings suggest that these bifidobacterial strains are potential candidates for the design of new fermented dairy products naturally containing very high concentrations of these bioactive lipids. To our knowledge, this is the first study describing CLNA production and coproduction of CLA and CLNA by Bifidobacterium breve strains isolated from human milk in reconstituted skim milk.

  5. Reconstitution activity of hypoxic cultured human cord blood CD34-positive cells in NOG mice

    International Nuclear Information System (INIS)

    Shima, Haruko; Takubo, Keiyo; Iwasaki, Hiroko; Yoshihara, Hiroki; Gomei, Yumiko; Hosokawa, Kentaro; Arai, Fumio; Takahashi, Takao; Suda, Toshio

    2009-01-01

    Hematopoietic stem cells (HSCs) reside in hypoxic areas of the bone marrow. However, the role of hypoxia in the maintenance of HSCs has not been fully characterized. We performed xenotransplantation of human cord blood cells cultured in hypoxic or normoxic conditions into adult NOD/SCID/IL-2Rγ null (NOG) mice. Hypoxic culture (1% O 2 ) for 6 days efficiently supported the maintenance of HSCs, although cell proliferation was suppressed compared to the normoxic culture. In contrast, hypoxia did not affect in vitro colony-forming ability. Upregulation of a cell cycle inhibitor, p21, was observed in hypoxic culture. Immunohistochemical analysis of recipient bone marrow revealed that engrafted CD34 + CD38 - cord blood HSCs were hypoxic. Taken together, these results demonstrate the significance of hypoxia in the maintenance of quiescent human cord blood HSCs.

  6. Redox proteomic evaluation of oxidative modification and recovery in a 3D reconstituted human skin tissue model exposed to UVB.

    Science.gov (United States)

    Dyer, J M; Haines, S R; Thomas, A; Wang, W; Walls, R J; Clerens, S; Harland, D P

    2017-04-01

    Exposure to UV in humans resulting in sunburn triggers a complex series of events that are a mix of immediate and delayed damage mediation and healing. While studies on the effects of UV exposure on DNA damage and repair have been reported, changes in the oxidative modification of skin proteins are poorly understood at the molecular level, despite the important role played by structural proteins in skin tissue, and the effect of the integrity of these proteins on skin appearance and health. Proteomic molecular mapping of oxidation was here applied to try to enhance understanding of skin damage and recovery from oxidative damage and UVB exposure. A redox proteomic-based approach was applied to evaluating skin protein modification when exposed to varying doses of UVB after initial oxidative stress, via tracking changes in protein oxidation during the healing process in vitro using a full-thickness reconstituted human skin tissue model. Bioassays and structural evaluation confirmed that our cultured skin tissues underwent a normal physiological response to UVB exposure. A set of potential skin marker peptides was generated, for use in tracking skin protein oxidative modification. Exposure to UVB after thermal oxidative stress was found to result in higher levels of skin protein oxidation than a non-irradiated control for up to seven days after exposure. Recovery of the skin proteins from oxidative stress, as assessed by the overall protein oxidation levels, was found to be impaired by UVB exposure. Oxidative modification was largely observed in skin structural proteins. Exposure of skin proteins to UVB exacerbates oxidative damage to structural skin proteins, with higher exposure levels leading to increasingly impaired recovery from this damage. This has potential implications for the functional performance of the proteins and inter-related skin health and cosmetic appearance. © 2016 Society of Cosmetic Scientists and the Société Française de Cosmétologie.

  7. [Human milk, immune responses and health effects].

    Science.gov (United States)

    Løland, Beate Fossum; Baerug, Anne B; Nylander, Gro

    2007-09-20

    Besides providing optimal nutrition to infants, human milk contains a multitude of immunological components. These components are important for protection against infections and also support the development and maturation of the infant's own immune system. This review focuses on the function of some classical immunocomponents of human milk. Relevant studies are presented that describe health benefits of human milk for the child and of lactation for the mother. Relevant articles were found mainly by searching PubMed. Humoral and cellular components of human milk confer protection against infections in the respiratory--, gastrointestinal--and urinary tract. Human milk also protects premature children from neonatal sepsis and necrotizing enterocolitis. There is evidence that human milk may confer long-term benefits such as lower risk of certain autoimmune diseases, inflammatory bowel disease and probably some malignancies. Human milk possibly affects components of the metabolic syndrome. Recent studies demonstrate long-term health benefits of lactation also for the mother. A reduced incidence of breast cancer is best documented. An increasing number of studies indicate protection against ovarian cancer, rheumatoid arthritis and type II diabetes.

  8. Recent advances in immunity to human schistosomiasis

    Directory of Open Access Journals (Sweden)

    Paul Hagan

    1992-01-01

    Full Text Available For many years the epidemiological significance of immunity in human schistosomiasis has been the subject of inconclusive debate. Recently, the results of studies from Brazil and Kenya, on Shistosoma mansoni and from Zimbabwe and The Gambia on S. haematobium have confirmed the importance of protective immunity. In communities in endemic areas the development of immunity to infection only occurs after many years of exposure. In part this due to the slow development of antibodies wich are protective but also to the earlier development of antibody isotypes which lack protective capacity and wich are capable of interfering with the functioning of protective antibodies. Protective antibodies appear to be of the IgE class but some IgG subclasses may be also be important. Initially, blocking antibodies were thought to be predominantly IgM and IgG2 but IgG4 also seems to posses blocking activity. The early production of blocking antibodies and late production of protective antibodies may be indicative of cytokine induced immunoglobulin class swiching caused by the sequential involvment of different lymphokines.

  9. Development of immune organs and functioning in humans and test animals: Implications for immune intervention studies.

    Science.gov (United States)

    Kuper, C Frieke; van Bilsen, Jolanda; Cnossen, Hilde; Houben, Geert; Garthoff, Jossie; Wolterbeek, Andre

    2016-09-01

    A healthy immune status is mostly determined during early life stages and many immune-related diseases may find their origin in utero and the first years of life. Therefore, immune health optimization may be most effective during early life. This review is an inventory of immune organ maturation events in relation to developmental timeframes in minipig, rat, mouse and human. It is concluded that time windows of immune organ development in rodents can be translated to human, but minipig reflects the human timeframes better; however the lack of prenatal maternal-fetal immune interaction in minipig may cause less responsiveness to prenatal intervention. It is too early to conclude which immune parameters are most appropriate, because there are not enough comparative immune parameters. Filling these gaps will increase the predictability of results observed in experimental animals, and guide future intervention studies by assessing relevant parameters in the right corresponding developmental time frames. Copyright © 2016 Elsevier Inc. All rights reserved.

  10. Secretion of interferon gamma from human immune cells is altered by exposure to tributyltin and dibutyltin.

    Science.gov (United States)

    Lawrence, Shanieek; Reid, Jacqueline; Whalen, Margaret

    2015-05-01

    Tributyltin (TBT) and dibutyltin (DBT) are widespread environmental contaminants found in food, beverages, and human blood samples. Both of these butyltins (BTs) interfere with the ability of human natural killer (NK) cells to lyse target cells and alter secretion of the pro-inflammatory cytokine tumor necrosis factor alpha (TNFα) from human immune cells in vitro. The capacity of BTs to interfere with secretion of other pro-inflammatory cytokines has not been examined. Interferon gamma (IFNγ) is a modulator of adaptive and innate immune responses, playing an important role in overall immune competence. This study shows that both TBT and DBT alter secretion of IFNγ from human immune cells. Peripheral blood cell preparations that were increasingly reconstituted were used to determine if exposures to either TBT or DBT affected IFNγ secretion and how the makeup of the cell preparation influenced that effect. IFNγ secretion was examined after 24 h, 48 h, and 6 day exposures to TBT (200 - 2.5 nM) and DBT (5 - 0.05 µM) in highly enriched human NK cells, a monocyte-depleted preparation of PBMCs, and monocyte-containing PBMCs. Both BTs altered IFNγ secretion from immune cells at most of the conditions tested (either increasing or decreasing secretion). However, there was significant variability among donors as to the concentrations and time points that showed changes as well as the baseline secretion of IFNγ. The majority of donors showed an increase in IFNγ secretion in response to at least one concentration of TBT or DBT at a minimum of one length of exposure. © 2013 Wiley Periodicals, Inc.

  11. Tissue Pharmacologic and Virologic Determinants of Duodenal and Rectal Gastrointestinal-Associated Lymphoid Tissue Immune Reconstitution in HIV-Infected Patients Initiating Antiretroviral Therapy.

    Science.gov (United States)

    Asmuth, David M; Thompson, Corbin G; Chun, Tae-Wook; Ma, Zhong-Min; Mann, Surinder; Sainz, Talia; Serrano-Villar, Sergio; Utay, Netanya S; Garcia, Juan Carlos; Troia-Cancio, Paolo; Pollard, Richard B; Miller, Christopher J; Landay, Alan; Kashuba, Angela D

    2017-10-17

    Plasma, duodenal, and rectal tissue antiretroviral therapy (ART) drug concentrations, human immunodeficiency virus (HIV) RNA and HIV DNA copy numbers, and recovery of mucosal immunity were measured before and 9 months after initiation of 3 different ART regimens in 26 subjects. Plasma and tissue HIV RNA correlated at baseline and when 9-month declines were compared, suggesting that these compartments are tightly associated. Antiretroviral tissue:blood penetration ratios were above the 50% inhibitory concentration values in almost 100% of cases. There were no correlations between drug concentrations and HIV DNA/RNA. Importantly, no evidence was found for residual viral replication or deficient tissue drug penetration to account for delayed gastrointestinal-associated lymphoid tissue immune recovery. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

  12. Toward The Reconstitution of the Maturation of Okazaki Fragments Multiprotein Complex in Human At The Single Molecule Level

    KAUST Repository

    Joudeh, Luay

    2017-04-01

    The maturation of Okazaki fragments on the lagging strand in eukaryotes is mediated by a highly coordinated multistep process involving several proteins that ensure the accurate and efficient replication of genomic DNA. Human proliferating cell nuclear antigen (PCNA) that slides on double-stranded DNA is the key player that coordinates the access of various proteins to the different intermediary steps in this process. In this study, I am focusing on characterizing how PCNA recruits and stimulates the structure specific flap endonuclease 1 (FEN1) to process the aberrant double flap (DF) structures that are produced during maturation of Okazaki fragments. FEN1 distorts the DF structures into a bent conformer to place the scissile phosphate into the active site for cleavage. The product is a nick substrate that can be sealed by DNA ligase I whose recruitment is also mediated by its interaction with PCNA. Using single-molecule Förster resonance energy transfer (smFRET) measurements that simultaneously monitored bending and cleavage of various DF substrates by FEN1 alone or in the presence of PCNA, we found that FEN1 and PCNA bends cognate and non-cognate substrates but display remarkable selectivity to stabilize the bent conformer in cognate substrate while promoting the dissociation of non-cognate substrates. This mechanism provides efficiency and accuracy for FEN1 and PCNA to cleave the correct substrate while avoiding the deleterious cleavage of incorrect substrates. This work provides a true molecular level understanding of the key step during the maturation of Okazaki fragment and contributes towards the reconstitution of its entire activity at the single molecule level.

  13. Human IgG repertoire of malaria antigen-immunized human immune system (HIS) mice.

    Science.gov (United States)

    Nogueira, Raquel Tayar; Sahi, Vincent; Huang, Jing; Tsuji, Moriya

    2017-08-01

    Humanized mouse models present an important tool for preclinical evaluation of new vaccines and therapeutics. Here we show the human variable repertoire of antibody sequences cloned from a previously described human immune system (HIS) mouse model that possesses functional human CD4+ T cells and B cells, namely HIS-CD4/B mice. We sequenced variable IgG genes from single memory B-cell and plasma-cell sorted from splenocytes or whole blood lymphocytes of HIS-CD4/B mice that were vaccinated with a human plasmodial antigen, a recombinant Plasmodium falciparum circumsporozoite protein (rPfCSP). We demonstrate that rPfCSP immunization triggers a diverse B-cell IgG repertoire composed of various human VH family genes and distinct V(D)J recombinations that constitute diverse CDR3 sequences similar to humans, although low hypermutated sequences were generated. These results demonstrate the substantial genetic diversity of responding human B cells of HIS-CD4/B mice and their capacity to mount human IgG class-switched antibody response upon vaccination. Copyright © 2017 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

  14. 21 CFR 640.102 - Manufacture of Immune Globulin (Human).

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 7 2010-04-01 2010-04-01 false Manufacture of Immune Globulin (Human). 640.102 Section 640.102 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES....102 Manufacture of Immune Globulin (Human). (a) Processing method. The processing method shall be one...

  15. Sex hormones and the immune response in humans

    NARCIS (Netherlands)

    Bouman, Annechien; Heineman, Maas Jan; Faas, Marijke M.

    2005-01-01

    In addition to their effects on sexual differentiation and reproduction, sex hormones appear to influence the immune system. This results in a sexual dimorphism in the immune response in humans: for instance, females produce more vigorous cellular and more vigorous humoral immune reactions, are more

  16. Intermittent viraemia and immune reconstitution in patients with more than 10–15 years of antiretroviral therapy: baseline values still matter

    Science.gov (United States)

    Erdbeer, Gesa; Sabranski, Michael; Sonntag, Ina; Stoehr, Albrecht; Horst, Heinz-A; Plettenberg, Andreas; Schewe, Knud; Unger, Stefan; Stellbrink, Hans-J; Fenske, Stefan; Hoffmann, Christian

    2014-01-01

    Introduction Data on patients with long-term exposure to ART is scarce because controlled studies usually do not follow up patients for more than five to seven years. We were interested whether baseline parameters such as CD4 T-cell nadir or pre-treatment viraemia do have an impact on ART success after more than a decade of treatment. Methods ELBE is a cross-sectional study on adult HIV+ patients presenting consecutively with viral suppression (<50 HIV RNA copies/mL) and with ART exposure of at least five years. In this sub-analysis, all patients with more than 10 years of ART exposure were evaluated for immune reconstitution and for intermittent transient viraemia (50–1000 copies/mL, defined as “blips”) during the last five years. Results From a total of 894 patients included in the three participating ELBE centres, 524 patients had an ART exposure of at least 10 years and had been treated continuously during the last 5 years. Of these, 33.4% had at least one “blip” while 63.5% did not show any transient viraemia of more than 50 copies/mL. Patients with at least one blip had a higher pre-treatment viraemia compared to patients without blips (5.30 versus 5.06 log copies/mL, p=0.0003). In patients with a pre-treatment viraemia of more than 100,000, 50,000–100,000 and less than 50,000 copies/mL, the proportions of patients with blips during the last five years were 39.5%, 30.5% and 21.8% (p=0.007), respectively. The history of an AIDS-defining illness or the CD4 T-cell nadir was not associated with a higher frequency of blips. However, CD4 T-cell nadir was a strong predictor for current CD4 T-cell counts. In patient groups with a CD4 T-cell nadir of 0–99, 100–199, 200–349, 350+ cells/µL, the median current CD4 T cells were 571, 667, 710 and 890 cells/µL, respectively. These differences remained significant when the analysis was restricted to patients with more than 15 years of ART exposure (n=268). Conclusions In this large group of positively

  17. Innate immune defences in the human endometrium

    Directory of Open Access Journals (Sweden)

    Kelly Rodney W

    2003-11-01

    Full Text Available Abstract The human endometrium is an important site of innate immune defence, giving protection against uterine infection. Such protection is critical to successful implantation and pregnancy. Infection is a major cause of preterm birth and can also cause infertility and ectopic pregnancy. Natural anti-microbial peptides are key mediators of the innate immune system. These peptides, between them, have anti-bacterial, anti-fungal and anti-viral activity and are expressed at epithelial surfaces throughout the female genital tract. Two families of natural anti-microbials, the defensins and the whey acidic protein (WAP motif proteins, appear to be prominent in endometrium. The human endometrial epithelium expresses beta-defensins 1–4 and the WAP motif protein, secretory leukocyte protease inhibitor. Each beta-defensin has a different expression profile in relation to the stage of the menstrual cycle, providing potential protection throughout the cycle. Secretory leukocyte protease inhibitor is expressed during the secretory phase of the cycle and has a range of possible roles including anti-protease and anti-microbial activity as well as having effects on epithelial cell growth. The leukocyte populations in the endometrium are also a source of anti-microbial production. Neutrophils are a particularly rich source of alpha-defensins, lactoferrin, lysozyme and the WAP motif protein, elafin. The presence of neutrophils during menstruation will enhance anti-microbial protection at a time when the epithelial barrier is disrupted. Several other anti-microbials including the natural killer cell product, granulysin, are likely to have a role in endometrium. The sequential production of natural anti-microbial peptides by the endometrium throughout the menstrual cycle and at other sites in the female genital tract will offer protection from many pathogens, including those that are sexually transmitted.

  18. Tributyltin alters secretion of interleukin 1 beta from human immune cells.

    Science.gov (United States)

    Brown, Shyretha; Whalen, Margaret

    2015-08-01

    Tributyltin (TBT) has been used as a biocide in industrial applications such as wood preservation, antifouling paint and antifungal agents. Owing to its many uses, it contaminates the environment and has been found in human blood samples. Interleukin-1 beta (IL-1β) is a pro-inflammatory cytokine that promotes cell growth, tissue repair and immune response regulation. Produced predominately by both monocytes and macrophages, IL-1β appears to increase the invasiveness of certain tumors. This study shows that TBT modifies the secretion of IL-1β from increasingly reconstituted preparations of human immune cells. IL-1β secretion was examined after 24-, 48-h or 6-day exposures to TBT in highly enriched human natural killer (NK) cells, monocyte-depleted peripheral blood mononuclear cells (MD-PBMCs), PBMCs, granulocytes and a preparation combining both PBMCs and granulocytes (PBMCs+granulocytes). TBT altered IL-1β secretion from all of the cell preparations. The 200 nM concentration of TBT normally blocked the secretion of IL-1β, whereas lower concentrations (usually 5-50 nM) elevated secretion of IL-1β. Examination of the signaling pathway(s) responsible for the elevated secretion of IL-1β was carried out in MD-PBMCs. Pathways examined were IL-1β processing (Caspase-1), mitogen-activated protein kinases (MAPKs) and nuclear factor kappa B (NFκB). Results indicated that MAPK pathways (p44/42 and p38) appear to be the targets of TBT that lead to increased IL-1β secretion from immune cells. These results from human immune cells show IL-1β dysregulation by TBT is occurring ex vivo. Thus, the potential for in vivo effects on pro-inflammatory cytokine levels may possibly be a consequence of TBT exposures. Copyright © 2014 John Wiley & Sons, Ltd.

  19. 6. THE ROLE OF SELENIUM IN HUMAN IMMUNITY

    African Journals Online (AJOL)

    Esem

    lymphocyte (CD3+) immune response was enhanced in persons that ... Selenium and Disease Conditions ... In China, Keshan and Kashin-Beck diseases are human. 21,22,23 ... and cytotoxic cell activities that act against the HIV virus.

  20. Evasion of host immune defenses by human papillomavirus.

    Science.gov (United States)

    Westrich, Joseph A; Warren, Cody J; Pyeon, Dohun

    2017-03-02

    A majority of human papillomavirus (HPV) infections are asymptomatic and self-resolving in the absence of medical interventions. Various innate and adaptive immune responses, as well as physical barriers, have been implicated in controlling early HPV infections. However, if HPV overcomes these host immune defenses and establishes persistence in basal keratinocytes, it becomes very difficult for the host to eliminate the infection. The HPV oncoproteins E5, E6, and E7 are important in regulating host immune responses. These oncoproteins dysregulate gene expression, protein-protein interactions, posttranslational modifications, and cellular trafficking of critical host immune modulators. In addition to the HPV oncoproteins, sequence variation and dinucleotide depletion in papillomavirus genomes has been suggested as an alternative strategy for evasion of host immune defenses. Since anti-HPV host immune responses are also considered to be important for antitumor immunity, immune dysregulation by HPV during virus persistence may contribute to immune suppression essential for HPV-associated cancer progression. Here, we discuss cellular pathways dysregulated by HPV that allow the virus to evade various host immune defenses. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  1. Development and function of human innate immune cells in a humanized mouse model.

    Science.gov (United States)

    Rongvaux, Anthony; Willinger, Tim; Martinek, Jan; Strowig, Till; Gearty, Sofia V; Teichmann, Lino L; Saito, Yasuyuki; Marches, Florentina; Halene, Stephanie; Palucka, A Karolina; Manz, Markus G; Flavell, Richard A

    2014-04-01

    Mice repopulated with human hematopoietic cells are a powerful tool for the study of human hematopoiesis and immune function in vivo. However, existing humanized mouse models cannot support development of human innate immune cells, including myeloid cells and natural killer (NK) cells. Here we describe two mouse strains called MITRG and MISTRG, in which human versions of four genes encoding cytokines important for innate immune cell development are knocked into their respective mouse loci. The human cytokines support the development and function of monocytes, macrophages and NK cells derived from human fetal liver or adult CD34(+) progenitor cells injected into the mice. Human macrophages infiltrated a human tumor xenograft in MITRG and MISTRG mice in a manner resembling that observed in tumors obtained from human patients. This humanized mouse model may be used to model the human immune system in scenarios of health and pathology, and may enable evaluation of therapeutic candidates in an in vivo setting relevant to human physiology.

  2. Innate immune functions of microglia isolated from human glioma patients

    Directory of Open Access Journals (Sweden)

    Grimm Elizabeth

    2006-03-01

    Full Text Available Abstract Background Innate immunity is considered the first line of host defense and microglia presumably play a critical role in mediating potent innate immune responses to traumatic and infectious challenges in the human brain. Fundamental impairments of the adaptive immune system in glioma patients have been investigated; however, it is unknown whether microglia are capable of innate immunity and subsequent adaptive anti-tumor immune responses within the immunosuppressive tumor micro-environment of human glioma patients. We therefore undertook a novel characterization of the innate immune phenotype and function of freshly isolated human glioma-infiltrating microglia (GIM. Methods GIM were isolated by sequential Percoll purification from patient tumors immediately after surgical resection. Flow cytometry, phagocytosis and tumor cytotoxicity assays were used to analyze the phenotype and function of these cells. Results GIM expressed significant levels of Toll-like receptors (TLRs, however they do not secrete any of the cytokines (IL-1β, IL-6, TNF-α critical in developing effective innate immune responses. Similar to innate macrophage functions, GIM can mediate phagocytosis and non-MHC restricted cytotoxicity. However, they were statistically less able to mediate tumor cytotoxicity compared to microglia isolated from normal brain. In addition, the expression of Fas ligand (FasL was low to absent, indicating that apoptosis of the incoming lymphocyte population may not be a predominant mode of immunosuppression by microglia. Conclusion We show for the first time that despite the immunosuppressive environment of human gliomas, GIM are capable of innate immune responses such as phagocytosis, cytotoxicity and TLR expression but yet are not competent in secreting key cytokines. Further understanding of these innate immune functions could play a critical role in understanding and developing effective immunotherapies to malignant human gliomas.

  3. Estimation of the in vitro eye irritating and inflammatory potential of lipopolysaccharide (LPS) and dust by using reconstituted human corneal epithelium tissue cultures

    DEFF Research Database (Denmark)

    Cao, Yi; Arenholt-Bindslev, Dorthe; Kjærgaard, Søren K

    2015-01-01

    CONTEXT: Eye irritation is a common complaint in indoor environment, but the causes have still not been identified among the multiple exposures in house environments. To identify the potential environmental factors responsible for eye irritation and study the possible mechanisms, an in vitro model...... AND CONCLUSION: LPS and dust showed in vitro eye irritating and inflammatory potential, and cytokines/chemokines like IL-1β and IL-8 may be involved in the mechanisms of eye irritation. The HCE tissue culture may be used as an in vitro model to study environmental exposure induced eye irritation and inflammation....... for eye irritation is suggested. MATERIALS AND METHODS: In this study, reconstituted human corneal epithelium (HCE) tissue cultures were used to study the eye irritating and inflammatory potential of lipopolysaccharide (LPS) and dust. HCE tissue cultures were exposed to a range of concentrations of LPS...

  4. Differential Secondary Reconstitution of In Vivo-Selected Human SCID-Repopulating Cells in NOD/SCID versus NOD/SCID/γ chainnull Mice

    Directory of Open Access Journals (Sweden)

    Shanbao Cai

    2011-01-01

    Full Text Available Humanized bone-marrow xenograft models that can monitor the long-term impact of gene-therapy strategies will help facilitate evaluation of clinical utility. The ability of the murine bone-marrow microenvironment in NOD/SCID versus NOD/SCID/γ chainnull mice to support long-term engraftment of MGMTP140K-transduced human-hematopoietic cells following alkylator-mediated in vivo selection was investigated. Mice were transplanted with MGMTP140K-transduced CD34+ cells and transduced cells selected in vivo. At 4 months after transplantation, levels of human-cell engraftment, and MGMTP140K-transduced cells in the bone marrow of NOD/SCID versus NSG mice varied slightly in vehicle- and drug-treated mice. In secondary transplants, although equal numbers of MGMTP140K-transduced human cells were transplanted, engraftment was significantly higher in NOD/SCID/γ chainnull mice compared to NOD/SCID mice at 2 months after transplantation. These data indicate that reconstitution of NOD/SCID/γ chainnull mice with human-hematopoietic cells represents a more promising model in which to test for genotoxicity and efficacy of strategies that focus on manipulation of long-term repopulating cells of human origin.

  5. Human Immune Response to Dengue Infections

    Science.gov (United States)

    1991-06-30

    had been immunized with yellow fever vaccine and later became infected with dengue 3 virus, responded best to dengue 3 antigen but also responded to...effective dengue virus subunit vaccines . We found evidence of marked T cell activation in patients with DHF. T cell activation in patients with DF was similar...Treatment and Control of Dengue Hemorrhagic Fever. World Health Organization, Geneva, Switzerland 7. Sabin AB (1952) Research on dengue during World

  6. Effects of ultraviolet radiation on the immune system in humans

    International Nuclear Information System (INIS)

    Morison, W.L.

    1989-01-01

    In experimental animals, exposure to UV-B radiation produces selective alterations of immune function which are mainly in the form of suppression of normal immune responses. This immune suppression is important in the development of nonmelanoma skin cancer, may influence the development and course of infectious disease and possibly protects against autoimmune reactions. The evidence that this form of immune suppression occurs in humans is less compelling and very incomplete. The wavelengths of radiation most affected by a depletion of the stratospheric ozone layer are those known to be most immunosuppressive in animals and it is likely that such depletion will increase any suppressive effect of sunlight on immunity in humans. In addition to establishing whether or not UV-B radiation can cause suppression of immune function in humans, studies are required to determine if melanin can provide protection against such suppression, the role of this suppression in the pathogenesis of skin cancer, the development of infectious disease and vaccine effectiveness, and the capacity for humans to develop adaptive, protective mechanisms which may limit damage from continued exposure to UV-B radiation. (author)

  7. Human immune system mouse models of Ebola virus infection.

    Science.gov (United States)

    Spengler, Jessica R; Prescott, Joseph; Feldmann, Heinz; Spiropoulou, Christina F

    2017-08-01

    Human immune system (HIS) mice, immunodeficient mice engrafted with human cells (with or without donor-matched tissue), offer a unique opportunity to study pathogens that cause disease predominantly or exclusively in humans. Several HIS mouse models have recently been used to study Ebola virus (EBOV) infection and disease. The results of these studies are encouraging and support further development and use of these models in Ebola research. HIS mice provide a small animal model to study EBOV isolates, investigate early viral interactions with human immune cells, screen vaccines and therapeutics that modulate the immune system, and investigate sequelae in survivors. Here we review existing models, discuss their use in pathogenesis studies and therapeutic screening, and highlight considerations for study design and analysis. Finally, we point out caveats to current models, and recommend future efforts for modeling EBOV infection in HIS mice. Published by Elsevier B.V.

  8. The immune response of the human brain to abdominal surgery

    DEFF Research Database (Denmark)

    Forsberg, Anton; Cervenka, Simon; Jonsson Fagerlund, Malin

    2017-01-01

    OBJECTIVE: Surgery launches a systemic inflammatory reaction that reaches the brain and associates with immune activation and cognitive decline. Although preclinical studies have in part described this systemic-to-brain signaling pathway, we lack information on how these changes appear in humans....... This study examines the short- and long-term impact of abdominal surgery on the human brain immune system by positron emission tomography (PET) in relation to blood immune reactivity, plasma inflammatory biomarkers, and cognitive function. METHODS: Eight males undergoing prostatectomy under general...... anesthesia were included. Prior to surgery (baseline), at postoperative days 3 to 4, and after 3 months, patients were examined using [11C]PBR28 brain PET imaging to assess brain immune cell activation. Concurrently, systemic inflammatory biomarkers, ex vivo blood tests on immunoreactivity...

  9. Human intestinal dendritic cells as controllers of mucosal immunity

    Directory of Open Access Journals (Sweden)

    David Bernardo

    2013-06-01

    Full Text Available Dendritic cells are the most potent, professional antigen-presenting cells in the body; following antigen presentation they control the type (proinflammatory/regulatory of immune response that will take place, as well as its location. Given their high plasticity and maturation ability in response to local danger signals derived from innate immunity, dendritic cells are key actors in the connection between innate immunity and adaptive immunity responses. In the gut dendritic cells control immune tolerance mechanisms against food and/or commensal flora antigens, and are also capable of initiating an active immune response in the presence of invading pathogens. Dendritic cells are thus highly efficient in controlling the delicate balance between tolerance and immunity in an environment so rich in antigens as the gut, and any factor involving these cells may impact their function, ultimately leading to the development of bowel conditions such as celiac disease or inflammatory bowel disease. In this review we shall summarize our understanding of human intestinal dendritic cells, their ability to express and induce migration markers, the various environmental factors modulating their properties, their subsets in the gut, and the problems entailed by their study, including identification strategies, differences between humans and murine models, and phenotypical variations along the gastrointestinal tract.

  10. Reconstitution of halorhodopsin

    Energy Technology Data Exchange (ETDEWEB)

    Kong, T.

    1989-11-01

    Halobacterium halobium contains a family of retinal-bound proteins: bacteriorhodopsin (bR) which mediates phototrophic growth as a light-riven proton pump, halorhodopsin (hR) which is a light-driven chloride pump, and one or more sensory rhodopsins (sR) which mediate a phototactic response. Two-dimensional crystallization of halorhodopsin has been attempted though the reconstitution of purified halorhodopsin with purple membrane lipid for electron microscopy work. The first important step for crystallization is to get a homogeneous protein which is pure and not denatured. Homogeneous halorhodopsin has been obtained by a modification of existing purification methods. Some nice looking membrane patches which have the same density as purple membrane have been obtained. But unfortunately, they are not crystalline. The procedure of hR reconstitution is described in detail and some other strategies to induce the protein crystal in the reconstituted membrane are discussed in this dissertation. 76 refs., 20 figs., 6 tabs.

  11. Plant innate immunity against human bacterial pathogens

    Directory of Open Access Journals (Sweden)

    Maeli eMelotto

    2014-08-01

    Full Text Available Certain human bacterial pathogens such as the enterohemorrhagic Escherichia coli and Salmonella enterica are not proven to be plant pathogens yet. Nonetheless, under certain conditions they can survive on, penetrate into, and colonize internal plant tissues causing serious food borne disease outbreaks. In this review, we highlight current understanding on the molecular mechanisms of plant responses against human bacterial pathogens and discuss salient common and contrasting themes of plant interactions with phytopathogens or human pathogens.

  12. Immunologic reconstitution during PEG-ADA therapy in an unusual mosaic ADA deficient patient.

    Science.gov (United States)

    Liu, Ping; Santisteban, Ines; Burroughs, Lauri M; Ochs, Hans D; Torgerson, Troy R; Hershfield, Michael S; Rawlings, David J; Scharenberg, Andrew M

    2009-02-01

    We report detailed genetic and immunologic studies in a patient diagnosed with adenosine deaminase (ADA) deficiency and combined immune deficiency at age 5 years. At the time of diagnosis, although all other lymphocyte subsets were depleted, circulating CD8(+) T cells with a terminally differentiated phenotype were abundant and expressed normal ADA activity due to a reversion mutation in a CD8(+) T cell or precursor. Over the first 9 months of replacement therapy with PEG-ADA, the patient steadily accumulated mature naïve CD4(+) and CD8(+) T cells, as well as CD4(+)/FOXP3(+) regulatory T cells, consistent with restoration of a functional cellular immune system. While CD19(+) naïve B cells also accumulated in response to PEG-ADA therapy, a high proportion of these B cells exhibited an immature surface marker phenotype even after 9 months, and immunization with neoantigen bacteriophage varphiX174 demonstrated a markedly subnormal humoral immune response. Our observations in this single patient have important implications for gene therapy of human ADA deficiency, as they indicate that ADA expression within even a large circulating lymphocyte population may not be sufficient to support adequate immune reconstitution. They also suggest that an immature surface marker phenotype of the peripheral B cell compartment may be a useful surrogate marker for incomplete humoral immune reconstitution during enzyme replacement, and possibly other forms of hematopoietic cell therapies.

  13. Secretion of Interferon gamma (IFNγ) from Human Immune Cells is Altered by Exposure to Tributyltin (TBT) and Dibutyltin (DBT)

    Science.gov (United States)

    Lawrence, Shanieek; Reid, Jacqueline; Whalen, Margaret

    2013-01-01

    Tributyltin (TBT) and dibutyltin (DBT) are widespread environmental contaminants found in food, beverages, and human blood samples. Both of these butyltins (BTs) interfere with the ability of human natural killer (NK) cells to lyse target cells and also alter secretion of the pro-inflammatory cytokine tumor necrosis factor alpha (TNFα) from human immune cells in vitro. The capacity of BTs to interfere with secretion of other pro-inflammatory cytokines has not been examined. Interferon gamma (IFNγ) is a modulator of adaptive and innate immune responses, playing an important role in overall immune competence. This study shows that both TBT and DBT alter secretion of IFNγ from human immune cells. Peripheral blood cell preparations that were increasingly reconstituted were used to determine if exposures to either TBT or DBT affected IFNγ secretion and how the makeup of the cell preparation influenced that effect. IFNγ secretion was examined after 24 h, 48 h and 6 day exposures to TBT (200- 2.5 nM) and DBT (5- 0.05 μM) in highly enriched human NK cells, a monocyte-depleted preparation of PBMCs, and monocyte-containing PBMCs. Both BTs altered IFNγ secretion from NK cells at most of the conditions tested (either increasing or decreasing secretion). However, there was significant variability among donors as to the concentrations and time points that showed changes as well as the baseline secretion of IFNγ. The majority of donors showed an increase in IFNγ secretion in response to at least one concentration of TBT or DBT at a minimum of one length of exposure. PMID:24357260

  14. Reconstituted products from oak

    Science.gov (United States)

    W. C. Lewis; B. G. Heebink

    1971-01-01

    "Reconstituted" describes a family of panel products made from fractionated oak, bonded with either a synthetic resin or a natural lignin bond. Several current commercial fiber panel products from oak are described, and the status of research on experimental products and processes is presented. Recent technological developments are removing the stigma...

  15. The Reconstituted Family

    OpenAIRE

    Talbot, Yves

    1981-01-01

    The reconstituted or step-family is becoming more prevalent. The physician who cares for families should be acquainted with the different aspects of such family structure and family functioning. This will enable professionals to better understand and assist their patients, by anticipating the different stresses related to the new family formation, and supporting their adaptation.

  16. Effects of recombinant human granulocyte colony-stimulating factor on central and peripheral T lymphocyte reconstitution after sublethal irradiation in mice

    International Nuclear Information System (INIS)

    Zhao Hongxia; Guo Mei; Sun Xuedong; Ai Huisheng; Sun Wanjun; Hu Hailan; Wei Li

    2013-01-01

    Granulocyte colony-stimulating factor (G-CSF) is one of the most critical cytokines used for the treatment of acute radiation syndrome (ARS). In addition to the hematopoietic effects of G-CSF on the differentiation and proliferation of myeloid progenitor cells, G-CSF is also known to have immunomodulatory effects. The aim of the present study was to investigate whether G-CSF could accelerate central and peripheral T lymphocyte recovery after a sublethal dose of irradiation. Female BALB/c mice were subjected to 6 Gy of total body irradiation and then were treated with either 100 μg/kg G-CSF or an equal volume of PBS once daily for 14 days. Percentages of thymocyte subpopulations including CD4- CD8-, CD4+ CD8+, CD4+ CD8- and CD4- CD8+ T cells, peripheral CD3+, CD4+ and CD8+ cells were analyzed by flow cytometry. Recent thymic emigrants (RTEs) were assessed by real-time polymerase chain reaction (PCR) using primers specific to the 257-bp T cell receptor rearrangement excision circles (sjTRECs). The proliferative capacity of splenic mononuclear cells upon exposure to ConA was measured by using the Cell Count Kit-8 (CCK-8). G-CSF treatment promoted thymocyte regeneration, accelerated the recovery of CD4+ CD8+ cells and increased the frequency of thymocyte sjTRECs. These effects were more prominent at early time points (Day 28) after irradiation. G-CSF also increased the rate of recovery of peripheral CD3+, CD4+ and CD8+ cells and shortened the period of severe lymphopenia following irradiation. G-CSF also increased the splenic mononuclear cell mitotic responsiveness to ConA more than control-treated cells. Our results show that G-CSF accelerates T cell recovery through both thymic-dependent and thymic-independent pathways, which could be used to increase the rate of immune reconstitution after sublethal irradiation. (author)

  17. The behavioural immune system and the psychology of human sociality.

    Science.gov (United States)

    Schaller, Mark

    2011-12-12

    Because immunological defence against pathogens is costly and merely reactive, human anti-pathogen defence is also characterized by proactive behavioural mechanisms that inhibit contact with pathogens in the first place. This behavioural immune system comprises psychological processes that infer infection risk from perceptual cues, and that respond to these perceptual cues through the activation of aversive emotions, cognitions and behavioural impulses. These processes are engaged flexibly, producing context-contingent variation in the nature and magnitude of aversive responses. These processes have important implications for human social cognition and social behaviour-including implications for social gregariousness, person perception, intergroup prejudice, mate preferences, sexual behaviour and conformity. Empirical evidence bearing on these many implications is reviewed and discussed. This review also identifies important directions for future research on the human behavioural immune system--including the need for enquiry into underlying mechanisms, additional behavioural consequences and implications for human health and well-being.

  18. Human immune cell targeting of protein nanoparticles - caveospheres

    Science.gov (United States)

    Glass, Joshua J.; Yuen, Daniel; Rae, James; Johnston, Angus P. R.; Parton, Robert G.; Kent, Stephen J.; de Rose, Robert

    2016-04-01

    Nanotechnology has the power to transform vaccine and drug delivery through protection of payloads from both metabolism and off-target effects, while facilitating specific delivery of cargo to immune cells. However, evaluation of immune cell nanoparticle targeting is conventionally restricted to monocultured cell line models. We generated human caveolin-1 nanoparticles, termed caveospheres, which were efficiently functionalized with monoclonal antibodies. Using this platform, we investigated CD4+ T cell and CD20+ B cell targeting within physiological mixtures of primary human blood immune cells using flow cytometry, imaging flow cytometry and confocal microscopy. Antibody-functionalization enhanced caveosphere binding to targeted immune cells (6.6 to 43.9-fold) within mixed populations and in the presence of protein-containing fluids. Moreover, targeting caveospheres to CCR5 enabled caveosphere internalization by non-phagocytic CD4+ T cells--an important therapeutic target for HIV treatment. This efficient and flexible system of immune cell-targeted caveosphere nanoparticles holds promise for the development of advanced immunotherapeutics and vaccines.

  19. Genetic adaptation of the antibacterial human innate immunity network

    Directory of Open Access Journals (Sweden)

    Lazarus Ross

    2011-07-01

    Full Text Available Abstract Background Pathogens have represented an important selective force during the adaptation of modern human populations to changing social and other environmental conditions. The evolution of the immune system has therefore been influenced by these pressures. Genomic scans have revealed that immune system is one of the functions enriched with genes under adaptive selection. Results Here, we describe how the innate immune system has responded to these challenges, through the analysis of resequencing data for 132 innate immunity genes in two human populations. Results are interpreted in the context of the functional and interaction networks defined by these genes. Nucleotide diversity is lower in the adaptors and modulators functional classes, and is negatively correlated with the centrality of the proteins within the interaction network. We also produced a list of candidate genes under positive or balancing selection in each population detected by neutrality tests and showed that some functional classes are preferential targets for selection. Conclusions We found evidence that the role of each gene in the network conditions the capacity to evolve or their evolvability: genes at the core of the network are more constrained, while adaptation mostly occurred at particular positions at the network edges. Interestingly, the functional classes containing most of the genes with signatures of balancing selection are involved in autoinflammatory and autoimmune diseases, suggesting a counterbalance between the beneficial and deleterious effects of the immune response.

  20. Genetic adaptation of the antibacterial human innate immunity network.

    Science.gov (United States)

    Casals, Ferran; Sikora, Martin; Laayouni, Hafid; Montanucci, Ludovica; Muntasell, Aura; Lazarus, Ross; Calafell, Francesc; Awadalla, Philip; Netea, Mihai G; Bertranpetit, Jaume

    2011-07-11

    Pathogens have represented an important selective force during the adaptation of modern human populations to changing social and other environmental conditions. The evolution of the immune system has therefore been influenced by these pressures. Genomic scans have revealed that immune system is one of the functions enriched with genes under adaptive selection. Here, we describe how the innate immune system has responded to these challenges, through the analysis of resequencing data for 132 innate immunity genes in two human populations. Results are interpreted in the context of the functional and interaction networks defined by these genes. Nucleotide diversity is lower in the adaptors and modulators functional classes, and is negatively correlated with the centrality of the proteins within the interaction network. We also produced a list of candidate genes under positive or balancing selection in each population detected by neutrality tests and showed that some functional classes are preferential targets for selection. We found evidence that the role of each gene in the network conditions the capacity to evolve or their evolvability: genes at the core of the network are more constrained, while adaptation mostly occurred at particular positions at the network edges. Interestingly, the functional classes containing most of the genes with signatures of balancing selection are involved in autoinflammatory and autoimmune diseases, suggesting a counterbalance between the beneficial and deleterious effects of the immune response.

  1. Humanized mouse model for assessing the human immune response to xenogeneic and allogeneic decellularized biomaterials.

    Science.gov (United States)

    Wang, Raymond M; Johnson, Todd D; He, Jingjin; Rong, Zhili; Wong, Michelle; Nigam, Vishal; Behfar, Atta; Xu, Yang; Christman, Karen L

    2017-06-01

    Current assessment of biomaterial biocompatibility is typically implemented in wild type rodent models. Unfortunately, different characteristics of the immune systems in rodents versus humans limit the capability of these models to mimic the human immune response to naturally derived biomaterials. Here we investigated the utility of humanized mice as an improved model for testing naturally derived biomaterials. Two injectable hydrogels derived from decellularized porcine or human cadaveric myocardium were compared. Three days and one week after subcutaneous injection, the hydrogels were analyzed for early and mid-phase immune responses, respectively. Immune cells in the humanized mouse model, particularly T-helper cells, responded distinctly between the xenogeneic and allogeneic biomaterials. The allogeneic extracellular matrix derived hydrogels elicited significantly reduced total, human specific, and CD4 + T-helper cell infiltration in humanized mice compared to xenogeneic extracellular matrix hydrogels, which was not recapitulated in wild type mice. T-helper cells, in response to the allogeneic hydrogel material, were also less polarized towards a pro-remodeling Th2 phenotype compared to xenogeneic extracellular matrix hydrogels in humanized mice. In both models, both biomaterials induced the infiltration of macrophages polarized towards a M2 phenotype and T-helper cells polarized towards a Th2 phenotype. In conclusion, these studies showed the importance of testing naturally derived biomaterials in immune competent animals and the potential of utilizing this humanized mouse model for further studying human immune cell responses to biomaterials in an in vivo environment. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. Toward The Reconstitution of the Maturation of Okazaki Fragments Multiprotein Complex in Human At The Single Molecule Level

    KAUST Repository

    Joudeh, Luay

    2017-01-01

    The maturation of Okazaki fragments on the lagging strand in eukaryotes is mediated by a highly coordinated multistep process involving several proteins that ensure the accurate and efficient replication of genomic DNA. Human proliferating cell

  3. Estimation of the in vitro eye irritating and inflammatory potential of lipopolysaccharide (LPS) and dust by using reconstituted human corneal epithelium tissue cultures.

    Science.gov (United States)

    Cao, Yi; Bindslev, Dorthe A; Kjærgaard, Søren K

    2015-01-01

    Eye irritation is a common complaint in indoor environment, but the causes have still not been identified among the multiple exposures in house environments. To identify the potential environmental factors responsible for eye irritation and study the possible mechanisms, an in vitro model for eye irritation is suggested. In this study, reconstituted human corneal epithelium (HCE) tissue cultures were used to study the eye irritating and inflammatory potential of lipopolysaccharide (LPS) and dust. HCE tissue cultures were exposed to a range of concentrations of LPS for 6 h and dust for 24 h, respectively. After exposure, viability and secretion of interleukins (IL) IL-1β, IL-8, and tumor necrosis factor (TNFα) were examined. Histology was used to indicate the morphological changes after dust exposure. Both LPS and dust affected HCE viability. There was an increased level of IL-8 after LPS exposure, while the concentrations of IL-1β and TNFα remained unaffected. Dust exposure resulted in an elevation of both IL-1β and IL-8, but not TNFα. Histology study showed increased vacuolization and reduced thickness after 24 h exposure to 5 mg/mL dust. LPS and dust showed in vitro eye irritating and inflammatory potential, and cytokines/chemokines like IL-1β and IL-8 may be involved in the mechanisms of eye irritation. The HCE tissue culture may be used as an in vitro model to study environmental exposure induced eye irritation and inflammation.

  4. Vitamin D, d-dimer, Interferon γ, and sCD14 Levels are Independently Associated with Immune Reconstitution Inflammatory Syndrome: A Prospective, International Study

    Directory of Open Access Journals (Sweden)

    Laura W. Musselwhite

    2016-02-01

    Full Text Available To determine the immunological profile most important for IRIS prediction, we evaluated 20 baseline plasma biomarkers in Acquired Immunodeficiency Syndrome (AIDS patients initiating antiretroviral therapy (ART. Patients were enrolled in a randomized, placebo-controlled ART initiation trial in South Africa and Mexico to test whether maraviroc could prevent IRIS. Participants were classified prospectively as having IRIS within 6 months of ART initiation. Twenty plasma biomarkers were measured at study enrollment for 267 participants. Biomarkers were tested for predicting IRIS with adjustment for covariates chosen through forward stepwise selection. Sixty-two participants developed IRIS and of these 19 were tuberculosis (TB-IRIS. Baseline levels of vitamin D and higher d-dimer, interferon gamma (IFNγ, and sCD14 were independently associated with risk of IRIS in multivariate analyses. TB-IRIS cases exhibited a distinct biosignature from IRIS related to other pathogens, with increased levels of C-reactive protein (CRP, sCD14, IFNγ, and lower levels of Hb that could be captured by a composite risk score. Elevated markers of Type 1 T helper (Th1 response, monocyte activation, coagulation and low vitamin D were independently associated with IRIS risk. Interventions that decrease immune activation and increase vitamin D levels warrant further study.

  5. Pathogens and host immunity in the ancient human oral cavity

    Science.gov (United States)

    Warinner, Christina; Matias Rodrigues, João F.; Vyas, Rounak; Trachsel, Christian; Shved, Natallia; Grossmann, Jonas; Radini, Anita; Hancock, Y.; Tito, Raul Y.; Fiddyment, Sarah; Speller, Camilla; Hendy, Jessica; Charlton, Sophy; Luder, Hans Ulrich; Salazar-García, Domingo C.; Eppler, Elisabeth; Seiler, Roger; Hansen, Lars; Samaniego Castruita, José Alfredo; Barkow-Oesterreicher, Simon; Teoh, Kai Yik; Kelstrup, Christian; Olsen, Jesper V.; Nanni, Paolo; Kawai, Toshihisa; Willerslev, Eske; von Mering, Christian; Lewis, Cecil M.; Collins, Matthew J.; Gilbert, M. Thomas P.; Rühli, Frank; Cappellini, Enrico

    2014-01-01

    Calcified dental plaque (dental calculus) preserves for millennia and entraps biomolecules from all domains of life and viruses. We report the first high-resolution taxonomic and protein functional characterization of the ancient oral microbiome and demonstrate that the oral cavity has long served as a reservoir for bacteria implicated in both local and systemic disease. We characterize: (i) the ancient oral microbiome in a diseased state, (ii) 40 opportunistic pathogens, (iii) the first evidence of ancient human-associated putative antibiotic resistance genes, (iv) a genome reconstruction of the periodontal pathogen Tannerella forsythia, (v) 239 bacterial and 43 human proteins, allowing confirmation of a long-term association between host immune factors, “red-complex” pathogens, and periodontal disease, and (vi) DNA sequences matching dietary sources. Directly datable and nearly ubiquitous, dental calculus permits the simultaneous investigation of pathogen activity, host immunity, and diet, thereby extending the direct investigation of common diseases into the human evolutionary past. PMID:24562188

  6. Fuel assembly reconstitution

    International Nuclear Information System (INIS)

    Morgado, Mario M.; Oliveira, Monica G.N.; Ferreira Junior, Decio B.M.; Santos, Barbara O. dos; Santos, Jorge E. dos

    2009-01-01

    Fuel failures have been happened in Nuclear Power Plants worldwide, without lost of integrity and safety, mainly for the public, environment and power plants workers. The most common causes of these events are corrosion (CRUD), fretting and pellet cladding interaction. These failures are identified by increasing the activity of fission products, verified by chemical analyses of reactor coolant. Through these analyses, during the fourth operation cycle of Angra 2 Nuclear Power Plant, was possible to observe fuel failure indication. This indication was confirmed in the end of the cycle during the unloading of reactor core through leakage tests of fuel assembly, using the equipment called 'In Mast Sipping' and 'Box Sipping'. After confirmed, the fuel assembly reconstitution was scheduled, and happened in April, 2007, where was identified the cause and the fuel rod failure, which was substitute by dummy rods (zircaloy). The cause was fretting by 'debris'. The actions to avoid and prevent fuel assemblies failures are important. The goals of this work are to describe the methodology of fuel assembly reconstitution using the FARE (Fuel Assembly Reconstitution Equipment) system, to describe the results of this task in economic and security factors of the company and show how the fuel assembly failures are identified during operation and during the outage. (author)

  7. Expansion on stromal cells preserves the undifferentiated state of human hematopoietic stem cells despite compromised reconstitution ability.

    Science.gov (United States)

    Magnusson, Mattias; Sierra, Maria I; Sasidharan, Rajkumar; Prashad, Sacha L; Romero, Melissa; Saarikoski, Pamela; Van Handel, Ben; Huang, Andy; Li, Xinmin; Mikkola, Hanna K A

    2013-01-01

    Lack of HLA-matched hematopoietic stem cells (HSC) limits the number of patients with life-threatening blood disorders that can be treated by HSC transplantation. So far, insufficient understanding of the regulatory mechanisms governing human HSC has precluded the development of effective protocols for culturing HSC for therapeutic use and molecular studies. We defined a culture system using OP9M2 mesenchymal stem cell (MSC) stroma that protects human hematopoietic stem/progenitor cells (HSPC) from differentiation and apoptosis. In addition, it facilitates a dramatic expansion of multipotent progenitors that retain the immunophenotype (CD34+CD38-CD90+) characteristic of human HSPC and proliferative potential over several weeks in culture. In contrast, transplantable HSC could be maintained, but not significantly expanded, during 2-week culture. Temporal analysis of the transcriptome of the ex vivo expanded CD34+CD38-CD90+ cells documented remarkable stability of most transcriptional regulators known to govern the undifferentiated HSC state. Nevertheless, it revealed dynamic fluctuations in transcriptional programs that associate with HSC behavior and may compromise HSC function, such as dysregulation of PBX1 regulated genetic networks. This culture system serves now as a platform for modeling human multilineage hematopoietic stem/progenitor cell hierarchy and studying the complex regulation of HSC identity and function required for successful ex vivo expansion of transplantable HSC.

  8. Expansion on stromal cells preserves the undifferentiated state of human hematopoietic stem cells despite compromised reconstitution ability.

    Directory of Open Access Journals (Sweden)

    Mattias Magnusson

    Full Text Available Lack of HLA-matched hematopoietic stem cells (HSC limits the number of patients with life-threatening blood disorders that can be treated by HSC transplantation. So far, insufficient understanding of the regulatory mechanisms governing human HSC has precluded the development of effective protocols for culturing HSC for therapeutic use and molecular studies. We defined a culture system using OP9M2 mesenchymal stem cell (MSC stroma that protects human hematopoietic stem/progenitor cells (HSPC from differentiation and apoptosis. In addition, it facilitates a dramatic expansion of multipotent progenitors that retain the immunophenotype (CD34+CD38-CD90+ characteristic of human HSPC and proliferative potential over several weeks in culture. In contrast, transplantable HSC could be maintained, but not significantly expanded, during 2-week culture. Temporal analysis of the transcriptome of the ex vivo expanded CD34+CD38-CD90+ cells documented remarkable stability of most transcriptional regulators known to govern the undifferentiated HSC state. Nevertheless, it revealed dynamic fluctuations in transcriptional programs that associate with HSC behavior and may compromise HSC function, such as dysregulation of PBX1 regulated genetic networks. This culture system serves now as a platform for modeling human multilineage hematopoietic stem/progenitor cell hierarchy and studying the complex regulation of HSC identity and function required for successful ex vivo expansion of transplantable HSC.

  9. Effect of Nadir CD4+ T cell count on clinical measures of periodontal disease in HIV+ adults before and during immune reconstitution on HAART.

    Directory of Open Access Journals (Sweden)

    Lance T Vernon

    Full Text Available The contribution of HIV-infection to periodontal disease (PD is poorly understood. We proposed that immunological markers would be associated with improved clinical measures of PD.We performed a longitudinal cohort study of HIV-infected adults who had started highly active antiretroviral therapy (HAART 0mm, clinical attachment level (CAL ≥ 4.0mm, and bleeding on probing (BOP at ≥ 4 sites/tooth and microbiologically as specific periodontopathogen concentration. Linear mixed-effects models were used to assess the associations between immune function and PD.Forty (40 subjects with median 2.7 months on HAART and median nadir CD4+ T-cell count of 212 cells/μl completed a median 3 visits. Over 24 months, CD4+ T-cell count increased by a mean 173 cells/µl (p<0.001 and HIV RNA decreased by 0.5 log10 copies/ml (p<0.001; concurrently, PPD, CAL and BOP decreased by a mean 11.7%, 12.1%, and 14.7% respectively (all p<0.001. Lower nadir CD4+ T-cell count was associated with worse baseline REC (-6.72%; p=0.04 and CAL (9.06%; p<0.001. Further, lower nadir CD4+ T-cell count was associated with a greater relative longitudinal improvement in PPD in subjects with higher baseline levels of Porphyromonas gingivalis (p=0.027, and BOP in subjects with higher baseline levels of Porphyromonas gingivalis or Treponema denticola (p=0.001 and p=0.006 respectively. Longitudinal changes from baseline in CD4+ T-cell count and level of HIV RNA were not independently associated with longitudinal changes in any clinical markers of PD.Degree of immunosuppression was associated with baseline gingival recession. After HAART initiation, measures of active PD improved most in those with lower nadir CD4+ T-cell counts and higher baseline levels of specific periodontopathogens. Nadir CD4+ T-cell count differentially influences periodontal disease both before and after HAART in HIV-infected adults.

  10. Influence of diabetes mellitus on immunity to human tuberculosis.

    Science.gov (United States)

    Kumar Nathella, Pavan; Babu, Subash

    2017-09-01

    Type 2 diabetes mellitus(DM) is a major risk factor for the development of active pulmonary tuberculosis (TB), with development of DM pandemic in countries where TB is also endemic. Understanding the impact of DM on TB and the determinants of co-morbidity is essential in responding to this growing public health problem with improved therapeutic approaches. Despite the clinical and public health significance posed by the dual burden of TB and DM, little is known about the immunological and biochemical mechanisms of susceptibility. One possible mechanism is that an impaired immune response in patients with DM facilitates either primary infection with Mycobacterium tuberculosis or reactivation of latent TB. Diabetes is associated with immune dysfunction and alterations in the components of the immune system, including altered levels of specific cytokines and chemokines. Some effects of DM on adaptive immunity that are potentially relevant to TB defence have been identified in humans. In this review, we summarize current findings regarding the alterations in the innate and adaptive immune responses and immunological mechanisms of susceptibility of patients with DM to M. tuberculosis infection and disease. © 2017 John Wiley & Sons Ltd.

  11. RT-PCR detection of Candida albicans ALS gene expression in the reconstituted human epithelium (RHE) model of oral candidiasis and in model biofilms.

    Science.gov (United States)

    Green, Clayton B; Cheng, Georgina; Chandra, Jyotsna; Mukherjee, Pranab; Ghannoum, Mahmoud A; Hoyer, Lois L

    2004-02-01

    An RT-PCR assay was developed to analyse expression patterns of genes in the Candida albicans ALS (agglutinin-like sequence) family. Inoculation of a reconstituted human buccal epithelium (RHE) model of mucocutaneous candidiasis with strain SC5314 showed destruction of the epithelial layer by C. albicans and also formation of an upper fungal layer that had characteristics similar to a biofilm. RT-PCR analysis of total RNA samples extracted from C. albicans-inoculated buccal RHE showed that ALS1, ALS2, ALS3, ALS4, ALS5 and ALS9 were consistently detected over time as destruction of the RHE progressed. Detection of transcripts from ALS7, and particularly from ALS6, was more sporadic, but not associated with a strictly temporal pattern. The expression pattern of ALS genes in C. albicans cultures used to inoculate the RHE was similar to that observed in the RHE model, suggesting that contact of C. albicans with buccal RHE does little to alter ALS gene expression. RT-PCR analysis of RNA samples extracted from model denture and catheter biofilms showed similar gene expression patterns to the buccal RHE specimens. Results from the RT-PCR analysis of biofilm RNA specimens were consistent between various C. albicans strains during biofilm development and were comparable to gene expression patterns in planktonic cells. The RT-PCR assay described here will be useful for analysis of human clinical specimens and samples from other disease models. The method will provide further insight into the role of ALS genes and their encoded proteins in the diverse interactions between C. albicans and its host.

  12. A new 3D reconstituted human corneal epithelium model as an alternative method for the eye irritation test.

    Science.gov (United States)

    Jung, Kyoung-Mi; Lee, Su-Hyon; Ryu, Yang-Hwan; Jang, Won-Hee; Jung, Haeng-Sun; Han, Ju-Hee; Seok, Seung-Hyeok; Park, Jae-Hak; Son, Youngsook; Park, Young-Ho; Lim, Kyung-Min

    2011-02-01

    Many efforts are being made to develop new alternative in vitro test methods for the eye irritation test. Here we report a new reconstructed human corneal epithelial model (MCTT HCE model) prepared from primary-cultured human limbal epithelial cells as a new alternative in vitro eye irritation test method. In histological and immunohistochemical observation, MCTT HCE model displayed a morphology and biomarker expressions similar to intact human cornea. Moreover, the barrier function was well preserved as measured by high transepithelial electrical resistance, effective time-50 for Triton X-100, and corneal thickness. To employ the model as a new alternative method for eye irritation test, protocol refinement was performed and optimum assay condition was determined including treatment time, treatment volume, post-incubation time and rinsing method. Using the refined protocol, 25 reference chemicals with known eye irritation potentials were tested. With the viability cut-off value at 50%, chemicals were classified to irritant or non-irritant. When compared with GHS classification, the MCTT HCE model showed the accuracy of 88%, sensitivity of 100% and specificity of 77%. These results suggest that the MCTT HCE model might be useful as a new alternative eye irritation test method. Copyright © 2010 Elsevier Ltd. All rights reserved.

  13. Immune surveillance properties of human NK cell-derived exosomes.

    Science.gov (United States)

    Lugini, Luana; Cecchetti, Serena; Huber, Veronica; Luciani, Francesca; Macchia, Gianfranco; Spadaro, Francesca; Paris, Luisa; Abalsamo, Laura; Colone, Marisa; Molinari, Agnese; Podo, Franca; Rivoltini, Licia; Ramoni, Carlo; Fais, Stefano

    2012-09-15

    Exosomes are nanovesicles released by normal and tumor cells, which are detectable in cell culture supernatant and human biological fluids, such as plasma. Functions of exosomes released by "normal" cells are not well understood. In fact, several studies have been carried out on exosomes derived from hematopoietic cells, but very little is known about NK cell exosomes, despite the importance of these cells in innate and adaptive immunity. In this paper, we report that resting and activated NK cells, freshly isolated from blood of healthy donors, release exosomes expressing typical protein markers of NK cells and containing killer proteins (i.e., Fas ligand and perforin molecules). These nanovesicles display cytotoxic activity against several tumor cell lines and activated, but not resting, immune cells. We also show that NK-derived exosomes undergo uptake by tumor target cells but not by resting PBMC. Exosomes purified from plasma of healthy donors express NK cell markers, including CD56+ and perforin, and exert cytotoxic activity against different human tumor target cells and activated immune cells as well. The results of this study propose an important role of NK cell-derived exosomes in immune surveillance and homeostasis. Moreover, this study supports the use of exosomes as an almost perfect example of biomimetic nanovesicles possibly useful in future therapeutic approaches against various diseases, including tumors.

  14. Curcumin prevents human dendritic cell response to immune stimulants

    International Nuclear Information System (INIS)

    Shirley, Shawna A.; Montpetit, Alison J.; Lockey, R.F.; Mohapatra, Shyam S.

    2008-01-01

    Curcumin, a compound found in the Indian spice turmeric, has anti-inflammatory and immunomodulatory properties, though the mechanism remains unclear. Dendritic cells (DCs) are important to generating an immune response and the effect of curcumin on human DCs has not been explored. The role curcumin in the DC response to bacterial and viral infection was investigated in vitro using LPS and Poly I:C as models of infection. CD14 + monocytes, isolated from human peripheral blood, were cultured in GM-CSF- and IL-4-supplemented medium to generate immature DCs. Cultures were incubated with curcumin, stimulated with LPS or Poly I:C and functional assays were performed. Curcumin prevents DCs from responding to immunostimulants and inducing CD4 + T cell proliferation by blocking maturation marker, cytokine and chemokine expression and reducing both migration and endocytosis. These data suggest a therapeutic role for curcumin as an immune suppressant

  15. Immune activation is associated with decreased thymic function in ...

    African Journals Online (AJOL)

    Background: Reduced thymic function causes poor immunological reconstitution in human immunodeficiency virus (HIV)-positive patients on combined antiretroviral therapy (cART). The association between immune activation and thymic function in asymptomatic HIVpositive treatment-naive individuals has thus far not been ...

  16. Immune responses to implanted human collagen graft in rats

    International Nuclear Information System (INIS)

    Quteish, D.; Dolby, A.E.

    1991-01-01

    Immunity to collagen implants may be mediated by cellular and humoral immune responses. To examine the possibility of such immunological reactivity and crossreactivity to collagen, 39 Sprague-Dawley rats (female, 10 weeks old, approximately 250 g wt) were implanted subcutaneously at thigh sites with crosslinked, freeze-dried human placental type I collagen grafts (4x4x2 mm) which had been irradiated (520 Gray) or left untreated. Blood was obtained by intracardiac sampling prior to implantation or from normal rats, and at various times afterwards when the animals were sacrificed. The sera from these animals were examined for circulating antibodies to human, bovine and rat tail (type I) collagens by enzyme-linked immunosorbent assay (ELISA). Also, the lymphoblastogenic responses of spleen lymphocytes from the irradiated collagen-implanted animals were assessed in culture by measuring thymidine uptake with autologous and normal rat sera in the presence of human bovine type I collagens. Implantation of the irradiated and non-irradiated collagen graft in rats led to a significant increase in the level of circulating antibodies to human collagen. Also antibody to bovine and rat tail collagens was detectable in the animals implanted with irradiated collagen grafts but at a lower level than the human collagen. There was a raised lymphoblastogenic response to both human and bovine collagens. The antibody level and lymphoblastogenesis to the tested collagens gradually decreased towards the end of the post-implantation period. (author)

  17. Immune and Inflammatory Cell Composition of Human Lung Cancer Stroma.

    Directory of Open Access Journals (Sweden)

    G-Andre Banat

    Full Text Available Recent studies indicate that the abnormal microenvironment of tumors may play a critical role in carcinogenesis, including lung cancer. We comprehensively assessed the number of stromal cells, especially immune/inflammatory cells, in lung cancer and evaluated their infiltration in cancers of different stages, types and metastatic characteristics potential. Immunohistochemical analysis of lung cancer tissue arrays containing normal and lung cancer sections was performed. This analysis was combined with cyto-/histomorphological assessment and quantification of cells to classify/subclassify tumors accurately and to perform a high throughput analysis of stromal cell composition in different types of lung cancer. In human lung cancer sections we observed a significant elevation/infiltration of total-T lymphocytes (CD3+, cytotoxic-T cells (CD8+, T-helper cells (CD4+, B cells (CD20+, macrophages (CD68+, mast cells (CD117+, mononuclear cells (CD11c+, plasma cells, activated-T cells (MUM1+, B cells, myeloid cells (PD1+ and neutrophilic granulocytes (myeloperoxidase+ compared with healthy donor specimens. We observed all of these immune cell markers in different types of lung cancers including squamous cell carcinoma, adenocarcinoma, adenosquamous cell carcinoma, small cell carcinoma, papillary adenocarcinoma, metastatic adenocarcinoma, and bronchioloalveolar carcinoma. The numbers of all tumor-associated immune cells (except MUM1+ cells in stage III cancer specimens was significantly greater than those in stage I samples. We observed substantial stage-dependent immune cell infiltration in human lung tumors suggesting that the tumor microenvironment plays a critical role during lung carcinogenesis. Strategies for therapeutic interference with lung cancer microenvironment should consider the complexity of its immune cell composition.

  18. Genetic reconstitution of the human Adenovirus type 2 temperature-sensitive 1 mutant defective in endosomal escape

    Directory of Open Access Journals (Sweden)

    Gastaldelli Michele

    2009-10-01

    Full Text Available Abstract Human Adenoviruses infect the upper and lower respiratory tracts, the urinary and digestive tracts, lymphoid systems and heart, and give rise to epidemic conjunctivitis. More than 51 human serotypes have been identified to-date, and classified into 6 species A-F. The species C Adenoviruses Ad2 and Ad5 (Ad2/5 cause upper and lower respiratory disease, but how viral structure relates to the selection of particular infectious uptake pathways is not known. An adenovirus mutant, Ad2-ts1 had been isolated upon chemical mutagenesis in the past, and shown to have unprocessed capsid proteins. Ad2-ts1 fails to package the viral protease L3/p23, and Ad2-ts1 virions do not efficiently escape from endosomes. It had been suggested that the C22187T point mutation leading to the substitution of the conserved proline 137 to leucine (P137L in the L3/p23 protease was at least in part responsible for this phenotype. To clarify if the C22187T mutation is necessary and sufficient for the Ad2-ts1 phenotype, we sequenced the genes encoding the structural proteins of Ad2-ts1, and confirmed that the Ad2-ts1 DNA carries the point mutation C22187T. Introduction of C22187T to the wild-type Ad2 genome in a bacterial artificial chromosome (Ad2-BAC gave Ad2-BAC46 virions with the full Ad2-ts1 phenotype. Reversion of Ad2-BAC46 gave wild-type Ad2 particles indicating that P137L is necessary and sufficient for the Ad2-ts1 phenotype. The kinetics of Ad2-ts1 uptake into cells were comparable to Ad2 suggesting similar endocytic uptake mechanisms. Surprisingly, infectious Ad2 or Ad5 but not Ad2-ts1 uptake required CALM (clathrin assembly lymphoid myeloid protein, which controls clathrin-mediated endocytosis and membrane transport between endosomes and the trans-Golgi-network. The data show that no other mutations than P137L in the viral protease are necessary to give rise to particles that are defective in capsid processing and endosomal escape. This provides a basis for

  19. Identification of Differential Gene Expression Patterns after Acute Exposure to High and Low Doses of Low-LET Ionizing Radiation in a Reconstituted Human Skin Tissue

    Energy Technology Data Exchange (ETDEWEB)

    Tilton, Susan C.; Markillie, Lye Meng; Hays, Spencer; Taylor, Ronald C.; Stenoien, David L.

    2016-11-01

    Our goal here was to identify dose and temporal dependent radiation responses in a complex tissue, reconstituted human skin. Direct sequencing of RNA (RNA-seq) was used to quantify altered transcripts following exposure to 0.1, 2 and 10 Gy of ionizing radiation at 3 and 8 hours. These doses include a low dose in the range of some medical diagnostic procedures (0.1 Gy), a dose typically received during radiotherapy (2.0 Gy) and a lethal dose (10 Gy). These doses could be received after an intentional or accidental radiation exposure and biomarkers are needed to rapidly and accurately triage exposed individuals. A total of 1701 genes were deemed to be significantly affected by high dose radiation exposure with the majority of genes affected at 10 Gy. A group of 29 genes including GDF15, BBC3, PPM1D, FDXR, GADD45A, MDM2, CDKN1A, TP53INP1, CYCSP27, SESN1, SESN2, PCNA, and AEN were similarly altered at both 2 and 10 Gy, but not 0.1 Gy, at multiple time points. A much larger group of up regulated genes, including those involved in inflammatory responses, was significantly altered only after a 10 Gy exposure. At high doses, down regulated genes were associated with cell cycle regulation and exhibited an apparent linear response between 2 and 10 Gy. While only a handful of genes were significantly affected by 0.1 Gy exposure using stringent statistical filters, groups of related genes regulating cell cycle progression and inflammatory responses consistently exhibited opposite trends in their regulation compared to the high dose exposures. Differential regulation of PLK1 signaling at low and high doses was confirmed using qRT-PCR. These results indicate that some alterations in gene expression are qualitatively different at low and high doses of radiation in this model system.

  20. Pathogens and host immunity in the ancient human oral cavity

    DEFF Research Database (Denmark)

    Warinner, Christina; Rodrigues, João F Matias; Vyas, Rounak

    2014-01-01

    Calcified dental plaque (dental calculus) preserves for millennia and entraps biomolecules from all domains of life and viruses. We report the first, to our knowledge, high-resolution taxonomic and protein functional characterization of the ancient oral microbiome and demonstrate that the oral...... cavity has long served as a reservoir for bacteria implicated in both local and systemic disease. We characterize (i) the ancient oral microbiome in a diseased state, (ii) 40 opportunistic pathogens, (iii) ancient human-associated putative antibiotic resistance genes, (iv) a genome reconstruction...... calculus permits the simultaneous investigation of pathogen activity, host immunity and diet, thereby extending direct investigation of common diseases into the human evolutionary past....

  1. Convergence of the innate and adaptive immunity during human aging

    Directory of Open Access Journals (Sweden)

    Branca Isabel Pereira

    2016-11-01

    Full Text Available Aging is associated with profound changes in the human immune system, a phenomenon referred to as immunosenescence. This complex immune remodeling affects the adaptive immune system and the CD8+ T cell compartment in particular, leading to the accumulation of terminally differentiated T cells, which can rapidly exert their effector functions at the expenses of a limited proliferative potential. In this review we will discuss evidence suggesting that senescent αβCD8+ T cells acquire the hallmarks of innate-like T cells and use recently acquired NK cell receptors as an alternative mechanism to mediate rapid effector functions. These cells concomitantly lose expression of co-stimulatory receptors and exhibit decreased TCR signaling suggesting a functional shift away from antigen specific activation. The convergence of innate and adaptive features in senescent T cells challenges the classic division between innate and adaptive immune systems. Innate-like T cells are particularly important for stress and tumor surveillance and we propose a new role for these cells in aging, where the acquisition of innate-like functions may represent a beneficial adaptation to an increased burden of malignancy with age, although it may also pose a higher risk of autoimmune disorders.

  2. Homogeneous antibodies in lethally irradiated and autologous bone marrow reconstituted Rhesus monkeys

    International Nuclear Information System (INIS)

    Berg, P. Van Den; Radl, J.; Loewenberg, B.; Swart, A.C.W.

    1976-01-01

    Ten Rhesus monkeys were lethally irradiated and reconstituted with autologous bone marrow. During the restoration period, the animals were immunized with DNP-Rhesus albumin and IgA1lambda-10S human paraprotein. One or more transient homogenous immunoglobulin components appeared in sera of all experimental monkeys. In four animals, these homogeneous immunoglobulins were shown to be specific antibodies against DNP-Rhesus albumin. They gradually became as heterogeneous as those in control monkeys which were immunized but not irradiated and transplanted. The onset of the specific antibody response after immunization was slightly delayed in the experimental group. On determining the time necessary to reach normalization of the overall immunoglobulin levels and the normal heterogeneity of the immunoglobulin spectrum, it was found to be more than 1 year in most of the animals. (author)

  3. Articulated Human Motion Tracking Using Sequential Immune Genetic Algorithm

    Directory of Open Access Journals (Sweden)

    Yi Li

    2013-01-01

    Full Text Available We formulate human motion tracking as a high-dimensional constrained optimization problem. A novel generative method is proposed for human motion tracking in the framework of evolutionary computation. The main contribution is that we introduce immune genetic algorithm (IGA for pose optimization in latent space of human motion. Firstly, we perform human motion analysis in the learnt latent space of human motion. As the latent space is low dimensional and contents the prior knowledge of human motion, it makes pose analysis more efficient and accurate. Then, in the search strategy, we apply IGA for pose optimization. Compared with genetic algorithm and other evolutionary methods, its main advantage is the ability to use the prior knowledge of human motion. We design an IGA-based method to estimate human pose from static images for initialization of motion tracking. And we propose a sequential IGA (S-IGA algorithm for motion tracking by incorporating the temporal continuity information into the traditional IGA. Experimental results on different videos of different motion types show that our IGA-based pose estimation method can be used for initialization of motion tracking. The S-IGA-based motion tracking method can achieve accurate and stable tracking of 3D human motion.

  4. Immune evasion mechanisms of human papillomavirus: An update.

    Science.gov (United States)

    Steinbach, Alina; Riemer, Angelika B

    2018-01-15

    Human papillomavirus (HPV) is the most frequently sexually transmitted agent in the world. It can cause cervical and other anogenital malignancies, and oropharyngeal cancer. HPV has the unique ability to persist in the host's epithelium for a long time-longer than most viruses do-which is necessary to complete its replication cycle. To this end, HPV has developed a variety of immune evasion mechanisms, which unfortunately also favor the progression of the disease from infection to chronic dysplasia and eventually to cancer. This article summarizes the current knowledge about HPV immune evasion strategies. A special emphasis lies in HPV-mediated changes of the antigen processing machinery, which is generating epitopes for T cells and contributes to the detectability of infected cells. © 2017 UICC.

  5. Cell mediated immune response in human antirabies revaccination

    Directory of Open Access Journals (Sweden)

    Débora Regina Veiga

    1987-04-01

    Full Text Available The occurrence of secondary cell mediated immune response (CMI in human antirabies immunization was studied. The Puenzalida & Palácios vaccine was used because it is routinely used in Brazil. CMI was evaluated by lymphoblastic transformation indices obtained in whole blood culture in the presence of rabies and control (nervous tissue antigens. Eleven volunteers submitted to revaccination constituted the group under study, while three other volunteers submitted primo vaccination were utilized as control group. A clear secondary CMI to rabies antigen was detected in all the revaccinated volunteers who showed earlier and more intense response than the control group. Response to the control antigen, however, present in all the components of the first group was not detectable in two out of the three primovaccinated and very low in the third one.

  6. Immune reconstitution inflammatory syndrome in children | Rabie ...

    African Journals Online (AJOL)

    IRIS) occurs in up to 21% of children initiating antiretroviral therapy. Mycobacterial diseases are the most common, with BCG-vaccine adenitis predominating in infants and Mycobacterium tuberculosis (TB) in older children. The difficulty of ...

  7. Humanized Mouse Model of Ebola Virus Disease Mimics the Immune Responses in Human Disease.

    Science.gov (United States)

    Bird, Brian H; Spengler, Jessica R; Chakrabarti, Ayan K; Khristova, Marina L; Sealy, Tara K; Coleman-McCray, JoAnn D; Martin, Brock E; Dodd, Kimberly A; Goldsmith, Cynthia S; Sanders, Jeanine; Zaki, Sherif R; Nichol, Stuart T; Spiropoulou, Christina F

    2016-03-01

    Animal models recapitulating human Ebola virus disease (EVD) are critical for insights into virus pathogenesis. Ebola virus (EBOV) isolates derived directly from human specimens do not, without adaptation, cause disease in immunocompetent adult rodents. Here, we describe EVD in mice engrafted with human immune cells (hu-BLT). hu-BLT mice developed EVD following wild-type EBOV infection. Infection with high-dose EBOV resulted in rapid, lethal EVD with high viral loads, alterations in key human antiviral immune cytokines and chemokines, and severe histopathologic findings similar to those shown in the limited human postmortem data available. A dose- and donor-dependent clinical course was observed in hu-BLT mice infected with lower doses of either Mayinga (1976) or Makona (2014) isolates derived from human EBOV cases. Engraftment of the human cellular immune system appeared to be essential for the observed virulence, as nonengrafted mice did not support productive EBOV replication or develop lethal disease. hu-BLT mice offer a unique model for investigating the human immune response in EVD and an alternative animal model for EVD pathogenesis studies and therapeutic screening. Published by Oxford University Press for the Infectious Diseases Society of America 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.

  8. Immunization

    Science.gov (United States)

    ... a lot worse. Some are even life-threatening. Immunization shots, or vaccinations, are essential. They protect against ... B, polio, tetanus, diphtheria, and pertussis (whooping cough). Immunizations are important for adults as well as children. ...

  9. Immune response capacity after human splenic autotransplantation - Restoration of response to individual pneumococcal vaccine subtypes

    NARCIS (Netherlands)

    Leemans, R; Manson, W; Snijder, JAM; Smit, JW; Klasen, HJ; The, TH; Timens, W

    Objective To evaluate features of general immune function, in particular the restoration of the humoral immune response to pneumococcal capsular polysaccharides, in humans undergoing a spleen autotransplantation after splenectomy because of trauma. Summary Background Data After splenectomy, patients

  10. The shaping of modern human immune systems by multiregional admixture with archaic humans.

    Science.gov (United States)

    Abi-Rached, Laurent; Jobin, Matthew J; Kulkarni, Subhash; McWhinnie, Alasdair; Dalva, Klara; Gragert, Loren; Babrzadeh, Farbod; Gharizadeh, Baback; Luo, Ma; Plummer, Francis A; Kimani, Joshua; Carrington, Mary; Middleton, Derek; Rajalingam, Raja; Beksac, Meral; Marsh, Steven G E; Maiers, Martin; Guethlein, Lisbeth A; Tavoularis, Sofia; Little, Ann-Margaret; Green, Richard E; Norman, Paul J; Parham, Peter

    2011-10-07

    Whole genome comparisons identified introgression from archaic to modern humans. Our analysis of highly polymorphic human leukocyte antigen (HLA) class I, vital immune system components subject to strong balancing selection, shows how modern humans acquired the HLA-B*73 allele in west Asia through admixture with archaic humans called Denisovans, a likely sister group to the Neandertals. Virtual genotyping of Denisovan and Neandertal genomes identified archaic HLA haplotypes carrying functionally distinctive alleles that have introgressed into modern Eurasian and Oceanian populations. These alleles, of which several encode unique or strong ligands for natural killer cell receptors, now represent more than half the HLA alleles of modern Eurasians and also appear to have been later introduced into Africans. Thus, adaptive introgression of archaic alleles has significantly shaped modern human immune systems.

  11. A DNA Vaccine Protects Human Immune Cells against Zika Virus Infection in Humanized Mice

    Directory of Open Access Journals (Sweden)

    Guohua Yi

    2017-11-01

    Full Text Available A DNA vaccine encoding prM and E protein has been shown to induce protection against Zika virus (ZIKV infection in mice and monkeys. However, its effectiveness in humans remains undefined. Moreover, identification of which immune cell types are specifically infected in humans is unclear. We show that human myeloid cells and B cells are primary targets of ZIKV in humanized mice. We also show that a DNA vaccine encoding full length prM and E protein protects humanized mice from ZIKV infection. Following administration of the DNA vaccine, humanized DRAG mice developed antibodies targeting ZIKV as measured by ELISA and neutralization assays. Moreover, following ZIKV challenge, vaccinated animals presented virtually no detectable virus in human cells and in serum, whereas unvaccinated animals displayed robust infection, as measured by qRT-PCR. Our results utilizing humanized mice show potential efficacy for a targeted DNA vaccine against ZIKV in humans.

  12. Manifestations of Immune Privilege in the Human Reproductive Tract

    Directory of Open Access Journals (Sweden)

    Gary F Clark

    2013-02-01

    Full Text Available Like other mucosal surfaces (e.g., the gastrointestinal tract, the respiratory tract, the human female reproductive tract acts as an initial barrier to foreign antigens. In this role, the epithelial surface and subepithelial immune cells must balance protection against pathogenic insults against harmful inflammatory reactions and acceptance of particular foreign antigens. Two common examples of these acceptable foreign antigens are the fetal allograft and human semen/sperm. Both are purposely deposited into the female genital tract and appropriate immunologic response to these non-self antigens is essential to the survival of the species. In light of the weight of this task, it is not surprising that multiple, redundant and overlapping mechanisms are involved. For instance, cells at the immunologic interface between self (female reproductive tract epithelium and non-self (placental trophoblast cells or human sperm express glycosylation patterns that mimic those on many metastatic cancer cells and successful pathogens. The cytokine/chemokine milieu at this interface is altered through endocrine and immunologic mechanisms to favor tolerance of non-self. The foreign cells themselves also play an integral role in their own immunologic acceptance, since sperm and placental trophoblast cells are unusual and unique in their antigen presenting molecule expression patterns. Here, we will discuss these and other mechanisms that allow the human female reproductive tract to perform this delicate and indispensible balancing act.

  13. Immune Reconstitution After Autologous Hematopoietic Stem Cell Transplantation in Crohn’s Disease: Current Status and Future Directions. A Review on Behalf of the EBMT Autoimmune Diseases Working Party and the Autologous Stem Cell Transplantation In Refractory CD—Low Intensity Therapy Evaluation Study Investigators

    Directory of Open Access Journals (Sweden)

    Alan Graham Pockley

    2018-04-01

    Full Text Available Patients with treatment refractory Crohn’s disease (CD suffer debilitating symptoms, poor quality of life, and reduced work productivity. Surgery to resect inflamed and fibrotic intestine may mandate creation of a stoma and is often declined by patients. Such patients continue to be exposed to medical therapy that is ineffective, often expensive and still associated with a burden of adverse effects. Over the last two decades, autologous hematopoietic stem cell transplantation (auto-HSCT has emerged as a promising treatment option for patients with severe autoimmune diseases (ADs. Mechanistic studies have provided proof of concept that auto-HSCT can restore immunological tolerance in chronic autoimmunity via the eradication of pathological immune responses and a profound reconfiguration of the immune system. Herein, we review current experience of auto-HSCT for the treatment of CD as well as approaches that have been used to monitor immune reconstitution following auto-HSCT in patients with ADs, including CD. We also detail immune reconstitution studies that have been integrated into the randomized controlled Autologous Stem cell Transplantation In refractory CD—Low Intensity Therapy Evaluation trial, which is designed to test the hypothesis that auto-HSCT using reduced intensity mobilization and conditioning regimens will be a safe and effective means of inducing sustained control in refractory CD compared to standard of care. Immunological profiling will generate insight into the pathogenesis of the disease, restoration of responsiveness to anti-TNF therapy in patients with recurrence of endoscopic disease and immunological events that precede the onset of disease in patients that relapse after auto-HSCT.

  14. Characterization of enzymatic properties of human ribonucleotide reductase holoenzyme reconstituted in vitro from hRRM1, hRRM2, and p53R2 subunits.

    Science.gov (United States)

    Qiu, Weihua; Zhou, Bingsen; Darwish, Dana; Shao, Jimin; Yen, Yun

    2006-02-10

    Ribonucleotide reductase (RR) is a highly regulated enzyme in the deoxyribonucleotide synthesis pathway. RR is responsible for the de novo conversion of ribonucleoside diphosphates to deoxyribonucleoside diphosphates, which are essential for DNA synthesis and repair. Besides two subunits, hRRM1 and hRRM2, p53R2 is a newly identified member of RR family that is induced by ultraviolet light in a p53-dependent manner. To understand the molecular interaction of RR subunits, we employed a eukaryotic expression system to express and purify all three subunits. After in vitro reconstitution, the results of [(3)H]CDP reduction assay showed that both eukaryotic recombinant hRRM2 and p53R2 proteins could interact with hRRM1 to form functional RR holoenzyme. The reconstituted RR activity was time-dependent and the reaction rate reached the plateau phase after 40min incubation. No matter the concentration, RR holoenzyme reconstituted from p53R2 and hRRM1 could only achieve about 40-75% kinetic activity of that from hRRM2 and hRRM1. The synthetic C-terminal heptapeptide competition assays confirmed that hRRM2 and p53R2 share the same binding site on hRRM1, but the binding site on hRRM1 demonstrated higher affinity for hRRM2 than for p53R2. In allosteric regulation assay, the effect of activation or inhibition of hRRM1 with ATP or dATP suggested that these effectors could regulate RR activity independent of different RR small subunits. Taken together, the eukaryotic expression system RR holoenzyme will provide a very useful tool to understand the molecular mechanisms of RR activity and the interactions of its subunits.

  15. CTA1-DD adjuvant promotes strong immunity against human immunodeficiency virus type 1 envelope glycoproteins following mucosal immunization.

    Science.gov (United States)

    Sundling, Christopher; Schön, Karin; Mörner, Andreas; Forsell, Mattias N E; Wyatt, Richard T; Thorstensson, Rigmor; Karlsson Hedestam, Gunilla B; Lycke, Nils Y

    2008-12-01

    Strategies to induce potent and broad antibody responses against the human immunodeficiency virus type 1 (HIV-1) envelope glycoproteins (Env) at both systemic and mucosal sites represent a central goal for HIV-1 vaccine development. Here, we show that the non-toxic CTA1-DD adjuvant promoted mucosal and systemic humoral and cell-mediated immune responses following intranasal (i.n.) immunizations with trimeric or monomeric forms of HIV-1 Env in mice and in non-human primates. Env-specific IgG subclasses in the serum of immunized mice reflected a balanced Th1/Th2 type of response. Strikingly, i.n. immunizations with Env and the CTA1-DD adjuvant induced substantial levels of mucosal anti-Env IgA in bronchial alveolar lavage and also detectable levels in vaginal secretions. By contrast, parenteral immunizations of Env formulated in Ribi did not stimulate mucosal IgA responses, while the two adjuvants induced a similar distribution of Env-specific IgG-subclasses in serum. A single parenteral boost with Env in Ribi adjuvant into mice previously primed i.n. with Env and CTA1-DD, augmented the serum anti-Env IgG levels to similar magnitudes as those observed after three intraperitoneal immunizations with Env in Ribi. The augmenting potency of CTA1-DD was similar to that of LTK63 or CpG oligodeoxynucleotides (ODN). However, in contrast to CpG ODN, the effect of CTA1-DD and LTK63 appeared to be independent of MyD88 and toll-like receptor signalling. This is the first demonstration that CTA1-DD augments specific immune responses also in non-human primates, suggesting that this adjuvant could be explored further as a clinically safe mucosal vaccine adjuvant for humoral and cell-mediated immunity against HIV-1 Env.

  16. Abnormal humoral immune response to influenza vaccination in pediatric type-1 human immunodeficiency virus infected patients receiving highly active antiretroviral therapy

    Directory of Open Access Journals (Sweden)

    Carlos J Montoya

    2007-06-01

    Full Text Available Given that highly active antiretroviral therapy (HAART has been demonstrated useful to restore immune competence in type-1 human immunodeficiency virus (HIV-1-infected subjects, we evaluated the specific antibody response to influenza vaccine in a cohort of HIV-1-infected children on HAART so as to analyze the quality of this immune response in patients under antiretroviral therapy. Sixteen HIV-1-infected children and 10 HIV-1 seronegative controls were immunized with a commercially available trivalent inactivated influenza vaccine containing the strains A/H1N1, A/H3N2, and B. Serum hemagglutinin inhibition (HI antibody titers were determined for the three viral strains at the time of vaccination and 1 month later. Immunization induced a significantly increased humoral response against the three influenza virus strains in controls, and only against A/H3N2 in HIV-1-infected children. The comparison of post-vaccination HI titers between HIV-1+ patients and HIV-1 negative controls showed significantly higher HI titers against the three strains in controls. In addition, post vaccination protective HI titers (defined as equal to or higher than 1:40 against the strains A/H3N2 and B were observed in a lower proportion of HIV-1+ children than in controls, while a similar proportion of individuals from each group achieved protective HI titers against the A/H1N1 strain. The CD4+ T cell count, CD4/CD8 T cells ratio, and serum viral load were not affected by influenza virus vaccination when pre- vs post-vaccination values were compared. These findings suggest that despite the fact that HAART is efficient in controlling HIV-1 replication and in increasing CD4+ T cell count in HIV-1-infected children, restoration of immune competence and response to cognate antigens remain incomplete, indicating that additional therapeutic strategies are required to achieve a full reconstitution of immune functions.

  17. Measuring the immune system: a comprehensive approach for the analysis of immune functions in humans.

    Science.gov (United States)

    Claus, Maren; Dychus, Nicole; Ebel, Melanie; Damaschke, Jürgen; Maydych, Viktoriya; Wolf, Oliver T; Kleinsorge, Thomas; Watzl, Carsten

    2016-10-01

    The immune system is essential to provide protection from infections and cancer. Disturbances in immune function can therefore directly affect the health of the affected individual. Many extrinsic and intrinsic factors such as exposure to chemicals, stress, nutrition and age have been reported to influence the immune system. These influences can affect various components of the immune system, and we are just beginning to understand the causalities of these changes. To investigate such disturbances, it is therefore essential to analyze the different components of the immune system in a comprehensive fashion. Here, we demonstrate such an approach which provides information about total number of leukocytes, detailed quantitative and qualitative changes in the composition of lymphocyte subsets, cytokine levels in serum and functional properties of T cells, NK cells and monocytes. Using samples from a cohort of 24 healthy volunteers, we demonstrate the feasibility of our approach to detect changes in immune functions.

  18. The skin immune system (SIS): distribution and immunophenotype of lymphocyte subpopulations in normal human skin

    NARCIS (Netherlands)

    Bos, J. D.; Zonneveld, I.; Das, P. K.; Krieg, S. R.; van der Loos, C. M.; Kapsenberg, M. L.

    1987-01-01

    The complexity of immune response-associated cells present in normal human skin was recently redefined as the skin immune system (SIS). In the present study, the exact immunophenotypes of lymphocyte subpopulations with their localizations in normal human skin were determined quantitatively. B cells

  19. Human erythrocytes inhibit complement-mediated solubilization of immune complexes by human serum

    International Nuclear Information System (INIS)

    Dorval, B.L.

    1987-01-01

    The aim of this study was to develop an autologus human system to evaluate the effects of human erythrocytes on solubilization of immune complex precipitates (IC) by human serum. Incubation of IC with fresh human serum or guinea pig serum resulted in solubilization of IC. When packed erythrocytes were added to human serum or guinea pig serum binding of IC to the erythrocyte occurred and IC solubilization was inhibited significantly (p <.025). Sheep erythrocytes did not bind IC or inhibit IC solubilization. To evaluate the role of human erythrocyte complement receptor (CR1) on these findings, human erythrocytes were treated with trypsin or anti-CR1 antibodies. Both treatments abrogated IC binding to human erythrocytes but did not affect the ability of the human erythrocyte to inhibit IC solubilization. Radioimmunoassay was used to measure C3, C4 and C5 activation in human serum after incubation with IC, human erythrocytes, human erythrocytes plus IC, whole blood or in whole blood plus IC

  20. Soft tissue abscess and lymphadenitis due to Mycobacterium avium Complex as an expression of immune reconstitution inflammatory syndrome after a second scheme of highly active antiretroviral therapy Linfadenitis y absceso subcutáneo por Complejo Mycobacterium avium como manifestación de síndrome inflamatorio de reconstitución inmune luego de un segundo esquema de terapia antirretroviral de gran actividad

    Directory of Open Access Journals (Sweden)

    Marcelo Corti

    2007-08-01

    Full Text Available Immune reconstitution inflammatory syndrome (IRIS is an atypical and unexpected reaction related to highly active antiretroviral therapy (HAART in human immunodeficiency virus (HIV infected patients. IRIS includes an atypical response to an opportunistic pathogen (generally Mycobacterium tuberculosis, Mycobacterium avium complex, cytomegalovirus and herpes varicella-zoster, in patients responding to HAART with a reduction of plasma viral load and evidence of immune restoration based on increase of CD4+ T-cell count. We reported a case of a patient with AIDS which, after a first failure of HAART, developed a subcutaneous abscess and supraclavicular lymphadenitis as an expression of IRIS due to Mycobacterium avium complex after starting a second scheme of HAART.El síndrome inflamatorio de reconstitución inmune (SIRI es una reacción atípica e inesperada relacionada con el tratamiento antirretroviral de gran actividad (TARGA en pacientes infectados por el virus de la inmunodeficiencia humana (VIH. El SIRI representa una respuesta inflamatoria frente a un patógeno oportunista (generalmente Mycobacterium tuberculosis, Complejo Mycobacterium avium, citomegalovirus y herpes varicela-zóster en pacientes que responden a la TARGA con una marcada reducción de la carga viral en plasma y evidencia de una recuperación inmunológica expresada por el incremento de los niveles de linfocitos T CD4+. Presentamos el caso de un paciente con síndrome de inmunodeficiencia adquirida que desarrolló un absceso subcutáneo en muslo derecho y una adenitis supraclavicular izquierda como manifestación de SIRI por Complejo Mycobacterium avium luego del inicio de un segundo esquema de TARGA.

  1. Experimental model for the study of the human immune system: production and monitoring of "human immune system" Rag2-/-gamma c-/- mice

    NARCIS (Netherlands)

    Legrand, Nicolas; Weijer, Kees; Spits, Hergen

    2008-01-01

    Since the late 1980s, the study of the function and development of the human immune system has made intensive use of humanized animal models, among which mouse models have been proven extremely efficient and handy. Recent advances have lead to the establishment of new models with improved

  2. DMPD: Nod1 and Nod2 in innate immunity and human inflammatory disorders. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 18031249 Nod1 and Nod2 in innate immunity and human inflammatory disorders. Le Bour...w Nod1 and Nod2 in innate immunity and human inflammatory disorders. PubmedID 18031249 Title Nod1 and Nod2 in innate immunity and hum...an inflammatory disorders. Authors Le Bourhis L, Benko S

  3. immune response can measuring immunity to hiv during ...

    African Journals Online (AJOL)

    2005-11-01

    Nov 1, 2005 ... inhibitors (PIs), have resulted in significant suppression of viral replication. ... thymus, with the potential for immune reconstitution when ..... HIV-exposed but uninfected Gambian women [published erratum appears in. Nat Med ...

  4. A model for personalized in vivo analysis of human immune responsiveness

    NARCIS (Netherlands)

    Kalscheuer, Hannes; Danzl, Nichole; Onoe, Takashi; Faust, Ted; Winchester, Robert; Goland, Robin; Greenberg, Ellen; Spitzer, Thomas R; Savage, David G; Tahara, Hiroyuki; Choi, Goda; Yang, Yong-Guang; Sykes, Megan

    2012-01-01

    Studies of human immune diseases are generally limited to the analysis of peripheral blood lymphocytes of heterogeneous patient populations. Improved models are needed to allow analysis of fundamental immunologic abnormalities predisposing to disease and in which to assess immunotherapies.

  5. The genetic architecture of the human immune system: a bioresource for autoimmunity and disease pathogenesis.

    Science.gov (United States)

    Roederer, Mario; Quaye, Lydia; Mangino, Massimo; Beddall, Margaret H; Mahnke, Yolanda; Chattopadhyay, Pratip; Tosi, Isabella; Napolitano, Luca; Terranova Barberio, Manuela; Menni, Cristina; Villanova, Federica; Di Meglio, Paola; Spector, Tim D; Nestle, Frank O

    2015-04-09

    Despite recent discoveries of genetic variants associated with autoimmunity and infection, genetic control of the human immune system during homeostasis is poorly understood. We undertook a comprehensive immunophenotyping approach, analyzing 78,000 immune traits in 669 female twins. From the top 151 heritable traits (up to 96% heritable), we used replicated GWAS to obtain 297 SNP associations at 11 genetic loci, explaining up to 36% of the variation of 19 traits. We found multiple associations with canonical traits of all major immune cell subsets and uncovered insights into genetic control for regulatory T cells. This data set also revealed traits associated with loci known to confer autoimmune susceptibility, providing mechanistic hypotheses linking immune traits with the etiology of disease. Our data establish a bioresource that links genetic control elements associated with normal immune traits to common autoimmune and infectious diseases, providing a shortcut to identifying potential mechanisms of immune-related diseases. Copyright © 2015 Elsevier Inc. All rights reserved.

  6. Conformational occlusion of blockade antibody epitopes, a novel mechanism of GII.4 human norovirus immune evasion

    OpenAIRE

    Lindesmith, Lisa C.; Mallory, Michael L.; Debbink, Kari; Donaldson, Eric F.; Brewer-Jensen, Paul D.; Swann, Excel W.; Sheahan, Timothy P.; Graham, Rachel L.; Beltramello, Martina; Corti, Davide; Lanzavecchia, Antonio; Baric, Ralph S.

    2018-01-01

    ABSTRACT Extensive antigenic diversity within the GII.4 genotype of human norovirus is a major driver of pandemic emergence and a significant obstacle to development of cross-protective immunity after natural infection and vaccination. However, human and mouse monoclonal antibody studies indicate that, although rare, antibodies to conserved GII.4 blockade epitopes are generated. The mechanisms by which these epitopes evade immune surveillance are uncertain. Here, we developed a new approach f...

  7. The role of STAT3 in leading the crosstalk between human cancers and the immune system.

    Science.gov (United States)

    Wang, Yu; Shen, Yicheng; Wang, Sinan; Shen, Qiang; Zhou, Xuan

    2018-02-28

    The development and progression of human cancers are continuously and dynamically regulated by intrinsic and extrinsic factors. As a converging point of multiple oncogenic pathways, signal transducer and activator of transcription 3 (STAT3) is constitutively activated both in tumor cells and tumor-infiltrated immune cells. Activated STAT3 persistently triggers tumor progression through direct regulation of oncogenic gene expression. Apart from its oncogenic role in regulating gene expression in tumor cells, STAT3 also paves the way for human cancer growth through immunosuppression. Activated STAT3 in immune cells results in inhibition of immune mediators and promotion of immunosuppressive factors. Therefore, STAT3 modulates the interaction between tumor cells and host immunity. Accumulating evidence suggests that targeting STAT3 may enhance anti-cancer immune responses and rescue the suppressed immunologic microenvironment in tumors. Taken together, STAT3 has emerged as a promising target in cancer immunotherapy. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. T-cell independent reconstitution of the immunoglobulin levels in nu/nu mice

    International Nuclear Information System (INIS)

    Mannhardt, W.; Schulte-Wissermann, H.; Gardilcic, S.; Leon, F. de

    1982-01-01

    Nude mice were transplanted under the renal capsule either with allogeneic or human thymus that were long-term precultured or pretreated in vitro with Carrageenan for three days. None of the thymus tissue transplants showed lymphatic repopulation 9 wk after transplantation. Histological investigation of the peripheral lymphatic tissue did not reveal any change in the thymus-dependent area. On the other hand, plasma cells and germinal centers could be found in significantly increased numbers. In addition, a normalization of the serum immunoglobulin concentrations could be found, as no specific antibodies against thymus-dependent antigens were present after immunization and T-cell function did not improve. Similar results were obtained 9 wk after injection of irradiated thymocyte suspensions or of peritoneal macrophages from immunocompetent donors. It is concluded that thymus epithelial cells could act via macrophages on the polyclonal maturation and differentiation of B cells without involvement of T cells. This would be in agreement with the experience in some patients with severe combined immunodeficiency (SCID) in which reconstitution of the immunoglobulin levels is observed after transplantation of cultured thymus tissue before T-cell reconstitution can be demonstrated. (Auth.)

  9. Human embryo immune escape mechanisms rediscovered by the tumor.

    Science.gov (United States)

    Ridolfi, Laura; Petrini, Massimiliano; Fiammenghi, Laura; Riccobon, Angela; Ridolfi, Ruggero

    2009-01-01

    Towards the end of the 1990s, the two opposing theories on immunosurveillance and immunostimulation were extensively studied by researchers in an attempt to understand the complex mechanisms that regulate the relation between tumors and the host's immune system. Both theories probably have elements that would help us to comprehend how the host can induce anti-tumor clinical responses through stimulation of the immune system and which could also give us a deeper insight into the mechanisms of tumor immunosuppression. The model that most resembles the behavior of tumor cells in terms of growth, infiltration and suppression of the immune system of the environment in which they live is undoubtedly that of the embryonic cell. The fetus behaves like an allogenic transplant within the mother's body, using every means it has to escape from and defend itself against the mother's immune system. The majority of these mechanisms are the same as those found in tumor cells: antigenic loss, lack of expression of classic HLA-I molecules, production of immunosuppressive cytokines, induction of lack of expression of co-stimulatory molecules in antigen presenting cells, and induction of apoptosis in infiltrating lymphocytes, with activation of a type Th2 regulatory lymphocyte response. A careful and comparative study of key mechanisms capable of triggering tolerance or cytotoxicity in both embryonic and tumor cells could prove immensely valuable in designing new strategies for anti-tumor immunotherapy.

  10. Human perinatal immunity in physiological conditions and during infection.

    Science.gov (United States)

    van Well, Gijs T J; Daalderop, Leonie A; Wolfs, Tim; Kramer, Boris W

    2017-12-01

    The intrauterine environment was long considered sterile. However, several infectious threats are already present during fetal life. This review focuses on the postnatal immunological consequences of prenatal exposure to microorganisms and related inflammatory stimuli. Both the innate and adaptive immune systems of the fetus and neonate are immature, which makes them highly susceptible to infections. There is good evidence that prenatal infections are a primary cause of preterm births. Additionally, the association between antenatal inflammation and adverse neonatal outcomes has been well established. The lung, gastrointestinal tract, and skin are exposed to amniotic fluid during pregnancy and are probable targets of infection and subsequent inflammation during pregnancy. We found a large number of studies focusing on prenatal infection and the host response. Intrauterine infection and fetal immune responses are well studied, and we describe clinical data on cellular, cytokine, and humoral responses to different microbial challenges. The link to postnatal immunological effects including immune paralysis and/or excessive immune activation, however, turned out to be much more complicated. We found studies relating prenatal infectious or inflammatory hits to well-known neonatal diseases such as respiratory distress syndrome, bronchopulmonary dysplasia, and necrotizing enterocolitis. Despite these data, a direct link between prenatal hits and postnatal immunological outcome could not be undisputedly established. We did however identify several unresolved topics and propose questions for further research.

  11. Predictive Virtual Infection Modeling of Fungal Immune Evasion in Human Whole Blood.

    Science.gov (United States)

    Prauße, Maria T E; Lehnert, Teresa; Timme, Sandra; Hünniger, Kerstin; Leonhardt, Ines; Kurzai, Oliver; Figge, Marc Thilo

    2018-01-01

    Bloodstream infections by the human-pathogenic fungi Candida albicans and Candida glabrata increasingly occur in hospitalized patients and are associated with high mortality rates. The early immune response against these fungi in human blood comprises a concerted action of humoral and cellular components of the innate immune system. Upon entering the blood, the majority of fungal cells will be eliminated by innate immune cells, i.e., neutrophils and monocytes. However, recent studies identified a population of fungal cells that can evade the immune response and thereby may disseminate and cause organ dissemination, which is frequently observed during candidemia. In this study, we investigate the so far unresolved mechanism of fungal immune evasion in human whole blood by testing hypotheses with the help of mathematical modeling. We use a previously established state-based virtual infection model for whole-blood infection with C. albicans to quantify the immune response and identified the fungal immune-evasion mechanism. While this process was assumed to be spontaneous in the previous model, we now hypothesize that the immune-evasion process is mediated by host factors and incorporate such a mechanism in the model. In particular, we propose, based on previous studies that the fungal immune-evasion mechanism could possibly arise through modification of the fungal surface by as of yet unknown proteins that are assumed to be secreted by activated neutrophils. To validate or reject any of the immune-evasion mechanisms, we compared the simulation of both immune-evasion models for different infection scenarios, i.e., infection of whole blood with either C. albicans or C. glabrata under non-neutropenic and neutropenic conditions. We found that under non-neutropenic conditions, both immune-evasion models fit the experimental data from whole-blood infection with C. albicans and C. glabrata . However, differences between the immune-evasion models could be observed for the

  12. Predictive Virtual Infection Modeling of Fungal Immune Evasion in Human Whole Blood

    Directory of Open Access Journals (Sweden)

    Maria T. E. Prauße

    2018-03-01

    Full Text Available Bloodstream infections by the human-pathogenic fungi Candida albicans and Candida glabrata increasingly occur in hospitalized patients and are associated with high mortality rates. The early immune response against these fungi in human blood comprises a concerted action of humoral and cellular components of the innate immune system. Upon entering the blood, the majority of fungal cells will be eliminated by innate immune cells, i.e., neutrophils and monocytes. However, recent studies identified a population of fungal cells that can evade the immune response and thereby may disseminate and cause organ dissemination, which is frequently observed during candidemia. In this study, we investigate the so far unresolved mechanism of fungal immune evasion in human whole blood by testing hypotheses with the help of mathematical modeling. We use a previously established state-based virtual infection model for whole-blood infection with C. albicans to quantify the immune response and identified the fungal immune-evasion mechanism. While this process was assumed to be spontaneous in the previous model, we now hypothesize that the immune-evasion process is mediated by host factors and incorporate such a mechanism in the model. In particular, we propose, based on previous studies that the fungal immune-evasion mechanism could possibly arise through modification of the fungal surface by as of yet unknown proteins that are assumed to be secreted by activated neutrophils. To validate or reject any of the immune-evasion mechanisms, we compared the simulation of both immune-evasion models for different infection scenarios, i.e., infection of whole blood with either C. albicans or C. glabrata under non-neutropenic and neutropenic conditions. We found that under non-neutropenic conditions, both immune-evasion models fit the experimental data from whole-blood infection with C. albicans and C. glabrata. However, differences between the immune-evasion models could be

  13. Low cost delivery of proteins bioencapsulated in plant cells to human non-immune or immune modulatory cells.

    Science.gov (United States)

    Xiao, Yuhong; Kwon, Kwang-Chul; Hoffman, Brad E; Kamesh, Aditya; Jones, Noah T; Herzog, Roland W; Daniell, Henry

    2016-02-01

    Targeted oral delivery of GFP fused with a GM1 receptor binding protein (CTB) or human cell penetrating peptide (PTD) or dendritic cell peptide (DCpep) was investigated. Presence of GFP(+) intact plant cells between villi of ileum confirm their protection in the digestive system from acids/enzymes. Efficient delivery of GFP to gut-epithelial cells by PTD or CTB and to M cells by all these fusion tags confirm uptake of GFP in the small intestine. PTD fusion delivered GFP more efficiently to most tissues or organs than the other two tags. GFP was efficiently delivered to the liver by all fusion tags, likely through the gut-liver axis. In confocal imaging studies of human cell lines using purified GFP fused with different tags, GFP signal of DCpep-GFP was only detected within dendritic cells. PTD-GFP was only detected within kidney or pancreatic cells but not in immune modulatory cells (macrophages, dendritic, T, B, or mast cells). In contrast, CTB-GFP was detected in all tested cell types, confirming ubiquitous presence of GM1 receptors. Such low-cost oral delivery of protein drugs to sera, immune system or non-immune cells should dramatically lower their cost by elimination of prohibitively expensive fermentation, protein purification cold storage/transportation and increase patient compliance. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  14. Aggression, Social Stress, and the Immune System in Humans and Animal Models

    Directory of Open Access Journals (Sweden)

    Aki Takahashi

    2018-03-01

    Full Text Available Social stress can lead to the development of psychological problems ranging from exaggerated anxiety and depression to antisocial and violence-related behaviors. Increasing evidence suggests that the immune system is involved in responses to social stress in adulthood. For example, human studies show that individuals with high aggression traits display heightened inflammatory cytokine levels and dysregulated immune responses such as slower wound healing. Similar findings have been observed in patients with depression, and comorbidity of depression and aggression was correlated with stronger immune dysregulation. Therefore, dysregulation of the immune system may be one of the mediators of social stress that produces aggression and/or depression. Similar to humans, aggressive animals also show increased levels of several proinflammatory cytokines, however, unlike humans these animals are more protected from infectious organisms and have faster wound healing than animals with low aggression. On the other hand, subordinate animals that receive repeated social defeat stress have been shown to develop escalated and dysregulated immune responses such as glucocorticoid insensitivity in monocytes. In this review we synthesize the current evidence in humans, non-human primates, and rodents to show a role for the immune system in responses to social stress leading to psychiatric problems such as aggression or depression. We argue that while depression and aggression represent two fundamentally different behavioral and physiological responses to social stress, it is possible that some overlapped, as well as distinct, pattern of immune signaling may underlie both of them. We also argue the necessity of studying animal models of maladaptive aggression induced by social stress (i.e., social isolation for understanding neuro-immune mechanism of aggression, which may be relevant to human aggression.

  15. Aggression, Social Stress, and the Immune System in Humans and Animal Models.

    Science.gov (United States)

    Takahashi, Aki; Flanigan, Meghan E; McEwen, Bruce S; Russo, Scott J

    2018-01-01

    Social stress can lead to the development of psychological problems ranging from exaggerated anxiety and depression to antisocial and violence-related behaviors. Increasing evidence suggests that the immune system is involved in responses to social stress in adulthood. For example, human studies show that individuals with high aggression traits display heightened inflammatory cytokine levels and dysregulated immune responses such as slower wound healing. Similar findings have been observed in patients with depression, and comorbidity of depression and aggression was correlated with stronger immune dysregulation. Therefore, dysregulation of the immune system may be one of the mediators of social stress that produces aggression and/or depression. Similar to humans, aggressive animals also show increased levels of several proinflammatory cytokines, however, unlike humans these animals are more protected from infectious organisms and have faster wound healing than animals with low aggression. On the other hand, subordinate animals that receive repeated social defeat stress have been shown to develop escalated and dysregulated immune responses such as glucocorticoid insensitivity in monocytes. In this review we synthesize the current evidence in humans, non-human primates, and rodents to show a role for the immune system in responses to social stress leading to psychiatric problems such as aggression or depression. We argue that while depression and aggression represent two fundamentally different behavioral and physiological responses to social stress, it is possible that some overlapped, as well as distinct, pattern of immune signaling may underlie both of them. We also argue the necessity of studying animal models of maladaptive aggression induced by social stress (i.e., social isolation) for understanding neuro-immune mechanism of aggression, which may be relevant to human aggression.

  16. Psychological Stress and the Human Immune System: A Meta-Analytic Study of 30 Years of Inquiry

    OpenAIRE

    Segerstrom, Suzanne C.; Miller, Gregory E.

    2004-01-01

    The present report meta-analyzes more than 300 empirical articles describing a relationship between psychological stress and parameters of the immune system in human participants. Acute stressors (lasting minutes) were associated with potentially adaptive upregulation of some parameters of natural immunity and downregulation of some functions of specific immunity. Brief naturalistic stressors (such as exams) tended to suppress cellular immunity while preserving humoral immunity. Chronic stres...

  17. Incomplete immune recovery in HIV infection

    DEFF Research Database (Denmark)

    Gaardbo, Julie C; Hartling, Hans J; Gerstoft, Jan

    2012-01-01

    -infected patients do not achieve optimal immune reconstitution despite suppression of viral replication. These patients are referred to as immunological nonresponders (INRs). INRs present with severely altered immunological functions, including malfunction and diminished production of cells within lymphopoetic...... tissue, perturbed frequencies of immune regulators such as regulatory T cells and Th17 cells, and increased immune activation, immunosenescence, and apoptosis. Importantly, INRs have an increased risk of morbidity and mortality compared to HIV-infected patients with an optimal immune reconstitution....... Additional treatment to HAART that may improve immune reconstitution has been investigated, but results thus far have proved disappointing. The reason for immunological nonresponse is incompletely understood. This paper summarizes the known and unknown factors regarding the incomplete immune reconstitution...

  18. Does immunity regulate ejaculate quality and fertility in humans?

    OpenAIRE

    Philip A. Skau; Ivar Folstad

    2005-01-01

    The production of high-quality ejaculates may represent significant costs during male reproduction. Spermatozoa are perceived as nonself by the immune system and are exposed to immunological attacks in the male reproductive tract. Autoimmunity to spermatozoa results in the production of antisperm antibodies that reduce sperm quality and hence fertility. Thus, males are dependent on the testis being an immunoprivileged site to reduce immunological reactions against their own sperm, and immunop...

  19. Immunomodulatory constituents of human breast milk and immunity from bronchiolitis.

    Science.gov (United States)

    Li, Chunyu; Liu, Yanbo; Jiang, Yanfang; Xu, Naijun; Lei, Jie

    2017-01-14

    The mother's immune status can be achieved by genetic and breastfeeding impact descendants of the immune system. The study aimed to determine whether a mother's immune status and breastfeeding practices were related to development of bronchiolitis in her infant. The frequency of T, B and natural kill (NK) cells in patients' blood and their mothers' breast milk was determined using flow cytometry. The concentrations of serum and breast milk IgG and IgD in individual patients and healthy control were determined by enzyme-linked immunosorbent assay (ELISA). The relationships between immunocytes, immunoglobulin and respiratory score (RS) were analyzed by Spearman's rank correlation test. The mothers of bronchiolitis patients had lower IgG concentrations in their breast milk when compared to the mothers of healthy children. There was no significant difference in the frequency of T cells, B cells, and NK cells in samples of breast milk. However, significant decreases of CD3+, CD8+ T cells, as well as significant increases of CD4+ T cells and CD19+ B cells were found in the serum of bronchiolitis infants. There were positive correlation relationships between RS and CD3+, CD4+ T cells, IgG and IgD concentrations. Our data suggested that the mothers of bronchiolitis patients had lower IgG concentration in their breast milk. The breast milk IgG might be absorbed by the breastfeeding infants, which could play important role in resistance of bronchiolitis.

  20. Effects of ascent to high altitude on human antimycobacterial immunity.

    Directory of Open Access Journals (Sweden)

    Sarah Eisen

    Full Text Available Tuberculosis infection, disease and mortality are all less common at high than low altitude and ascent to high altitude was historically recommended for treatment. The immunological and mycobacterial mechanisms underlying the association between altitude and tuberculosis are unclear. We studied the effects of altitude on mycobacteria and antimycobacterial immunity.Antimycobacterial immunity was assayed in 15 healthy adults residing at low altitude before and after they ascended to 3400 meters; and in 47 long-term high-altitude residents. Antimycobacterial immunity was assessed as the extent to which participants' whole blood supported or restricted growth of genetically modified luminescent Bacille Calmette-Guérin (BCG mycobacteria during 96 hours incubation. We developed a simplified whole blood assay that could be used by a technician in a low-technology setting. We used this to compare mycobacterial growth in participants' whole blood versus positive-control culture broth and versus negative-control plasma.Measurements of mycobacterial luminescence predicted the number of mycobacterial colonies cultured six weeks later. At low altitude, mycobacteria grew in blood at similar rates to positive-control culture broth whereas ascent to high altitude was associated with restriction (p ≤ 0.002 of mycobacterial growth to be 4-times less than in culture broth. At low altitude, mycobacteria grew in blood 25-times more than negative-control plasma whereas ascent to high altitude was associated with restriction (p ≤ 0.01 of mycobacterial growth to be only 6-times more than in plasma. There was no evidence of differences in antimycobacterial immunity at high altitude between people who had recently ascended to high altitude versus long-term high-altitude residents.An assay of luminescent mycobacterial growth in whole blood was adapted and found to be feasible in low-resource settings. This demonstrated that ascent to or residence at high altitude was

  1. FINE SPECIFICITY OF CELLULAR IMMUNE-RESPONSES IN HUMANS TO HUMAN CYTOMEGALOVIRUS IMMEDIATE-EARLY 1-PROTEIN

    NARCIS (Netherlands)

    ALP, NJ; ALLPORT, TD; VANZANTEN, J; RODGERS, B; SISSONS, JGP; BORYSIEWICZ, LK

    Cell-mediated immunity is important in maintaining the virus-host equilibrium in persistent human cytomegalovirus (HCMV) infection. The HCMV 72-kDa major immediate early 1 protein (IE1) is a target for CD8+ cytotoxic T cells in humans, as is the equivalent 89-kDa protein in mouse. Less is known

  2. Reconstitutable control rod spider assembly

    International Nuclear Information System (INIS)

    Shallenberger, J.M.; Ferian, S.J.

    1990-01-01

    A reconstitutable control rod/spider assembly includes a hollow connecting finger of the spider having a pair of opposing flat segments formed on the interior thereof and engaging a pair of opposing flat sectors formed on the exterior of a stem extending form the upper end of control rod. The stem also has an externally-threaded portion engaging a nut and a pilot aligning portion for the nut. The nut has a radially flexible and expandable thread-defining element captured in its bore. The segments and sectors allow the rod to be removed and reattached after turning through 180 0 to allow more even wear on the rod. (author)

  3. Human resource management in the Georgian National Immunization Program: a baseline assessment.

    Science.gov (United States)

    Esmail, Laura C; Cohen-Kohler, Jillian Clare; Djibuti, Mamuka

    2007-07-31

    Georgia's health care system underwent dramatic reform after gaining independence in 1991. The decentralization of the health care system was one of the core elements of health care reform but reports suggest that human resource management issues were overlooked. The Georgian national immunization program was affected by these reforms and is not functioning at optimum levels. This paper describes the state of human resource management practices within the Georgian national immunization program in late 2004. Thirty districts were selected for the study. Within these districts, 392 providers and thirty immunization managers participated in the study. Survey questionnaires were administered through face-to-face interviews to immunization managers and a mail survey was administered to immunization providers. Qualitative data collection involved four focus groups. Analysis of variance (ANOVA) and Chi-square tests were used to test for differences between groups for continuous and categorical variables. Content analysis identified main themes within the focus groups. Weak administrative links exist between the Centres of Public Health (CPH) and Primary Health Care (PHC) health facilities. There is a lack of clear management guidelines and only 49.6% of all health providers had written job descriptions. A common concern among all respondents was the extremely inadequate salary. Managers cited lack of authority and poor knowledge and skills in human resource management. Lack of resources and infrastructure were identified as major barriers to improving immunization. Our study found that the National Immunization Program in Georgia was characterized by weak organizational structure and processes and a lack of knowledge and skills in management and supervision, especially at peripheral levels. The development of the skills and processes of a well-managed workforce may help improve immunization rates, facilitate successful implementation of remaining health care reforms and

  4. Immune Recognition of Latency-insitigating Pathogens by Human Dendritic Cells

    DEFF Research Database (Denmark)

    Søndergaard, Jonas Nørskov

    for society. Consequently there is a pressing need to search for new treatment strategies. Nowadays it is known that HIV-1 and Mtb have acquired the ability to escape the removal from the body by exploiting the immune system for their own benefits. Dendritic cells (DCs) determine the way the immune response......Latent infections with the human pathogenic microorganisms Mycobacterium tuberculosis (Mtb) and the human immunodeficiency virus (HIV) are creating some of the most devastating pandemics to date, with great impact on the infected people’s lives, their expected lifetime, as well as general costs...... unfolds by signaling other immune cells how to respond. An early deregulation of the DCs may therefore propagate into detrimental effects in later stages of the immune response, and may permit HIV-1 and Mtb to become latent. Hence, understanding the way HIV-1 and Mtb interacts with DCs could lead to novel...

  5. Earthworms and Humans in Vitro: Characterizing Evolutionarily Conserved Stress and Immune Responses to Silver Nanoparticles

    DEFF Research Database (Denmark)

    Hayashi, Yuya; Engelmann, Péter; Foldbjerg, Rasmus

    2012-01-01

    Little is known about the potential threats of silver nanoparticles (AgNPs) to ecosystem health, with no detailed report existing on the stress and immune responses of soil invertebrates. Here we use earthworm primary cells, cross-referencing to human cell cultures with a particular emphasis on t...... in the coelomocytes and THP-1 cells. Our findings provide mechanistic clues on cellular innate immunity toward AgNPs that is likely to be evolutionarily conserved across the animal kingdom....

  6. Human Ebola virus infection results in substantial immune activation.

    Science.gov (United States)

    McElroy, Anita K; Akondy, Rama S; Davis, Carl W; Ellebedy, Ali H; Mehta, Aneesh K; Kraft, Colleen S; Lyon, G Marshall; Ribner, Bruce S; Varkey, Jay; Sidney, John; Sette, Alessandro; Campbell, Shelley; Ströher, Ute; Damon, Inger; Nichol, Stuart T; Spiropoulou, Christina F; Ahmed, Rafi

    2015-04-14

    Four Ebola patients received care at Emory University Hospital, presenting a unique opportunity to examine the cellular immune responses during acute Ebola virus infection. We found striking activation of both B and T cells in all four patients. Plasmablast frequencies were 10-50% of B cells, compared with less than 1% in healthy individuals. Many of these proliferating plasmablasts were IgG-positive, and this finding coincided with the presence of Ebola virus-specific IgG in the serum. Activated CD4 T cells ranged from 5 to 30%, compared with 1-2% in healthy controls. The most pronounced responses were seen in CD8 T cells, with over 50% of the CD8 T cells expressing markers of activation and proliferation. Taken together, these results suggest that all four patients developed robust immune responses during the acute phase of Ebola virus infection, a finding that would not have been predicted based on our current assumptions about the highly immunosuppressive nature of Ebola virus. Also, quite surprisingly, we found sustained immune activation after the virus was cleared from the plasma, observed most strikingly in the persistence of activated CD8 T cells, even 1 mo after the patients' discharge from the hospital. These results suggest continued antigen stimulation after resolution of the disease. From these convalescent time points, we identified CD4 and CD8 T-cell responses to several Ebola virus proteins, most notably the viral nucleoprotein. Knowledge of the viral proteins targeted by T cells during natural infection should be useful in designing vaccines against Ebola virus.

  7. Superior therapeutic efficacy of alphavirus-mediated immunization against human papilloma virus type 16 antigens in a murine tumour model : effects of the route of immunization

    NARCIS (Netherlands)

    Daemen, T; Riezebos-Brilman, A; Regts, J; Dontje, B; van der Zee, A; Wilschut, J

    2004-01-01

    In our efforts to develop a strong, effective immune response against cervical carcinoma and premalignant disease, we study the use of recombinant Semliki Forest virus (SFV) encoding the oncoproteins E6 and E7 from high-risk human papilloma viruses (HPVs). Optimal immunization conditions are

  8. Implications of the behavioural immune system for social behaviour and human health in the modern world.

    Science.gov (United States)

    Schaller, Mark; Murray, Damian R; Bangerter, Adrian

    2015-05-26

    The 'behavioural immune system' is composed of mechanisms that evolved as a means of facilitating behaviours that minimized infection risk and enhanced fitness. Recent empirical research on human populations suggests that these mechanisms have unique consequences for many aspects of human sociality--including sexual attitudes, gregariousness, xenophobia, conformity to majority opinion and conservative sociopolitical attitudes. Throughout much of human evolutionary history, these consequences may have had beneficial health implications; but health implications in modern human societies remain unclear. This article summarizes pertinent ways in which modern human societies are similar to and different from the ecologies within which the behavioural immune system evolved. By attending to these similarities and differences, we identify a set of plausible implications-both positive and negative-that the behavioural immune system may have on health outcomes in contemporary human contexts. We discuss both individual-level infection risk and population-level epidemiological outcomes. We also discuss a variety of additional implications, including compliance with public health policies, the adoption of novel therapeutic interventions and actual immunological functioning. Research on the behavioural immune system, and its implications in contemporary human societies, can provide unique insights into relationships between fitness, sociality and health. © 2015 The Author(s) Published by the Royal Society. All rights reserved.

  9. Preparation of antisera specific for human B cells by immunization of rabbits with immune complexes

    International Nuclear Information System (INIS)

    Welsh, K.I.; Turner, M.J.

    1976-01-01

    Three rabbit antisera are described which are specific without absorption (titer 1:100) for separated human B cells, as measured by complement and non-complement fixing assays. The method of production of these sera involved injections of rabbits with precipitin lines formed between 10μ1 of three separate detergent solubilized membrane preparations and 4μ1 aliquots of rabbit antisera to human B cells. In addition to being B cell specific, the three sera block the MLC reaction, inhibit aggregated IgG binding to B cells, and show differential degrees of B cell lysis when tested on a panel of separated B and T cells. These and other properties suggest that the target specificities of the antibodies are the human equivalent of the murine Ia antigens. (author)

  10. Molecular cloning of a second subunit of the receptor for human granulocyte - macrophage colony-stimulating factor (GM-CSF): Reconstitution of a high-affinity GM-CSF receptor

    International Nuclear Information System (INIS)

    Hayashida, Kazuhiro; Kitamura, Toshio; Gorman, D.M.; Miyajima, Atsushi; Arai, Kenichi; Yokota, Takashi

    1990-01-01

    Using the mouse interleukin 3 (IL-3) receptor cDNA as a probe, the authors obtained a monologous cDNA (KH97) from a cDNA library of a human hemopoietic cell line, TF-1. The protein encoded by the KH97 cDNA has 56% amino acid sequence identity with the mouse IL-3 receptor and retains features common to the family of cytokine receptors. Fibroblasts transfected with the KH97 cDNA expressed a protein of 120 kDa but did not bind any human cytokines, including IL-3 and granulocyte - macrophage colony-stimulating factor (GM-CSF). Interestingly, cotransfection of cDNAs for KH97 and the low-affinity human GM-CSF receptor in fibroblasts resulted in formation of a high-affinity receptor for GM-CSF. The dissociation rate of GM-CSF from the reconstituted high-affinity receptor was slower than that from the low-affinity site, whereas the association rate was unchanged. Cross-linking of 125 I-labeled GM-CSF to fibroblasts cotransfected with both cDNAs revealed the same cross-linking patterns as in TF-1 cells - i.e., two major proteins of 80 and 120 kDa which correspond to the low-affinity GM-CSF receptor and the KH97 protein, respectively. These results indicate that the high-affinity GM-CSF receptor is composed of at least two components in a manner analogous to the IL-2 receptor. They therefore propose to designate the low-affinity GM-CSF receptor and the KH97 protein as the α and β subunits of the GM-CSF receptor, respectively

  11. Humoral and cellular immune responses to Yersinia pestis Pla antigen in humans immunized with live plague vaccine.

    Science.gov (United States)

    Feodorova, Valentina A; Lyapina, Anna M; Khizhnyakova, Maria A; Zaitsev, Sergey S; Sayapina, Lidiya V; Arseneva, Tatiana E; Trukhachev, Alexey L; Lebedeva, Svetlana A; Telepnev, Maxim V; Ulianova, Onega V; Lyapina, Elena P; Ulyanov, Sergey S; Motin, Vladimir L

    2018-06-01

    To establish correlates of human immunity to the live plague vaccine (LPV), we analyzed parameters of cellular and antibody response to the plasminogen activator Pla of Y. pestis. This outer membrane protease is an essential virulence factor that is steadily expressed by Y. pestis. PBMCs and sera were obtained from a cohort of naïve (n = 17) and LPV-vaccinated (n = 34) donors. Anti-Pla antibodies of different classes and IgG subclasses were determined by ELISA and immunoblotting. The analysis of antibody response was complicated with a strong reactivity of Pla with normal human sera. The linear Pla B-cell epitopes were mapped using a library of 15-mer overlapping peptides. Twelve peptides that reacted specifically with sera of vaccinated donors were found together with a major cross-reacting peptide IPNISPDSFTVAAST located at the N-terminus. PBMCs were stimulated with recombinant Pla followed by proliferative analysis and cytokine profiling. The T-cell recall response was pronounced in vaccinees less than a year post-immunization, and became Th17-polarized over time after many rounds of vaccination. The Pla protein can serve as a biomarker of successful vaccination with LPV. The diagnostic use of Pla will require elimination of cross-reactive parts of the antigen.

  12. Immune Cell-Supplemented Human Skin Model for Studying Fungal Infections.

    Science.gov (United States)

    Kühbacher, Andreas; Sohn, Kai; Burger-Kentischer, Anke; Rupp, Steffen

    2017-01-01

    Human skin is a niche for various fungal species which either colonize the surface of this tissue as commensals or, primarily under conditions of immunosuppression, invade the skin and cause infection. Here we present a method for generation of a human in vitro skin model supplemented with immune cells of choice. This model represents a complex yet amenable tool to study molecular mechanisms of host-fungi interactions at human skin.

  13. Preventive immunization of aged and juvenile non-human primates to beta-amyloid

    Directory of Open Access Journals (Sweden)

    Kofler Julia

    2012-05-01

    Full Text Available Abstract Background Immunization against beta-amyloid (Aβ is a promising approach for the treatment of Alzheimer’s disease, but the optimal timing for the vaccination remains to be determined. Preventive immunization approaches may be more efficacious and associated with fewer side-effects; however, there is only limited information available from primate models about the effects of preclinical vaccination on brain amyloid composition and the neuroinflammatory milieu. Methods Ten non-human primates (NHP of advanced age (18–26 years and eight 2-year-old juvenile NHPs were immunized at 0, 2, 6, 10 and 14 weeks with aggregated Aβ42 admixed with monophosphoryl lipid A as adjuvant, and monitored for up to 6 months. Anti-Aβ antibody levels and immune activation markers were assessed in plasma and cerebrospinal fluid samples before and at several time-points after immunization. Microglial activity was determined by [11C]PK11195 PET scans acquired before and after immunization, and by post-mortem immunohistochemical and real-time PCR evaluation. Aβ oligomer composition was assessed by immunoblot analysis in the frontal cortex of aged immunized and non-immunized control animals. Results All juvenile animals developed a strong and sustained serum anti-Aβ IgG antibody response, whereas only 80 % of aged animals developed detectable antibodies. The immune response in aged monkeys was more delayed and significantly weaker, and was also more variable between animals. Pre- and post-immunization [11C]PK11195 PET scans showed no evidence of vaccine-related microglial activation. Post-mortem brain tissue analysis indicated a low overall amyloid burden, but revealed a significant shift in oligomer size with an increase in the dimer:pentamer ratio in aged immunized animals compared with non-immunized controls (P  Conclusions Our results indicate that preventive Aβ immunization is a safe therapeutic approach lacking adverse CNS immune system

  14. Reconstitution of fuel assemblies and core components

    Energy Technology Data Exchange (ETDEWEB)

    Hummel, Wolfgang; Langenberger, Jan [AREVA NP GmbH (Germany)

    2012-11-01

    Due to AREVA's experience and big portfolio of techniques, reconstitution of fuel assemblies and core components at light water reactors is possible within a reasonable timeframe and with interesting cost benefit. Customer feedback indicates the sustainability of such reconstitutions. As a result, a long-term maintenance of value can be assured and early waste disposal can be avoided. (orig.)

  15. Drosophila as a Model for Human Diseases-Focus on Innate Immunity in Barrier Epithelia.

    Science.gov (United States)

    Bergman, P; Seyedoleslami Esfahani, S; Engström, Y

    2017-01-01

    Epithelial immunity protects the host from harmful microbial invaders but also controls the beneficial microbiota on epithelial surfaces. When this delicate balance between pathogen and symbiont is disturbed, clinical disease often occurs, such as in inflammatory bowel disease, cystic fibrosis, or atopic dermatitis, which all can be in part linked to impairment of barrier epithelia. Many innate immune receptors, signaling pathways, and effector molecules are evolutionarily conserved between human and Drosophila. This review describes the current knowledge on Drosophila as a model for human diseases, with a special focus on innate immune-related disorders of the gut, lung, and skin. The discovery of antimicrobial peptides, the crucial role of Toll and Toll-like receptors, and the evolutionary conservation of signaling to the immune systems of both human and Drosophila are described in a historical perspective. Similarities and differences between human and Drosophila are discussed; current knowledge on receptors, signaling pathways, and effectors are reviewed, including antimicrobial peptides, reactive oxygen species, as well as autophagy. We also give examples of human diseases for which Drosophila appears to be a useful model. In addition, the limitations of the Drosophila model are mentioned. Finally, we propose areas for future research, which include using the Drosophila model for drug screening, as a validation tool for novel genetic mutations in humans and for exploratory research of microbiota-host interactions, with relevance for infection, wound healing, and cancer. © 2017 Elsevier Inc. All rights reserved.

  16. Humoral immune response to the entire human immunodeficiency virus envelope glycoprotein made in insect cells

    Energy Technology Data Exchange (ETDEWEB)

    Rusche, J.R.; Lynn, D.L.; Robert-Guroff, M.; Langlois, A.J.; Lyerly, H.K.; Carson, H.; Krohn, K.; Ranki, A.; Gallo, R.C.; Bolognesi, D.P.; Putney, S.D.

    1987-10-01

    The human immunodeficiency virus envelope gene was expressed in insect cells by using a Baculovirus expression vector. The protein has an apparent molecular mass of 160 kDa, appears on the surface of infected insect cells, and does not appear to be cleaved to glycoproteins gp120 and gp41. Goats immunized with the 160-kDa protein have high titers of antibody that neutralizes virus infection as measured by viral gene expression or cell cytolysis. In addition, immune sera can block fusion of human immunodeficiency virus-infected cells in culture. Both neutralization and fusion-blocking activities are bound to and eluted from immobilized gp120.

  17. Humoral immune response to the entire human immunodeficiency virus envelope glycoprotein made in insect cells

    International Nuclear Information System (INIS)

    Rusche, J.R.; Lynn, D.L.; Robert-Guroff, M.

    1987-01-01

    The human immunodeficiency virus envelope gene was expressed in insect cells by using a Baculovirus expression vector. The protein has an apparent molecular mass of 160 kDa, appears on the surface of infected insect cells, and does not appear to be cleaved to glycoproteins gp120 and gp41. Goats immunized with the 160-kDa protein have high titers of antibody that neutralizes virus infection as measured by viral gene expression or cell cytolysis. In addition, immune sera can block fusion of human immunodeficiency virus-infected cells in culture. Both neutralization and fusion-blocking activities are bound to and eluted from immobilized gp120

  18. Altered parenting and the reconstituted family.

    Science.gov (United States)

    Whitley, G G; Kachel, J M

    1991-01-01

    Reconstituted families are a high incidence phenomena in contemporary society. Because the family continues to be a focus for the delivery of nursing care, nurses must now address the special needs of individuals who are members of reconstituted families. Studies in this area provide important background information regarding behavioral patterns in reconstituted families that can be used for assessment and intervention with these families. Through the use of focused assessment parameters, nurses can collect data that will indicate the special needs of members of reconstituted families. In general, nursing interventions with clients who are a part of a reconstituted family fall into two major categories: (a) developing positive parenting behaviors, and (b) protecting the development of the stepchild.

  19. Recent advances on Charpy specimen reconstitution techniques

    Energy Technology Data Exchange (ETDEWEB)

    Andrade, Arnaldo H.P.; Lobo, Raquel M.; Miranda, Carlos Alexandre J., E-mail: aandrade@ipen.br [Instituto de Pesquisas Energeticas e Nucleares (IPEN/CNEN-SP), Sao Paulo, SP (Brazil)

    2017-07-01

    Charpy specimen reconstitution is widely used around the world as a tool to enhance or supplement surveillance programs of nuclear reactor pressure vessels. The reconstitution technique consists in the incorporation of a small piece from a previously tested specimen into a compound specimen, allowing to increase the number of tests. This is especially important if the available materials is restricted and fracture mechanics parameter have to be determined. The reconstitution technique must fulfill some demands, among them tests results like the original standard specimens and the loaded material of the insert must not be influenced by the welding and machining procedure. It is known that reconstitution of Charpy specimens may affect the impact energy in a consequence of the constraint of plastic deformation by the hardened weldment and HAZ. This paper reviews some recent advances of the reconstitution technique and its applications. (author)

  20. Recent advances on Charpy specimen reconstitution techniques

    International Nuclear Information System (INIS)

    Andrade, Arnaldo H.P.; Lobo, Raquel M.; Miranda, Carlos Alexandre J.

    2017-01-01

    Charpy specimen reconstitution is widely used around the world as a tool to enhance or supplement surveillance programs of nuclear reactor pressure vessels. The reconstitution technique consists in the incorporation of a small piece from a previously tested specimen into a compound specimen, allowing to increase the number of tests. This is especially important if the available materials is restricted and fracture mechanics parameter have to be determined. The reconstitution technique must fulfill some demands, among them tests results like the original standard specimens and the loaded material of the insert must not be influenced by the welding and machining procedure. It is known that reconstitution of Charpy specimens may affect the impact energy in a consequence of the constraint of plastic deformation by the hardened weldment and HAZ. This paper reviews some recent advances of the reconstitution technique and its applications. (author)

  1. Early determinants of long-term T-cell reconstitution after hematopoietic stem cell transplantation for severe combined immunodeficiency

    NARCIS (Netherlands)

    Borghans, José A.; Bredius, Robbert G.; Hazenberg, Mette D.; Roelofs, Helene; Jol-van der Zijde, Els C.; Heidt, Jeroen; Otto, Sigrid A.; Kuijpers, Taco W.; Fibbe, Willem E.; Vossen, Jaak M.; Miedema, Frank; van Tol, Maarten J.

    2006-01-01

    The immune system of patients with severe combined immunodeficiency (SCID) reconstitutes to a large extent during the first years after hematopoietic stem cell transplantation (HSCT). It was suggested, however, that accelerated loss of thymus output may cause impaired immune function at the long

  2. Social network architecture of human immune cells unveiled by quantitative proteomics.

    Science.gov (United States)

    Rieckmann, Jan C; Geiger, Roger; Hornburg, Daniel; Wolf, Tobias; Kveler, Ksenya; Jarrossay, David; Sallusto, Federica; Shen-Orr, Shai S; Lanzavecchia, Antonio; Mann, Matthias; Meissner, Felix

    2017-05-01

    The immune system is unique in its dynamic interplay between numerous cell types. However, a system-wide view of how immune cells communicate to protect against disease has not yet been established. We applied high-resolution mass-spectrometry-based proteomics to characterize 28 primary human hematopoietic cell populations in steady and activated states at a depth of >10,000 proteins in total. Protein copy numbers revealed a specialization of immune cells for ligand and receptor expression, thereby connecting distinct immune functions. By integrating total and secreted proteomes, we discovered fundamental intercellular communication structures and previously unknown connections between cell types. Our publicly accessible (http://www.immprot.org/) proteomic resource provides a framework for the orchestration of cellular interplay and a reference for altered communication associated with pathology.

  3. Human papillomavirus immunization uptake among girls with a refugee background compared with Danish-born girls

    DEFF Research Database (Denmark)

    P. Møller, Sanne; Kristiansen, Maria; Norredam, Marie

    2018-01-01

    Refugee children and their families may experience impaired access to healthcare; therefore, we aimed to uncover human papillomavirus (HPV) immunization patterns among a large group of refugee girls compared with Danish-born girls. We also examined possible predictors of uptake among refugee girls....... We used aregister-based cohort design where refugee girls (n = 3264) who, between 1 January 1994 and 31 December 2010, obtained residency permits in Denmark, were included and matched on age and sex with Danish-born girls (n = 19 584). Personal identification numbers were cross-linked to the National...... Danish Health Service Register, identifying all contacts for HPV-immunization in both the ordinary HPV-immunization program and in a catch-up program. We applied logistic regression to estimate the odds ratios (OR) of uptake. We found that refugee girls had significantly lower HPV-immunization uptake...

  4. Induction and Subversion of Human Protective Immunity: Contrasting Influenza and Respiratory Syncytial Virus

    Science.gov (United States)

    Ascough, Stephanie; Paterson, Suzanna; Chiu, Christopher

    2018-01-01

    Respiratory syncytial virus (RSV) and influenza are among the most important causes of severe respiratory disease worldwide. Despite the clinical need, barriers to developing reliably effective vaccines against these viruses have remained firmly in place for decades. Overcoming these hurdles requires better understanding of human immunity and the strategies by which these pathogens evade it. Although superficially similar, the virology and host response to RSV and influenza are strikingly distinct. Influenza induces robust strain-specific immunity following natural infection, although protection by current vaccines is short-lived. In contrast, even strain-specific protection is incomplete after RSV and there are currently no licensed RSV vaccines. Although animal models have been critical for developing a fundamental understanding of antiviral immunity, extrapolating to human disease has been problematic. It is only with recent translational advances (such as controlled human infection models and high-dimensional technologies) that the mechanisms responsible for differences in protection against RSV compared to influenza have begun to be elucidated in the human context. Influenza infection elicits high-affinity IgA in the respiratory tract and virus-specific IgG, which correlates with protection. Long-lived influenza-specific T cells have also been shown to ameliorate disease. This robust immunity promotes rapid emergence of antigenic variants leading to immune escape. RSV differs markedly, as reinfection with similar strains occurs despite natural infection inducing high levels of antibody against conserved antigens. The immunomodulatory mechanisms of RSV are thus highly effective in inhibiting long-term protection, with disturbance of type I interferon signaling, antigen presentation and chemokine-induced inflammation possibly all contributing. These lead to widespread effects on adaptive immunity with impaired B cell memory and reduced T cell generation and

  5. Induction and Subversion of Human Protective Immunity: Contrasting Influenza and Respiratory Syncytial Virus

    Directory of Open Access Journals (Sweden)

    Stephanie Ascough

    2018-03-01

    Full Text Available Respiratory syncytial virus (RSV and influenza are among the most important causes of severe respiratory disease worldwide. Despite the clinical need, barriers to developing reliably effective vaccines against these viruses have remained firmly in place for decades. Overcoming these hurdles requires better understanding of human immunity and the strategies by which these pathogens evade it. Although superficially similar, the virology and host response to RSV and influenza are strikingly distinct. Influenza induces robust strain-specific immunity following natural infection, although protection by current vaccines is short-lived. In contrast, even strain-specific protection is incomplete after RSV and there are currently no licensed RSV vaccines. Although animal models have been critical for developing a fundamental understanding of antiviral immunity, extrapolating to human disease has been problematic. It is only with recent translational advances (such as controlled human infection models and high-dimensional technologies that the mechanisms responsible for differences in protection against RSV compared to influenza have begun to be elucidated in the human context. Influenza infection elicits high-affinity IgA in the respiratory tract and virus-specific IgG, which correlates with protection. Long-lived influenza-specific T cells have also been shown to ameliorate disease. This robust immunity promotes rapid emergence of antigenic variants leading to immune escape. RSV differs markedly, as reinfection with similar strains occurs despite natural infection inducing high levels of antibody against conserved antigens. The immunomodulatory mechanisms of RSV are thus highly effective in inhibiting long-term protection, with disturbance of type I interferon signaling, antigen presentation and chemokine-induced inflammation possibly all contributing. These lead to widespread effects on adaptive immunity with impaired B cell memory and reduced T cell

  6. Reconstituted human corneal epithelium: a new alternative to the Draize eye test for the assessment of the eye irritation potential of chemicals and cosmetic products.

    Science.gov (United States)

    Doucet, O; Lanvin, M; Thillou, C; Linossier, C; Pupat, C; Merlin, B; Zastrow, L

    2006-06-01

    The aim of this study was to evaluate the interest of a new three-dimensional epithelial model cultivated from human corneal cells to replace animal testing in the assessment of eye tolerance. To this end, 65 formulated cosmetic products and 36 chemicals were tested by means of this in vitro model using a simplified toxicokinetic approach. The chemicals were selected from the ECETOC data bank and the EC/HO International validation study list. Very satisfactory results were obtained in terms of concordance with the Draize test data for the formulated cosmetic products. Moreover, the response of the corneal model appeared predictive of human ocular response clinically observed by ophthalmologists. The in vitro scores for the chemicals tested strongly correlated with their respective scores in vivo. For all the compounds tested, the response of the corneal model to irritants was similar regardless of their chemical structure, suggesting a good robustness of the prediction model proposed. We concluded that this new three-dimensional epithelial model, developed from human corneal cells, could be promising for the prediction of eye irritation induced by chemicals and complex formulated products, and that these two types of materials should be tested using a similar protocol. A simple shortening of the exposure period was required for the chemicals assumed to be more aggressively irritant to the epithelial tissues than the cosmetic formulae.

  7. Directed diffusion of reconstituting dimers

    International Nuclear Information System (INIS)

    Barma, Mustansir; Grynberg, Marcelo D; Stinchcombe, Robin B

    2007-01-01

    We discuss the dynamical aspects of an asymmetric version of assisted diffusion of hard core particles on a ring studied by Menon et al (1997 J. Stat. Phys. 86 1237). The asymmetry brings in phenomena like kinematic waves and effects of the Kardar-Parisi-Zhang non-linearity, which combine with the feature of strongly broken ergodicity, a characteristic of the model. A central role is played by a single non-local invariant, the irreducible string, whose interplay with the driven motion of reconstituting dimers, arising from the assisted hopping, determines the asymptotic dynamics and scaling regimes. These are investigated both analytically and numerically through sector-dependent mappings to the asymmetric simple exclusion process

  8. Directed diffusion of reconstituting dimers

    Energy Technology Data Exchange (ETDEWEB)

    Barma, Mustansir [Department of Theoretical Physics, Tata Institute of Fundamental Research, Mumbai 400005 (India); Grynberg, Marcelo D [Departamento de Fisica, Universidad Nacional de La Plata (1900) La Plata (Argentina); Stinchcombe, Robin B [Isaac Newton Institute for Mathematical Sciences, 20 Clarkson Road, Cambridge CB3 0EH (United Kingdom)

    2007-02-14

    We discuss the dynamical aspects of an asymmetric version of assisted diffusion of hard core particles on a ring studied by Menon et al (1997 J. Stat. Phys. 86 1237). The asymmetry brings in phenomena like kinematic waves and effects of the Kardar-Parisi-Zhang non-linearity, which combine with the feature of strongly broken ergodicity, a characteristic of the model. A central role is played by a single non-local invariant, the irreducible string, whose interplay with the driven motion of reconstituting dimers, arising from the assisted hopping, determines the asymptotic dynamics and scaling regimes. These are investigated both analytically and numerically through sector-dependent mappings to the asymmetric simple exclusion process.

  9. The role of glycans in immune evasion: the human fetoembryonic defence system hypothesis revisited.

    Science.gov (United States)

    Clark, Gary F

    2014-03-01

    Emerging data suggest that mechanisms to evade the human immune system may be shared by the conceptus, tumour cells, persistent pathogens and viruses. It is therefore timely to revisit the human fetoembryonic defense system (Hu-FEDS) hypothesis that was proposed in two papers in the 1990s. The initial paper suggested that glycoconjugates expressed in the human reproductive system inhibited immune responses directed against gametes and the developing human by employing their carbohydrate sequences as functional groups. These glycoconjugates were proposed to block specific binding interactions and interact with lectins linked to signal transduction pathways that modulated immune cell functions. The second article suggested that aggressive tumour cells and persistent pathogens (HIV, H. pylori, schistosomes) either mimicked or acquired the same carbohydrate functional groups employed in this system to evade immune responses. This subterfuge enabled these pathogens and tumour cells to couple their survival to the human reproductive imperative. The Hu-FEDS model has been repeatedly tested since its inception. Data relevant to this model have also been obtained in other studies. Herein, the Hu-FEDS hypothesis is revisited in the context of these more recent findings. Far more supportive evidence for this model now exists than when it was first proposed, and many of the original predictions have been validated. This type of subterfuge by pathogens and tumour cells likely applies to all sexually reproducing metazoans that must protect their gametes from immune responses. Intervention in these pathological states will likely remain problematic until this system of immune evasion is fully understood and appreciated.

  10. Structural and functional analyses of DNA-sensing and immune activation by human cGAS.

    Science.gov (United States)

    Kato, Kazuki; Ishii, Ryohei; Goto, Eiji; Ishitani, Ryuichiro; Tokunaga, Fuminori; Nureki, Osamu

    2013-01-01

    The detection of cytosolic DNA, derived from pathogens or host cells, by cytosolic receptors is essential for appropriate host immune responses. Cyclic GMP-AMP synthase (cGAS) is a newly identified cytosolic DNA receptor that produces cyclic GMP-AMP, which activates stimulator of interferon genes (STING), resulting in TBK1-IRF3 pathway activation followed by the production of type I interferons. Here we report the crystal structure of human cGAS. The structure revealed that a cluster of lysine and arginine residues forms the positively charged DNA binding surface of human cGAS, which is important for the STING-dependent immune activation. A structural comparison with other previously determined cGASs and our functional analyses suggested that a conserved zinc finger motif and a leucine residue on the DNA binding surface are crucial for the DNA-specific immune response of human cGAS, consistent with previous work. These structural features properly orient the DNA binding to cGAS, which is critical for DNA-induced cGAS activation and STING-dependent immune activation. Furthermore, we showed that the cGAS-induced activation of STING also involves the activation of the NF-κB and IRF3 pathways. Our results indicated that cGAS is a DNA sensor that efficiently activates the host immune system by inducing two distinct pathways.

  11. Structural and functional analyses of DNA-sensing and immune activation by human cGAS.

    Directory of Open Access Journals (Sweden)

    Kazuki Kato

    Full Text Available The detection of cytosolic DNA, derived from pathogens or host cells, by cytosolic receptors is essential for appropriate host immune responses. Cyclic GMP-AMP synthase (cGAS is a newly identified cytosolic DNA receptor that produces cyclic GMP-AMP, which activates stimulator of interferon genes (STING, resulting in TBK1-IRF3 pathway activation followed by the production of type I interferons. Here we report the crystal structure of human cGAS. The structure revealed that a cluster of lysine and arginine residues forms the positively charged DNA binding surface of human cGAS, which is important for the STING-dependent immune activation. A structural comparison with other previously determined cGASs and our functional analyses suggested that a conserved zinc finger motif and a leucine residue on the DNA binding surface are crucial for the DNA-specific immune response of human cGAS, consistent with previous work. These structural features properly orient the DNA binding to cGAS, which is critical for DNA-induced cGAS activation and STING-dependent immune activation. Furthermore, we showed that the cGAS-induced activation of STING also involves the activation of the NF-κB and IRF3 pathways. Our results indicated that cGAS is a DNA sensor that efficiently activates the host immune system by inducing two distinct pathways.

  12. Vesicular trafficking of immune mediators in human eosinophils revealed by immunoelectron microscopy

    Energy Technology Data Exchange (ETDEWEB)

    Melo, Rossana C.N., E-mail: rossana.melo@ufjf.edu.br [Laboratory of Cellular Biology, Department of Biology, ICB, Federal University of Juiz de Fora, UFJF, Rua José Lourenço Kelmer, Juiz de Fora, MG 36036-900 (Brazil); Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, CLS 943, Boston, MA 02215 (United States); Weller, Peter F. [Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, CLS 943, Boston, MA 02215 (United States)

    2016-10-01

    Electron microscopy (EM)-based techniques are mostly responsible for our current view of cell morphology at the subcellular level and continue to play an essential role in biological research. In cells from the immune system, such as eosinophils, EM has helped to understand how cells package and release mediators involved in immune responses. Ultrastructural investigations of human eosinophils enabled visualization of secretory processes in detail and identification of a robust, vesicular trafficking essential for the secretion of immune mediators via a non-classical secretory pathway associated with secretory (specific) granules. This vesicular system is mainly organized as large tubular-vesicular carriers (Eosinophil Sombrero Vesicles – EoSVs) actively formed in response to cell activation and provides a sophisticated structural mechanism for delivery of granule-stored mediators. In this review, we highlight the application of EM techniques to recognize pools of immune mediators at vesicular compartments and to understand the complex secretory pathway within human eosinophils involved in inflammatory and allergic responses. - Highlights: • Application of EM to understand the complex secretory pathway in human eosinophils. • EM techniques reveal an active vesicular system associated with secretory granules. • Tubular vesicles are involved in the transport of granule-derived immune mediators.

  13. Vesicular trafficking of immune mediators in human eosinophils revealed by immunoelectron microscopy

    International Nuclear Information System (INIS)

    Melo, Rossana C.N.; Weller, Peter F.

    2016-01-01

    Electron microscopy (EM)-based techniques are mostly responsible for our current view of cell morphology at the subcellular level and continue to play an essential role in biological research. In cells from the immune system, such as eosinophils, EM has helped to understand how cells package and release mediators involved in immune responses. Ultrastructural investigations of human eosinophils enabled visualization of secretory processes in detail and identification of a robust, vesicular trafficking essential for the secretion of immune mediators via a non-classical secretory pathway associated with secretory (specific) granules. This vesicular system is mainly organized as large tubular-vesicular carriers (Eosinophil Sombrero Vesicles – EoSVs) actively formed in response to cell activation and provides a sophisticated structural mechanism for delivery of granule-stored mediators. In this review, we highlight the application of EM techniques to recognize pools of immune mediators at vesicular compartments and to understand the complex secretory pathway within human eosinophils involved in inflammatory and allergic responses. - Highlights: • Application of EM to understand the complex secretory pathway in human eosinophils. • EM techniques reveal an active vesicular system associated with secretory granules. • Tubular vesicles are involved in the transport of granule-derived immune mediators.

  14. Modulation of Host Immunity by Human Respiratory Syncytial Virus Virulence Factors: A Synergic Inhibition of Both Innate and Adaptive Immunity

    Directory of Open Access Journals (Sweden)

    Gisela Canedo-Marroquín

    2017-08-01

    Full Text Available The Human Respiratory Syncytial Virus (hRSV is a major cause of acute lower respiratory tract infections (ARTIs and high rates of hospitalizations in children and in the elderly worldwide. Symptoms of hRSV infection include bronchiolitis and pneumonia. The lung pathology observed during hRSV infection is due in part to an exacerbated host immune response, characterized by immune cell infiltration to the lungs. HRSV is an enveloped virus, a member of the Pneumoviridae family, with a non-segmented genome and negative polarity-single RNA that contains 10 genes encoding for 11 proteins. These include the Fusion protein (F, the Glycoprotein (G, and the Small Hydrophobic (SH protein, which are located on the virus surface. In addition, the Nucleoprotein (N, Phosphoprotein (P large polymerase protein (L part of the RNA-dependent RNA polymerase complex, the M2-1 protein as a transcription elongation factor, the M2-2 protein as a regulator of viral transcription and (M protein all of which locate inside the virion. Apart from the structural proteins, the hRSV genome encodes for the non-structural 1 and 2 proteins (NS1 and NS2. HRSV has developed different strategies to evade the host immunity by means of the function of some of these proteins that work as virulence factors to improve the infection in the lung tissue. Also, hRSV NS-1 and NS-2 proteins have been shown to inhibit the activation of the type I interferon response. Furthermore, the hRSV nucleoprotein has been shown to inhibit the immunological synapsis between the dendritic cells and T cells during infection, resulting in an inefficient T cell activation. Here, we discuss the hRSV virulence factors and the host immunological features raised during infection with this virus.

  15. Human Leukocyte Antigen (HLA and Immune Regulation: How Do Classical and Non-Classical HLA Alleles Modulate Immune Response to Human Immunodeficiency Virus and Hepatitis C Virus Infections?

    Directory of Open Access Journals (Sweden)

    Nicole B. Crux

    2017-07-01

    Full Text Available The genetic factors associated with susceptibility or resistance to viral infections are likely to involve a sophisticated array of immune response. These genetic elements may modulate other biological factors that account for significant influence on the gene expression and/or protein function in the host. Among them, the role of the major histocompatibility complex in viral pathogenesis in particular human immunodeficiency virus (HIV and hepatitis C virus (HCV, is very well documented. We, recently, added a novel insight into the field by identifying the molecular mechanism associated with the protective role of human leukocyte antigen (HLA-B27/B57 CD8+ T cells in the context of HIV-1 infection and why these alleles act as a double-edged sword protecting against viral infections but predisposing the host to autoimmune diseases. The focus of this review will be reexamining the role of classical and non-classical HLA alleles, including class Ia (HLA-A, -B, -C, class Ib (HLA-E, -F, -G, -H, and class II (HLA-DR, -DQ, -DM, and -DP in immune regulation and viral pathogenesis (e.g., HIV and HCV. To our knowledge, this is the very first review of its kind to comprehensively analyze the role of these molecules in immune regulation associated with chronic viral infections.

  16. Somatostatin receptors and their ligands in the human immune system

    NARCIS (Netherlands)

    V.A.S.H. Dalm (Virgil)

    2003-01-01

    textabstractMaintenance of homeostasis is essential for survival of the mammalian organism. For a long time it was believed that the different systems in the human body act independently from each other to achieve this goal. However, during the last decades it has become more evident that the

  17. Gene expression profiles of cryopreserved CD34{sup +} human umbilical cord blood cells are related to their bone marrow reconstitution abilities in mouse xenografts

    Energy Technology Data Exchange (ETDEWEB)

    Sudo, Kazuhiro [Cell Engineering Division, RIKEN BioResource Center, Tsukuba (Japan); Yasuda, Jun, E-mail: yasuda-jun@umin.ac.jp [Omics Science Center, RIKEN, Yokohama (Japan); Department of Cell Biology, The JFCR-Cancer Institute (Japan); Nakamura, Yukio, E-mail: yukionak@brc.riken.jp [Cell Engineering Division, RIKEN BioResource Center, Tsukuba (Japan)

    2010-07-09

    Human umbilical cord blood (UCB) cells are an alternative source of hematopoietic stem cells for treatment of leukemia and other diseases. It is very difficult to assess the quality of UCB cells in the clinical situation. Here, we sought to assess the quality of UCB cells by transplantation to immunodeficient mice. Cryopreserved CD34{sup +} UCB cells from twelve different human donors were transplanted into sublethally irradiated NOD/shi-scid Jic mice. In parallel, the gene expression profiles of the UCB cells were determined from oligonucleotide microarrays. UCB cells from three donors failed to establish an engraftment in the host mice, while the other nine succeeded to various extents. Gene expression profiling indicated that 71 genes, including HOXB4, C/EBP-{beta}, and ETS2, were specifically overexpressed and 23 genes were suppressed more than 2-fold in the successful UCB cells compared to those that failed. Functional annotation revealed that cell growth and cell cycle regulators were more abundant in the successful UCB cells. Our results suggest that hematopoietic ability may vary among cryopreserved UCB cells and that this ability can be distinguished by profiling expression of certain sets of genes.

  18. Exploration of alternative test methods to evaluate phototoxicity of ophthalmic agents by using Statens Seruminstitut Rabbit Cornea cell lines and 3D human reconstituted cornea models.

    Directory of Open Access Journals (Sweden)

    Soyoung Kim

    Full Text Available Many chemicals have been reported to induce phototoxicity. The absorbance of light energy within the sunlight range is a common characteristic of phototoxicity. The 3T3 NRU phototoxicity test (PT in 3T3 mouse skin fibroblasts has been used to identify the phototoxic potential induced by excited chemicals after exposure to ultra violet (UV. However, as phototoxicity may occur in ocular cells, it is necessary to develop a more suitable test for cornea-derived cells. In this study, we attempted to establish a new in vitro PT method in rabbit corneal cell lines (SIRC. We evaluated five ophthalmic agents, ciprofloxacin, levofloxacin, lomefloxacin, norfloxacin, and tetracycline, for their cytotoxic potential and in vitro phototoxicity. The results obtained using 3D human corneal models revealed that the UV-induced eye tissue toxicity by the test substances showed good correlation with those obtained using the in vitro phototoxicity test. However, the results from the 3D PT for ciprofloxacin, norfloxacin, and tetracycline in the 3D human cornea model were only partially comparable. Therefore, we suggest the SIRC cell line as a new phototoxicity test model; however, a sequential testing strategy, such as 3D PT, was also proposed to obtain relevant information for topical eye agents.

  19. Human body motion tracking based on quantum-inspired immune cloning algorithm

    Science.gov (United States)

    Han, Hong; Yue, Lichuan; Jiao, Licheng; Wu, Xing

    2009-10-01

    In a static monocular camera system, to gain a perfect 3D human body posture is a great challenge for Computer Vision technology now. This paper presented human postures recognition from video sequences using the Quantum-Inspired Immune Cloning Algorithm (QICA). The algorithm included three parts. Firstly, prior knowledge of human beings was used, the key joint points of human could be detected automatically from the human contours and skeletons which could be thinning from the contours; And due to the complexity of human movement, a forecasting mechanism of occlusion joint points was addressed to get optimum 2D key joint points of human body; And then pose estimation recovered by optimizing between the 2D projection of 3D human key joint points and 2D detection key joint points using QICA, which recovered the movement of human body perfectly, because this algorithm could acquire not only the global optimal solution, but the local optimal solution.

  20. Alloimmune Responses of Humanized Mice to Human Pluripotent Stem Cell Therapeutics

    Directory of Open Access Journals (Sweden)

    Nigel G. Kooreman

    2017-08-01

    Full Text Available There is growing interest in using embryonic stem cell (ESC and induced pluripotent stem cell (iPSC derivatives for tissue regeneration. However, an increased understanding of human immune responses to stem cell-derived allografts is necessary for maintaining long-term graft persistence. To model this alloimmunity, humanized mice engrafted with human hematopoietic and immune cells could prove to be useful. In this study, an in-depth analysis of graft-infiltrating human lymphocytes and splenocytes revealed that humanized mice incompletely model human immune responses toward allogeneic stem cells and their derivatives. Furthermore, using an “allogenized” mouse model, we show the feasibility of reconstituting immunodeficient mice with a functional mouse immune system and describe a key role of innate immune cells in the rejection of mouse stem cell allografts.

  1. Development of Reconstitution Technology for Surveillance Specimens

    International Nuclear Information System (INIS)

    Yasushi Atago; Shunichi Hatano; Eiichiro Otsuka

    2002-01-01

    The Japan Power Engineering and Inspection Corporation (JAPEIC) has been carrying out the project titled 'Nuclear Power Plant Integrated Management Technology (PLIM)' consigned by Japanese Ministry of Economy, Trade and Industry (METI) since 1996FY as a 10-years project. As one of the project themes, development of reconstitution technology for reactor pressure vessel (RPV/RV) surveillance specimens, which are installed in RPVs to monitor the neutron irradiation embrittlement on RPV/RV materials, is now on being carried out to deal with the long-term operation of nuclear power plants. The target of this theme is to establish the technical standard for applicability of reconstituted surveillance specimens including the reconstitution of the Charpy specimens and Compact Tension (CT) specimens. With the Charpy specimen reconstitution, application of 10 mm length inserts is used, which enables the conversion of tests from the LT-direction to the TL-direction. This paper presents the basic data from Charpy and CT specimens of RPV materials using the surveillance specimens obtained for un-irradiated materials including the following. 1) Reconstitution Technology of Charpy Specimens. a) The interaction between plastic zone and Heat Affected Zone (HAZ). b) The effects of the possible deviations from the standard specimens for the reconstituted specimens. 2) Reconstitution Technology of CT specimens. a) The correlation between fracture toughness and plastic zone width. Because the project is now in progress, this paper describes the outline of the results obtained as of the end of 2000 FY. (authors)

  2. Frequent detection of human papillomavirus 16 E2-specific T-helper immunity in healthy subjects

    NARCIS (Netherlands)

    de Jong, Annemieke; van der Burg, Sjoerd H.; Kwappenberg, Kitty M. C.; van der Hulst, Jeanette M.; Franken, Kees L. M. C.; Geluk, Annemieke; van Meijgaarden, Krista E.; Drijfhout, Jan Wouter; Kenter, Gemma; Vermeij, Pieter; Melief, Cornelis J. M.; Offringa, Rienk

    2002-01-01

    The incidence of genital human papillomavirus (HPV) infections is high in young, sexually active individuals. Most infections are cleared within 1 year after infection. The targets for the cellular immune response in this process of viral clearance remain to be identified, but the expression pattern

  3. Advances in the quantification of mitochondrial function in primary human immune cells through extracellular flux analysis.

    Directory of Open Access Journals (Sweden)

    Dequina Nicholas

    Full Text Available Numerous studies show that mitochondrial energy generation determines the effectiveness of immune responses. Furthermore, changes in mitochondrial function may regulate lymphocyte function in inflammatory diseases like type 2 diabetes. Analysis of lymphocyte mitochondrial function has been facilitated by introduction of 96-well format extracellular flux (XF96 analyzers, but the technology remains imperfect for analysis of human lymphocytes. Limitations in XF technology include the lack of practical protocols for analysis of archived human cells, and inadequate data analysis tools that require manual quality checks. Current analysis tools for XF outcomes are also unable to automatically assess data quality and delete untenable data from the relatively high number of biological replicates needed to power complex human cell studies. The objectives of work presented herein are to test the impact of common cellular manipulations on XF outcomes, and to develop and validate a new automated tool that objectively analyzes a virtually unlimited number of samples to quantitate mitochondrial function in immune cells. We present significant improvements on previous XF analyses of primary human cells that will be absolutely essential to test the prediction that changes in immune cell mitochondrial function and fuel sources support immune dysfunction in chronic inflammatory diseases like type 2 diabetes.

  4. Using Human Factors Techniques to Design Text Message Reminders for Childhood Immunization

    Science.gov (United States)

    Ahlers-Schmidt, Carolyn R.; Hart, Traci; Chesser, Amy; Williams, Katherine S.; Yaghmai, Beryl; Shah-Haque, Sapna; Wittler, Robert R.

    2012-01-01

    This study engaged parents to develop concise, informative, and comprehensible text messages for an immunization reminder system using Human Factors techniques. Fifty parents completed a structured interview including demographics, technology questions, willingness to receive texts from their child's doctor, and health literacy. Each participant…

  5. Human resource management in the Georgian National Immunization Program: a baseline assessment

    OpenAIRE

    Cohen-Kohler Jillian; Esmail Laura C; Djibuti Mamuka

    2007-01-01

    Abstract Background Georgia's health care system underwent dramatic reform after gaining independence in 1991. The decentralization of the health care system was one of the core elements of health care reform but reports suggest that human resource management issues were overlooked. The Georgian national immunization program was affected by these reforms and is not functioning at optimum levels. This paper describes the state of human resource management practices within the Georgian national...

  6. Mathematical modeling provides kinetic details of the human immune response to vaccination

    Directory of Open Access Journals (Sweden)

    Dustin eLe

    2015-01-01

    Full Text Available With major advances in experimental techniques to track antigen-specific immune responses many basic questions on the kinetics of virus-specific immunity in humans remain unanswered. To gain insights into kinetics of T and B cell responses in human volunteers we combine mathematical models and experimental data from recent studies employing vaccines against yellow fever and smallpox. Yellow fever virus-specific CD8 T cell population expanded slowly with the average doubling time of 2 days peaking 2.5 weeks post immunization. Interestingly, we found that the peak of the yellow fever-specific CD8 T cell response is determined by the rate of T cell proliferation and not by the precursor frequency of antigen-specific cells as has been suggested in several studies in mice. We also found that while the frequency of virus-specific T cells increases slowly, the slow increase can still accurately explain clearance of yellow fever virus in the blood. Our additional mathematical model describes well the kinetics of virus-specific antibody-secreting cell and antibody response to vaccinia virus in vaccinated individuals suggesting that most of antibodies in 3 months post immunization are derived from the population of circulating antibody-secreting cells. Taken together, our analysis provides novel insights into mechanisms by which live vaccines induce immunity to viral infections and highlight challenges of applying methods of mathematical modeling to the current, state-of-the-art yet limited immunological data.

  7. Mathematical modeling provides kinetic details of the human immune response to vaccination.

    Science.gov (United States)

    Le, Dustin; Miller, Joseph D; Ganusov, Vitaly V

    2014-01-01

    With major advances in experimental techniques to track antigen-specific immune responses many basic questions on the kinetics of virus-specific immunity in humans remain unanswered. To gain insights into kinetics of T and B cell responses in human volunteers we combined mathematical models and experimental data from recent studies employing vaccines against yellow fever and smallpox. Yellow fever virus-specific CD8 T cell population expanded slowly with the average doubling time of 2 days peaking 2.5 weeks post immunization. Interestingly, we found that the peak of the yellow fever-specific CD8 T cell response was determined by the rate of T cell proliferation and not by the precursor frequency of antigen-specific cells as has been suggested in several studies in mice. We also found that while the frequency of virus-specific T cells increased slowly, the slow increase could still accurately explain clearance of yellow fever virus in the blood. Our additional mathematical model described well the kinetics of virus-specific antibody-secreting cell and antibody response to vaccinia virus in vaccinated individuals suggesting that most of antibodies in 3 months post immunization were derived from the population of circulating antibody-secreting cells. Taken together, our analysis provided novel insights into mechanisms by which live vaccines induce immunity to viral infections and highlighted challenges of applying methods of mathematical modeling to the current, state-of-the-art yet limited immunological data.

  8. Web-based e-learning and virtual lab of human-artificial immune system.

    Science.gov (United States)

    Gong, Tao; Ding, Yongsheng; Xiong, Qin

    2014-05-01

    Human immune system is as important in keeping the body healthy as the brain in supporting the intelligence. However, the traditional models of the human immune system are built on the mathematics equations, which are not easy for students to understand. To help the students to understand the immune systems, a web-based e-learning approach with virtual lab is designed for the intelligent system control course by using new intelligent educational technology. Comparing the traditional graduate educational model within the classroom, the web-based e-learning with the virtual lab shows the higher inspiration in guiding the graduate students to think independently and innovatively, as the students said. It has been found that this web-based immune e-learning system with the online virtual lab is useful for teaching the graduate students to understand the immune systems in an easier way and design their simulations more creatively and cooperatively. The teaching practice shows that the optimum web-based e-learning system can be used to increase the learning effectiveness of the students.

  9. Virion Glycoprotein-Mediated Immune Evasion by Human Cytomegalovirus: a Sticky Virus Makes a Slick Getaway

    Science.gov (United States)

    Gardner, Thomas J.

    2016-01-01

    SUMMARY The prototypic herpesvirus human cytomegalovirus (CMV) exhibits the extraordinary ability to establish latency and maintain a chronic infection throughout the life of its human host. This is even more remarkable considering the robust adaptive immune response elicited by infection and reactivation from latency. In addition to the ability of CMV to exist in a quiescent latent state, its persistence is enabled by a large repertoire of viral proteins that subvert immune defense mechanisms, such as NK cell activation and major histocompatibility complex antigen presentation, within the cell. However, dissemination outside the cell presents a unique existential challenge to the CMV virion, which is studded with antigenic glycoprotein complexes targeted by a potent neutralizing antibody response. The CMV virion envelope proteins, which are critical mediators of cell attachment and entry, possess various characteristics that can mitigate the humoral immune response and prevent viral clearance. Here we review the CMV glycoprotein complexes crucial for cell attachment and entry and propose inherent properties of these proteins involved in evading the CMV humoral immune response. These include viral glycoprotein polymorphism, epitope competition, Fc receptor-mediated endocytosis, glycan shielding, and cell-to-cell spread. The consequences of CMV virion glycoprotein-mediated immune evasion have a major impact on persistence of the virus in the population, and a comprehensive understanding of these evasion strategies will assist in designing effective CMV biologics and vaccines to limit CMV-associated disease. PMID:27307580

  10. Human resource management in the Georgian National Immunization Program: a baseline assessment

    Directory of Open Access Journals (Sweden)

    Cohen-Kohler Jillian

    2007-07-01

    Full Text Available Abstract Background Georgia's health care system underwent dramatic reform after gaining independence in 1991. The decentralization of the health care system was one of the core elements of health care reform but reports suggest that human resource management issues were overlooked. The Georgian national immunization program was affected by these reforms and is not functioning at optimum levels. This paper describes the state of human resource management practices within the Georgian national immunization program in late 2004. Methods Thirty districts were selected for the study. Within these districts, 392 providers and thirty immunization managers participated in the study. Survey questionnaires were administered through face-to-face interviews to immunization managers and a mail survey was administered to immunization providers. Qualitative data collection involved four focus groups. Analysis of variance (ANOVA and Chi-square tests were used to test for differences between groups for continuous and categorical variables. Content analysis identified main themes within the focus groups. Results Weak administrative links exist between the Centres of Public Health (CPH and Primary Health Care (PHC health facilities. There is a lack of clear management guidelines and only 49.6% of all health providers had written job descriptions. A common concern among all respondents was the extremely inadequate salary. Managers cited lack of authority and poor knowledge and skills in human resource management. Lack of resources and infrastructure were identified as major barriers to improving immunization. Conclusion Our study found that the National Immunization Program in Georgia was characterized by weak organizational structure and processes and a lack of knowledge and skills in management and supervision, especially at peripheral levels. The development of the skills and processes of a well-managed workforce may help improve immunization rates, facilitate

  11. Immune Humanization of Immunodeficient Mice Using Diagnostic Bone Marrow Aspirates from Carcinoma Patients

    Science.gov (United States)

    Werner-Klein, Melanie; Proske, Judith; Werno, Christian; Schneider, Katharina; Hofmann, Hans-Stefan; Rack, Brigitte; Buchholz, Stefan; Ganzer, Roman; Blana, Andreas; Seelbach-Göbel, Birgit; Nitsche, Ulrich

    2014-01-01

    Tumor xenografts in immunodeficient mice, while routinely used in cancer research, preclude studying interactions of immune and cancer cells or, if humanized by allogeneic immune cells, are of limited use for tumor-immunological questions. Here, we explore a novel way to generate cancer models with an autologous humanized immune system. We demonstrate that hematopoietic stem and progenitor cells (HSPCs) from bone marrow aspirates of non-metastasized carcinoma patients, which are taken at specialized centers for diagnostic purposes, can be used to generate a human immune system in NOD-scid IL2rγ(null) (NSG) and HLA-I expressing NSG mice (NSG-HLA-A2/HHD) comprising both, lymphoid and myeloid cell lineages. Using NSG-HLA-A2/HHD mice, we show that responsive and self-tolerant human T cells develop and human antigen presenting cells can activate human T cells. As critical factors we identified the low potential of bone marrow HSPCs to engraft, generally low HSPC numbers in patient-derived bone marrow samples, cryopreservation and routes of cell administration. We provide here an optimized protocol that uses a minimum number of HSPCs, preselects high-quality bone marrow samples defined by the number of initially isolated leukocytes and intra-femoral or intra-venous injection. In conclusion, the use of diagnostic bone marrow aspirates from non-metastasized carcinoma patients for the immunological humanization of immunodeficient mice is feasible and opens the chance for individualized analyses of anti-tumoral T cell responses. PMID:24830425

  12. Immune humanization of immunodeficient mice using diagnostic bone marrow aspirates from carcinoma patients.

    Directory of Open Access Journals (Sweden)

    Melanie Werner-Klein

    Full Text Available Tumor xenografts in immunodeficient mice, while routinely used in cancer research, preclude studying interactions of immune and cancer cells or, if humanized by allogeneic immune cells, are of limited use for tumor-immunological questions. Here, we explore a novel way to generate cancer models with an autologous humanized immune system. We demonstrate that hematopoietic stem and progenitor cells (HSPCs from bone marrow aspirates of non-metastasized carcinoma patients, which are taken at specialized centers for diagnostic purposes, can be used to generate a human immune system in NOD-scid IL2rγ(null (NSG and HLA-I expressing NSG mice (NSG-HLA-A2/HHD comprising both, lymphoid and myeloid cell lineages. Using NSG-HLA-A2/HHD mice, we show that responsive and self-tolerant human T cells develop and human antigen presenting cells can activate human T cells. As critical factors we identified the low potential of bone marrow HSPCs to engraft, generally low HSPC numbers in patient-derived bone marrow samples, cryopreservation and routes of cell administration. We provide here an optimized protocol that uses a minimum number of HSPCs, preselects high-quality bone marrow samples defined by the number of initially isolated leukocytes and intra-femoral or intra-venous injection. In conclusion, the use of diagnostic bone marrow aspirates from non-metastasized carcinoma patients for the immunological humanization of immunodeficient mice is feasible and opens the chance for individualized analyses of anti-tumoral T cell responses.

  13. Characterization of humoral and cellular immune responses in patients with human papilloma virus

    International Nuclear Information System (INIS)

    Clares Pochet, Maria del Carmen; Ferrer Cosme, Belkis Maria; Dominguez Cardosa, Magda

    2012-01-01

    A descriptive and cross-sectional study was carried out in 30 females infected with the human papilloma virus, attended in the office of Immunology of the Specialty Polyclinic belonging to 'Saturnino Lora' Provincial Clinical Surgical Teaching Hospital in Santiago de Cuba, from June 2009 to June 2010, in order to characterize them according to immune response. To evaluate the humoral and cellular immune response rosetting assay and quantification of immunoglobulins were used respectively. Women between 25-36 years of age (40 %) infected with this virus, especially those coming from urban areas, prevailed in the series, and a significant decrease of the cellular response as compared to the humoral response was evidenced

  14. Quantitative assay for the measurement of immune responses directed against the human placenta

    Energy Technology Data Exchange (ETDEWEB)

    Davies, M; Sutcliffe, R G [Glasgow Univ. (UK)

    1982-02-12

    A quantitative in vitro immune assay based on the classical chromium release assay has been developed to detect immune responses directed against alien antigens expressed by the developing foetus and present on the maternal-facing surface of the human placenta. A plasma membrane fraction from the surface of the placenta was prepared and the vesicles thus formed were radiolabelled with /sup 51/Cr. The /sup 51/Cr-labelled vesicles, by various criteria, were found to be suitable for use as targets in a release assay. Further, by means of experimentally immunised animals, the target membranes were shown to be capable of detecting both cellular and humoral anti-placental activity.

  15. Human prealbumin fraction: effects on cell-mediated immunity and tumor rejection

    International Nuclear Information System (INIS)

    Leung, K.H.; Ehrke, M.J.; Bercsenyi, K.; Mihich, E.

    1982-01-01

    The effect of human prealbumin fraction as allogeneic cell-mediated immunity in primary sensitization cultures of murine spleen cells was studied by 3H-thymidine uptake and specific 51Cr release assays. Prealbumin caused a dose-dependent augmentation of these responses. Human serum albumin, bovine serum albumin, and calf-thymosin fraction 5 had little effect. Prealbumin was active when added on day 0 or 1 but not thereafter. Prealbumin added to effector cells from immunized mice did not change their lytic activity. Prealbumin, but not human serum albumin or thymosin fraction 5, augmented secondary cell-mediated immunity in culture after primary immunization in mice. A slow growing mammary tumor line, which originated as a spontaneous mammary tumor in a DBA/2 HaDD breeder mouse, initially grows in 100% of DBA/2J mice but is then rejected in 10 to 20% of them. When prealbumin (59 microgram/day) was given subcutaneously for 2 weeks to DBA/2J mice and the tumor implanted 2 weeks later. 78% of the mice rejected the tumor and were then resistant to a rechallenge

  16. Suppression of Antitumor Immune Responses by Human Papillomavirus through Epigenetic Downregulation of CXCL14

    Directory of Open Access Journals (Sweden)

    Louis Cicchini

    2016-05-01

    Full Text Available High-risk human papillomaviruses (HPVs are causally associated with multiple human cancers. Previous studies have shown that the HPV oncoprotein E7 induces immune suppression; however, the underlying mechanisms remain unknown. To understand the mechanisms by which HPV deregulates host immune responses in the tumor microenvironment, we analyzed gene expression changes of all known chemokines and their receptors using our global gene expression data sets from human HPV-positive and -negative head/neck cancer and cervical tissue specimens in different disease stages. We report that, while many proinflammatory chemokines increase expression throughout cancer progression, CXCL14 is dramatically downregulated in HPV-positive cancers. HPV suppression of CXCL14 is dependent on E7 and associated with DNA hypermethylation in the CXCL14 promoter. Using in vivo mouse models, we revealed that restoration of Cxcl14 expression in HPV-positive mouse oropharyngeal carcinoma cells clears tumors in immunocompetent syngeneic mice, but not in Rag1-deficient mice. Further, Cxcl14 reexpression significantly increases natural killer (NK, CD4+ T, and CD8+ T cell infiltration into the tumor-draining lymph nodes in vivo. In vitro transwell migration assays show that Cxcl14 reexpression induces chemotaxis of NK, CD4+ T, and CD8+ T cells. These results suggest that CXCL14 downregulation by HPV plays an important role in suppression of antitumor immune responses. Our findings provide a new mechanistic understanding of virus-induced immune evasion that contributes to cancer progression.

  17. Anthrax lethal factor as an immune target in humans and transgenic mice and the impact of HLA polymorphism on CD4+ T cell immunity.

    Science.gov (United States)

    Ascough, Stephanie; Ingram, Rebecca J; Chu, Karen K; Reynolds, Catherine J; Musson, Julie A; Doganay, Mehmet; Metan, Gökhan; Ozkul, Yusuf; Baillie, Les; Sriskandan, Shiranee; Moore, Stephen J; Gallagher, Theresa B; Dyson, Hugh; Williamson, E Diane; Robinson, John H; Maillere, Bernard; Boyton, Rosemary J; Altmann, Daniel M

    2014-05-01

    Bacillus anthracis produces a binary toxin composed of protective antigen (PA) and one of two subunits, lethal factor (LF) or edema factor (EF). Most studies have concentrated on induction of toxin-specific antibodies as the correlate of protective immunity, in contrast to which understanding of cellular immunity to these toxins and its impact on infection is limited. We characterized CD4+ T cell immunity to LF in a panel of humanized HLA-DR and DQ transgenic mice and in naturally exposed patients. As the variation in antigen presentation governed by HLA polymorphism has a major impact on protective immunity to specific epitopes, we examined relative binding affinities of LF peptides to purified HLA class II molecules, identifying those regions likely to be of broad applicability to human immune studies through their ability to bind multiple alleles. Transgenics differing only in their expression of human HLA class II alleles showed a marked hierarchy of immunity to LF. Immunogenicity in HLA transgenics was primarily restricted to epitopes from domains II and IV of LF and promiscuous, dominant epitopes, common to all HLA types, were identified in domain II. The relevance of this model was further demonstrated by the fact that a number of the immunodominant epitopes identified in mice were recognized by T cells from humans previously infected with cutaneous anthrax and from vaccinated individuals. The ability of the identified epitopes to confer protective immunity was demonstrated by lethal anthrax challenge of HLA transgenic mice immunized with a peptide subunit vaccine comprising the immunodominant epitopes that we identified.

  18. Defence mechanisms and immune evasion in the interplay between the humane immune system and Plasmodium falciparum

    DEFF Research Database (Denmark)

    Theander, T G

    1992-01-01

    Immunity to P. falciparum malaria is developed as a result of long term exposure to the parasite and depends on immunological memory. The key directors in immune recognition and regulation of the immunological responses are the T-cells. It seems reasonable to propose that immunity is acquired when...... with development of immunity. Several mechanisms seem to be operating. 1) Induction of the immune response to some macromolecules is avoided because the parasites are living inside host cells during part of their life cycle, and the reaction to other molecules is apparently avoided by mimicry of host molecules. 2...

  19. Characterization of the early local immune response to Ixodes ricinus tick bites in human skin.

    Science.gov (United States)

    Glatz, Martin; Means, Terry; Haas, Josef; Steere, Allen C; Müllegger, Robert R

    2017-03-01

    Little is known about the immunomodulation by tick saliva during a natural tick bite in human skin, the site of the tick-host interaction. We examined the expression of chemokines, cytokines and leucocyte markers on the mRNA levels and histopathologic changes in human skin biopsies of tick bites (n=37) compared to unaffected skin (n=9). Early tick-bite skin lesions (skin. With longer tick attachment (>24 hours), the numbers of innate immune cells and mediators (not significantly) declined, whereas the numbers of lymphocytes (not significantly) increased. Natural tick bites by Ixodes ricinus ticks initially elicit a strong local innate immune response in human skin. Beyond 24 hours of tick attachment, this response usually becomes less, perhaps because of immunomodulation by tick saliva. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  20. Innate Immune Responses of Bat and Human Cells to Filoviruses: Commonalities and Distinctions.

    Science.gov (United States)

    Kuzmin, Ivan V; Schwarz, Toni M; Ilinykh, Philipp A; Jordan, Ingo; Ksiazek, Thomas G; Sachidanandam, Ravi; Basler, Christopher F; Bukreyev, Alexander

    2017-04-15

    Marburg (MARV) and Ebola (EBOV) viruses are zoonotic pathogens that cause severe hemorrhagic fever in humans. The natural reservoir of MARV is the Egyptian rousette bat ( Rousettus aegyptiacus ); that of EBOV is unknown but believed to be another bat species. The Egyptian rousette develops subclinical productive infection with MARV but is refractory to EBOV. Interaction of filoviruses with hosts is greatly affected by the viral interferon (IFN)-inhibiting domains (IID). Our study was aimed at characterization of innate immune responses to filoviruses and the role of filovirus IID in bat and human cells. The study demonstrated that EBOV and MARV replicate to similar levels in all tested cell lines, indicating that permissiveness for EBOV at cell and organism levels do not necessarily correlate. Filoviruses, particularly MARV, induced a potent innate immune response in rousette cells, which was generally stronger than that in human cells. Both EBOV VP35 and VP24 IID were found to suppress the innate immune response in rousette cells, but only VP35 IID appeared to promote virus replication. Along with IFN-α and IFN-β, IFN-γ was demonstrated to control filovirus infection in bat cells but not in human cells, suggesting host species specificity of the antiviral effect. The antiviral effects of bat IFNs appeared not to correlate with induction of IFN-stimulated genes 54 and 56, which were detected in human cells ectopically expressing bat IFN-α and IFN-β. As bat IFN-γ induced the type I IFN pathway, its antiviral effect is likely to be partially induced via cross talk. IMPORTANCE Bats serve as reservoirs for multiple emerging viruses, including filoviruses, henipaviruses, lyssaviruses, and zoonotic coronaviruses. Although there is no evidence for symptomatic disease caused by either Marburg or Ebola viruses in bats, spillover of these viruses into human populations causes deadly outbreaks. The reason for the lack of symptomatic disease in bats infected with

  1. Complement and innate immune evasion strategies of the human pathogenic fungus Candida albicans.

    Science.gov (United States)

    Luo, Shanshan; Skerka, Christine; Kurzai, Oliver; Zipfel, Peter F

    2013-12-15

    Candida albicans is a medically important fungus that can cause a wide range of diseases ranging from superficial infections to disseminated disease, which manifests primarily in immuno-compromised individuals. Despite the currently applied anti-fungal therapies, both mortality and morbidity caused by this human pathogenic fungus are still unacceptably high. Therefore new prophylactic and therapeutic strategies are urgently needed to prevent fungal infection. In order to define new targets for combating fungal disease, there is a need to understand the immune evasion strategies of C. albicans in detail. In this review, we summarize different sophisticated immune evasion strategies that are utilized by C. albicans. The description of the molecular mechanisms used for immune evasion does on one hand help to understand the infection process, and on the other hand provides valuable information to define new strategies and diagnostic approaches to fight and interfere with Candida infections. Copyright © 2013 Elsevier Ltd. All rights reserved.

  2. Active Immunization and Evaluation Against Luteinizing Hormone for Radioimmunoassay Technique in Human Serum

    International Nuclear Information System (INIS)

    Ebeid, N.H.; Shafik, H.M.; Ayoub, S.M.; Mehany, N.L.

    2014-01-01

    This study evaluated the antigenicity of luteinizing hormone conjugate with Bovine Serum Albumin (LH-BSA). The conjugation of LH- BSA was carried out by 1-Ethyl-3-(3-Dimethylaminopropyl) Carbodiimide HCl (ECDI). Three rabbits were immunized against LH-BSA. Two rabbits were immunized against nonconjugated LH and two rabbits against BSA only. Immunization was carried out through primary injection and 4 boosters. The preparation of the radioiodinated 125 I-LH was carried out using N- Bromo-Succinimide as oxidizing agent. The preparation of LH standards was carried out. The obtained LH antisera were characterized of titer, immuno response and displacement profile formulation, optimization and validation of the local liquid phase LH- Radioimmunoassay (RIA) system was carried out. The results provide a highly sensitive and accurate RIA system of LH-BSA. This technique could be used in measuring LH in human serum to investigate fertility especially disorders of the hypothalamic / pituitary / gonadal axis

  3. Reuse prevention syringes for reconstitution of lyophilized vaccines: Operational study and UNICEF plans for expanding introduction.

    Science.gov (United States)

    Fleming, Jessica A; Hoekstra, Edward John; Moniaga, Vanda; Widjaya, Anton; Soepardi, Jane; Supartha, Nyoman; Salovaara, Annika; Khamassi, Selma; Nelson, Carib

    2009-01-01

    Since the 1990s, the United Nation's Children's Fund has encouraged injection safety for immunizations through bundling vaccines with appropriate amounts of supporting equipment and by supplying autodisable (AD) syringes for injections. However, poor vaccine reconstitution practices continue to be reported worldwide. By 2009, UNICEF will begin to phase out the distribution of standard disposable syringes for vaccine reconstitution and replace them with reuse prevention (RUP) syringes, with a full transition expected by the end of 2010. A field evaluation in Indonesia was conducted to identify introduction requirements, issues with healthcare worker training and acceptance, and RUP syringe performance and safety. Managers and health workers felt that RUP syringes improved injection safety and fit easily into country logistical systems. Healthcare workers felt they were intuitive to use, but recommended special training. The integration of RUP reconstitution syringes by UNICEF could increase injection safety by preventing the reuse of syringes and reducing vaccine contamination.

  4. Functional motifs responsible for human metapneumovirus M2-2-mediated innate immune evasion.

    Science.gov (United States)

    Chen, Yu; Deng, Xiaoling; Deng, Junfang; Zhou, Jiehua; Ren, Yuping; Liu, Shengxuan; Prusak, Deborah J; Wood, Thomas G; Bao, Xiaoyong

    2016-12-01

    Human metapneumovirus (hMPV) is a major cause of lower respiratory infection in young children. Repeated infections occur throughout life, but its immune evasion mechanisms are largely unknown. We recently found that hMPV M2-2 protein elicits immune evasion by targeting mitochondrial antiviral-signaling protein (MAVS), an antiviral signaling molecule. However, the molecular mechanisms underlying such inhibition are not known. Our mutagenesis studies revealed that PDZ-binding motifs, 29-DEMI-32 and 39-KEALSDGI-46, located in an immune inhibitory region of M2-2, are responsible for M2-2-mediated immune evasion. We also found both motifs prevent TRAF5 and TRAF6, the MAVS downstream adaptors, to be recruited to MAVS, while the motif 39-KEALSDGI-46 also blocks TRAF3 migrating to MAVS. In parallel, these TRAFs are important in activating transcription factors NF-kB and/or IRF-3 by hMPV. Our findings collectively demonstrate that M2-2 uses its PDZ motifs to launch the hMPV immune evasion through blocking the interaction of MAVS and its downstream TRAFs. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. Patterns of Early-Life Gut Microbial Colonization during Human Immune Development: An Ecological Perspective

    Directory of Open Access Journals (Sweden)

    Isabelle Laforest-Lapointe

    2017-07-01

    Full Text Available Alterations in gut microbial colonization during early life have been reported in infants that later developed asthma, allergies, type 1 diabetes, as well as in inflammatory bowel disease patients, previous to disease flares. Mechanistic studies in animal models have established that microbial alterations influence disease pathogenesis via changes in immune system maturation. Strong evidence points to the presence of a window of opportunity in early life, during which changes in gut microbial colonization can result in immune dysregulation that predisposes susceptible hosts to disease. Although the ecological patterns of microbial succession in the first year of life have been partly defined in specific human cohorts, the taxonomic and functional features, and diversity thresholds that characterize these microbial alterations are, for the most part, unknown. In this review, we summarize the most important links between the temporal mosaics of gut microbial colonization and the age-dependent immune functions that rely on them. We also highlight the importance of applying ecology theory to design studies that explore the interactions between this complex ecosystem and the host immune system. Focusing research efforts on understanding the importance of temporally structured patterns of diversity, keystone groups, and inter-kingdom microbial interactions for ecosystem functions has great potential to enable the development of biologically sound interventions aimed at maintaining and/or improving immune system development and preventing disease.

  6. Systemic and Terminal Ileum Mucosal Immunity Elicited by Oral Immunization With the Ty21a Typhoid Vaccine in HumansSummary

    Directory of Open Access Journals (Sweden)

    Jayaum S. Booth

    2017-11-01

    Full Text Available Background & Aims: Systemic cellular immunity elicited by the Ty21a oral typhoid vaccine has been extensively characterized. However, very limited data are available in humans regarding mucosal immunity at the site of infection (terminal ileum [TI]. Here we investigated the host immunity elicited by Ty21a immunization on terminal ileum–lamina propria mononuclear cells (LPMC and peripheral blood in volunteers undergoing routine colonoscopy. Methods: We characterized LPMC-T memory (TM subsets and assessed Salmonella enterica serovar Typhi (S Typhi–specific responses by multichromatic flow cytometry. Results: No differences were observed in cell yields and phenotypes in LPMC CD8+-TM subsets following Ty21a immunization. However, Ty21a immunization elicited LPMC CD8+ T cells exhibiting significant S Typhi–specific responses (interferon-γ, tumor necrosis factor-α, interleukin-17A, and/or CD107a in all major TM subsets (T-effector/memory [TEM], T-central/memory, and TEM-CD45RA+, although each TM subset exhibited unique characteristics. We also investigated whether Ty21a immunization elicited S Typhi–specific multifunctional effectors in LPMC CD8+ TEM. We observed that LPMC CD8+ TEM responses were mostly multifunctional, except for those cells exhibiting the characteristics associated with cytotoxic responses. Finally, we compared mucosal with systemic responses and made the important observation that LPMC CD8+ S Typhi–specific responses were unique and distinct from their systemic counterparts. Conclusions: This study provides the first demonstration of S Typhi–specific responses in the human terminal ileum mucosa and provides novel insights into the generation of mucosal immune responses following oral Ty21a immunization. Keywords: Lamina Propria Mononuclear Cells, Multifunctional T Cells, CD8+-T Memory Cells, Typhoid, Vaccines

  7. Human Immune System Mice for the Study of Human Immunodeficiency Virus-Type 1 Infection of the Central Nervous System

    Science.gov (United States)

    Evering, Teresa H.; Tsuji, Moriya

    2018-01-01

    Immunodeficient mice transplanted with human cell populations or tissues, also known as human immune system (HIS) mice, have emerged as an important and versatile tool for the in vivo study of human immunodeficiency virus-type 1 (HIV-1) pathogenesis, treatment, and persistence in various biological compartments. Recent work in HIS mice has demonstrated their ability to recapitulate critical aspects of human immune responses to HIV-1 infection, and such studies have informed our knowledge of HIV-1 persistence and latency in the context of combination antiretroviral therapy. The central nervous system (CNS) is a unique, immunologically privileged compartment susceptible to HIV-1 infection, replication, and immune-mediated damage. The unique, neural, and glia-rich cellular composition of this compartment, as well as the important role of infiltrating cells of the myeloid lineage in HIV-1 seeding and replication makes its study of paramount importance, particularly in the context of HIV-1 cure research. Current work on the replication and persistence of HIV-1 in the CNS, as well as cells of the myeloid lineage thought to be important in HIV-1 infection of this compartment, has been aided by the expanded use of these HIS mouse models. In this review, we describe the major HIS mouse models currently in use for the study of HIV-1 neuropathogenesis, recent insights from the field, limitations of the available models, and promising advances in HIS mouse model development. PMID:29670623

  8. A virtual infection model quantifies innate effector mechanisms and Candida albicans immune escape in human blood.

    Directory of Open Access Journals (Sweden)

    Kerstin Hünniger

    2014-02-01

    Full Text Available Candida albicans bloodstream infection is increasingly frequent and can result in disseminated candidiasis associated with high mortality rates. To analyze the innate immune response against C. albicans, fungal cells were added to human whole-blood samples. After inoculation, C. albicans started to filament and predominantly associate with neutrophils, whereas only a minority of fungal cells became attached to monocytes. While many parameters of host-pathogen interaction were accessible to direct experimental quantification in the whole-blood infection assay, others were not. To overcome these limitations, we generated a virtual infection model that allowed detailed and quantitative predictions on the dynamics of host-pathogen interaction. Experimental time-resolved data were simulated using a state-based modeling approach combined with the Monte Carlo method of simulated annealing to obtain quantitative predictions on a priori unknown transition rates and to identify the main axis of antifungal immunity. Results clearly demonstrated a predominant role of neutrophils, mediated by phagocytosis and intracellular killing as well as the release of antifungal effector molecules upon activation, resulting in extracellular fungicidal activity. Both mechanisms together account for almost [Formula: see text] of C. albicans killing, clearly proving that beside being present in larger numbers than other leukocytes, neutrophils functionally dominate the immune response against C. albicans in human blood. A fraction of C. albicans cells escaped phagocytosis and remained extracellular and viable for up to four hours. This immune escape was independent of filamentation and fungal activity and not linked to exhaustion or inactivation of innate immune cells. The occurrence of C. albicans cells being resistant against phagocytosis may account for the high proportion of dissemination in C. albicans bloodstream infection. Taken together, iterative experiment

  9. Harnessing what lies within: Programming immunity with biocompatible devices to treat human disease

    Science.gov (United States)

    Roberts, Reid Austin

    Advances in our mechanistic insight of cellular function and how this relates to host physiology have revealed a world which is intimately connected at the macro and micro level. Our increasing understanding of biology exemplifies this, where cells respond to environmental cues through interconnected networks of proteins which function as receptors and adaptors to elicit gene expression changes that drive appropriate cellular programs for a given stimulus. Consequently, our deeper molecular appreciation of host homeostasis implicates aberrations of these pathways in nearly all major human disease categories, including those of infectious, metabolic, neurologic, oncogenic, and autoimmune etiology. We have come to recognize the mammalian immune system as a common network hub among all these varied pathologies. As such, the major goal of this dissertation is to identify a platform to program immune responses in mammals so that we may enhance our ability to treat disease and improve health in the 21st century. Using advances in materials science, in particular a recently developed particle fabrication technology termed Particle Replication in Non-wetting Templates (PRINT), our studies systematically assess the murine and human immune response to precisely fabricated nano- and microscale particles composed of biodegradable and biocompatible materials. We then build on these findings and present particle design parameters to program a number of clinically attractive immune responses by targeting endogenous cellular signaling pathways. These include control of particle uptake through surface modification, design parameters that modulate the magnitude and kinetics of biological signaling dynamics that can be used to exacerbate or dampen inflammatory responses, as well as particle designs which may be of use in treating allergies and autoimmune disorders. In total, this dissertation provides evidence that rational design of biocompatible nano- and microparticles is a viable

  10. The Effect of Simulated Flash-Heat Pasteurization on Immune Components of Human Milk

    Directory of Open Access Journals (Sweden)

    Brodie Daniels

    2017-02-01

    Full Text Available A pasteurization temperature monitoring system has been designed using FoneAstra, a cellphone-based networked sensing system, to monitor simulated flash-heat (FH pasteurization. This study compared the effect of the FoneAstra FH (F-FH method with the Sterifeed Holder method currently used by human milk banks on human milk immune components (immunoglobulin A (IgA, lactoferrin activity, lysozyme activity, interleukin (IL-8 and IL-10. Donor milk samples (N = 50 were obtained from a human milk bank, and pasteurized. Concentrations of IgA, IL-8, IL-10, lysozyme activity and lactoferrin activity were compared to their controls using the Student’s t-test. Both methods demonstrated no destruction of interleukins. While the Holder method retained all lysozyme activity, the F-FH method only retained 78.4% activity (p < 0.0001, and both methods showed a decrease in lactoferrin activity (71.1% Holder vs. 38.6% F-FH; p < 0.0001 and a decrease in the retention of total IgA (78.9% Holder vs. 25.2% F-FH; p < 0.0001. Despite increased destruction of immune components compared to Holder pasteurization, the benefits of F-FH in terms of its low cost, feasibility, safety and retention of immune components make it a valuable resource in low-income countries for pasteurizing human milk, potentially saving infants’ lives.

  11. Effect of borax on immune cell proliferation and sister chromatid exchange in human chromosomes.

    Science.gov (United States)

    Pongsavee, Malinee

    2009-10-30

    Borax is used as a food additive. It becomes toxic when accumulated in the body. It causes vomiting, fatigue and renal failure. The heparinized blood samples from 40 healthy men were studied for the impact of borax toxicity on immune cell proliferation (lymphocyte proliferation) and sister chromatid exchange in human chromosomes. The MTT assay and Sister Chromatid Exchange (SCE) technic were used in this experiment with the borax concentrations of 0.1, 0.15, 0.2, 0.3 and 0.6 mg/ml. It showed that the immune cell proliferation (lymphocyte proliferation) was decreased when the concentrations of borax increased. The borax concentration of 0.6 mg/ml had the most effectiveness to the lymphocyte proliferation and had the highest cytotoxicity index (CI). The borax concentrations of 0.15, 0.2, 0.3 and 0.6 mg/ml significantly induced sister chromatid exchange in human chromosomes (P Borax had effects on immune cell proliferation (lymphocyte proliferation) and induced sister chromatid exchange in human chromosomes. Toxicity of borax may lead to cellular toxicity and genetic defect in human.

  12. Effect of borax on immune cell proliferation and sister chromatid exchange in human chromosomes

    Directory of Open Access Journals (Sweden)

    Pongsavee Malinee

    2009-10-01

    Full Text Available Abstract Background Borax is used as a food additive. It becomes toxic when accumulated in the body. It causes vomiting, fatigue and renal failure. Methods The heparinized blood samples from 40 healthy men were studied for the impact of borax toxicity on immune cell proliferation (lymphocyte proliferation and sister chromatid exchange in human chromosomes. The MTT assay and Sister Chromatid Exchange (SCE technic were used in this experiment with the borax concentrations of 0.1, 0.15, 0.2, 0.3 and 0.6 mg/ml. Results It showed that the immune cell proliferation (lymphocyte proliferation was decreased when the concentrations of borax increased. The borax concentration of 0.6 mg/ml had the most effectiveness to the lymphocyte proliferation and had the highest cytotoxicity index (CI. The borax concentrations of 0.15, 0.2, 0.3 and 0.6 mg/ml significantly induced sister chromatid exchange in human chromosomes (P Conclusion Borax had effects on immune cell proliferation (lymphocyte proliferation and induced sister chromatid exchange in human chromosomes. Toxicity of borax may lead to cellular toxicity and genetic defect in human.

  13. Induction of immunity to human immunodeficiency virus type-1 by vaccination.

    Science.gov (United States)

    McElrath, M Juliana; Haynes, Barton F

    2010-10-29

    Recent findings have brought optimism that development of a successful human immunodeficiency virus type-1 (HIV-1) vaccine lies within reach. Studies of early events in HIV-1 infection have revealed when and where HIV-1 is potentially vulnerable to vaccine-targeted immune responses. With technical advances in human antibody production, clues about how antibodies recognize HIV-1 envelope proteins have uncovered new targets for immunogen design. A recent vaccine regimen has shown modest efficacy against HIV-1 acquisition. However, inducing long-term T and B cell memory and coping with HIV-1 diversity remain high priorities. Mediators of innate immunity may play pivotal roles in blocking infection and shaping immunity; vaccine strategies to capture these activities are under investigation. Challenges remain in integrating basic, preclinical and clinical research to improve predictions of types of immunity associated with vaccine efficacy, to apply these insights to immunogen design, and to accelerate evaluation of vaccine efficacy in persons at-risk for infection. Copyright © 2010 Elsevier Inc. All rights reserved.

  14. Soluble CD14 in human breast milk and its role in innate immune responses.

    Science.gov (United States)

    Vidal, K; Labéta, M O; Schiffrin, E J; Donnet-Hughes, A

    2001-10-01

    Immune factors secreted in milk are important for health in the neonatal gut. We have detected the bacterial pattern recognition receptor, soluble CD14 (sCD14) in human breast milk at different times during lactation. The molecule occurs in a single form in milk, in contrast to human serum, in which there are two isoforms. Produced by mammary epithelial cells, milk sCD14 mediates secretion of innate immune response molecules such as interleukin-8, tumor necrosis factor-alpha, and epithelial neutrophil activator-78 by CD14-negative intestinal epithelial cells exposed to lipopolysaccharide (LPS) or bacteria. Although present at low concentrations in milk, LPS-binding protein may be implicated in the biological effects observed. Our findings support the premise that milk sCD14 acts as a 'sentinel' molecule and immune modulator in homeostasis and in the defense of the neonatal intestine. In so doing, it may prevent the immune and inflammatory conditions of the gut to which non-breastfed infants are predisposed.

  15. Astaxanthin decreased oxidative stress and inflammation and enhanced immune response in humans

    Directory of Open Access Journals (Sweden)

    Line Larry L

    2010-03-01

    Full Text Available Abstract Background Astaxanthin modulates immune response, inhibits cancer cell growth, reduces bacterial load and gastric inflammation, and protects against UVA-induced oxidative stress in in vitro and rodent models. Similar clinical studies in humans are unavailable. Our objective is to study the action of dietary astaxanthin in modulating immune response, oxidative status and inflammation in young healthy adult female human subjects. Methods Participants (averaged 21.5 yr received 0, 2, or 8 mg astaxanthin (n = 14/diet daily for 8 wk in a randomized double-blind, placebo-controlled study. Immune response was assessed on wk 0, 4 and 8, and tuberculin test performed on wk 8. Results Plasma astaxanthin increased (P helper, Tcytotoxic or natural killer cells. A higher percentage of leukocytes expressed the LFA-1 marker in subjects given 2 mg astaxanthin on wk 8. Subjects fed 2 mg astaxanthin had a higher tuberculin response than unsupplemented subjects. There was no difference in TNF and IL-2 concentrations, but plasma IFN-γ and IL-6 increased on wk 8 in subjects given 8 mg astaxanthin. Conclusion Therefore, dietary astaxanthin decreases a DNA damage biomarker and acute phase protein, and enhances immune response in young healthy females.

  16. Will Global Climate Change Alter Fundamental Human Immune Reactivity: Implications for Child Health?

    Science.gov (United States)

    Swaminathan, Ashwin; Lucas, Robyn M; Harley, David; McMichael, Anthony J

    2014-11-11

    The human immune system is an interface across which many climate change sensitive exposures can affect health outcomes. Gaining an understanding of the range of potential effects that climate change could have on immune function will be of considerable importance, particularly for child health, but has, as yet, received minimal research attention. We postulate several mechanisms whereby climate change sensitive exposures and conditions will subtly impair aspects of the human immune response, thereby altering the distribution of vulnerability within populations-particularly for children-to infection and disease. Key climate change-sensitive pathways include under-nutrition, psychological stress and exposure to ambient ultraviolet radiation, with effects on susceptibility to infection, allergy and autoimmune diseases. Other climate change sensitive exposures may also be important and interact, either additively or synergistically, to alter health risks. Conducting directed research in this area is imperative as the potential public health implications of climate change-induced weakening of the immune system at both individual and population levels are profound. This is particularly relevant for the already vulnerable children of the developing world, who will bear a disproportionate burden of future adverse environmental and geopolitical consequences of climate change.

  17. Will Global Climate Change Alter Fundamental Human Immune Reactivity: Implications for Child Health?

    Directory of Open Access Journals (Sweden)

    Ashwin Swaminathan

    2014-11-01

    Full Text Available The human immune system is an interface across which many climate change sensitive exposures can affect health outcomes. Gaining an understanding of the range of potential effects that climate change could have on immune function will be of considerable importance, particularly for child health, but has, as yet, received minimal research attention. We postulate several mechanisms whereby climate change sensitive exposures and conditions will subtly impair aspects of the human immune response, thereby altering the distribution of vulnerability within populations—particularly for children—to infection and disease. Key climate change-sensitive pathways include under-nutrition, psychological stress and exposure to ambient ultraviolet radiation, with effects on susceptibility to infection, allergy and autoimmune diseases. Other climate change sensitive exposures may also be important and interact, either additively or synergistically, to alter health risks. Conducting directed research in this area is imperative as the potential public health implications of climate change-induced weakening of the immune system at both individual and population levels are profound. This is particularly relevant for the already vulnerable children of the developing world, who will bear a disproportionate burden of future adverse environmental and geopolitical consequences of climate change.

  18. Autologous Stem Cell Transplantation Disrupts Adaptive Immune Responses during Rebound Simian/Human Immunodeficiency Virus Viremia.

    Science.gov (United States)

    Reeves, Daniel B; Peterson, Christopher W; Kiem, Hans-Peter; Schiffer, Joshua T

    2017-07-01

    Primary HIV-1 infection induces a virus-specific adaptive/cytolytic immune response that impacts the plasma viral load set point and the rate of progression to AIDS. Combination antiretroviral therapy (cART) suppresses plasma viremia to undetectable levels that rebound upon cART treatment interruption. Following cART withdrawal, the memory component of the virus-specific adaptive immune response may improve viral control compared to primary infection. Here, using primary infection and treatment interruption data from macaques infected with simian/human immunodeficiency virus (SHIV), we observe a lower peak viral load but an unchanged viral set point during viral rebound. The addition of an autologous stem cell transplant before cART withdrawal alters viral dynamics: we found a higher rebound set point but similar peak viral loads compared to the primary infection. Mathematical modeling of the data that accounts for fundamental immune parameters achieves excellent fit to heterogeneous viral loads. Analysis of model output suggests that the rapid memory immune response following treatment interruption does not ultimately lead to better viral containment. Transplantation decreases the durability of the adaptive immune response following cART withdrawal and viral rebound. Our model's results highlight the impact of the endogenous adaptive immune response during primary SHIV infection. Moreover, because we capture adaptive immune memory and the impact of transplantation, this model will provide insight into further studies of cure strategies inspired by the Berlin patient. IMPORTANCE HIV patients who interrupt combination antiretroviral therapy (cART) eventually experience viral rebound, the return of viral loads to pretreatment levels. However, the "Berlin patient" remained free of HIV rebound over a decade after stopping cART. His cure is attributed to leukemia treatment that included an HIV-resistant stem cell transplant. Inspired by this case, we studied the impact

  19. Long term lymphocyte reconstitution after alemtuzumab treatment of multiple sclerosis

    KAUST Repository

    Hill-Cawthorne, Grant A.; Button, Tom; Tuohy, Orla C.; Jones, Joanne L.; May, Karen; Somerfield, Jennifer; Green, Alison J E; Giovannoni, Gavin; Compston, Alastair D.; Fahey, Michael T.; Coles, Alasdair J.

    2011-01-01

    Background: Alemtuzumab is a lymphocyte depleting monoclonal antibody that has demonstrated superior efficacy over interferon β-1a for relapsing-remitting multiple sclerosis (MS), and is currently under investigation in phase 3 trials. One unresolved issue is the duration and significance of the lymphopenia induced. The long term effects on lymphocyte reconstitution of a single course, and the consequences that this has on disability, morbidity, mortality and autoimmunity, were examined. Methods: The lymphocyte reconstitution (n=36; 384 person years) and crude safety data (n=37; 447 person years) are reported for the first patients with progressive MS to receive alemtuzumab (1991-1997). Reconstitution time was expressed as a geometric mean or, when a non-negligible number of individuals failed to recover, as a median using survival analysis. Results: Geometric mean recovery time (GMRT) of total lymphocyte counts to the lower limit of the normal range (LLN; ≥1.0×10 9 cells/l) was 12.7 months (95% CI 8.8 to 18.2 months). For B cells, GMRT to LLN (≥0.1×10 9/l) was 7.1 months (95% CI 5.3 to 9.5); median recovery times for CD8 (LLN ≥0.2×10 9 cells/l) and CD4 lymphocytes (LLN ≥0.4×10 9 cells/l) were 20 months and 35 months, respectively. However, CD8 and CD4 counts recovered to baseline levels in only 30% and 21% of patients, respectively. No infective safety concerns arose during 447 person years of follow-up. Conclusions: Lymphocyte counts recovered to LLN after a single course of alemtuzumab in approximately 8 months (B cells) and 3 years (T cell subsets), but usually did not recover to baseline values. However, this long lasting lymphopenia in patients with a previously normal immune system was not associated with an increased risk of serious opportunistic infection.

  20. Long term lymphocyte reconstitution after alemtuzumab treatment of multiple sclerosis

    KAUST Repository

    Hill-Cawthorne, Grant A.

    2011-11-05

    Background: Alemtuzumab is a lymphocyte depleting monoclonal antibody that has demonstrated superior efficacy over interferon β-1a for relapsing-remitting multiple sclerosis (MS), and is currently under investigation in phase 3 trials. One unresolved issue is the duration and significance of the lymphopenia induced. The long term effects on lymphocyte reconstitution of a single course, and the consequences that this has on disability, morbidity, mortality and autoimmunity, were examined. Methods: The lymphocyte reconstitution (n=36; 384 person years) and crude safety data (n=37; 447 person years) are reported for the first patients with progressive MS to receive alemtuzumab (1991-1997). Reconstitution time was expressed as a geometric mean or, when a non-negligible number of individuals failed to recover, as a median using survival analysis. Results: Geometric mean recovery time (GMRT) of total lymphocyte counts to the lower limit of the normal range (LLN; ≥1.0×10 9 cells/l) was 12.7 months (95% CI 8.8 to 18.2 months). For B cells, GMRT to LLN (≥0.1×10 9/l) was 7.1 months (95% CI 5.3 to 9.5); median recovery times for CD8 (LLN ≥0.2×10 9 cells/l) and CD4 lymphocytes (LLN ≥0.4×10 9 cells/l) were 20 months and 35 months, respectively. However, CD8 and CD4 counts recovered to baseline levels in only 30% and 21% of patients, respectively. No infective safety concerns arose during 447 person years of follow-up. Conclusions: Lymphocyte counts recovered to LLN after a single course of alemtuzumab in approximately 8 months (B cells) and 3 years (T cell subsets), but usually did not recover to baseline values. However, this long lasting lymphopenia in patients with a previously normal immune system was not associated with an increased risk of serious opportunistic infection.

  1. Effect of borax on immune cell proliferation and sister chromatid exchange in human chromosomes

    OpenAIRE

    Pongsavee Malinee

    2009-01-01

    Abstract Background Borax is used as a food additive. It becomes toxic when accumulated in the body. It causes vomiting, fatigue and renal failure. Methods The heparinized blood samples from 40 healthy men were studied for the impact of borax toxicity on immune cell proliferation (lymphocyte proliferation) and sister chromatid exchange in human chromosomes. The MTT assay and Sister Chromatid Exchange (SCE) technic were used in this experiment with the borax concentrations of 0.1, 0.15, 0.2, 0...

  2. Composition and Variation of Macronutrients, Immune Proteins, and Human Milk Oligosaccharides in Human Milk From Nonprofit and Commercial Milk Banks.

    Science.gov (United States)

    Meredith-Dennis, Laura; Xu, Gege; Goonatilleke, Elisha; Lebrilla, Carlito B; Underwood, Mark A; Smilowitz, Jennifer T

    2018-02-01

    When human milk is unavailable, banked milk is recommended for feeding premature infants. Milk banks use processes to eliminate pathogens; however, variability among methods exists. Research aim: The aim of this study was to compare the macronutrient (protein, carbohydrate, fat, energy), immune-protective protein, and human milk oligosaccharide (HMO) content of human milk from three independent milk banks that use pasteurization (Holder vs. vat techniques) or retort sterilization. Randomly acquired human milk samples from three different milk banks ( n = 3 from each bank) were analyzed for macronutrient concentrations using a Fourier transform mid-infrared spectroscopy human milk analyzer. The concentrations of IgA, IgM, IgG, lactoferrin, lysozyme, α-lactalbumin, α antitrypsin, casein, and HMO were analyzed by mass spectrometry. The concentrations of protein and fat were significantly ( p < .05) less in the retort sterilized compared with the Holder and vat pasteurized samples, respectively. The concentrations of all immune-modulating proteins were significantly ( p < .05) less in the retort sterilized samples compared with vat and/or Holder pasteurized samples. The total HMO concentration and HMOs containing fucose, sialic acid, and nonfucosylated neutral sugars were significantly ( p < .05) less in retort sterilized compared with Holder pasteurized samples. Random milk samples that had undergone retort sterilization had significantly less immune-protective proteins and total and specific HMOs compared with samples that had undergone Holder and vat pasteurization. These data suggest that further analysis of the effect of retort sterilization on human milk components is needed prior to widespread adoption of this process.

  3. Can the hair follicle become a model for studying selected aspects of human ocular immune privilege?

    Science.gov (United States)

    Kinori, Michael; Kloepper, Jennifer E; Paus, Ralf

    2011-06-23

    Immune privilege (IP) is important in maintaining ocular health. Understanding the mechanism underlying this dynamic state would assist in treating inflammatory eye diseases. Despite substantial progress in defining eye IP mechanisms, because of the scarcity of human ocular tissue for research purposes, most of what we know about ocular IP is based on rodent models (of unclear relevance to human eye immunology) and on cultured human eye-derived cells that cannot faithfully mirror the complex cell-tissue interactions that underlie normal human ocular IP in situ. Therefore, accessible, instructive, and clinically relevant human in vitro models are needed for exploring the general principles of why and how IP collapses under clinically relevant experimental conditions and how it can be protected or even restored therapeutically. Among the few human IP sites, the easily accessible and abundantly available hair follicle (HF) may offer one such surrogate model. There are excellent human HF organ culture systems for the study of HF IP in situ that instructively complement in vivo autoimmunity research in the human system. In this article, we delineate that the human eye and HF, despite their obvious differences, share key molecular and cellular mechanisms for maintaining IP. We argue that, therefore, human scalp HFs can provide an unconventional, but highly instructive, accessible, easily manipulated, and clinically relevant preclinical model for selected aspects of ocular IP. This essay is an attempt to encourage professional eye researchers to turn their attention, with appropriate caveats, to this candidate surrogate model for ocular IP in the human system.

  4. Trichinella spiralis Calreticulin Binds Human Complement C1q As an Immune Evasion Strategy.

    Science.gov (United States)

    Zhao, Limei; Shao, Shuai; Chen, Yi; Sun, Ximeng; Sun, Ran; Huang, Jingjing; Zhan, Bin; Zhu, Xinping

    2017-01-01

    As a multicellular parasitic nematode, Trichinella spiralis regulates host immune responses by producing a variety of immunomodulatory molecules to escape from host immune attack, but the mechanisms underlying the immune evasion are not well understood. Here, we identified that T. spiralis calreticulin ( Ts -CRT), a Ca 2+ -binding protein, facilitated T. spiralis immune evasion by interacting with the first component of human classical complement pathway, C1q. In the present study, Ts -CRT was found to be expressed on the surface of different developmental stages of T. spiralis as well as in the secreted products of adult and muscle larval worms. Functional analysis identified that Ts -CRT was able to bind to human C1q, resulting in the inhibition of C1q-initiated complement classical activation pathway reflected by reduced C4/C3 generation and C1q-dependent lysis of antibody-sensitized sheep erythrocytes. Moreover, recombinant Ts -CRT (r Ts -CRT) binding to C1q suppressed C1q-induced THP-1-derived macrophages chemotaxis and reduced monocyte-macrophages release of reactive oxygen intermediates (ROIs). Blocking Ts -CRT on the surface of newborn larvae (NBL) of T. spiralis with anti- Ts -CRT antibody increased the C1q-mediated adherence of monocyte-macrophages to larvae and impaired larval infectivity. All of these results suggest that T. spiralis -expressed Ts -CRT plays crucial roles in T. spiralis immune evasion and survival in host mostly by directly binding to host complement C1q, which not only reduces C1q-mediated activation of classical complement pathway but also inhibits the C1q-induced non-complement activation of macrophages.

  5. Psychological Stress and the Human Immune System: A Meta-Analytic Study of 30 Years of Inquiry

    Science.gov (United States)

    Segerstrom, Suzanne C.; Miller, Gregory E.

    2004-01-01

    The present report meta-analyzes more than 300 empirical articles describing a relationship between psychological stress and parameters of the immune system in human participants. Acute stressors (lasting minutes) were associated with potentially adaptive upregulation of some parameters of natural immunity and downregulation of some functions of…

  6. Reevaluation of Epidemiological Data Demonstrates That It Is Consistent With Cross-Immunity Among Human Papillomavirus Types

    OpenAIRE

    Durham, David P.; Poolman, Eric M.; Ibuka, Yoko; Townsend, Jeffrey P.; Galvani , Alison P.

    2012-01-01

    Background. The degree of cross-immunity between human papillomavirus (HPV) types is fundamental both to the epidemiological dynamics of HPV and to the impact of HPV vaccination. Epidemiological data on HPV infections has been repeatedly interpreted as inconsistent with cross-immunity.

  7. A haptoglobin-hemoglobin receptor conveys innate immunity to Trypanosoma brucei in humans

    DEFF Research Database (Denmark)

    Vanhollebeke, Benoit; De Muylder, Géraldine; Nielsen, Marianne J

    2008-01-01

    The protozoan parasite Trypanosoma brucei is lysed by apolipoprotein L-I, a component of human high-density lipoprotein (HDL) particles that are also characterized by the presence of haptoglobin-related protein. We report that this process is mediated by a parasite glycoprotein receptor, which...... binds the haptoglobin-hemoglobin complex with high affinity for the uptake and incorporation of heme into intracellular hemoproteins. In mice, this receptor was required for optimal parasite growth and the resistance of parasites to the oxidative burst by host macrophages. In humans, the trypanosome...... immunity against the parasite....

  8. Labeling of human immune gamma globulin with sup(99m)Tc

    International Nuclear Information System (INIS)

    Wong, D.W.; Huang, J.T.

    1977-01-01

    Human immune serum gamma globulin and rabbit anti-Stap. aureus antibody have been successfully labeled with sup(99m)Tc at pH 7.4 with an average binding efficiency of 86 and 82%, respectively. The labeled proteins behave similarly to unlabeled gamma-globulin fraction in the normal human serum as demonstrated by protein electrophoresis. The biological half-time of sup(99m)Tc-gamma-globulin in dog has been determined to be 54 min for the fast component and 14.7 hr for a slower component. Immunological assays demonstrate no significant change in antibody activity after labeling process. (author)

  9. Functional reconstitution of the glycine receptor

    Energy Technology Data Exchange (ETDEWEB)

    Garcia-Calvo, M.; Ruiz-Gomez, A.; Vazquez, J.; Morato, E.; Valdivieso, F.; Mayor, F. Jr. (Universidad Autonoma de Madrid (Spain))

    1989-07-25

    The functional reconstitution of the chloride channel coupled glycine receptor is described. Glycine receptors were purified from the cholate extract of rat spinal cord membranes by affinity chromatography and incorporated into phospholipid vesicles by the addition of phosphatidylcholine and removal of detergent by gel filtration. The reconstituted vesicles showed the same polypeptide composition as the purified receptor. The pharmacological characteristics of the glycine receptor were also preserved in the proteoliposomes, as demonstrated by the displacement of ({sup 3}H)strychnine binding by several glycinergic ligands and by photoaffinity labeling experiments. In order to observe functional responses (i.e., specific agonist-induced anion translocation), the authors have developed an assay based on the fluorescence quenching of an anion-sensitive entrapped probe, SPQ (6-methoxy-N-(3-sulfopropyl)quinolinium). Reconstituted vesicles were loaded with the fluorescent probe during a freeze-thaw-sonication cycle in the presence of added liposomes containing cholesterol. In such a reconstituted system, glycine receptor agonists are able to increase the rate of anion influx into the vesicles. The action of agonists is blocked by the simultaneous presence of strychnine or other glycine antagonists. The results show that the purified 48,000- and 58,000-dalton polypeptides reconstituted into phospholipid vesicles can bind ligands and promote specific ion translocation in a way similar to the glycine receptor in its native environment.

  10. Comparative study on Charpy specimen reconstitution techniques

    International Nuclear Information System (INIS)

    Bourdiliau, B.; Decroix, G.-M.; Averty, X.; Wident, P.; Bienvenu, Y.

    2011-01-01

    Highlights: → Welding processes are used to reconstitute previously tested Charpy specimens. → Stud welding is preferred for a quick installation, almost immediately operational. → Friction welding produces better quality welds, but requires a development effort. - Abstract: Reconstitution techniques are often used to allow material from previously fractured Charpy-V specimens to be reused for additional experiments. This paper presents a comparative experimental study of various reconstitution techniques and evaluates the feasibility of these methods for future use in shielded cells. The following techniques were investigated: arc stud welding, 6.0 kW CO 2 continuous wave laser welding, 4.5 kW YAG continuous wave laser welding and friction welding. Subsize Charpy specimens were reconstituted using a 400 W YAG pulsed wave laser. The best result was obtained with arc stud welding; the resilience of the reconstituted specimens and the load-displacement curves agreed well with the reference specimens, and the temperature elevation caused by the welding process was limited to the vicinity of the weld. Good results were also obtained with friction welding; this process led to the best quality welds. Laser welding seems to have affected the central part of the specimens, thus leading to different resilience values and load-displacement curves.

  11. The immunomodulatory effects of shark cartilage on the mouse and human immune system

    Directory of Open Access Journals (Sweden)

    ali Sheikhian

    2007-01-01

    Materials and methods: In an experimental study, the effects of different doses of shark cartilage on humoral (antibody titer immune response against sheep red blood cells (SRBC, were measured in mouse. In addition, we evaluated the modulatory effects of the shark cartilage on the natural killer (NK activity of the peritoneal cells of mouse against a tumor cell line called K562, according to the standard methods. The proliferative response of the human peripheral blood mononuclear cells was measured under the influence of shark cartilage. Results: Pure shark cartilage enhanced antibody response against SRBC in vivo. The hemagglutination titer which was 1/147 in the control group (injected with hen cartilage, increased to 1/1355 in the test group. The optimal dose was 100 mg/ml. both type of cartilage had blastogenic effect on peripheral blood mononuclear cells (the blastogenic index was 6.7 and 4.9 for impure shark cartilage and hen cartilage, respectively. NK activity was inhibited completely by pure shark cartilage (the amount of the killing activity of the effector peritoneal cells for the control and test groups against target cells was 25.9% and 5.5% respectively. Conclusion: Shark cartilage has a potent immunomodulatory effect on the specific immune mechanisms and some inhibitory effects on the innate immune mechanisms such as NC activity. Since the specific immunity has a more pivotal role against tumor formation, shark cartilage can be used as a cancer immunotherapeutic.

  12. Differential susceptibility of HIV strains to innate immune factors in human cervical-vaginal secretions

    Directory of Open Access Journals (Sweden)

    Mimi Ghosh

    2010-07-01

    Full Text Available Mimi Ghosh, John V Fahey, Charles R WiraDepartment of Physiology and Neurobiology, Dartmouth Medical School, Lebanon, New Hampshire, USAAbstract: The female reproductive tract (FRT is protected by innate and adaptive immune mechanisms, which work in concert to defend against human immunodeficiency virus (HIV and other sexually transmitted infections (STIs. Under the control of sex hormones throughout a woman’s life, the immune system in the FRT has evolved to meet the challenges of protection against STIs, coupled with the need to sustain the development of new life. The studies presented in this review focus on the threat of HIV infection and the levels of protection present in the FRT during the menstrual cycle. Studies from our laboratory and others, examined the presence and variability of immune components against viral infection in the FRT. Our findings indicate that there are some factors in the FRT secretions that inhibit and enhance infectivity of individual strains of HIV. Given the complexities of hormonal regulation, identification of the elements involved in susceptibility to and protection against HIV in women must involve a careful analysis of transmitted viruses and a clear understanding of immune protection in the FRT.Keywords: HIV susceptibility, CVL

  13. The neonicotinoid insecticide Clothianidin adversely affects immune signaling in a human cell line.

    Science.gov (United States)

    Di Prisco, Gennaro; Iannaccone, Marco; Ianniello, Flora; Ferrara, Rosalba; Caprio, Emilio; Pennacchio, Francesco; Capparelli, Rosanna

    2017-10-18

    Clothianidin is a widely used neonicotinoid insecticide, which is a potent agonist of the nicotinic acetylcholine receptor in insects. This neurotoxic compound has a negative impact on insect immunity, as it down-regulates the activation of the transcription factor NF-κB. Given the evolutionary conserved role of NF-κB in the modulation of the immune response in the animal kingdom, here we want to assess any effect of Clothianidin on vertebrate defense barriers. In presence of this neonicotinoid insecticide, a pro-inflammatory challenge with LPS on the human monocytic cell line THP-1 results both in a reduced production of the cytokine TNF-α and in a down-regulation of a reporter gene under control of NF-κB promoter. This finding is corroborated by a significant impact of Clothianidin on the transcription levels of different immune genes, characterized by a core disruption of TRAF4 and TRAF6 that negatively influences NF-κB signaling. Moreover, exposure to Clothianidin concurrently induces a remarkable up-regulation of NGFR, which supports the occurrence of functional ties between the immune and nervous systems. These results suggest a potential risk of immunotoxicity that neonicotinoids may have on vertebrates, which needs to be carefully assessed at the organism level.

  14. Conformational Occlusion of Blockade Antibody Epitopes, a Novel Mechanism of GII.4 Human Norovirus Immune Evasion.

    Science.gov (United States)

    Lindesmith, Lisa C; Mallory, Michael L; Debbink, Kari; Donaldson, Eric F; Brewer-Jensen, Paul D; Swann, Excel W; Sheahan, Timothy P; Graham, Rachel L; Beltramello, Martina; Corti, Davide; Lanzavecchia, Antonio; Baric, Ralph S

    2018-01-01

    Extensive antigenic diversity within the GII.4 genotype of human norovirus is a major driver of pandemic emergence and a significant obstacle to development of cross-protective immunity after natural infection and vaccination. However, human and mouse monoclonal antibody studies indicate that, although rare, antibodies to conserved GII.4 blockade epitopes are generated. The mechanisms by which these epitopes evade immune surveillance are uncertain. Here, we developed a new approach for identifying conserved GII.4 norovirus epitopes. Utilizing a unique set of virus-like particles (VLPs) representing the in vivo -evolved sequence diversity within an immunocompromised person, we identify key residues within epitope F, a conserved GII.4 blockade antibody epitope. The residues critical for antibody binding are proximal to evolving blockade epitope E. Like epitope F, antibody blockade of epitope E was temperature sensitive, indicating that particle conformation regulates antibody access not only to the conserved GII.4 blockade epitope F but also to the evolving epitope E. These data highlight novel GII.4 mechanisms to protect blockade antibody epitopes, map essential residues of a GII.4 conserved epitope, and expand our understanding of how viral particle dynamics may drive antigenicity and antibody-mediated protection by effectively shielding blockade epitopes. Our data support the notion that GII.4 particle breathing may well represent a major mechanism of humoral immune evasion supporting cyclic pandemic virus persistence and spread in human populations. IMPORTANCE In this study, we use norovirus virus-like particles to identify key residues of a conserved GII.4 blockade antibody epitope. Further, we identify an additional GII.4 blockade antibody epitope to be occluded, with antibody access governed by temperature and particle dynamics. These findings provide additional support for particle conformation-based presentation of binding residues mediated by a particle

  15. Innate Immunity and Human Milk MicroRNAs Content: A New Perspective for Premature Newborns

    Directory of Open Access Journals (Sweden)

    Erika Cione

    2017-02-01

    Full Text Available Context The premature newborns are prone to develop both early onset and late onset neonatal sepsis. The major causes of this phenomenon rely on the immaturity of the immune system, which has reduced capability to respond adequately to pathogens. Evidence Acquisition Titles and abstracts of previous papers were scanned before reading the full-text, in order to retrieve appropriate information. The databases used for searching were PubMed, Cochrane, and Embase for articles published before 1st of July, 2016. Secondary search for articles cited in reference lists were identified by the primary search. This review focused on neonatal sepsis incidence and the associated immune response with regards to microRNAs of human milk as a new microelement that enables regulation of innate immunity functions. Results Since human milk is a valuable source of microRNAs, a better understanding of its content will open a new therapeutic avenue for the clinical management of infectious diseases affecting premature newborns. The variation in miRNAs quantity in human milk needs to be considered. Mother’s milk can have different amounts of miRNAs and the identification of a microMilk batch richer of miRNAs can be a nutrition intervention method for modulating innate immunity in clinical management of premature newborns. Conclusions Routine translation of the microMilk concept for neonatal intensive care unit (NICU, in the management of premature newborns could be a way of defending premature newborns and Very Low Birth Weight (VLBW infants from both early and late sepsis.

  16. Human metapneumovirus M2-2 protein inhibits innate immune response in monocyte-derived dendritic cells.

    Directory of Open Access Journals (Sweden)

    Junping Ren

    Full Text Available Human metapneumovirus (hMPV is a leading cause of lower respiratory infection in young children, the elderly and immunocompromised patients. Repeated hMPV infections occur throughout life. However, immune evasion mechanisms of hMPV infection are largely unknown. Recently, our group has demonstrated that hMPV M2-2 protein, an important virulence factor, contributes to immune evasion in airway epithelial cells by targeting the mitochondrial antiviral-signaling protein (MAVS. Whether M2-2 regulates the innate immunity in human dendritic cells (DC, an important family of immune cells controlling antigen presenting, is currently unknown. We found that human DC infected with a virus lacking M2-2 protein expression (rhMPV-ΔM2-2 produced higher levels of cytokines, chemokines and IFNs, compared to cells infected with wild-type virus (rhMPV-WT, suggesting that M2-2 protein inhibits innate immunity in human DC. In parallel, we found that myeloid differentiation primary response gene 88 (MyD88, an essential adaptor for Toll-like receptors (TLRs, plays a critical role in inducing immune response of human DC, as downregulation of MyD88 by siRNA blocked the induction of immune regulatory molecules by hMPV. Since M2-2 is a cytoplasmic protein, we investigated whether M2-2 interferes with MyD88-mediated antiviral signaling. We found that indeed M2-2 protein associated with MyD88 and inhibited MyD88-dependent gene transcription. In this study, we also identified the domains of M2-2 responsible for its immune inhibitory function in human DC. In summary, our results demonstrate that M2-2 contributes to hMPV immune evasion by inhibiting MyD88-dependent cellular responses in human DC.

  17. Suppression of Innate Immune Response by Primary Human Keratinocytes Expressing HPV-16 E6 and E7

    National Research Council Canada - National Science Library

    Guess, Jennifer L

    2005-01-01

    Human papillomavims (HPV) types infect the skin and mucosal epithelium. Lesions resulting from HPV infection can linger for months or years suggesting that HPV - presence goes unnoticed by the host immune system...

  18. Cell-mediated immunity against human retinal extract, S-antigen, and interphotoreceptor retinoid binding protein in onchocercal chorioretinopathy

    NARCIS (Netherlands)

    van der Lelij, A.; Rothova, A.; Stilma, J. S.; Hoekzema, R.; Kijlstra, A.

    1990-01-01

    Autoimmune mechanisms are thought to be involved in the pathogenesis of onchocercal chorioretinopathy. Cell-mediated immune responses to human retinal S-antigen, interphotoreceptor retinoid binding protein (IRBP), and crude retinal extract were investigated in patients with onchocerciasis from

  19. Partial reconstitution of virus-specific memory CD8+ T cells following whole body γ-irradiation

    International Nuclear Information System (INIS)

    Grayson, Jason M.; Laniewski, Nathan G.; Holbrook, Beth C.

    2006-01-01

    CD8 + memory T cells are critical in providing immunity to viral infection. Previous studies documented that antigen-specific CD8 + memory T cells are more resistant to radiation-induced apoptosis than naive T cells. Here, we determined the number and in vivo function of memory CD8 + T cells as immune reconstitution progressed following irradiation. Immediately following irradiation, the number of memory CD8 + T cells declined 80%. As reconstitution progressed, the number of memory cells reached a zenith at 33% of pre-irradiation levels, and was maintained for 120 days post-irradiation. In vitro, memory CD8 + T cells were able to produce cytokines at all times post-irradiation, but when adoptively transferred, they were not able to expand upon rechallenge immediately following irradiation, but regained this ability as reconstitution progressed. When proliferation was examined in vitro, irradiated memory CD8 + T cells were able to respond to mitogenic growth but were unable to divide

  20. Effect of human papillomavirus infection on the immune system and its role in the course of cervical cancer.

    Science.gov (United States)

    Song, Dan; Li, Hong; Li, Haibo; Dai, Jianrong

    2015-08-01

    Human papillomavirus (HPV) is widely known as a cause of cervical intraepithelial neoplasia (CIN) and cervical cancer. The mechanisms involved have been studied by numerous studies. The integration of the virus genome into the host cells results in the abnormal regulation of cell cycle control. HPV can also induce immune evasion of the infected cells, which enable the virus to be undetectable for long periods of time. The induction of immunotolerance of the host's immune system by the persistent infection of HPV is one of the most important mechanisms for cervical lesions. The present review elaborates on the roles of several types of immune cells, such as macrophages and natural killer cells, which are classified as innate immune cells, and dendritic cells (DCs), cluster of differentiation (CD)4 + /CD8 + T cells and regulatory T cells, which are classified as adaptive immune cells. HPV infection could effect the differentiation of these immune cells in a unique way, resulting in the host's immune tolerance to the infection. The immune system modifications induced by HPV infection include tumor-associated macrophage differentiation, a compromised cellular immune response, an abnormal imbalance between type 1 T-helper cells (Th1) and Th2 cells, regulatory T cell infiltration, and downregulated DC activation and maturation. To date, numerous types of preventative vaccines have been created to slow down carcinogenesis. Immune response activation-based therapeutic vaccine is becoming more and more attractive for the treatment of HPV-associated diseases.

  1. The people factor: An analysis of the human resources landscape for immunization supply chain management.

    Science.gov (United States)

    Kasonde, Musonda; Steele, Pamela

    2017-04-19

    Human resources is the backbone of any system and the key enabler for all other functions to effectively perform. This is no different with the Immunization Supply Chain, more so in todays' complex operating environment with the increasing strain caused by new vaccines and expanding immunization programmes (Source: WHO, UNICEF). In order to drive the change that is required for sustainability and continuous improvement, every immunization supply chain needs an effective leader. A dedicated and competent immunization supply chain leader with adequate numbers of skilled, accountable, motivated and empowered personnel at all levels of the health system to overcome existing and emerging immunization supply chain (ISC) challenges. Without an effective supply chain leader supported by capable and motivated staff, none of the interventions designed to strengthen the supply chain can be effective or sustainable (Source: Gavi Alliance SC Strategy 2014). This landscape analysis was preceded by an HR Evidence Review (March 2014) and has served to inform global partner strategies and country activities, as well as highlight where most support is required. The study also aimed to define the status quo in order to create some form of baseline against which to measure the impact of interventions related to HR going forward. The analysis was comprised of a comprehensive desk review, a survey of 40 respondents from 32 countries and consultations with ISC practitioners in several forums. The findings highlight key areas that should inform the pillars of a HR capacity development plan. At the same time, it revealed that there are some positive examples of where countries are actively addressing some of the issues identified and putting in place mechanisms and structures to optimize the SC function. Copyright © 2017. Published by Elsevier Ltd.

  2. Human immunodeficiency virus-like particles activate multiple types of immune cells

    International Nuclear Information System (INIS)

    Sailaja, Gangadhara; Skountzou, Ioanna; Quan, Fu-Shi; Compans, Richard W.; Kang, Sang-Moo

    2007-01-01

    The rapid spread of human immunodeficiency virus (HIV) worldwide makes it a high priority to develop an effective vaccine. Since live attenuated or inactivated HIV is not likely to be approved as a vaccine due to safety concerns, HIV virus like particles (VLPs) offer an attractive alternative because they are safe due to the lack of a viral genome. Although HIV VLPs have been shown to induce humoral and cellular immune responses, it is important to understand the mechanisms by which they induce such responses and to improve their immunogenicity. We generated HIV VLPs, and VLPs containing Flt3 ligand (FL), a dendritic cell growth factor, to target VLPs to dendritic cells, and investigated the roles of these VLPs in the initiation of adaptive immune responses in vitro and in vivo. We found that HIV-1 VLPs induced maturation of dendritic cells and monocyte/macrophage populations in vitro and in vivo, with enhanced expression of maturation markers and cytokines. Dendritic cells pulsed with VLPs induced activation of splenocytes resulting in increased production of cytokines. VLPs containing FL were found to increase dendritic cells and monocyte/macrophage populations in the spleen when administered to mice. Administration of VLPs induced acute activation of multiple types of cells including T and B cells as indicated by enhanced expression of the early activation marker CD69 and down-regulation of the homing receptor CD62L. VLPs containing FL were an effective form of antigen in activating immune cells via dendritic cells, and immunization with HIV VLPs containing FL resulted in enhanced T helper type 2-like immune responses

  3. Human Papillomavirus Prevalence and Herd Immunity after Introduction of Vaccination Program, Scotland, 2009–2013

    Science.gov (United States)

    Kavanagh, Kimberley; Pan, Jiafeng; Love, John; Cuschieri, Kate; Robertson, Chris; Ahmed, Syed; Palmer, Timothy; Pollock, Kevin G.J.

    2016-01-01

    In 2008, a national human papillomavirus (HPV) immunization program using a bivalent vaccine against HPV types 16 and 18 was implemented in Scotland along with a national surveillance program designed to determine the longitudinal effects of vaccination on HPV infection at the population level. Each year during 2009–2013, the surveillance program conducted HPV testing on a proportion of liquid-based cytology samples from women undergoing their first cervical screening test for precancerous cervical disease. By linking vaccination, cervical screening, and HPV testing data, over the study period we found a decline in HPV types 16 and 18, significant decreases in HPV types 31, 33, and 45 (suggesting cross-protection), and a nonsignificant increase in HPV 51. In addition, among nonvaccinated women, HPV types 16 and 18 infections were significantly lower in 2013 than in 2009. Our results preliminarily indicate herd immunity and sustained effectiveness of the bivalent vaccine on virologic outcomes at the population level. PMID:26692336

  4. Human Papillomavirus Prevalence and Herd Immunity after Introduction of Vaccination Program, Scotland, 2009-2013.

    Science.gov (United States)

    Cameron, Ross L; Kavanagh, Kimberley; Pan, Jiafeng; Love, John; Cuschieri, Kate; Robertson, Chris; Ahmed, Syed; Palmer, Timothy; Pollock, Kevin G J

    2016-01-01

    In 2008, a national human papillomavirus (HPV) immunization program using a bivalent vaccine against HPV types 16 and 18 was implemented in Scotland along with a national surveillance program designed to determine the longitudinal effects of vaccination on HPV infection at the population level. Each year during 2009-2013, the surveillance program conducted HPV testing on a proportion of liquid-based cytology samples from women undergoing their first cervical screening test for precancerous cervical disease. By linking vaccination, cervical screening, and HPV testing data, over the study period we found a decline in HPV types 16 and 18, significant decreases in HPV types 31, 33, and 45 (suggesting cross-protection), and a nonsignificant increase in HPV 51. In addition, among nonvaccinated women, HPV types 16 and 18 infections were significantly lower in 2013 than in 2009. Our results preliminarily indicate herd immunity and sustained effectiveness of the bivalent vaccine on virologic outcomes at the population level.

  5. The Effect of Simulated Flash-Heat Pasteurization on Immune Components of Human Milk.

    Science.gov (United States)

    Daniels, Brodie; Schmidt, Stefan; King, Tracy; Israel-Ballard, Kiersten; Amundson Mansen, Kimberly; Coutsoudis, Anna

    2017-02-22

    A pasteurization temperature monitoring system has been designed using FoneAstra, a cellphone-based networked sensing system, to monitor simulated flash-heat (FH) pasteurization. This study compared the effect of the FoneAstra FH (F-FH) method with the Sterifeed Holder method currently used by human milk banks on human milk immune components (immunoglobulin A (IgA), lactoferrin activity, lysozyme activity, interleukin (IL)-8 and IL-10). Donor milk samples ( N = 50) were obtained from a human milk bank, and pasteurized. Concentrations of IgA, IL-8, IL-10, lysozyme activity and lactoferrin activity were compared to their controls using the Student's t -test. Both methods demonstrated no destruction of interleukins. While the Holder method retained all lysozyme activity, the F-FH method only retained 78.4% activity ( p pasteurization, the benefits of F-FH in terms of its low cost, feasibility, safety and retention of immune components make it a valuable resource in low-income countries for pasteurizing human milk, potentially saving infants' lives.

  6. Exploitation of herpesvirus immune evasion strategies to modify the immunogenicity of human mesenchymal stem cell transplants.

    Directory of Open Access Journals (Sweden)

    Anabel S de la Garza-Rodea

    Full Text Available BACKGROUND: Mesenchymal stem cells (MSCs are multipotent cells residing in the connective tissue of many organs and holding great potential for tissue repair. In culture, human MSCs (hMSCs are capable of extensive proliferation without showing chromosomal aberrations. Large numbers of hMSCs can thus be acquired from small samples of easily obtainable tissues like fat and bone marrow. MSCs can contribute to regeneration indirectly by secretion of cytokines or directly by differentiation into specialized cell types. The latter mechanism requires their long-term acceptance by the recipient. Although MSCs do not elicit immune responses in vitro, animal studies have revealed that allogeneic and xenogeneic MSCs are rejected. METHODOLOGY/PRINCIPAL FINDINGS: We aim to overcome MSC immune rejection through permanent down-regulation of major histocompatibility complex (MHC class I proteins on the surface of these MHC class II-negative cells through the use of viral immune evasion proteins. Transduction of hMSCs with a retroviral vector encoding the human cytomegalovirus US11 protein resulted in strong inhibition of MHC class I surface expression. When transplanted into immunocompetent mice, persistence of the US11-expressing and HLA-ABC-negative hMSCs at levels resembling those found in immunodeficient (i.e., NOD/SCID mice could be attained provided that recipients' natural killer (NK cells were depleted prior to cell transplantation. CONCLUSIONS/SIGNIFICANCE: Our findings demonstrate the potential utility of herpesviral immunoevasins to prevent rejection of xenogeneic MSCs. The observation that down-regulation of MHC class I surface expression renders hMSCs vulnerable to NK cell recognition and cytolysis implies that multiple viral immune evasion proteins are likely required to make hMSCs non-immunogenic and thereby universally transplantable.

  7. Prolonging herd immunity to cholera via vaccination: Accounting for human mobility and waning vaccine effects.

    Directory of Open Access Journals (Sweden)

    Corey M Peak

    2018-02-01

    Full Text Available Oral cholera vaccination is an approach to preventing outbreaks in at-risk settings and controlling cholera in endemic settings. However, vaccine-derived herd immunity may be short-lived due to interactions between human mobility and imperfect or waning vaccine efficacy. As the supply and utilization of oral cholera vaccines grows, critical questions related to herd immunity are emerging, including: who should be targeted; when should revaccination be performed; and why have cholera outbreaks occurred in recently vaccinated populations?We use mathematical models to simulate routine and mass oral cholera vaccination in populations with varying degrees of migration, transmission intensity, and vaccine coverage. We show that migration and waning vaccine efficacy strongly influence the duration of herd immunity while birth and death rates have relatively minimal impacts. As compared to either periodic mass vaccination or routine vaccination alone, a community could be protected longer by a blended "Mass and Maintain" strategy. We show that vaccination may be best targeted at populations with intermediate degrees of mobility as compared to communities with very high or very low population turnover. Using a case study of an internally displaced person camp in South Sudan which underwent high-coverage mass vaccination in 2014 and 2015, we show that waning vaccine direct effects and high population turnover rendered the camp over 80% susceptible at the time of the cholera outbreak beginning in October 2016.Oral cholera vaccines can be powerful tools for quickly protecting a population for a period of time that depends critically on vaccine coverage, vaccine efficacy over time, and the rate of population turnover through human mobility. Due to waning herd immunity, epidemics in vaccinated communities are possible but become less likely through complementary interventions or data-driven revaccination strategies.

  8. In vivo immune signatures of healthy human pregnancy: Inherently inflammatory or anti-inflammatory?

    Directory of Open Access Journals (Sweden)

    Caroline Graham

    Full Text Available Changes in maternal innate immunity during healthy human pregnancy are not well understood. Whether basal immune status in vivo is largely unaffected by pregnancy, is constitutively biased towards an inflammatory phenotype (transiently enhancing host defense or exhibits anti-inflammatory bias (reducing potential responsiveness to the fetus is unclear. Here, in a longitudinal study of healthy women who gave birth to healthy infants following uncomplicated pregnancies within the Canadian Healthy Infant Longitudinal Development (CHILD cohort, we test the hypothesis that a progressively altered bias in resting innate immune status develops. Women were examined during pregnancy and again, one and/or three years postpartum. Most pro-inflammatory cytokine expression, including CCL2, CXCL10, IL-18 and TNFα, was reduced in vivo during pregnancy (20-57%, p<0.0001. Anti-inflammatory biomarkers (sTNF-RI, sTNF-RII, and IL-1Ra were elevated by ~50-100% (p<0.0001. Systemic IL-10 levels were unaltered during vs. post-pregnancy. Kinetic studies demonstrate that while decreased pro-inflammatory biomarker expression (CCL2, CXCL10, IL-18, and TNFα was constant, anti-inflammatory expression increased progressively with increasing gestational age (p<0.0001. We conclude that healthy resting maternal immune status is characterized by an increasingly pronounced bias towards a systemic anti-inflammatory innate phenotype during the last two trimesters of pregnancy. This is resolved by one year postpartum in the absence of repeat pregnancy. The findings provide enhanced understanding of immunological changes that occur in vivo during healthy human pregnancy.

  9. Human study of the herbal preparation(HemoHIM) on enhancement of immune and hematopoietic functions

    Energy Technology Data Exchange (ETDEWEB)

    Choi, Hee-Jeong; Park, Jong-Nam; Jeon, Sun-Hee [Eulji Univ. Hospital, Daejeon (Korea, Republic of)

    2006-01-15

    This study was aimed to evaluate the human efficacy of the herbal preparation(HemoHIM) on the immune and hematopoiesis enhancement in sub-healthy volunteers. It was conducted as a double-blind, placebo-controlled human study. The sub-healthy volunteers with peripheral White Blood Cell (WBC) counts below 5000/μl were recruited and randomly allocated to 3 groups and administered with HemoHIM 6g/day, HemoHIM 12g/day, or placebo throughout the test. Peripheral blood was collected 4 times before or after the administration and analyzed for the hematological and serum biochemical values, immune cell activities, antioxidant status of plasma. The data of 38 volunteers were finally included in the analysis. Although there were no statistical significances, a trend was observed that the dose and duration of HemoHIM administration was correlated to the increased number of immune cells (white blood cells and lymphocytes). NK cell activity was increased significantly in the male group administered with HemoHIM 6g/day. The cytokines involved in immune activation (IL-2, IFN-γ, IL-6) were significantly increased or showed the trends of increases in HemoHIM administered groups, while IL-4 involved in allergy and asthma was not changed or showed the trends of decreases in HemoHIM administered groups. On the other hand, the antioxidant biomarkers such as total GSH, MDA, and TAS, were not affected by HemoHIM administration. The toxicological safety of HemoHIM administration was confirmed by the serum biochemical analysis of liver and kidney function markers and the questionnaire of HemoHIM administration and the consultation with the doctor, which showed no side effects of HemoHIM administration. The results of this study may provide the basic data for further clinical study on HemoHIM.

  10. Differential reactivity of immune sera from human vaccinees with field strains of eastern equine encephalitis virus.

    Science.gov (United States)

    Strizki, J M; Repik, P M

    1995-11-01

    Eastern equine encephalitis (EEE) virus is a mosquito-borne alphavirus that can produce a severe and often fatal acute encephalitis in humans, with significant neurologic sequelae in survivors. Due to the serious nature of the disease, an investigational inactivated EEE vaccine (PE-6) is available to individuals at risk for infection. Both serologic and recent molecular analyses of EEE viruses have demonstrated marked differences between the two antigenic varieties of EEE virus, designated North American (NA) and South American (SA). In view of these findings, we have examined the reactivity of sera from three individuals immunized with the EEE vaccine, derived from an NA isolate, with field strains of EEE virus. Anti-EEE serum antibodies from vaccinees reacted strongly in Western blot assays with both of the envelope (E1 and E2) glycoproteins of each NA strain examined, while reactivities with the glycoproteins of SA strains were substantially weaker and variable and dependent upon both the immune response of the vaccinee and the virus isolate assayed. Most striking was the modest to virtual lack of reactivity with the E2 protein of SA strains. Antigenic differences among the glycoproteins of EEE viruses were not as pronounced in immunoprecipitation analysis. Most significantly, although human immune sera displayed high neutralizing titers against each of the NA isolates examined, only negligible neutralizing titers were obtained against SA isolates. These data suggest that immunized individuals would mount an effective antibody response against infection with NA strains of EEE virus, but that further investigation is clearly warranted to fully assess the protective capability of the vaccine against infection with SA strains.

  11. Large Scale Immune Profiling of Infected Humans and Goats Reveals Differential Recognition of Brucella melitensis Antigens

    Science.gov (United States)

    Liang, Li; Leng, Diana; Burk, Chad; Nakajima-Sasaki, Rie; Kayala, Matthew A.; Atluri, Vidya L.; Pablo, Jozelyn; Unal, Berkay; Ficht, Thomas A.; Gotuzzo, Eduardo; Saito, Mayuko; Morrow, W. John W.; Liang, Xiaowu; Baldi, Pierre; Gilman, Robert H.; Vinetz, Joseph M.; Tsolis, Renée M.; Felgner, Philip L.

    2010-01-01

    Brucellosis is a widespread zoonotic disease that is also a potential agent of bioterrorism. Current serological assays to diagnose human brucellosis in clinical settings are based on detection of agglutinating anti-LPS antibodies. To better understand the universe of antibody responses that develop after B. melitensis infection, a protein microarray was fabricated containing 1,406 predicted B. melitensis proteins. The array was probed with sera from experimentally infected goats and naturally infected humans from an endemic region in Peru. The assay identified 18 antigens differentially recognized by infected and non-infected goats, and 13 serodiagnostic antigens that differentiate human patients proven to have acute brucellosis from syndromically similar patients. There were 31 cross-reactive antigens in healthy goats and 20 cross-reactive antigens in healthy humans. Only two of the serodiagnostic antigens and eight of the cross-reactive antigens overlap between humans and goats. Based on these results, a nitrocellulose line blot containing the human serodiagnostic antigens was fabricated and applied in a simple assay that validated the accuracy of the protein microarray results in the diagnosis of humans. These data demonstrate that an experimentally infected natural reservoir host produces a fundamentally different immune response than a naturally infected accidental human host. PMID:20454614

  12. Application of human erythrocytes to a radioimmune assay of immune complexes in serum. [Lupus erythematosus, type B hepatitis

    Energy Technology Data Exchange (ETDEWEB)

    Tsuda, F; Miyakawa, Y; Mayumi, M [Tokyo Metropolitan Lab. of Public Health (Japan)

    1979-07-01

    An immune adherence receptor exists on the surface of primate erythrocytes, and has been characterized as a receptor for the activated third component of complement (C3b). Human red blood cells (RCBs, blood group O) were applied to a sensitive determination of complement-fixing, soluble immune complexes in serum. The method involved the binding of immune complexes with RBCs in the presence of complement and the detection of cell-bound IgG molecules by radiolabelled anti-human IgG antibodies. Since the binding of RBCs with monomeric IgG was minimal, cell bound IgG molecules were taken as representing immune complexes. When aggregated human gammaglobulin (AHG) was used as a model of immune complexes, as little as 5 ..mu..g dissolved in 1 ml of normal human serum were detected. The binding of RBCs with AHG was inhibited in EDTA solution where the classical complement pathway could not be activated. The RBC radioimmune assay was successfully applied to the determination of soluble immune complexes in pathological serum samples obtained from the patients with systemic lupus erythematosus and those with fulminant Type B hepatitis. False-positive results by autoantibodies against RBCs could be excluded by a Coombs test and by comparing the binding in the presence of complement with that in EDTA solution. The ubiquitous availability of RBCs coupled with a high sensitivity would allow the RBC radioimmune assay to be used as a further method of determining immune complexes in the serum.

  13. A human type 5 adenovirus-based tuberculosis vaccine induces robust T cell responses in humans despite preexisting anti-adenovirus immunity.

    Science.gov (United States)

    Smaill, Fiona; Jeyanathan, Mangalakumari; Smieja, Marek; Medina, Maria Fe; Thanthrige-Don, Niroshan; Zganiacz, Anna; Yin, Cindy; Heriazon, Armando; Damjanovic, Daniela; Puri, Laura; Hamid, Jemila; Xie, Feng; Foley, Ronan; Bramson, Jonathan; Gauldie, Jack; Xing, Zhou

    2013-10-02

    There is an urgent need to develop new tuberculosis (TB) vaccines to safely and effectively boost Bacille Calmette-Guérin (BCG)-triggered T cell immunity in humans. AdHu5Ag85A is a recombinant human type 5 adenovirus (AdHu5)-based TB vaccine with demonstrated efficacy in a number of animal species, yet it remains to be translated to human applications. In this phase 1 study, we evaluated the safety and immunogenicity of AdHu5Ag85A in both BCG-naïve and previously BCG-immunized healthy adults. Intramuscular immunization of AdHu5Ag85A was safe and well tolerated in both trial volunteer groups. Moreover, although AdHu5Ag85A was immunogenic in both trial volunteer groups, it much more potently boosted polyfunctional CD4(+) and CD8(+) T cell immunity in previously BCG-vaccinated volunteers. Furthermore, despite prevalent preexisting anti-AdHu5 humoral immunity in most of the trial volunteers, we found little evidence that such preexisting anti-AdHu5 immunity significantly dampened the potency of AdHu5Ag85A vaccine. This study supports further clinical investigations of the AdHu5Ag85A vaccine for human applications. It also suggests that the widely perceived negative effect of preexisting anti-AdHu5 immunity may not be universally applied to all AdHu5-based vaccines against different types of human pathogens.

  14. Cell-mediated immune response: a clinical review of the therapeutic potential of human papillomavirus vaccination.

    Science.gov (United States)

    Meyer, Sonja Izquierdo; Fuglsang, Katrine; Blaakaer, Jan

    2014-12-01

    This clinical review aims to assess the efficacy of human papillomavirus 16/18 (HPV16/18) vaccination on the cell-mediated immune response in women with existing cervical intraepithelial neoplasia or cervical cancer induced by HPV16 or HPV18. A focused and thorough literature search conducted in five different databases found 996 publications. Six relevant articles were chosen for further review. In total, 154 patients (>18 years of age) were enrolled in prospective study trials with 3-15 months of follow up. The vaccine applications were administered two to four times. The vaccines contained different combinations of HPV16 and HPV18 and early proteins, E6 and E7. The primary outcome was the cell-mediated immune response. Correlation to clinical outcome (histopathology) and human leukocyte antigen genes were secondary endpoints. All vaccines triggered a detectable cell-mediated immune response, some of which were statistically significant. Correlations between immunological response and clinical outcome (histopathology) were not significant, so neoplasms may not be susceptible to vaccine-generated cytotoxic T cells (CD8(+)). Prophylactic HPV vaccines have been introduced to reduce the incidence of cervical cancer in young women. Women already infected with HPV could benefit from a therapeutic HPV vaccination. Hence, it is important to continue the development of therapeutic HPV vaccines to lower the rate of HPV-associated malignancies and crucial to evaluate vaccine efficacy clinically. This clinical review represents an attempt to elucidate the theories supporting the development of an HPV vaccine with a therapeutic effect on human papillomavirus-induced malignancies of the cervix. © 2014 Nordic Federation of Societies of Obstetrics and Gynecology.

  15. IL-17 suppresses immune effector functions in human papillomavirus-associated epithelial hyperplasia.

    Science.gov (United States)

    Gosmann, Christina; Mattarollo, Stephen R; Bridge, Jennifer A; Frazer, Ian H; Blumenthal, Antje

    2014-09-01

    Persistent infection with high-risk human papillomaviruses (HPV) causes epithelial hyperplasia that can progress to cancer and is thought to depend on immunosuppressive mechanisms that prevent viral clearance by the host. IL-17 is a cytokine with diverse functions in host defense and in the pathology of autoimmune disorders, chronic inflammatory diseases, and cancer. We analyzed biopsies from patients with HPV-associated cervical intraepithelial neoplasia grade 2/3 and murine skin displaying HPV16 E7 protein-induced epithelial hyperplasia, which closely models hyperplasia in chronic HPV lesions. Expression of IL-17 and IL-23, a major inducer of IL-17, was elevated in both human HPV-infected and murine E7-expressing lesions. Using a skin-grafting model, we demonstrated that IL-17 in HPV16 E7 transgenic skin grafts inhibited effective host immune responses against the graft. IL-17 was produced by CD3(+) T cells, predominantly CD4(+) T cells in human, and CD4(+) and γδ T cells in mouse hyperplastic lesions. IL-23 and IL-1β, but not IL-18, induced IL-17 production in E7 transgenic skin. Together, these findings demonstrate an immunosuppressive role for IL-17 in HPV-associated epithelial hyperplasia and suggest that blocking IL-17 in persistent viral infection may promote antiviral immunity and prevent progression to cancer. Copyright © 2014 by The American Association of Immunologists, Inc.

  16. Genes involved in immunity and apoptosis are associated with human presbycusis based on microarray analysis.

    Science.gov (United States)

    Dong, Yang; Li, Ming; Liu, Puzhao; Song, Haiyan; Zhao, Yuping; Shi, Jianrong

    2014-06-01

    Genes involved in immunity and apoptosis were associated with human presbycusis. CCR3 and GILZ played an important role in the pathogenesis of presbycusis, probably through regulating chemokine receptor, T-cell apoptosis, or T-cell activation pathways. To identify genes associated with human presbycusis and explore the molecular mechanism of presbycusis. Hearing function was tested by pure-tone audiometry. Microarray analysis was performed to identify presbycusis-correlated genes by Illumina Human-6 BeadChip using the peripheral blood samples of subjects. To identify biological process categories and pathways associated with presbycusis-correlated genes, bioinformatics analysis was carried out by Gene Ontology Tree Machine (GOTM) and database for annotation, visualization, and integrated discovery (DAVID). Quantitative RT-PCR (qRT-PCR) was used to validate the microarray data. Microarray analysis identified 469 up-regulated genes and 323 down-regulated genes. Both the dominant biological processes by Gene Ontology (GO) analysis and the enriched pathways by Kyoto encyclopedia of genes and genomes (KEGG) and BIOCARTA showed that genes involved in immunity and apoptosis were associated with presbycusis. In addition, CCR3, GILZ, CXCL10, and CX3CR1 genes showed consistent difference between groups for both the gene chip and qRT-PCR data. The differences of CCR3 and GILZ between presbycusis patients and controls were statistically significant (p < 0.05).

  17. Common Developmental Tasks in Forming Reconstituted Families.

    Science.gov (United States)

    Kleinman, Judith

    1979-01-01

    Developmental tasks common to the formation of a reconstituted family are described, particularly the continued mourning of the old family; the formation of a solid marital relationship despite the difficulties presented by past failures and the presence of children; and the formation of sibling alliances across family lines. (Author)

  18. Serosal and Endometrial Reconstitution During Myomectomy ...

    African Journals Online (AJOL)

    Context: Myomectomy is usually performed when uterine fibroids are associated with infertility. Serosal and endometrial reconstitution are some of the subtle challenges that the gynaecologist has to deal with during myomectomy, in an attempt to minimise postoperative pelvic and intrauterine adhesions. Objective: This ...

  19. Detergent-Mediated Reconstitution of Membrane Proteins

    NARCIS (Netherlands)

    Knol, J; Sjollema, K.A; Poolman, B.

    1998-01-01

    The efficiency of reconstitution of the lactose transport protein (LacS) of Streptococcus thermophilus is markedly higher with Triton X-100 than with other detergents commonly employed to mediate the membrane insertion. To rationalize these differences, the lipid/detergent structures that are formed

  20. Stability issues in reconstitution by weapon addition

    Energy Technology Data Exchange (ETDEWEB)

    Canavan, G.H.

    1997-08-01

    Reconstitution of strategic forces by the unilateral uploading of additional weapons from initially symmetric modest force levels reduces first strike stability. These changes are quantified and traced to changes in first and second strike costs in a model of missile exchanges in which both strikes are optimized analytically.

  1. Glucose transport machinery reconstituted in cell models.

    Science.gov (United States)

    Hansen, Jesper S; Elbing, Karin; Thompson, James R; Malmstadt, Noah; Lindkvist-Petersson, Karin

    2015-02-11

    Here we demonstrate the production of a functioning cell model by formation of giant vesicles reconstituted with the GLUT1 glucose transporter and a glucose oxidase and hydrogen peroxidase linked fluorescent reporter internally. Hence, a simplified artificial cell is formed that is able to take up glucose and process it.

  2. What’s Normal? Immune Profiling of Human Milk from Healthy Women Living in Different Geographical and Socioeconomic Settings

    Science.gov (United States)

    Ruiz, Lorena; Espinosa-Martos, Irene; García-Carral, Cristina; Manzano, Susana; McGuire, Michelle K.; Meehan, Courtney L.; McGuire, Mark A.; Williams, Janet E.; Foster, James; Sellen, Daniel W.; Kamau-Mbuthia, Elizabeth W.; Kamundia, Egidioh W.; Mbugua, Samwel; Moore, Sophie E.; Kvist, Linda J.; Otoo, Gloria E.; Lackey, Kimberly A.; Flores, Katherine; Pareja, Rossina G.; Bode, Lars; Rodríguez, Juan M.

    2017-01-01

    Human milk provides a very wide range of nutrients and bioactive components, including immune factors, human milk oligosaccharides, and a commensal microbiota. These factors are essential for interconnected processes including immunity programming and the development of a normal infant gastrointestinal microbiome. Newborn immune protection mostly relies on maternal immune factors provided through milk. However, studies dealing with an in-depth profiling of the different immune compounds present in human milk and with the assessment of their natural variation in healthy women from different populations are scarce. In this context, the objective of this work was the detection and quantification of a wide array of immune compounds, including innate immunity factors (IL1β, IL6, IL12, INFγ, TNFα), acquired immunity factors (IL2, IL4, IL10, IL13, IL17), chemokines (IL8, Groα, MCP1, MIP1β), growth factors [IL5, IL7, epidermal growth factor (EGF), granulocyte colony-stimulating factor, granulocyte–macrophage colony-stimulating factor, TGFβ2], and immunoglobulins (IgA, IgG, IgM), in milk produced by healthy women of different ethnicities living in different geographic, dietary, socioeconomic, and environmental settings. Among the analyzed factors, IgA, IgG, IgM, EGF, TGFβ2, IL7, IL8, Groα, and MIP1β were detected in all or most of the samples collected in each population and, therefore, this specific set of compounds might be considered as the “core” soluble immune factors in milk produced by healthy women worldwide. This approach may help define which immune factors are (or are not) common in milk produced by women living in various conditions, and to identify host, lifestyle, and environmental factors that affect the immunological composition of this complex biological fluid. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT02670278. PMID:28713365

  3. What’s Normal? Immune Profiling of Human Milk from Healthy Women Living in Different Geographical and Socioeconomic Settings

    Directory of Open Access Journals (Sweden)

    Lorena Ruiz

    2017-06-01

    Full Text Available Human milk provides a very wide range of nutrients and bioactive components, including immune factors, human milk oligosaccharides, and a commensal microbiota. These factors are essential for interconnected processes including immunity programming and the development of a normal infant gastrointestinal microbiome. Newborn immune protection mostly relies on maternal immune factors provided through milk. However, studies dealing with an in-depth profiling of the different immune compounds present in human milk and with the assessment of their natural variation in healthy women from different populations are scarce. In this context, the objective of this work was the detection and quantification of a wide array of immune compounds, including innate immunity factors (IL1β, IL6, IL12, INFγ, TNFα, acquired immunity factors (IL2, IL4, IL10, IL13, IL17, chemokines (IL8, Groα, MCP1, MIP1β, growth factors [IL5, IL7, epidermal growth factor (EGF, granulocyte colony-stimulating factor, granulocyte–macrophage colony-stimulating factor, TGFβ2], and immunoglobulins (IgA, IgG, IgM, in milk produced by healthy women of different ethnicities living in different geographic, dietary, socioeconomic, and environmental settings. Among the analyzed factors, IgA, IgG, IgM, EGF, TGFβ2, IL7, IL8, Groα, and MIP1β were detected in all or most of the samples collected in each population and, therefore, this specific set of compounds might be considered as the “core” soluble immune factors in milk produced by healthy women worldwide. This approach may help define which immune factors are (or are not common in milk produced by women living in various conditions, and to identify host, lifestyle, and environmental factors that affect the immunological composition of this complex biological fluid.Clinical Trial Registration:www.ClinicalTrials.gov, identifier NCT02670278.

  4. Analyses of 123 Peripheral Human Immune Cell Subsets: Defining Differences with Age and between Healthy Donors and Cancer Patients Not Detected in Analysis of Standard Immune Cell Types

    Directory of Open Access Journals (Sweden)

    Lauren M. Lepone

    2016-03-01

    Full Text Available Recent advances in human immunology have led to the identification of novel immune cell subsets and the biological function of many of these subsets has now been identified. The recent US Food and Drug Administration approval of several immunotherapeutics for the treatment of a variety of cancer types and the results of ongoing immunotherapy clinical studies requires a more thorough interrogation of the immune system. We report here the use of flow cytometry-based analyses to identify 123 immune cell subsets of peripheral blood mononuclear cells. The use of these panels defines multiple differences in younger (< 40 years vs. older (≥ 40 years individuals and between aged-matched apparently healthy individuals and metastatic cancer patients, aspects not seen in the analysis of the following standard immune cell types: CD8, CD4, natural killer, natural killer-T, regulatory T, myeloid derived suppressor cells, conventional dendritic cells (DCs, plasmacytoid DCs and B cells. The use of these panels identifying 123 immune cell subsets may aid in the identification of patients who may benefit from immunotherapy, either prior to therapy or early in the immunotherapeutic regimen, for the treatment of cancer or other chronic or infectious diseases.

  5. Influence of immune activation and inflammatory response on cardiovascular risk associated with the human immunodeficiency virus

    Directory of Open Access Journals (Sweden)

    Beltrán LM

    2015-01-01

    Full Text Available Luis M Beltrán,1 Alfonso Rubio-Navarro,2 Juan Manuel Amaro-Villalobos,2 Jesús Egido,2–4 Juan García-Puig,1 Juan Antonio Moreno21Metabolic-Vascular Unit, Fundación IdiPAZ-Hospital Universitario La Paz, Madrid, Spain; 2Vascular, Renal, and Diabetes Research Lab, IIS-Fundación Jiménez Díaz, Madrid, Spain; 3Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM, Madrid, Spain; 4Fundación Renal Iñigo Alvarez de Toledo-Instituto Reina Sofía de Investigaciones Nefrológicas (FRIAT-IRSIN, Madrid, SpainAbstract: Patients infected with the human immunodeficiency virus (HIV have an increased cardiovascular risk. Although initially this increased risk was attributed to metabolic alterations associated with antiretroviral treatment, in recent years, the attention has been focused on the HIV disease itself. Inflammation, immune system activation, and endothelial dysfunction facilitated by HIV infection have been identified as key factors in the development and progression of atherosclerosis. In this review, we describe the epidemiology and pathogenesis of cardiovascular disease in patients with HIV infection and summarize the latest knowledge on the relationship between traditional and novel inflammatory, immune activation, and endothelial dysfunction biomarkers on the cardiovascular risk associated with HIV infection.Keywords: HIV, cardiovascular disease, immune activation, inflammation, antiretroviral therapy

  6. Aflatoxin-Related Immune Dysfunction in Health and in Human Immunodeficiency Virus Disease

    Directory of Open Access Journals (Sweden)

    Yi Jiang

    2008-01-01

    Full Text Available Both aflatoxin and the human immunodeficiency virus (HIV cause immune suppression and millions of HIV-infected people in developing countries are chronically exposed to aflatoxin in their diets. We investigated the possible interaction of aflatoxin and HIV on immune suppression by comparing immune parameters in 116 HIV positive and 80 aged-matched HIV negative Ghanaians with high (≥0.91 pmol/mg albumin and low (<0.91 pmol/mg albumin aflatoxin B1 albumin adduct (AF-ALB levels. AF-ALB levels and HIV viral load were measured in plasma and the percentages of leukocyte immunophenotypes and cytokine expression were determined using flow cytometry. The cross-sectional comparisons found that (1 among both HIV positive and negative participants, high AF-ALB was associated with lower perforin expression on CD8+ T-cells (P=.012; (2 HIV positive participants with high AF-ALB had significantly lower percentages of CD4+ T regulatory cells (Tregs; P=.009 and naive CD4+ T cells (P=.029 compared to HIV positive participants with low AF-ALB; and (3 HIV positive participants with high AF-ALB had a significantly reduced percentage of B-cells (P=.03 compared to those with low AF-ALB. High AF-ALB appeared to accentuate some HIV associated changes in T-cell phenotypes and in B-cells in HIV positive participants.

  7. Up-and-down immunity of pregnancy in humans [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Philippe Le Bouteiller

    2017-07-01

    Full Text Available One part of the human placenta in early pregnancy is particularly important for local immunity: the decidua basalis, which is transformed endometrium located at the site of embryo implantation. This placental bed tissue contains both maternal uterine immune cells, including decidual natural killer (NK cells, the dominant leukocyte population exhibiting a unique phenotype, and fetal extravillous trophoblast which comes into direct contact with maternal decidual cells. To establish a successful placental development and healthy pregnancy outcome, the maternal immune system must tolerate paternal antigens expressed by trophoblast cells yet remain efficient for clearing any local pathogen infection. This review deals mainly with decidual NK cells. A key element, among others, to achieve such dual functions is the direct interaction between activating and inhibitory receptors expressed by decidual NK cells and their specific ligands presented by trophoblast or other decidual cells. Depending whether maternal decidual cells and trophoblast are infected by viruses, the balance between activating and inhibitory receptor signals mediated by decidual NK cell–trophoblast cross-talk results in tolerance (healthy pregnancy or specific killing (pathogen-infected cells.

  8. A compositional look at the human gastrointestinal microbiome and immune activation parameters in HIV infected subjects.

    Directory of Open Access Journals (Sweden)

    Ece A Mutlu

    2014-02-01

    Full Text Available HIV progression is characterized by immune activation and microbial translocation. One factor that may be contributing to HIV progression could be a dysbiotic microbiome. We therefore hypothesized that the GI mucosal microbiome is altered in HIV patients and this alteration correlates with immune activation in HIV. 121 specimens were collected from 21 HIV positive and 22 control human subjects during colonoscopy. The composition of the lower gastrointestinal tract mucosal and luminal bacterial microbiome was characterized using 16S rDNA pyrosequencing and was correlated to clinical parameters as well as immune activation and circulating bacterial products in HIV patients on ART. The composition of the HIV microbiome was significantly different than that of controls; it was less diverse in the right colon and terminal ileum, and was characterized by loss of bacterial taxa that are typically considered commensals. In HIV samples, there was a gain of some pathogenic bacterial taxa. This is the first report characterizing the terminal ileal and colonic mucosal microbiome in HIV patients with next generation sequencing. Limitations include use of HIV-infected subjects on HAART therapy.

  9. Could spaceflight-associated immune system weakening preclude the expansion of human presence beyond Earth's orbit?

    Science.gov (United States)

    Guéguinou, Nathan; Huin-Schohn, Cécile; Bascove, Matthieu; Bueb, Jean-Luc; Tschirhart, Eric; Legrand-Frossi, Christine; Frippiat, Jean-Pol

    2009-11-01

    This year, we celebrate the 40th birthday of the first landing of humans on the moon. By 2020, astronauts should return to the lunar surface and establish an outpost there that will provide a technical basis for future manned missions to Mars. This paper summarizes major constraints associated with a trip to Mars, presents immunological hazards associated with this type of mission, and shows that our current understanding of the immunosuppressive effects of spaceflight is limited. Weakening of the immune system associated with spaceflight is therefore an area that should be considered more thoroughly before we undertake prolonged space voyages.

  10. Potential of high resolution protein mapping as a method of monitoring the human immune system

    International Nuclear Information System (INIS)

    Anderson, N.L.; Anderson, N.G

    1980-01-01

    Immunology traditionally deals with complex cellular systems and heterogeneous mixtures of effector molecules (primarily antibodies). Some sense has emerged from this chaos through the use of functional assays. Such an approach however naturally leaves a great deal undiscovered since the assays are simple and the assayed objects are complex. In this chapter some experimental approaches to immunological problems are described using high-resolution two-dimensional electrophoresis, a method that can resolve thousands of proteins and can thus begin to treat immunological entities at their appropriate level of complexity. In addition, the possible application of this work to the problem of monitoring events in the individual human immune system are discussed

  11. Sick and tired: how molecular regulators of human sleep schedules and duration impact immune function.

    Science.gov (United States)

    Kurien, Philip A; Chong, S Y Christin; Ptáček, Louis J; Fu, Ying-Hui

    2013-10-01

    Why do we need to sleep? What regulates when we sleep? And what dictates the number of hours we require? These are often viewed as three separate biological questions. Here, we propose they share molecular etiologies, whereby regulators of sleep schedules and sleep duration also govern the physiological purposes of sleep. To support our hypothesis, we review Mendelian human genetic variants sufficient to advance sleep-wake onset (PER2) and shorten sleep length (DEC2), and evaluate their emerging roles in immune responses that may rely on a sound night of slumber. Copyright © 2013 Elsevier Ltd. All rights reserved.

  12. Use of a novel chimeric mouse model with a functionally active human immune system to study human immunodeficiency virus type 1 infection

    NARCIS (Netherlands)

    An, Dong Sung; Poon, Betty; Tsong Fang, Raphael Ho; Weijer, Kees; Blom, Bianca; Spits, Hergen; Chen, Irvin S. Y.; Uittenbogaart, Christel H.

    2007-01-01

    The goal of this study was to develop a small-animal model to study human immunodeficiency virus type 1 (HIV-1) pathogenesis in blood and primary and secondary lymphoid organs. Rag2(-/-)gamma(c)(-/-) mice that are neonatally injected with human CD34(+) cells develop a functional human immune system

  13. Reconstitution of Low Bandwidth Reaction History

    International Nuclear Information System (INIS)

    May, M.; Clancy, T.; Fittinghoff, D.; Gennaro, P.; Hagans, K.; Halvorson, G.; Lowry, M.; Perry, T.; Roberson, P.; Smith, D.; Teruya, A.; Blair, J.; Davis, B.; Hunt, E.; Emkeit, B.; Galbraith, J.; Kelly, B.; Montoya, R.; Nickel, G.; Ogle, J.; Wilson, K.; Wood, M.

    2004-01-01

    The goal of the Test Readiness Program is to transition to a 24 month test readiness posture and if approved move to an 18-month posture. One of the key components of the Test Readiness Program necessary to meet this goal is the reconstitution of the important diagnostics. Since the end of nuclear testing, the ability to field diagnostics on a nuclear test has deteriorated. Reconstitution of diagnostics before those who had experience in nuclear testing either retire or leave is essential to achieving a shorter test readiness posture. Also, the data recording systems have not been used since the end of testing. This report documents the reconstitution of one vital diagnostic: the low bandwidth reaction history diagnostic for FY04. Reaction history is one of the major diagnostics that has been used on all LLNL and LANL tests since the early days of nuclear testing. Reaction history refers to measuring the time history of the gamma and neutron output from a nuclear test. This gives direct information on the nuclear reactions taking place in the device. The reaction history measurements are one of the prime measurements the nuclear weapon scientists use to validate their models of device performance. All tests currently under consideration require the reaction history diagnostic. Thus moving to a shorter test readiness posture requires the reconstitution of the ability to make reaction history measurements. Reconstitution of reaction history was planned to be in two steps. Reaction history measurements that have been used in the past can be broadly placed into two categories. The most common type of reaction history and the one that has been performed on virtually all nuclear tests is termed low bandwidth reaction history. This measurement has a time response that is limited by the bandpass of kilometer length coaxial cables. When higher bandwidth has been required for specific measurements, fiber optic techniques have been used. This is referred to as high

  14. 7 CFR 58.522 - Reconstituting nonfat dry milk.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 3 2010-01-01 2010-01-01 false Reconstituting nonfat dry milk. 58.522 Section 58.522 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Standards... Procedures § 58.522 Reconstituting nonfat dry milk. Nonfat dry milk shall be reconstituted in a sanitary...

  15. 49 CFR 178.515 - Standards for reconstituted wood boxes.

    Science.gov (United States)

    2010-10-01

    ... wood boxes. (a) The identification code for a reconstituted wood box is 4F. (b) Construction requirements for reconstituted wood boxes are as follows: (1) The walls of boxes must be made of water... 49 Transportation 2 2010-10-01 2010-10-01 false Standards for reconstituted wood boxes. 178.515...

  16. A change in inflammatory footprint precedes plaque instability: a systematic evaluation of cellular aspects of the adaptive immune response in human atherosclerosis

    NARCIS (Netherlands)

    van Dijk, R. A.; Duinisveld, A. J. F.; Schaapherder, A. F.; Mulder-Stapel, A.; Hamming, J. F.; Kuiper, J.; de Boer, O. J.; van der Wal, A. C.; Kolodgie, F. D.; Virmani, R.; Lindeman, J. H. N.

    2015-01-01

    Experimental studies characterize adaptive immune response as a critical factor in the progression and complications of atherosclerosis. Yet, it is unclear whether these observations translate to the human situation. This study systematically evaluates cellular components of the adaptive immune

  17. Neonatal protection by an innate immune system of human milk consisting of oligosaccharides and glycans.

    Science.gov (United States)

    Newburg, D S

    2009-04-01

    This review discusses the role of human milk glycans in protecting infants, but the conclusion that the human milk glycans constitute an innate immune system whereby the mother protects her offspring may have general applicability in all mammals, including species of commercial importance. Infants that are not breastfed have a greater incidence of severe diarrhea and respiratory diseases than those who are breastfed. In the past, this had been attributed primarily to human milk secretory antibodies. However, the oligosaccharides are major components of human milk, and milk is also rich in other glycans, including glycoproteins, mucins, glycosaminoglycans, and glycolipids. These milk glycans, especially the oligosaccharides, are composed of thousands of components. The milk factor that promotes gut colonization by Bifidobacterium bifidum was found to be a glycan, and such prebiotic characteristics may contribute to protection against infectious agents. However, the ability of human milk glycans to protect the neonate seems primarily to be due to their inhibition of pathogen binding to their host cell target ligands. Many such examples include specific fucosylated oligosaccharides and glycans that inhibit specific pathogens. Most human milk oligosaccharides are fucosylated, and their production depends on fucosyltransferase enzymes; mutations in these fucosyltransferase genes are common and underlie the various Lewis blood types in humans. Variable expression of specific fucosylated oligosaccharides in milk, also a function of these genes (and maternal Lewis blood type), is significantly associated with the risk of infectious disease in breastfed infants. Human milk also contains major quantities and large numbers of sialylated oligosaccharides, many of which are also present in bovine colostrum. These could similarly inhibit several common viral pathogens. Moreover, human milk oligosaccharides strongly attenuate inflammatory processes in the intestinal mucosa. These

  18. Voluntary activation of the sympathetic nervous system and attenuation of the innate immune response in humans.

    Science.gov (United States)

    Kox, Matthijs; van Eijk, Lucas T; Zwaag, Jelle; van den Wildenberg, Joanne; Sweep, Fred C G J; van der Hoeven, Johannes G; Pickkers, Peter

    2014-05-20

    Excessive or persistent proinflammatory cytokine production plays a central role in autoimmune diseases. Acute activation of the sympathetic nervous system attenuates the innate immune response. However, both the autonomic nervous system and innate immune system are regarded as systems that cannot be voluntarily influenced. Herein, we evaluated the effects of a training program on the autonomic nervous system and innate immune response. Healthy volunteers were randomized to either the intervention (n = 12) or control group (n = 12). Subjects in the intervention group were trained for 10 d in meditation (third eye meditation), breathing techniques (i.a., cyclic hyperventilation followed by breath retention), and exposure to cold (i.a., immersions in ice cold water). The control group was not trained. Subsequently, all subjects underwent experimental endotoxemia (i.v. administration of 2 ng/kg Escherichia coli endotoxin). In the intervention group, practicing the learned techniques resulted in intermittent respiratory alkalosis and hypoxia resulting in profoundly increased plasma epinephrine levels. In the intervention group, plasma levels of the anti-inflammatory cytokine IL-10 increased more rapidly after endotoxin administration, correlated strongly with preceding epinephrine levels, and were higher. Levels of proinflammatory mediators TNF-α, IL-6, and IL-8 were lower in the intervention group and correlated negatively with IL-10 levels. Finally, flu-like symptoms were lower in the intervention group. In conclusion, we demonstrate that voluntary activation of the sympathetic nervous system results in epinephrine release and subsequent suppression of the innate immune response in humans in vivo. These results could have important implications for the treatment of conditions associated with excessive or persistent inflammation, such as autoimmune diseases.

  19. Reconstituted yogurt from yogurt cultured milk powder mix has better overall characteristics than reconstituted yogurt from commercial yogurt powder.

    Science.gov (United States)

    Song, Lijie; Aryana, Kayanush J

    2014-10-01

    For manufacture of commercial yogurt powder, yogurt has to go through a drying process, which substantially lowers the yogurt culture counts, so the potential health benefits of the yogurt culture bacteria are reduced. Also, upon reconstitution, commercial yogurt powder does not taste like yogurt and has an off-flavor. The objective was to study the microbial, physicochemical, and sensory characteristics of reconstituted yogurt from yogurt cultured milk powder (YCMP) mix and reconstituted yogurt from commercial yogurt powder (CYP). The CYP reconstituted yogurt was the control and YCMP mix reconstituted yogurt was the treatment. Microbial and physicochemical characteristics of the CYP reconstituted yogurt and YCMP mix reconstituted yogurt were analyzed daily for the first week and then weekly for a period of 8 wk. Sensory consumer testing of CYP reconstituted yogurt and YCMP mix reconstituted yogurt was conducted with 100 consumers. At 56 d, YCMP mix reconstituted yogurt had 5 log cfu/mL higher counts of Streptococcus thermophilus than the control (CYP reconstituted yogurt). Also, Lactobacillus bulgaricus counts of YCMP mix reconstituted yogurt were 6.55 log cfu/mL at 28 d and were 5.35 log cfu/mL at 56 d, whereas the CYP reconstituted yogurt from 28 d onwards had a count of yogurt also had significantly higher apparent viscosity and sensory scores for appearance, color, aroma, taste, thickness, overall liking, consumer acceptability, and purchase intent than CYP reconstituted yogurt. Overall, YCMP mix reconstituted yogurt had more desirable characteristics than CYP reconstituted yogurt. Copyright © 2014 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

  20. Assessment of humoral immune responses to blood-stage malaria antigens following ChAd63-MVA immunization, controlled human malaria infection and natural exposure.

    Science.gov (United States)

    Biswas, Sumi; Choudhary, Prateek; Elias, Sean C; Miura, Kazutoyo; Milne, Kathryn H; de Cassan, Simone C; Collins, Katharine A; Halstead, Fenella D; Bliss, Carly M; Ewer, Katie J; Osier, Faith H; Hodgson, Susanne H; Duncan, Christopher J A; O'Hara, Geraldine A; Long, Carole A; Hill, Adrian V S; Draper, Simon J

    2014-01-01

    The development of protective vaccines against many difficult infectious pathogens will necessitate the induction of effective antibody responses. Here we assess humoral immune responses against two antigens from the blood-stage merozoite of the Plasmodium falciparum human malaria parasite--MSP1 and AMA1. These antigens were delivered to healthy malaria-naïve adult volunteers in Phase Ia clinical trials using recombinant replication-deficient viral vectors--ChAd63 to prime the immune response and MVA to boost. In subsequent Phase IIa clinical trials, immunized volunteers underwent controlled human malaria infection (CHMI) with P. falciparum to assess vaccine efficacy, whereby all but one volunteer developed low-density blood-stage parasitemia. Here we assess serum antibody responses against both the MSP1 and AMA1 antigens following i) ChAd63-MVA immunization, ii) immunization and CHMI, and iii) primary malaria exposure in the context of CHMI in unimmunized control volunteers. Responses were also assessed in a cohort of naturally-immune Kenyan adults to provide comparison with those induced by a lifetime of natural malaria exposure. Serum antibody responses against MSP1 and AMA1 were characterized in terms of i) total IgG responses before and after CHMI, ii) responses to allelic variants of MSP1 and AMA1, iii) functional growth inhibitory activity (GIA), iv) IgG avidity, and v) isotype responses (IgG1-4, IgA and IgM). These data provide the first in-depth assessment of the quality of adenovirus-MVA vaccine-induced antibody responses in humans, along with assessment of how these responses are modulated by subsequent low-density parasite exposure. Notable differences were observed in qualitative aspects of the human antibody responses against these malaria antigens depending on the means of their induction and/or exposure of the host to the malaria parasite. Given the continued clinical development of viral vectored vaccines for malaria and a range of other diseases

  1. Assessment of humoral immune responses to blood-stage malaria antigens following ChAd63-MVA immunization, controlled human malaria infection and natural exposure.

    Directory of Open Access Journals (Sweden)

    Sumi Biswas

    Full Text Available The development of protective vaccines against many difficult infectious pathogens will necessitate the induction of effective antibody responses. Here we assess humoral immune responses against two antigens from the blood-stage merozoite of the Plasmodium falciparum human malaria parasite--MSP1 and AMA1. These antigens were delivered to healthy malaria-naïve adult volunteers in Phase Ia clinical trials using recombinant replication-deficient viral vectors--ChAd63 to prime the immune response and MVA to boost. In subsequent Phase IIa clinical trials, immunized volunteers underwent controlled human malaria infection (CHMI with P. falciparum to assess vaccine efficacy, whereby all but one volunteer developed low-density blood-stage parasitemia. Here we assess serum antibody responses against both the MSP1 and AMA1 antigens following i ChAd63-MVA immunization, ii immunization and CHMI, and iii primary malaria exposure in the context of CHMI in unimmunized control volunteers. Responses were also assessed in a cohort of naturally-immune Kenyan adults to provide comparison with those induced by a lifetime of natural malaria exposure. Serum antibody responses against MSP1 and AMA1 were characterized in terms of i total IgG responses before and after CHMI, ii responses to allelic variants of MSP1 and AMA1, iii functional growth inhibitory activity (GIA, iv IgG avidity, and v isotype responses (IgG1-4, IgA and IgM. These data provide the first in-depth assessment of the quality of adenovirus-MVA vaccine-induced antibody responses in humans, along with assessment of how these responses are modulated by subsequent low-density parasite exposure. Notable differences were observed in qualitative aspects of the human antibody responses against these malaria antigens depending on the means of their induction and/or exposure of the host to the malaria parasite. Given the continued clinical development of viral vectored vaccines for malaria and a range of other

  2. Physical characterization of plakophilin 1 reconstituted with and without zinc.

    Science.gov (United States)

    Hofmann, I; Mücke, N; Reed, J; Herrmann, H; Langowski, J

    2000-07-01

    Plakophilin 1 (PKP1) belongs to the arm-repeat protein family which is characterized by the presence of a conserved 42-amino-acid motif. Despite individual members of the family containing a similar type of structural domain, they exhibit diverse cellular functions. PKP1 is ubiquitously expressed in human tissues and, depending on the type of cell, found prominently in the karyoplasm and/or in desmosomes. In surface plasmon resonance detection experiments, we noticed that PKP1 specifically bound zinc but not calcium or magnesium. Therefore we have used circular dichroism spectroscopy, limited proteolysis, analytical ultracentrifugation, electron microscopy and dynamic light scattering to establish the physical properties of recombinant PKP1 depending on the presence or absence of zinc. The alpha helix content of PKP1 was considerably higher when reconstituted with zinc than without. By atomic absorption spectroscopy 7.3 atoms zinc were shown to be tightly associated with one molecule of wild-type PKP1. The zinc-reconstituted protein formed globular particles of 21.9 +/- 8.4 nm diameter, as measured by electron microscopy after glycerol spraying/rotary metal shadowing. In parallel, the average sedimentation coefficient (s20, w) for zinc-containing PKP1 was 41S and its diffusion coefficient, as obtained by dynamic light scattering, 1.48 x 10-7 cm2.s-1. The molecular mass of 2.44 x 106 obtained from s and D yields an average stoichiometry of 30 for the PKP1 oligomer. In contrast, PKP1, reconstituted without zinc, contained no significant amount of zinc, sedimented with 4.6S, and was present in monomeric form as determined by sedimentation equilibrium centrifugation.

  3. The human immune response to streptococcal extracellular antigens: clinical, diagnostic, and potential pathogenetic implications.

    Science.gov (United States)

    Johnson, Dwight R; Kurlan, Roger; Leckman, James; Kaplan, Edward L

    2010-02-15

    Determination of an immune response to group A Streptococcus (GAS) antigens, frequently anti-streptolysin O and anti-DNase B, is crucial for documentation of bona fide GAS infection. Although the importance of immunologic confirmation of infection is widely accepted, the immediate and long-term immunokinetics of the human antibody response are incompletely documented and poorly understood. Pediatric study participants (n = 160) were followed during a 2-year study with monthly throat cultures (n = 3491) and blood samples (n = 1679) obtained every 13 weeks. Recovered GAS were characterized; serum anti-streptolysin O and anti-DNase B antibody titers were determined. Antibody titers and GAS culture results were temporally correlated and analyzed. The analyses clearly document, in some instances for the first time, that an increase in antibody titer more accurately defines infection than does an absolute titer (eg, "upper limit of normal"), that antibody titers can remain elevated for many months even without GAS, and that some individuals may harbor GAS continuously for months or years without symptoms of infection and without an associated immune response. Measuring 2 different antibodies is more accurate in defining infection. Single time-point cultures and single antibody titers are often misleading. Sequential samples more accurately define infection, allowing correlation of titer increases with temporal confirmation of GAS acquisition. Understanding kinetics of the immune response(s) to GAS infection is necessary in formulating accurate clinical diagnostic conclusions, to appropriate design of clinical and epidemiological studies examining the association of GAS with subsequent sequelae, and to providing insight into pathogenetic mechanisms associated with this important human pathogen.

  4. A novel model to study neonatal Escherichia coli sepsis and the effect of treatment on the human immune system using humanized mice.

    Science.gov (United States)

    Schlieckau, Florian; Schulz, Daniela; Fill Malfertheiner, Sara; Entleutner, Kathrin; Seelbach-Goebel, Birgit; Ernst, Wolfgang

    2018-04-19

    Neonatal sepsis is a serious threat especially for preterm infants. As existing in vitro and in vivo models have limitations, we generated a novel neonatal sepsis model using humanized mice and tested the effect of Betamethasone and Indomethacin which are used in the clinic in case of premature birth. Humanized mice were infected with Escherichia coli (E. coli). Subsequently, the effect of the infection itself, and treatment with Betamethasone and Indomethacin on survival, recovery, bacterial burden, leukocyte populations, and cytokine production, was analyzed. The human immune system in the animals responded with leukocyte trafficking to the site of infection and granulopoiesis in the bone marrow. Treatment with Indomethacin had no pronounced effect on the immune system or bacterial burden. Betamethasone induced a decline of splenocytes. The human immune system in humanized mice responds to the infection, making them a suitable model to study neonatal E. coli sepsis and the immune response of the neonatal immune system. Treatment with Betamethasone could have potential negative long-term effects for the immune system of the child. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  5. Immune recognition of Onchocerca volvulus proteins in the human host and animal models of onchocerciasis.

    Science.gov (United States)

    Manchang, T K; Ajonina-Ekoti, I; Ndjonka, D; Eisenbarth, A; Achukwi, M D; Renz, A; Brattig, N W; Liebau, E; Breloer, M

    2015-05-01

    Onchocerca volvulus is a tissue-dwelling, vector-borne nematode parasite of humans and is the causative agent of onchocerciasis or river blindness. Natural infections of BALB/c mice with Litomosoides sigmodontis and of cattle with Onchocerca ochengi were used as models to study the immune responses to O. volvulus-derived recombinant proteins (OvALT-2, OvNLT-1, Ov103 and Ov7). The humoral immune response of O. volvulus-infected humans against OvALT-2, OvNLT-1 and Ov7 revealed pronounced immunoglobulin G (IgG) titres which were, however, significantly lower than against the lysate of O. volvulus adult female worms. Sera derived from patients displaying the hyperreactive form of onchocerciasis showed a uniform trend of higher IgG reactivity both to the single proteins and the O. volvulus lysate. Sera derived from L. sigmodontis-infected mice and from calves exposed to O. ochengi transmission in a hyperendemic area also contained IgM and IgG1 specific for O. volvulus-derived recombinant proteins. These results strongly suggest that L. sigmodontis-specific and O. ochengi-specific immunoglobulins elicited during natural infection of mice and cattle cross-reacted with O. volvulus-derived recombinant antigens. Monitoring O. ochengi-infected calves over a 26-month period, provided a comprehensive kinetic of the humoral response to infection that was strictly correlated with parasite load and occurrence of microfilariae.

  6. Innate immune defense in the inner ear - mucines are expressed by the human endolymphatic sac

    DEFF Research Database (Denmark)

    Møller, Martin N; Kirkeby, Svend; Cayé-Thomasen, Per

    2017-01-01

    The human endolymphatic sac has been shown recently to have immunological capacities and has thus been proposed as the main entity protecting the inner ear from pathogen invasion, equivalent to mucosa-associated lymphoid tissue (MALT). Although the sac expresses molecules of the innate immune...... system, the potential expression of members of the important mucin family has not been detailed. Thus, this paper explores endolymphatic sac expression of a number of mucins and mucin precursors. Twelve fresh tissue samples from the human endolymphatic sac were obtained during translabyrinthine surgery...... immunological tissue structure of the inner ear, equivalent to MALT in other organs. The mucins may also play a role in the formation and continuous homeostasis of the inner ear fluids, as well as the pathogenesis of Meniere's disease....

  7. Expression of Fas ligand by human gastric adenocarcinomas: a potential mechanism of immune escape in stomach cancer.

    Science.gov (United States)

    Bennett, M W; O'connell, J; O'sullivan, G C; Roche, D; Brady, C; Kelly, J; Collins, J K; Shanahan, F

    1999-02-01

    Despite being immunogenic, gastric cancers overcome antitumour immune responses by mechanisms that have yet to be fully elucidated. Fas ligand (FasL) is a molecule that induces Fas receptor mediated apoptosis of activated immunocytes, thereby mediating normal immune downregulatory roles including immune response termination, tolerance acquisition, and immune privilege. Colon cancer cell lines have previously been shown to express FasL and kill lymphoid cells by Fas mediated apoptosis in vitro. Many diverse tumours have since been found to express FasL suggesting that a "Fas counterattack" against antitumour immune effector cells may contribute to tumour immune escape. To ascertain if human gastric tumours express FasL in vivo, as a potential mediator of immune escape in stomach cancer. Thirty paraffin wax embedded human gastric adenocarcinomas. FasL protein was detected in gastric tumours using immunohistochemistry; FasL mRNA was detected in the tumours using in situ hybridisation. Cell death was detected in situ in tumour infiltrating lymphocytes using terminal deoxynucleotidyl transferase mediated dUTP nick end labelling (TUNEL). Prevalent expression of FasL was detected in all 30 resected gastric adenocarcinomas examined. In the tumours, FasL protein and mRNA were co-localised to neoplastic gastric epithelial cells, confirming expression by the tumour cells. FasL expression was independent of tumour stage, suggesting that it may be expressed throughout gastric cancer progression. TUNEL staining disclosed a high level of cell death among lymphocytes infiltrating FasL positive areas of tumour. Human gastric adenocarcinomas express the immune downregulatory molecule, FasL. The results suggest that FasL is a prevalent mediator of immune privilege in stomach cancer.

  8. Expression of Fas ligand by human gastric adenocarcinomas: a potential mechanism of immune escape in stomach cancer.

    LENUS (Irish Health Repository)

    Bennett, M W

    2012-02-03

    BACKGROUND: Despite being immunogenic, gastric cancers overcome antitumour immune responses by mechanisms that have yet to be fully elucidated. Fas ligand (FasL) is a molecule that induces Fas receptor mediated apoptosis of activated immunocytes, thereby mediating normal immune downregulatory roles including immune response termination, tolerance acquisition, and immune privilege. Colon cancer cell lines have previously been shown to express FasL and kill lymphoid cells by Fas mediated apoptosis in vitro. Many diverse tumours have since been found to express FasL suggesting that a "Fas counterattack" against antitumour immune effector cells may contribute to tumour immune escape. AIM: To ascertain if human gastric tumours express FasL in vivo, as a potential mediator of immune escape in stomach cancer. SPECIMENS: Thirty paraffin wax embedded human gastric adenocarcinomas. METHODS: FasL protein was detected in gastric tumours using immunohistochemistry; FasL mRNA was detected in the tumours using in situ hybridisation. Cell death was detected in situ in tumour infiltrating lymphocytes using terminal deoxynucleotidyl transferase mediated dUTP nick end labelling (TUNEL). RESULTS: Prevalent expression of FasL was detected in all 30 resected gastric adenocarcinomas examined. In the tumours, FasL protein and mRNA were co-localised to neoplastic gastric epithelial cells, confirming expression by the tumour cells. FasL expression was independent of tumour stage, suggesting that it may be expressed throughout gastric cancer progression. TUNEL staining disclosed a high level of cell death among lymphocytes infiltrating FasL positive areas of tumour. CONCLUSIONS: Human gastric adenocarcinomas express the immune downregulatory molecule, FasL. The results suggest that FasL is a prevalent mediator of immune privilege in stomach cancer.

  9. mEBT: multiple-matching Evidence-based Translator of Murine Genomic Responses for Human Immunity Studies.

    Science.gov (United States)

    Tae, Donghyun; Seok, Junhee

    2018-05-29

    In this paper, we introduce multiple-matching Evidence-based Translator (mEBT) to discover genomic responses from murine expression data for human immune studies, which are significant in the given condition of mice and likely have similar responses in the corresponding condition of human. mEBT is evaluated over multiple data sets and shows improved inter-species agreement. mEBT is expected to be useful for research groups who use murine models to study human immunity. http://cdal.korea.ac.kr/mebt/. jseok14@korea.ac.kr. Supplementary data are available at Bioinformatics online.

  10. Lacrimal drainage-associated lymphoid tissue (LDALT): a part of the human mucosal immune system.

    Science.gov (United States)

    Knop, E; Knop, N

    2001-03-01

    Mucosa-associated lymphoid tissue (MALT) specifically protects mucosal surfaces. In a previous study of the human conjunctiva, evidence was also found for the presence of MALT in the lacrimal sac. The present study, therefore, aims to investigate its morphology and topographical distribution in the human lacrimal drainage system. Lacrimal drainage systems (n = 51) obtained from human cadavers were investigated by clearing flat wholemounts or by serial sections of tissue embedded in paraffin, OCT compound, or epoxy resin. These were further analyzed by histology, immunohistochemistry, and electron microscopy. All specimens showed the presence of lymphocytes and plasma cells as a diffuse lymphoid tissue in the lamina propria, together with intraepithelial lymphocytes and occasional high endothelial venules (HEV). It formed a narrow layer along the canaliculi that became thicker in the cavernous parts. The majority of lymphocytes were T cells, whereas B cells were interspersed individually or formed follicular centers. T cells were positive for CD8 and the human mucosa lymphocyte antigen (HML-1). Most plasma cells were positive for IgA and the overlying epithelium expressed its transporter molecule secretory component (SC). Basal mucous glands were present in the lacrimal canaliculi and in the other parts accompanied by alveolar and acinar glands, all producing IgA-rich secretions. Primary and secondary lymphoid follicles possessing HEV were present in about half of the specimens. The term lacrimal drainage-associated lymphoid tissue (LDALT) is proposed here to describe the lymphoid tissue that is regularly present and belongs to the common mucosal immune system and to the secretory immune system. It is suggested that it may form a functional unit together with the lacrimal gland and conjunctiva, connected by tear flow, lymphocyte recirculation, and probably the neural reflex arc, and play a major role in preserving ocular surface integrity.

  11. Diversity of aging of the immune system classified in the cotton rat (Sigmodon hispidus) model of human infectious diseases.

    NARCIS (Netherlands)

    Guichelaar, Teun; van Erp, Elisabeth A; Hoeboer, Jeroen; Smits, Noortje A M; van Els, Cécile A C M; Pieren, Daan K J; Luytjes, Willem

    2018-01-01

    Susceptibility and declined resistance to human pathogens like respiratory syncytial virus (RSV) at old age is well represented in the cotton rat (Sigmodon hispidus). Despite providing a preferred model of human infectious diseases, little is known about aging of its adaptive immune system. We aimed

  12. Human Norovirus and Its Surrogates Induce Plant Immune Response in Arabidopsis thaliana and Lactuca sativa.

    Science.gov (United States)

    Markland, Sarah M; Bais, Harsh; Kniel, Kalmia E

    2017-08-01

    Human norovirus is the leading cause of foodborne illness worldwide with the majority of outbreaks linked to fresh produce and leafy greens. It is essential that we thoroughly understand the type of relationship and interactions that take place between plants and human norovirus to better utilize control strategies to reduce transmission of norovirus in the field onto plants harvested for human consumption. In this study the expression of gene markers for the salicylic acid (SA) and jasmonic acid (JA) plant defense pathways was measured and compared in romaine lettuce (Lactuca sativa) and Arabidopsis thaliana Col-0 plants that were inoculated with Murine Norovirus-1, Tulane Virus, human norovirus GII.4, or Hank's Balanced Salt Solution (control). Genes involving both the SA and JA pathways were expressed in both romaine lettuce and A. thaliana for all three viruses, as well as controls. Studies, including gene expression of SA- and JA-deficient A. thaliana mutant lines, suggest that the JA pathway is more likely involved in the plant immune response to human norovirus. This research provides the first pieces of information regarding how foodborne viruses interact with plants in the preharvest environment.

  13. Reevaluation of epidemiological data demonstrates that it is consistent with cross-immunity among human papillomavirus types.

    Science.gov (United States)

    Durham, David P; Poolman, Eric M; Ibuka, Yoko; Townsend, Jeffrey P; Galvani, Alison P

    2012-10-01

    The degree of cross-immunity between human papillomavirus (HPV) types is fundamental both to the epidemiological dynamics of HPV and to the impact of HPV vaccination. Epidemiological data on HPV infections has been repeatedly interpreted as inconsistent with cross-immunity. We reevaluate the epidemiological data using a model to determine the odds ratios of multiple to single infections expected in the presence or absence of cross-immunity. We simulate a virtual longitudinal survey to determine the effect cross-immunity has on the prevalence of multiple infections. We calibrate our model to epidemiological data and estimate the extent of type replacement following vaccination against specific HPV types. We find that cross-immunity can produce odds ratios of infection comparable with epidemiological observations. We show that the sample sizes underlying existing surveys have been insufficient to identify even intense cross-immunity. We also find that the removal of HPV type 16, type 18, and types 6 and 11 would increase the prevalence of nontargeted types by 50%, 29%, and 183%, respectively. Cross-immunity between HPV types is consistent with epidemiological data, contrary to previous interpretations. Cross-immunity may cause significant type replacement following vaccination, and therefore should be considered in future vaccine studies and epidemiological models.

  14. Innate and adaptive immune interactions at the fetal-maternal interface in healthy human pregnancy and preeclampsia

    Directory of Open Access Journals (Sweden)

    Peter eHsu

    2014-03-01

    Full Text Available Maternal immune tolerance of the fetus is indispensible for a healthy pregnancy outcome. Nowhere is this immune tolerance more important than at the fetal-maternal interface – the decidua, the site of implantation and placentation. Indeed, many lines of evidence suggest an immunological origin to the common pregnancy-related disorder, preeclampsia. Within the innate immune system, decidual NK cells and antigen presenting cells (including dendritic cells and macrophages make up a large proportion of the decidual leukocyte population, and are thought to modulate vascular remodeling and trophoblast invasion. On the other hand, within the adaptive immune system, Foxp3+ regulatory T (Treg cells are crucial for ensuring immune tolerance towards the semi-allogeneic fetus. Additionally, another population of CD4+HLA-G+ suppressor T cells has also been identified as a potential player in the maintenance of immune tolerance. More recently, studies are beginning to unravel the potential interactions between the innate and the adaptive immune system within the decidua, that are required to maintain a healthy pregnancy. In this review, we discuss the recent advances exploring the complex crosstalk between the innate and the adaptive immune system during human pregnancy.

  15. Challenges and Strategies for Proteome Analysis of the Interaction of Human Pathogenic Fungi with Host Immune Cells.

    Science.gov (United States)

    Krüger, Thomas; Luo, Ting; Schmidt, Hella; Shopova, Iordana; Kniemeyer, Olaf

    2015-12-14

    Opportunistic human pathogenic fungi including the saprotrophic mold Aspergillus fumigatus and the human commensal Candida albicans can cause severe fungal infections in immunocompromised or critically ill patients. The first line of defense against opportunistic fungal pathogens is the innate immune system. Phagocytes such as macrophages, neutrophils and dendritic cells are an important pillar of the innate immune response and have evolved versatile defense strategies against microbial pathogens. On the other hand, human-pathogenic fungi have sophisticated virulence strategies to counteract the innate immune defense. In this context, proteomic approaches can provide deeper insights into the molecular mechanisms of the interaction of host immune cells with fungal pathogens. This is crucial for the identification of both diagnostic biomarkers for fungal infections and therapeutic targets. Studying host-fungal interactions at the protein level is a challenging endeavor, yet there are few studies that have been undertaken. This review draws attention to proteomic techniques and their application to fungal pathogens and to challenges, difficulties, and limitations that may arise in the course of simultaneous dual proteome analysis of host immune cells interacting with diverse morphotypes of fungal pathogens. On this basis, we discuss strategies to overcome these multifaceted experimental and analytical challenges including the viability of immune cells during co-cultivation, the increased and heterogeneous protein complexity of the host proteome dynamically interacting with the fungal proteome, and the demands on normalization strategies in terms of relative quantitative proteome analysis.

  16. Potent innate immune response to pathogenic leptospira in human whole blood.

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    Marga G A Goris

    Full Text Available BACKGROUND: Leptospirosis is caused by pathogenic spirochetes of the genus Leptospira. The bacteria enter the human body via abraded skin or mucous membranes and may disseminate throughout. In general the clinical picture is mild but some patients develop rapidly progressive, severe disease with a high case fatality rate. Not much is known about the innate immune response to leptospires during haematogenous dissemination. Previous work showed that a human THP-1 cell line recognized heat-killed leptospires and leptospiral LPS through TLR2 instead of TLR4. The LPS of virulent leptospires displayed a lower potency to trigger TNF production by THP-1 cells compared to LPS of non-virulent leptospires. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the host response and killing of virulent and non-virulent Leptospira of different serovars by human THP-1 cells, human PBMC's and human whole blood. Virulence of each leptospiral strain was tested in a well accepted standard guinea pig model. Virulent leptospires displayed complement resistance in human serum and whole blood while in-vitro attenuated non-virulent leptospires were rapidly killed in a complement dependent manner. In vitro stimulation of THP-1 and PBMC's with heat-killed and living leptospires showed differential serovar and cell type dependence of cytokine induction. However, at low, physiological, leptospiral dose, living virulent complement resistant strains were consistently more potent in whole blood stimulations than the corresponding non-virulent complement sensitive strains. At higher dose living virulent and non-virulent leptospires were equipotent in whole blood. Inhibition of different TLRs indicated that both TLR2 and TLR4 as well as TLR5 play a role in the whole blood cytokine response to living leptospires. CONCLUSIONS/SIGNIFICANCE: Thus, in a minimally altered system as human whole blood, highly virulent Leptospira are potent inducers of the cytokine response.

  17. Progesterone Induces Mucosal Immunity in a Rodent Model of Human Taeniosis by Taenia solium

    Science.gov (United States)

    Escobedo, Galileo; Camacho-Arroyo, Ignacio; Nava-Luna, Paul; Olivos, Alfonso; Pérez-Torres, Armando; Leon-Cabrera, Sonia; Carrero, J.C.; Morales-Montor, Jorge

    2011-01-01

    More than one quarter of human world's population is exposed to intestinal helminth parasites. The Taenia solium tapeworm carrier is the main risk factor in the transmission of both human neurocysticercosis and porcine cysticercosis. Sex steroids play an important role during T. solium infection, particularly progesterone has been proposed as a key immunomodulatory hormone involved in susceptibility to human taeniosis in woman and cysticercosis in pregnant pigs. Thus, we evaluated the effect of progesterone administration upon the experimental taeniosis in golden hamsters (Mesocricetus auratus). Intact female adult hamsters were randomly divided into 3 groups: progesterone-subcutaneously treated; olive oil-treated as the vehicle group; and untreated controls. Animals were treated every other day during 4 weeks. After 2 weeks of treatment, all hamsters were orally infected with 4 viable T. solium cysticerci. After 2 weeks post infection, progesterone-treated hamsters showed reduction in adult worm recovery by 80%, compared to both vehicle-treated and non-manipulated infected animals. In contrast to control and vehicle groups, progesterone treatment diminished tapeworm length by 75% and increased proliferation rate of leukocytes from spleen and mesenteric lymph nodes of infected hamsters by 5-fold. The latter exhibited high expression levels of IL-4, IL-6 and TNF-α at the duodenal mucosa, accompanied with polymorphonuclear leukocytes infiltration. These results support that progesterone protects hamsters from the T. solium adult tapeworm establishment by improving the intestinal mucosal immunity, suggesting a potential use of analogues of this hormone as novel inductors of the gut immune response against intestinal helminth infections and probably other bowel-related disorders. PMID:22110394

  18. Progesterone induces mucosal immunity in a rodent model of human taeniosis by Taenia solium.

    Science.gov (United States)

    Escobedo, Galileo; Camacho-Arroyo, Ignacio; Nava-Luna, Paul; Olivos, Alfonso; Pérez-Torres, Armando; Leon-Cabrera, Sonia; Carrero, J C; Morales-Montor, Jorge

    2011-01-01

    More than one quarter of human world's population is exposed to intestinal helminth parasites. The Taenia solium tapeworm carrier is the main risk factor in the transmission of both human neurocysticercosis and porcine cysticercosis. Sex steroids play an important role during T. solium infection, particularly progesterone has been proposed as a key immunomodulatory hormone involved in susceptibility to human taeniosis in woman and cysticercosis in pregnant pigs. Thus, we evaluated the effect of progesterone administration upon the experimental taeniosis in golden hamsters (Mesocricetus auratus). Intact female adult hamsters were randomly divided into 3 groups: progesterone-subcutaneously treated; olive oil-treated as the vehicle group; and untreated controls. Animals were treated every other day during 4 weeks. After 2 weeks of treatment, all hamsters were orally infected with 4 viable T. solium cysticerci. After 2 weeks post infection, progesterone-treated hamsters showed reduction in adult worm recovery by 80%, compared to both vehicle-treated and non-manipulated infected animals. In contrast to control and vehicle groups, progesterone treatment diminished tapeworm length by 75% and increased proliferation rate of leukocytes from spleen and mesenteric lymph nodes of infected hamsters by 5-fold. The latter exhibited high expression levels of IL-4, IL-6 and TNF-α at the duodenal mucosa, accompanied with polymorphonuclear leukocytes infiltration. These results support that progesterone protects hamsters from the T. solium adult tapeworm establishment by improving the intestinal mucosal immunity, suggesting a potential use of analogues of this hormone as novel inductors of the gut immune response against intestinal helminth infections and probably other bowel-related disorders.

  19. Molecular genetics of human immune responsiveness to Lolium perenne (rye) allergen, Lol p III.

    Science.gov (United States)

    Ansari, A A; Freidhoff, L R; Marsh, D G

    1989-01-01

    Lol p II and III are each about 11-kD protein allergens from the pollen of Lolium perenne (rye grass). We have found that human immune responses (IgE and IgG antibodies) to both proteins are significantly associated with HLA-DR3. In addition, the two proteins are cross-reactive with the antibodies in many human sera (about 84% human sera showed the cross-reactivity). We have determined greater than 90% of the amino acid sequences of the two proteins and found that they are at least 54% homologous. Berzofsky found that 75% of the 23 known T cell sites in various proteins had an amphipathic structure. Our analysis by the same method showed that both Lol p II and III have a major region of amphipathicity (at residues 61-67, Lol p III numbering) which might contain sites for binding to an Ia molecule and a T cell receptor. This region is identical between Lol p II and III, except for an Arg-Lys substitution, and could account, in part, for the DR3 association with responsiveness to both molecules. An interesting difference between the two proteins is that immune response to Lol p III is associated with DR5 (in addition to DR3), whereas no DR5 association is found in the case of Lol p II. One possibility is that Lol p III has an additional site which binds to the DR5 Ia molecule. Lol p III indeed has a second highly amphiphathic peptide, 24-30 (Lol p III 24 R P G D T L A 30), which is different and not amphipathic in Lol p II.(ABSTRACT TRUNCATED AT 250 WORDS)

  20. The capsule of Porphyromonas gingivalis reduces the immune response of human gingival fibroblasts

    Directory of Open Access Journals (Sweden)

    van Winkelhoff Arie J

    2010-01-01

    Full Text Available Abstract Background Periodontitis is a bacterial infection of the periodontal tissues. The Gram-negative anaerobic bacterium Porphyromonas gingivalis is considered a major causative agent. One of the virulence factors of P. gingivalis is capsular polysaccharide (CPS. Non-encapsulated strains have been shown to be less virulent in mouse models than encapsulated strains. Results To examine the role of the CPS in host-pathogen interactions we constructed an insertional isogenic P. gingivalis knockout in the epimerase-coding gene epsC that is located at the end of the CPS biosynthesis locus. This mutant was subsequently shown to be non-encapsulated. K1 capsule biosynthesis could be restored by in trans expression of an intact epsC gene. We used the epsC mutant, the W83 wild type strain and the complemented mutant to challenge human gingival fibroblasts to examine the immune response by quantification of IL-1β, IL-6 and IL-8 transcription levels. For each of the cytokines significantly higher expression levels were found when fibroblasts were challenged with the epsC mutant compared to those challenged with the W83 wild type, ranging from two times higher for IL-1β to five times higher for IL-8. Conclusions These experiments provide the first evidence that P. gingivalis CPS acts as an interface between the pathogen and the host that may reduce the host's pro-inflammatory immune response. The higher virulence of encapsulated strains may be caused by this phenomenon which enables the bacteria to evade the immune system.

  1. Opportunistic Infections and Complications in Human Immunodeficiency Virus-1-Infected Children: Correlation with immune status

    Directory of Open Access Journals (Sweden)

    Jaivinder Yadav

    2014-10-01

    Full Text Available Objectives: The aim of this study was to ascertain the correlation between various opportunistic infections and complications in human immunodeficiency virus (HIV-1-infected children and the immune status of these patients, evaluated by absolute cluster of differentiation 4 (CD4 count and CD4 percentage. Methods: This study was conducted from January 2009 to June 2010 at the Antiretroviral Treatment Centre of the Pt. B.D. Sharma Post Graduate Institute of Medical Sciences, a tertiary care hospital in Rohtak, Haryana, in northern India. A total of 20 HIV-1-infected children aged 4–57 months were studied. Demographic and baseline investigations were performed prior to the start of highly active antiretroviral therapy (HAART. A fixed-dose combination of HAART was given based on the patient’s weight. Baseline investigations were repeated after six months of HAART. Results: There was a significant increase in the patients’ haemoglobin, weight, height and CD4 count after six months of HAART. Significant improvements (P <0.05 were also noted in the patients’ immune status, graded according to the World Health Organization. Conclusion: This study observed that the severity and frequency of opportunistic complications in paediatric patients with HIV-1 increased with a fall in the CD4 count. The treatment of opportunistic infections, along with antiretroviral therapy, may lead to both clinical and immunological recovery as well as a decreased incidence of future opportunistic infections. The CD4 count may give treating physicians an initial idea about the immune status of each child and could also be used as a biological marker of HAART efficacy. Patient compliance must be ensured during HAART as this is a key factor in improving outcomes.

  2. Functional analysis of the human cytomegalovirus immune evasion protein, pUS322kDa

    International Nuclear Information System (INIS)

    Zhao Yiqiang; Biegalke, Bonita J.

    2003-01-01

    Human cytomegalovirus (HCMV) is an important opportunistic pathogen that infrequently causes disease in individuals with mature immune systems. The HCMV US3 gene encodes a 22-kDa protein that interferes with immune recognition of virally infected cells. The 22-kDa US3 protein binds to major histocompatibility complex (MHC) class I complexes, retaining them in the endoplasmic reticulum (ER), thereby decreasing the presentation of viral antigen to cytotoxic T cells. Our studies demonstrate that correct folding of the ER lumenal domain of the US3 protein is essential, but insufficient for interactions with MHC class I complexes. We demonstrate a requirement for the transmembrane domain of the 22-kDa US3 protein, confirming the results of others, and also show that the cytosolic carboxyl-terminal tail influences the function of the protein. Anchoring of the ER-lumenal immunoglobulin-like fold of the US3 protein to the membrane of the endoplasmic reticulum is critical for the binding and retention of MHC class I complexes

  3. Monoclonal antibodies from rats immunized with fragment D of human fibrinogen

    International Nuclear Information System (INIS)

    Kennel, S.J.; Chen, J.P.; Lankford, P.K.; Foote, L.J.

    1981-01-01

    Fischer rats were immunized with fragment D (Fg-D) of human fibrinogen (Fg) to obtain antibody specific for neoantigens unique to this molecule. Absorption of serum with whole Fg indicated that some of the antibody produced reacted preferentially with Fg-D. Hybridoma cultures were prepared by fusion of immune rat spleen cells with mouse myeloma P3-X63-Ag8. Monoclonal antibodies obtained from these cultures fell into two classes: (a) Those reacting equally well with Fg and Fg-D. (b) Those reacting preferentially but not absolutely wth Fg-D. Antibody from hybridoma 104-14, a member of the first group had an affinity for Fg-D of 1.5 x 10 9 M -1 while antibodies from 106-59 and 106-71 (group 2) demonstrated much lower affinities of 1.0 x 10 7 and 4.7 x 10 6 M -1 , respectively. The cross reactivity of antibodies in the second group indicated that they react with protein conformations that are altered during production of Fg-D from Fg

  4. Isolation of Anti-Ricin Protective Antibodies Exhibiting High Affinity from Immunized Non-Human Primates

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    Tal Noy-Porat

    2016-03-01

    Full Text Available Ricin, derived from the castor bean plant Ricinus communis, is one of the most potent and lethal toxins known, against which there is no available antidote. To date, the use of neutralizing antibodies is the most promising post-exposure treatment for ricin intoxication. The aim of this study was to isolate high affinity anti-ricin antibodies that possess potent toxin-neutralization capabilities. Two non-human primates were immunized with either a ricin-holotoxin- or subunit-based vaccine, to ensure the elicitation of diverse high affinity antibodies. By using a comprehensive set of primers, immune scFv phage-displayed libraries were constructed and panned. A panel of 10 antibodies (five directed against the A subunit of ricin and five against the B subunit was isolated and reformatted into a full-length chimeric IgG. All of these antibodies were found to neutralize ricin in vitro, and several conferred full protection to ricin-intoxicated mice when given six hours after exposure. Six antibodies were found to possess exceptionally high affinity toward the toxin, with KD values below pM (koff < 1 × 10−7 s−1 that were well correlated with their ability to neutralize ricin. These antibodies, alone or in combination, could be used for the development of a highly-effective therapeutic preparation for post-exposure treatment of ricin intoxication.

  5. Heterologous humoral immune response in patients treated with human growth hormone from different sources

    International Nuclear Information System (INIS)

    Cardoso, A.I.; Llera, A.S.; Iacono, R.F.

    1993-01-01

    The existence of homologous anti-human growth hormone (anti-hGH) and heterologous anti-bovine growth hormone (anti-bGH) humoral immune responses in hypopituitary patients under hGH therapy has been reported previously. In order to study the influence of the hormone source, both responses were compared by radiobinding assays performed with [ 125 I]hGH or [ 125 I]bGH as tracers. 57 hypopituitary patients treated with extractive hGH, recombinant methionyl hGH or authentic recombinant hGH were studied. A very low incidence of heterologous antibodies was found in patients under recombinant hGH therapy, contrary to the high incidence observed in patients treated with extractive hGH preparations. In addition, immunochemical studies performed with a synthetic peptide (hGH 44-128) indicated that this peptide exhibited, in the anti-bGH/[ 125 I]bGH radioimmunoassay system, higher reactivity than the native hGH, suggesting that such fragment resembled an altered conformation of the hormone. The high heterologous response elicited only by the extractive hGH along with the behaviour of the hGH 44-128 fragment supports the fact that the extraction and purification procedures in extractive preparations may alter slightly the structure of the hGH molecule and trigger a heterologous immune response. 16 refs., 4 figs., 1 tab

  6. Heterologous humoral immune response in patients treated with human growth hormone from different sources

    Energy Technology Data Exchange (ETDEWEB)

    Cardoso, A.I.; Llera, A.S.; Iacono, R.F. (and others) (Inst. de Estudios de la Inmunidad Humoral, Buenos Aires (Argentina))

    1993-07-01

    The existence of homologous anti-human growth hormone (anti-hGH) and heterologous anti-bovine growth hormone (anti-bGH) humoral immune responses in hypopituitary patients under hGH therapy has been reported previously. In order to study the influence of the hormone source, both responses were compared by radiobinding assays performed with [[sup 125]I]hGH or [[sup 125]I]bGH as tracers. 57 hypopituitary patients treated with extractive hGH, recombinant methionyl hGH or authentic recombinant hGH were studied. A very low incidence of heterologous antibodies was found in patients under recombinant hGH therapy, contrary to the high incidence observed in patients treated with extractive hGH preparations. In addition, immunochemical studies performed with a synthetic peptide (hGH 44-128) indicated that this peptide exhibited, in the anti-bGH/[[sup 125]I]bGH radioimmunoassay system, higher reactivity than the native hGH, suggesting that such fragment resembled an altered conformation of the hormone. The high heterologous response elicited only by the extractive hGH along with the behaviour of the hGH 44-128 fragment supports the fact that the extraction and purification procedures in extractive preparations may alter slightly the structure of the hGH molecule and trigger a heterologous immune response. 16 refs., 4 figs., 1 tab.

  7. Binding of human papilloma virus L1 virus-like particles to dendritic cells is mediated through heparan sulfates and induces immune activation

    NARCIS (Netherlands)

    de Witte, Lot; Zoughlami, Younes; Aengeneyndt, Birgit; David, Guido; van Kooyk, Yvette; Gissmann, Lutz; Geijtenbeek, Teunis B. H.

    2007-01-01

    Immunization using human papilloma virus (HPV)-L1 virus-like particles (VLPs) induces a robust and effective immune response, which has recently resulted in the implementation of the HPV-L1 VLP vaccination in health programs. However, during infection, HPV can escape immune surveillance leading to

  8. Effects of the Commercial Flame Retardant Mixture DE-71 on Cytokine Production by Human Immune Cells

    DEFF Research Database (Denmark)

    Mynster Kronborg, Thit; Frohnert Hansen, Juliana; Nielsen, Claus Henrik

    2016-01-01

    Introduction Although production of polybrominated diphenyl ethers (PBDEs) is now banned, release from existing products will continue for many years. The PBDEs are assumed to be neurotoxic and toxic to endocrine organs at low concentrations. Their effect on the immune system has not been...... investigated thoroughly. We aimed to investigate the influence of DE-71 on cytokine production by peripheral blood mononuclear cells (PBMCs) stimulated with Escherichia Coli lipopolysaccharide (LPS) or phytohaemagglutinin-L (PHA-L). Material and Methods PBMCs isolated from healthy donors were pre....... Secretion of IL-1β, IL-2, IL-10, IL-8 and IL-6 was not significantly affected by DE-71. Conclusions We demonstrate an enhancing effect of DE-71 on cytokine production by normal human PBMCs stimulated with LPS or PHA-L ex vivo....

  9. Elsevier Trophoblast Research Award Lecture: Unique properties of decidual T cells and their role in immune regulation during human pregnancy.

    Science.gov (United States)

    Tilburgs, T; Claas, F H J; Scherjon, S A

    2010-03-01

    Maternal lymphocytes at the fetal-maternal interface play a key role in the immune acceptance of the allogeneic fetus. Most studies focus on decidual NK cells and their interaction with fetal trophoblasts, whereas limited data are available on the mechanisms of fetus specific immune recognition and immune regulation by decidual T cells at the fetal-maternal interface. The aim of this review is to describe the phenotypic characteristics of decidual T cell subsets present at the fetal-maternal interface, their interaction with HLA-C expressed by fetal trophoblasts and their role in immune recognition and regulation at the fetal-maternal interface during human pregnancy. Copyright 2010 Elsevier Ltd. All rights reserved.

  10. Human immune responses to H. pylori HLA Class II epitopes identified by immunoinformatic methods.

    Directory of Open Access Journals (Sweden)

    Songhua Zhang

    Full Text Available H. pylori persists in the human stomach over decades and promotes several adverse clinical sequelae including gastritis, peptic ulcers and gastric cancer that are linked to the induction and subsequent evasion of chronic gastric inflammation. Emerging evidence indicates that H. pylori infection may also protect against asthma and some other immune-mediated conditions through regulatory T cell effects outside the stomach. To characterize the complexity of the CD4+ T cell response generated during H. pylori infection, computational methods were previously used to generate a panel of 90 predicted epitopes conserved among H. pylori genomes that broadly cover HLA Class II diversity for maximum population coverage. Here, these sequences were tested individually for their ability to induce in vitro responses in peripheral blood mononuclear cells by interferon-γ ELISpot assay. The average number of spot-forming cells/million PBMCs was significantly elevated in H. pylori-infected subjects over uninfected persons. Ten of the 90 peptides stimulated IFN-γ secretion in the H. pylori-infected group only, whereas two out of the 90 peptides elicited a detectable IFN-γ response in the H. pylori-uninfected subjects but no response in the H. pylori-infected group. Cytokine ELISA measurements performed using in vitro PBMC culture supernatants demonstrated significantly higher levels of TNF-α, IL-2, IL-4, IL-6, IL-10, and TGF-β1 in the H. pylori-infected subjects, whereas IL-17A expression was not related to the subjects H. pylori-infection status. Our results indicate that the human T cell responses to these 90 peptides are generally increased in actively H. pylori-infected, compared with H. pylori-naïve, subjects. This information will improve understanding of the complex immune response to H. pylori, aiding rational epitope-driven vaccine design as well as helping identify other H. pylori epitopes with potentially immunoregulatory effects.

  11. Immune response to the West Nile virus in aged non-human primates.

    Directory of Open Access Journals (Sweden)

    Anne M Wertheimer

    2010-12-01

    Full Text Available Risk of encephalitis from West Nile virus (WNV infection increases dramatically with age. Understanding the basis of this susceptibility requires development of suitable animal models. Here, we investigated the immune response to WNV in old non-human primates.We investigated clinical, immunological and virological correlates of WNV infection in aging non-human primates. Aged (17-30 yrs and adult (6-9 yrs Rhesus macaques (RM were challenged with WNV in the presence or the absence of the mosquito salivary gland extract (SGE to approximate natural infection. None of the 26 animals exhibited clinical signs of the disease. Quantitative PCR suggested discrete and short-lived viremia, but infectious virus was never isolated. There was markedly increased, age-independent, proliferation of CD3(- non-B cells, followed by B-cell proliferation, which correlated to the loss of detectable WNV genomes. Moreover, animals primed with mosquito salivary gland extract exhibited reduced circulating WNV RNA. While we found the expected age-associated reduction in T cell proliferation, adaptive immunity did not correlate with infection outcome. That was further confirmed in a cohort of thymectomized and/or CD8 T-cell depleted Cynomolgus macaques (CM; N = 15, who also failed to develop WNV disease.Results are consistent with strong and age-independent innate resistance of macaques against WNV challenge. This animal model is therefore not suitable for vaccine and therapeutic testing against WNV. However, understanding the basis of their innate resistance against WNV in macaques could provide helpful clues to improve anti-WNV protection of older adults.

  12. Neisseria gonorrhoeae Modulates Immunity by Polarizing Human Macrophages to a M2 Profile.

    Directory of Open Access Journals (Sweden)

    María Carolina Ortiz

    Full Text Available Current data suggest that Neisseria gonorrhoeae is able to suppress the protective immune response at different levels, such as B and T lymphocytes and antigen-presenting cells. The present report is focused on gonococcus evasion mechanism on macrophages (MФ and its impact in the subsequent immune response. In response to various signals MФ may undergo classical-M1 (M1-MФ or alternative-M2 (M2-MФ activation. Until now there are no reports of the gonococcus effects on human MФ polarization. We assessed the phagocytic ability of monocyte-derived MФ (MDM upon gonococcal infection by immunofluorescence and gentamicin protection experiments. Then, we evaluated cytokine profile and M1/M2 specific-surface markers on MФ challenged with N. gonorrhoeae and their proliferative effect on T cells. Our findings lead us to suggest N. gonorrhoeae stimulates a M2-MФ phenotype in which some of the M2b and none of the M1-MФ-associated markers are induced. Interestingly, N. gonorrhoeae exposure leads to upregulation of a Programmed Death Ligand 1 (PD-L1, widely known as an immunosuppressive molecule. Moreover, functional results showed that N. gonorrhoeae-treated MФ are unable to induce proliferation of human T-cells, suggesting a more likely regulatory phenotype. Taken together, our data show that N. gonorroheae interferes with MФ polarization. This study has important implications for understanding the mechanisms of clearance versus long-term persistence of N. gonorroheae infection and might be applicable for the development of new therapeutic strategies.

  13. Evaluation of long-term effects of 50-Hz magnetic fields on immune functions in humans

    Energy Technology Data Exchange (ETDEWEB)

    Touitou, Y.; Auzeby, A.; Camus, F. [Faculty of Medicine Pierre et Marie Curie, 75 - Paris (France); Lambrozo, J.; Souques, M.; Verrier, A. [Gaz de France (EDF/GDF), SEM, 75 - Paris (France)

    2006-07-01

    The relationship between exposure to 50-Hz magnetic fields (E.L.F.) and human health is of increasing interest since this exposure has been implicated in many different diseases including cancers in epidemiological studies, though the results are controversial. The identification of possible mechanisms of interaction between E.L.F. and biological systems that could provide a biological plausibility to the observed effects has failed so far. In this study we investigate the possible chronic effects of exposure to E.L.F. in humans. We examine the circadian rhythm of CD{sub 3}, CD{sub 4}, CD{sub 8}, Nk cells and B cells in 15 men (38.0{+-}8.9 yrs) exposed chronically and daily for a period of 1-20 years, in the workplace and at home, to a 50-Hz magnetic field in search of any cumulative effect from those chronic conditions of exposure. The weekly geometric mean of individual exposures ranged from 0.1 to 2.6 {mu}T. The results are compared to those for 15 unexposed men similar in a (39.4 {+-}1.2 yrs), with the same synchronization and physical activity who served as controls (individual exposures ranged from 0.004 to 0.092 {mu}T). Blood samples were taken hourly from 2000 to 0800. This work shows that subjects exposed over a long period (up to 20 years) and on a daily basis to magnetic fields experienced no changes in their plasma immune variables. Our data suggest therefore that magnetic fields have no cumulative effects on immune functions, at least for the variables under study. (authors)

  14. Human disturbance alters endocrine and immune responses in the Galapagos marine iguana (Amblyrhynchus cristatus)

    Science.gov (United States)

    French, Susannah S; DeNardo, Dale F.; Greives, Timothy J.; Strand, Christine R.; Demas, Gregory E.

    2010-01-01

    Anthropogenic disturbance is a relevant and widespread facilitator of environmental change and there is clear evidence that it impacts natural populations. While population-level responses to major anthropogenic changes have been well studied, individual physiological responses to mild disturbance can be equally critical to the long-term survival of a species, yet they remain largely unexamined. The current study investigated the impact of seemingly low-level anthropogenic disturbance (ecotourism) on stress responsiveness and specific fitness-related immune measures in different breeding stages of the marine iguana (Amblyrhynchus cristatus). Specifically, we found stress-induced elevations in plasma corticosterone among tourist-exposed populations relative to undisturbed populations. We also found changes in multiple immunological responses associated with stress-related effects of human disturbance, including bacterial killing ability, cutaneous wound healing, and hemolytic complement activity, and the responses varied according to reproductive state. By identifying health-related consequences of human disturbance, this study provides critical insight into the conservation of a well-known species that has a very distinct ecology. The study also broadens the foundation of knowledge needed to understand the global significance of various levels of human disturbance. PMID:20708010

  15. Human disturbance alters endocrine and immune responses in the Galapagos marine iguana (Amblyrhynchus cristatus).

    Science.gov (United States)

    French, Susannah S; DeNardo, Dale F; Greives, Timothy J; Strand, Christine R; Demas, Gregory E

    2010-11-01

    Anthropogenic disturbance is a relevant and widespread facilitator of environmental change and there is clear evidence that it impacts natural populations. While population-level responses to major anthropogenic changes have been well studied, individual physiological responses to mild disturbance can be equally critical to the long-term survival of a species, yet they remain largely unexamined. The current study investigated the impact of seemingly low-level anthropogenic disturbance (ecotourism) on stress responsiveness and specific fitness-related immune measures in different breeding stages of the marine iguana (Amblyrhynchus cristatus). Specifically, we found stress-induced elevations in plasma corticosterone among tourist-exposed populations relative to undisturbed populations. We also found changes in multiple immunological responses associated with stress-related effects of human disturbance, including bacterial killing ability, cutaneous wound healing, and hemolytic complement activity, and the responses varied according to reproductive state. By identifying health-related consequences of human disturbance, this study provides critical insight into the conservation of a well-known species that has a very distinct ecology. The study also broadens the foundation of knowledge needed to understand the global significance of various levels of human disturbance. Copyright © 2010 Elsevier Inc. All rights reserved.

  16. Augmentation of Antitumor Immunity by Human and Mouse CAR T Cells Secreting IL-18

    Directory of Open Access Journals (Sweden)

    Biliang Hu

    2017-09-01

    Full Text Available The effects of transgenically encoded human and mouse IL-18 on T cell proliferation and its application in boosting chimeric antigen receptor (CAR T cells are presented. Robust enhancement of proliferation of IL-18-secreting human T cells occurred in a xenograft model, and this was dependent on TCR and IL-18R signaling. IL-18 augmented IFN-γ secretion and proliferation of T cells activated by the endogenous TCR. TCR-deficient, human IL-18-expressing CD19 CAR T cells exhibited enhanced proliferation and antitumor activity in the xenograft model. Antigen-propelled activation of cytokine helper ensemble (APACHE CAR T cells displayed inducible expression of IL-18 and enhanced antitumor immunity. In an intact mouse tumor model, CD19-IL-18 CAR T cells induced deeper B cell aplasia, significantly enhanced CAR T cell proliferation, and effectively augmented antitumor effects in mice with B16F10 melanoma. These findings point to a strategy to develop universal CAR T cells for patients with solid tumors.

  17. Regulatory T Cells in HIV-Infected Immunological Nonresponders Are Increased in Blood but Depleted in Lymphoid Tissue and Predict Immunological Reconstitution

    DEFF Research Database (Denmark)

    Gaardbo, Julie C; Hartling, Hans J; Ronit, Andreas

    2014-01-01

    BACKGROUND: HIV-infected immunological nonresponders fail to immune reconstitute despite optimal treatment. We hypothesized that regulatory T cells (Tregs) are involved in immunological reconstitution. Tregs and Treg subpopulations were measured in blood and Foxp3 cells in lymphoid tissue......, and the impact of Tregs on immunological reconstitution was determined. METHODS: HIV-infected individuals on combination antiretroviral therapy for a minimum of 2 years were included. The study population included 14 immunological nonresponders (INR; CD4 T-cell count .... In contrast, responders resembled healthy controls. Finally, in INR, high level of Tregs in blood and Foxp3 cells in lymphoid tissue were associated with higher level of immunological reconstitution after 1 year of follow-up. CONCLUSIONS: In conclusion, altered distribution of Tregs was found in INR...

  18. Genome-wide analysis of differential transcriptional and epigenetic variability across human immune cell types

    DEFF Research Database (Denmark)

    Ecker, Simone; Chen, Lu; Pancaldi, Vera

    2017-01-01

    Background: A healthy immune system requires immune cells that adapt rapidly to environmental challenges. This phenotypic plasticity can be mediated by transcriptional and epigenetic variability. Results: We apply a novel analytical approach to measure and compare transcriptional and epigenetic v...

  19. Mechanisms of virus immune evasion lead to development from chronic inflammation to cancer formation associated with human papillomavirus infection.

    Science.gov (United States)

    Senba, Masachika; Mori, Naoki

    2012-10-02

    Human papillomavirus (HPV) has developed strategies to escape eradication by innate and adaptive immunity. Immune response evasion has been considered an important aspect of HPV persistence, which is the main contributing factor leading to HPV-related cancers. HPV-induced cancers expressing viral oncogenes E6 and E7 are potentially recognized by the immune system. The major histocompatibility complex (MHC) class I molecules are patrolled by natural killer cells and CD8+ cytotoxic T lymphocytes, respectively. This system of recognition is a main target for the strategies of immune evasion deployed by viruses. The viral immune evasion proteins constitute useful tools to block defined stages of the MHC class I presentation pathway, and in this way HPV avoids the host immune response. The long latency period from initial infection to persistence signifies that HPV evolves mechanisms to escape the immune response. It has now been established that there are oncogenic mechanisms by which E7 binds to and degrades tumor suppressor Rb, while E6 binds to and inactivates tumor suppressor p53. Therefore, interaction of p53 and pRb proteins can give rise to an increased immortalization and genomic instability. Overexpression of NF-κB in cervical and penile cancers suggests that NF-κB activation is a key modulator in driving chronic inflammation to cancer. HPV oncogene-mediated suppression of NF-κB activity contributes to HPV escape from the immune system. This review focuses on the diverse mechanisms of the virus immune evasion with HPV that leads to chronic inflammation and cancer.

  20. ImmunoGrid: towards agent-based simulations of the human immune system at a natural scale

    DEFF Research Database (Denmark)

    Halling-Brown, M.; Pappalardo, F.; Rapin, Nicolas

    2010-01-01

    , such as the European Virtual Physiological Human initiative. Finally, we ask a key question: How long will it take us to resolve these challenges and when can we expect to have fully functional models that will deliver health-care benefits in the form of personalized care solutions and improved disease prevention?......The ultimate aim of the EU-funded ImmunoGrid project is to develop a natural-scale model of the human immune system-that is, one that reflects both the diversity and the relative proportions of the molecules and cells that comprise it-together with the grid infrastructure necessary to apply...... this model to specific applications in the field of immunology. These objectives present the ImmunoGrid Consortium with formidable challenges in terms of complexity of the immune system, our partial understanding about how the immune system works, the lack of reliable data and the scale of computational...

  1. Ocular myasthenia gravis induced by human acetylcholine receptor ϵ subunit immunization in HLA DR3 transgenic mice.

    Science.gov (United States)

    Wu, Xiaorong; Tuzun, Erdem; Saini, Shamsher S; Wang, Jun; Li, Jing; Aguilera-Aguirre, Leopoldo; Huda, Ruksana; Christadoss, Premkumar

    2015-12-01

    Extraocular muscles (EOM) are preferentially involved in myasthenia gravis (MG) and acetylcholine receptor (AChR) antibody positive MG patients may occasionally present with isolated ocular symptoms. Although experimental autoimmune myasthenia gravis (EAMG) induced by whole AChR immunization closely mimics clinical and immunopathological aspects of MG, EOM are usually not affected. We have previously developed an EAMG model, which imitates EOM symptoms of MG by immunization of human leukocyte antigen (HLA) transgenic mice with α or γ-subunits of human AChR (H-AChR). To investigate the significance of the ϵ-subunit in ocular MG, we immunized HLA-DR3 and HLA-DQ8 transgenic mice with recombinant H-AChR ϵ-subunit expressed in Escherichia coli. HLA-DR3 transgenic mice showed significantly higher clinical ocular and generalized MG severity scores and lower grip strength values than HLA-DQ8 mice. H-AChR ϵ-subunit-immunized HLA-DR3 transgenic mice had higher serum anti-AChR antibody (IgG, IgG1, IgG2b, IgG2c and IgM) levels, neuromuscular junction IgG and complement deposit percentages than ϵ-subunit-immunized HLA-DQ8 transgenic mice. Control mice immunized with E. coli extract or complete Freund adjuvant (CFA) did not show clinical and immunopathological features of ocular and generalized EAMG. Lymph node cells of ϵ-subunit-immunized HLA-DR3 mice showed significantly higher proliferative responses than those of ϵ-subunit-immunized HLA-DQ8 mice, crude E. coli extract-immunized and CFA-immunized transgenic mice. Our results indicate that the human AChR ϵ-subunit is capable of inducing myasthenic muscle weakness. Diversity of the autoimmune responses displayed by mice expressing different HLA class II molecules suggests that the interplay between HLA class II alleles and AChR subunits might have a profound impact on the clinical course of MG. Copyright © 2015 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

  2. An Analysis of Reconstituted Fluid Milk Pricing Policy

    OpenAIRE

    Glen D. Whipple

    1983-01-01

    This analysis suggests that alteration of the reconstituted fluid milk pricing provisions of federal and state milk market orders would have a substantial impact on market equilibrium. A reactive programming model of the U.S. milk market was used to simulate the effects of altered reconstituted fluid milk pricing policy. The solutions indicate that reconstituted fluid milk, as a lower cost alternative to fresh fluid milk, would make up a substantial portion of the fluid milk consumption in so...

  3. Catalog of Differentially Expressed Long Non-Coding RNA following Activation of Human and Mouse Innate Immune Response

    Directory of Open Access Journals (Sweden)

    Benoit T. Roux

    2017-08-01

    Full Text Available Despite increasing evidence to indicate that long non-coding RNAs (lncRNAs are novel regulators of immunity, there has been no systematic attempt to identify and characterize the lncRNAs whose expression is changed following the induction of the innate immune response. To address this issue, we have employed next-generation sequencing data to determine the changes in the lncRNA profile in four human (monocytes, macrophages, epithelium, and chondrocytes and four mouse cell types (RAW 264.7 macrophages, bone marrow-derived macrophages, peritoneal macrophages, and splenic dendritic cells following exposure to the pro-inflammatory mediators, lipopolysaccharides (LPS, or interleukin-1β. We show differential expression of 204 human and 210 mouse lncRNAs, with positional analysis demonstrating correlation with immune-related genes. These lncRNAs are predominantly cell-type specific, composed of large regions of repeat sequences, and show poor evolutionary conservation. Comparison within the human and mouse sequences showed less than 1% sequence conservation, although we identified multiple conserved motifs. Of the 204 human lncRNAs, 21 overlapped with syntenic mouse lncRNAs, of which five were differentially expressed in both species. Among these syntenic lncRNA was IL7-AS (antisense, which was induced in multiple cell types and shown to regulate the production of the pro-inflammatory mediator interleukin-6 in both human and mouse cells. In summary, we have identified and characterized those lncRNAs that are differentially expressed following activation of the human and mouse innate immune responses and believe that these catalogs will provide the foundation for the future analysis of the role of lncRNAs in immune and inflammatory responses.

  4. Clinical responses to adoptive T-cell transfer can be modeled in an autologous immune-humanized mouse model

    DEFF Research Database (Denmark)

    Jespersen, Henrik; Lindberg, Mattias F; Donia, Marco

    2017-01-01

    Immune checkpoint inhibitors and adoptive cell transfer (ACT) of autologous tumor-infiltrating T cells have shown durable responses in patients with melanoma. To study ACT and immunotherapies in a humanized model, we have developed PDXv2.0 - a melanoma PDX model where tumor cells and tumor...

  5. Sphingosine 1-phosphate receptor 5 mediates the immune quiescence of the human brain endothelial barrier

    Directory of Open Access Journals (Sweden)

    van Doorn Ruben

    2012-06-01

    Full Text Available Abstract Background The sphingosine 1-phosphate (S1P receptor modulator FTY720P (Gilenya® potently reduces relapse rate and lesion activity in the neuroinflammatory disorder multiple sclerosis. Although most of its efficacy has been shown to be related to immunosuppression through the induction of lymphopenia, it has been suggested that a number of its beneficial effects are related to altered endothelial and blood–brain barrier (BBB functionality. However, to date it remains unknown whether brain endothelial S1P receptors are involved in the maintenance of the function of the BBB thereby mediating immune quiescence of the brain. Here we demonstrate that the brain endothelial receptor S1P5 largely contributes to the maintenance of brain endothelial barrier function. Methods We analyzed the expression of S1P5 in human post-mortem tissues using immunohistochemistry. The function of S1P5 at the BBB was assessed in cultured human brain endothelial cells (ECs using agonists and lentivirus-mediated knockdown of S1P5. Subsequent analyses of different aspects of the brain EC barrier included the formation of a tight barrier, the expression of BBB proteins and markers of inflammation and monocyte transmigration. Results We show that activation of S1P5 on cultured human brain ECs by a selective agonist elicits enhanced barrier integrity and reduced transendothelial migration of monocytes in vitro. These results were corroborated by genetically silencing S1P5 in brain ECs. Interestingly, functional studies with these cells revealed that S1P5 strongly contributes to brain EC barrier function and underlies the expression of specific BBB endothelial characteristics such as tight junctions and permeability. In addition, S1P5 maintains the immunoquiescent state of brain ECs with low expression levels of leukocyte adhesion molecules and inflammatory chemokines and cytokines through lowering the activation of the transcription factor NFκB. Conclusion Our

  6. Characterising the mucosal and systemic immune responses to experimental human hookworm infection.

    Directory of Open Access Journals (Sweden)

    Soraya Gaze

    2012-02-01

    Full Text Available The mucosal cytokine response of healthy humans to parasitic helminths has never been reported. We investigated the systemic and mucosal cytokine responses to hookworm infection in experimentally infected, previously hookworm naive individuals from non-endemic areas. We collected both peripheral blood and duodenal biopsies to assess the systemic immune response, as well as the response at the site of adult worm establishment. Our results show that experimental hookworm infection leads to a strong systemic and mucosal Th2 (IL-4, IL-5, IL-9 and IL-13 and regulatory (IL-10 and TGF-β response, with some evidence of a Th1 (IFN-γ and IL-2 response. Despite upregulation after patency of both IL-15 and ALDH1A2, a known Th17-inducing combination in inflammatory diseases, we saw no evidence of a Th17 (IL-17 response. Moreover, we observed strong suppression of mucosal IL-23 and upregulation of IL-22 during established hookworm infection, suggesting a potential mechanism by which Th17 responses are suppressed, and highlighting the potential that hookworms and their secreted proteins offer as therapeutics for human inflammatory diseases.

  7. α-1 Antitrypsin regulates human neutrophil chemotaxis induced by soluble immune complexes and IL-8.

    LENUS (Irish Health Repository)

    Bergin, David A

    2010-12-01

    Hereditary deficiency of the protein α-1 antitrypsin (AAT) causes a chronic lung disease in humans that is characterized by excessive mobilization of neutrophils into the lung. However, the reason for the increased neutrophil burden has not been fully elucidated. In this study we have demonstrated using human neutrophils that serum AAT coordinates both CXCR1- and soluble immune complex (sIC) receptor-mediated chemotaxis by divergent pathways. We demonstrated that glycosylated AAT can bind to IL-8 (a ligand for CXCR1) and that AAT-IL-8 complex formation prevented IL-8 interaction with CXCR1. Second, AAT modulated neutrophil chemotaxis in response to sIC by controlling membrane expression of the glycosylphosphatidylinositol-anchored (GPI-anchored) Fc receptor FcγRIIIb. This process was mediated through inhibition of ADAM-17 enzymatic activity. Neutrophils isolated from clinically stable AAT-deficient patients were characterized by low membrane expression of FcγRIIIb and increased chemotaxis in response to IL-8 and sIC. Treatment of AAT-deficient individuals with AAT augmentation therapy resulted in increased AAT binding to IL-8, increased AAT binding to the neutrophil membrane, decreased FcγRIIIb release from the neutrophil membrane, and normalization of chemotaxis. These results provide new insight into the mechanism underlying the effect of AAT augmentation therapy in the pulmonary disease associated with AAT deficiency.

  8. Characterization of cellular immune response and innate immune signaling in human and nonhuman primate primary mononuclear cells exposed to Burkholderia mallei.

    Science.gov (United States)

    Alam, Shahabuddin; Amemiya, Kei; Bernhards, Robert C; Ulrich, Robert G; Waag, David M; Saikh, Kamal U

    2015-01-01

    Burkholderia pseudomallei infection causes melioidosis and is often characterized by severe sepsis. Although rare in humans, Burkholderia mallei has caused infections in laboratory workers, and the early innate cellular response to B. mallei in human and nonhuman primates has not been characterized. In this study, we examined the primary cellular immune response to B. mallei in PBMC cultures of non-human primates (NHPs), Chlorocebus aethiops (African Green Monkeys), Macaca fascicularis (Cynomolgus macaque), and Macaca mulatta (Rhesus macaque) and humans. Our results demonstrated that B. mallei elicited strong primary pro-inflammatory cytokines (IFN-γ, TNF-α, IL-1β, and IL-6) equivalent to the levels of B. pseudomallei in primary PBMC cultures of NHPs and humans. When we examined IL-1β and other cytokine responses by comparison to Escherichia coli LPS, African Green Monkeys appears to be most responsive to B. mallei than Cynomolgus or Rhesus. Characterization of the immune signaling mechanism for cellular response was conducted by using a ligand induced cell-based reporter assay, and our results demonstrated that MyD88 mediated signaling contributed to the B. mallei and B. pseudomallei induced pro-inflammatory responses. Notably, the induced reporter activity with B. mallei, B. pseudomallei, or purified LPS from these pathogens was inhibited and cytokine production was attenuated by a MyD88 inhibitor. Together, these results show that in the scenario of severe hyper-inflammatory responses to B. mallei infection, MyD88 targeted therapeutic intervention may be a successful strategy for therapy. Published by Elsevier Ltd.

  9. The human metapneumovirus matrix protein stimulates the inflammatory immune response in vitro.

    Directory of Open Access Journals (Sweden)

    Audrey Bagnaud-Baule

    Full Text Available Each year, during winter months, human Metapneumovirus (hMPV is associated with epidemics of bronchiolitis resulting in the hospitalization of many infants. Bronchiolitis is an acute illness of the lower respiratory tract with a consequent inflammation of the bronchioles. The rapid onset of inflammation suggests the innate immune response may have a role to play in the pathogenesis of this hMPV infection. Since, the matrix protein is one of the most abundant proteins in the Paramyxoviridae family virion, we hypothesized that the inflammatory modulation observed in hMPV infected patients may be partly associated with the matrix protein (M-hMPV response. By western blot analysis, we detected a soluble form of M-hMPV released from hMPV infected cell as well as from M-hMPV transfected HEK 293T cells suggesting that M-hMPV may be directly in contact with antigen presenting cells (APCs during the course of infection. Moreover, flow cytometry and confocal microscopy allowed determining that M-hMPV was taken up by dendritic cells (moDCs and macrophages inducing their activation. Furthermore, these moDCs enter into a maturation process inducing the secretion of a broad range of inflammatory cytokines when exposed to M-hMPV. Additionally, M-hMPV activated DCs were shown to stimulate IL-2 and IFN-γ production by allogeneic T lymphocytes. This M-hMPV-mediated activation and antigen presentation of APCs may in part explain the marked inflammatory immune response observed in pathology induced by hMPV in patients.

  10. Serological characterization of guinea pigs infected with H3N2 human influenza or immunized with hemagglutinin protein

    Directory of Open Access Journals (Sweden)

    Bushnell Ruth V

    2010-08-01

    Full Text Available Abstract Background Recent and previous studies have shown that guinea pigs can be infected with, and transmit, human influenza viruses. Therefore guinea pig may be a useful animal model for better understanding influenza infection and assessing vaccine strategies. To more fully characterize the model, antibody responses following either infection/re-infection with human influenza A/Wyoming/03/2003 H3N2 or immunization with its homologous recombinant hemagglutinin (HA protein were studied. Results Serological samples were collected and tested for anti-HA immunoglobulin by ELISA, antiviral antibodies by hemagglutination inhibition (HI, and recognition of linear epitopes by peptide scanning (PepScan. Animals inoculated with infectious virus demonstrated pronounced viral replication and subsequent serological conversion. Animals either immunized with the homologous HA antigen or infected, showed a relatively rapid rise in antibody titers to the HA glycoprotein in ELISA assays. Antiviral antibodies, measured by HI assay, were detectable after the second inoculation. PepScan data identified both previously recognized and newly defined linear epitopes. Conclusions Infection and/or recombinant HA immunization of guinea pigs with H3N2 Wyoming influenza virus resulted in a relatively rapid production of viral-specific antibody thus demonstrating the strong immunogenicity of the major viral structural proteins in this animal model for influenza infection. The sensitivity of the immune response supports the utility of the guinea pig as a useful animal model of influenza infection and immunization.

  11. Specific immune cell and cytokine characteristics of human testicular germ cell neoplasia.

    Science.gov (United States)

    Klein, Britta; Haggeney, Thomas; Fietz, Daniela; Indumathy, Sivanjah; Loveland, Kate L; Hedger, Mark; Kliesch, Sabine; Weidner, Wolfgang; Bergmann, Martin; Schuppe, Hans-Christian

    2016-10-01

    Which immune cells and cytokine profiles are characteristic for testicular germ cell neoplasia and what consequences does this have for the understanding of the related testicular immunopathology? The unique immune environment of testicular germ cell neoplasia comprises B cells and dendritic cells as well as high transcript levels of IL-6 and other B cell supporting or T helper cell type 1 (Th1)-driven cytokines and thus differs profoundly from normal testis or inflammatory lesions associated with hypospermatogenesis. T cells are known to be the major component of inflammatory infiltrates associated with either hypospermatogenesis or testicular cancer. It has previously been reported that B cells are only involved within infiltrates of seminoma samples, but this has not been investigated further. Immunohistochemical characterisation (IHC) of infiltrating immune cells and RT-qPCR-based analysis of corresponding cytokine microenvironments was performed on different testicular pathologies. Testicular biopsies, obtained from men undergoing andrological work-up of infertility or taken during surgery for testicular cancer, were used in this study. Samples were grouped as follows: (i) normal spermatogenesis (n = 18), (ii) hypospermatogenesis associated with lymphocytic infiltrates (n = 10), (iii) samples showing neoplasia [germ cell neoplasia in situ (GCNIS, n = 26) and seminoma, n = 18]. IHC was performed using antibodies against T cells (CD3+), B cells (CD20cy+), dendritic cells (CD11c+), macrophages (CD68+) and mast cells (mast cell tryptase+). Degree and compartmental localisation of immune cells throughout all groups analysed was evaluated semi-quantitatively. RT-qPCR on RNA extracted from cryo-preserved tissue samples was performed to analyse mRNA cytokine expression, specifically levels of IL-1β, IL-6, IL-17a, tumour necrosis factor (TNF)-α (pro-inflammatory), IL-10, transforming growth factor (TGF)-β1 (anti-inflammatory), IL-2, IL-12a, IL-12b

  12. Heterosybtypic T-cell immunity to influenza in humans: challenges for universal T-cell influenza vaccines

    Directory of Open Access Journals (Sweden)

    Saranya eSridhar

    2016-05-01

    Full Text Available Influenza A virus (IAV remains a significant global health issue causing annual epidemics, pandemics and sporadic human infections with highly pathogenic avian or swine influenza viruses. Current inactivated and live vaccines are the mainstay of the public health response to influenza although vaccine efficacy is lower against antigenically distinct viral strains. The first pandemic of the 21st century underlined the urgent need to develop new vaccines capable of protection against a broad range of influenza strains. Such universal influenza vaccines are based on the idea of heterosubtypic immunity wherein immune responses to epitopes conserved across IAV strains can confer protection against subsequent infection and disease. T-cells recognising conserved antigens are a key contributor to reducing viral load and limiting disease severity during heterosubtypic infection in animal models. Recent studies undertaken during the 2009 H1N1 pandemic provided key insights into the role of cross-reactive T-cells in mediating heterosubtypic protection in humans. This review focuses on human influenza to discuss the epidemiological observations that underpin cross-protective immunity, the role of T-cells as key players in mediating heterosubtypic immunity including recent data from natural history cohort studies and the ongoing clinical development of T-cell inducing universal influenza vaccines. The challenges and knowledge gaps for developing vaccines to generate long-lived protective T-cell responses is discussed.

  13. A systems model for immune cell interactions unravels the mechanism of inflammation in human skin.

    Science.gov (United States)

    Valeyev, Najl V; Hundhausen, Christian; Umezawa, Yoshinori; Kotov, Nikolay V; Williams, Gareth; Clop, Alex; Ainali, Crysanthi; Ouzounis, Christos; Tsoka, Sophia; Nestle, Frank O

    2010-12-02

    Inflammation is characterized by altered cytokine levels produced by cell populations in a highly interdependent manner. To elucidate the mechanism of an inflammatory reaction, we have developed a mathematical model for immune cell interactions via the specific, dose-dependent cytokine production rates of cell populations. The model describes the criteria required for normal and pathological immune system responses and suggests that alterations in the cytokine production rates can lead to various stable levels which manifest themselves in different disease phenotypes. The model predicts that pairs of interacting immune cell populations can maintain homeostatic and elevated extracellular cytokine concentration levels, enabling them to operate as an immune system switch. The concept described here is developed in the context of psoriasis, an immune-mediated disease, but it can also offer mechanistic insights into other inflammatory pathologies as it explains how interactions between immune cell populations can lead to disease phenotypes.

  14. A systems model for immune cell interactions unravels the mechanism of inflammation in human skin.

    Directory of Open Access Journals (Sweden)

    Najl V Valeyev

    2010-12-01

    Full Text Available Inflammation is characterized by altered cytokine levels produced by cell populations in a highly interdependent manner. To elucidate the mechanism of an inflammatory reaction, we have developed a mathematical model for immune cell interactions via the specific, dose-dependent cytokine production rates of cell populations. The model describes the criteria required for normal and pathological immune system responses and suggests that alterations in the cytokine production rates can lead to various stable levels which manifest themselves in different disease phenotypes. The model predicts that pairs of interacting immune cell populations can maintain homeostatic and elevated extracellular cytokine concentration levels, enabling them to operate as an immune system switch. The concept described here is developed in the context of psoriasis, an immune-mediated disease, but it can also offer mechanistic insights into other inflammatory pathologies as it explains how interactions between immune cell populations can lead to disease phenotypes.

  15. Early NK Cell Reconstitution Predicts Overall Survival in T-Cell Replete Allogeneic Hematopoietic Stem Cell Transplantation

    DEFF Research Database (Denmark)

    Minculescu, Lia; Marquart, Hanne Vibeke; Friis, Lone Smidstrups

    2016-01-01

    Early immune reconstitution plays a critical role in clinical outcome after allogeneic hematopoietic stem cell transplantation (HSCT). Natural killer (NK) cells are the first lymphocytes to recover after transplantation and are considered powerful effector cells in HSCT. We aimed to evaluate...... the clinical impact of early NK cell recovery in T-cell replete transplant recipients. Immune reconstitution was studied in 298 adult patients undergoing HSCT for acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL) and myelodysplastic syndrome (MDS) from 2005 to 2013. In multivariate analysis NK...... cell numbers day 30 (NK30) >150cells/µL were independently associated with superior overall survival (hazard ratio 0.79, 95% confidence interval 0.66-0.95, p=0.01). Cumulative incidence analyses showed that patients with NK30 >150cells/µL had significantly less transplant related mortality (TRM), p=0...

  16. Immune responses of mice and human breast cancer patients following immunization with synthetic sialyl-Tn conjugated to KLH plus detox adjuvant.

    Science.gov (United States)

    Longenecker, B M; Reddish, M; Koganty, R; MacLean, G D

    1993-08-12

    We generated a synthetic epitope, NANA alpha(2-6) GalNAc alpha-O-Crotyl (STn-crotyl), designed to "mimic" the natural O-linked epitope expressed on human carcinoma cells, NANA alpha(2-6)GalNAc alpha-O-Serine (STn-serine). STn-crotyl was conjugated to the carrier protein KLH through the crotyl linker arm, and a "vaccine" containing STn-KLH plus DETOX adjuvant was formulated. The immunogenicity of the vaccine was evaluated preclinically in CAF1 mice and subsequently in patients with metastatic breast cancer. The specificity and titers of IgG antibodies were evaluated by kinetic ELISA on synthetic STn-HSA and on ovine submaxillary mucin (OSM) solid phases. Ovine submaxillary mucin is a convenient source of repeating, natural O-linked STn-serine structures. Mice immunized three times with as little as 0.25 micrograms of STn-KLH produced IgG titers ranging from 1:10(4) to 1:10(5) when tested on solid phase OSM. Anti-OSM IgG, both polyclonal and monoclonal antibodies, generated from these mice were completely inhibited in their binding to solid phase OSM equally well by STn-serine and STn-crotyl synthetic haptens but not by several other closely related synthetic haptens. These monoclonal antibodies also bound to STn determinants on human tumor cell surfaces. Breast cancer patients immunized with 100 micrograms of the same vaccine produced median peak IgG titers 1:1280 measured on STn-HSA and 1:160 on OSM. Hapten inhibition experiments with the human sera demonstrated the specificities of the IgG antibodies for STn-crotyl and STn-serine, but not against several other related synthetic haptens. We found little evidence that the artificial linker arm (crotyl linker) contributed substantially to either the titer or affinity of the antibodies generated in either mice or human breast cancer patients. This suggests that the antibodies recognized the cancer-associated disaccharide NANA alpha(2-->6)-GalNAc. Small but not large doses of STn-KLH immunogen induced anti-STn DTH

  17. [Human papillomavirus vaccine. Statement of the Advisory Committee of Immunizations on behalf of the Chilean Infectious Diseases Society. September 2008].

    Science.gov (United States)

    Abarca, Katia; Valenzuela, M Teresa; Vergara, Rodrigo; Luchsinger, Vivian; Muñoz, Alma; Jiménez de la J, Jorge; Ripoll, Erna; O'Ryan, Miguel

    2008-11-01

    This article briefly reviews the epidemiology of human papillomavirus (HPV) infection and associated diseases globally and in Chile, and the scientific information of the licensed HPV vaccines: Gardasil and Cervari. Considering the available information, the Advisory Committee on Immunizations of the Chilean Society of Infectious Diseases recommends vaccination of teenage girls, ideally before initiating sexual activity, i.e., approximately at the age of 12 to 13 years and vaccination of women of any age if they have not started sexual activity. If women are vaccinated after initiating sexual activity, they should be informed of the lower efficacy of immunization if HPV infection has occurred. Education on responsible sexuality and sexually transmitted diseases should be maintained as a priority. Vaccination should be highly considered for inclusion in the National Immunization Program.

  18. The Arabidopsis homolog of human G3BP1 is a key regulator of stomatal and apoplastic immunity

    KAUST Repository

    Abulfaraj, Aala A.; Mariappan, Kiruthiga; Bigeard, Jean; Manickam, Prabhu; Blilou, Ikram; Guo, Xiujie; Al-Babili, Salim; Pflieger, Delphine; Hirt, Heribert; Rayapuram, Naganand

    2018-01-01

    Mammalian Ras-GTPase–activating protein SH3-domain–binding proteins (G3BPs) are a highly conserved family of RNA-binding proteins that link kinase receptor-mediated signaling to RNA metabolism. Mammalian G3BP1 is a multifunctional protein that functions in viral immunity. Here, we show that the Arabidopsis thaliana homolog of human G3BP1 negatively regulates plant immunity. Arabidopsis g3bp1 mutants showed enhanced resistance to the virulent bacterial pathogen Pseudomonas syringae pv. tomato. Pathogen resistance was mediated in Atg3bp1 mutants by altered stomatal and apoplastic immunity. Atg3bp1 mutants restricted pathogen entry into stomates showing insensitivity to bacterial coronatine–mediated stomatal reopening. AtG3BP1 was identified as a negative regulator of defense responses, which correlated with moderate up-regulation of salicylic acid biosynthesis and signaling without growth penalty.

  19. The Arabidopsis homolog of human G3BP1 is a key regulator of stomatal and apoplastic immunity

    KAUST Repository

    Abulfaraj, Aala Abdulaziz Hussien

    2018-05-31

    Mammalian Ras-GTPase–activating protein SH3-domain–binding proteins (G3BPs) are a highly conserved family of RNA-binding proteins that link kinase receptor-mediated signaling to RNA metabolism. Mammalian G3BP1 is a multifunctional protein that functions in viral immunity. Here, we show that the Arabidopsis thaliana homolog of human G3BP1 negatively regulates plant immunity. Arabidopsis g3bp1 mutants showed enhanced resistance to the virulent bacterial pathogen Pseudomonas syringae pv. tomato. Pathogen resistance was mediated in Atg3bp1 mutants by altered stomatal and apoplastic immunity. Atg3bp1 mutants restricted pathogen entry into stomates showing insensitivity to bacterial coronatine–mediated stomatal reopening. AtG3BP1 was identified as a negative regulator of defense responses, which correlated with moderate up-regulation of salicylic acid biosynthesis and signaling without growth penalty.

  20. Adenosine Deaminase (ADA)-Deficient Severe Combined Immune Deficiency (SCID): Molecular Pathogenesis and Clinical Manifestations.

    Science.gov (United States)

    Bradford, Kathryn L; Moretti, Federico A; Carbonaro-Sarracino, Denise A; Gaspar, Hubert B; Kohn, Donald B

    2017-10-01

    Deficiency of adenosine deaminase (ADA, EC3.5.4.4), a housekeeping enzyme of purine metabolism encoded by the Ada gene, is a cause of human severe combined immune deficiency (SCID). Numerous deleterious mutations occurring in the ADA gene have been found in patients with profound lymphopenia (T - B - NK - ), thus underscoring the importance of functional purine metabolism for the development of the immune defense. While untreated ADA SCID is a fatal disorder, there are multiple life-saving therapeutic modalities to restore ADA activity and reconstitute protective immunity, including enzyme replacement therapy (ERT), allogeneic hematopoietic stem cell transplantation (HSCT) and gene therapy (GT) with autologous gene-corrected hematopoietic stem cells (HSC). We review the pathogenic mechanisms and clinical manifestations of ADA SCID.

  1. Indigenous enteric eosinophils control DCs to initiate a primary Th2 immune response in vivo

    Science.gov (United States)

    Chu, Derek K.; Jimenez-Saiz, Rodrigo; Verschoor, Christopher P.; Walker, Tina D.; Goncharova, Susanna; Llop-Guevara, Alba; Shen, Pamela; Gordon, Melissa E.; Barra, Nicole G.; Bassett, Jennifer D.; Kong, Joshua; Fattouh, Ramzi; McCoy, Kathy D.; Bowdish, Dawn M.; Erjefält, Jonas S.; Pabst, Oliver; Humbles, Alison A.; Kolbeck, Roland; Waserman, Susan

    2014-01-01

    Eosinophils natively inhabit the small intestine, but a functional role for them there has remained elusive. Here, we show that eosinophil-deficient mice were protected from induction of Th2-mediated peanut food allergy and anaphylaxis, and Th2 priming was restored by reconstitution with il4+/+ or il4−/− eosinophils. Eosinophils controlled CD103+ dendritic cell (DC) activation and migration from the intestine to draining lymph nodes, events necessary for Th2 priming. Eosinophil activation in vitro and in vivo led to degranulation of eosinophil peroxidase, a granule protein whose enzymatic activity promoted DC activation in mice and humans in vitro, and intestinal and extraintestinal mouse DC activation and mobilization to lymph nodes in vivo. Further, eosinophil peroxidase enhanced responses to ovalbumin seen after immunization. Thus, eosinophils can be critical contributors to the intestinal immune system, and granule-mediated shaping of DC responses can promote both intestinal and extraintestinal adaptive immunity. PMID:25071163

  2. Reconstituted AIM2 inflammasome in cell-free system.

    Science.gov (United States)

    Kaneko, Naoe; Ito, Yuki; Iwasaki, Tomoyuki; Takeda, Hiroyuki; Sawasaki, Tatsuya; Migita, Kiyoshi; Agematsu, Kazunaga; Kawakami, Atsushi; Morikawa, Shinnosuke; Mokuda, Sho; Kurata, Mie; Masumoto, Junya

    2015-11-01

    Absent in melanoma 2 (AIM2) is an intracellular pattern-recognition receptor, which is a member of the PYHIN protein family, consisting of a PYD domain and an IFN-inducible nuclear localization (HIN) domain. AIM2 is reported to oligomerize with adaptor protein ASC upon sensing bacterial and viral cytosolic DNA in order to form the AIM2 inflammasome, which activates caspase-1 leading to IL-1β secretion. Dysregulation of AIM2 inflammasome is supposed to result in autoinflammatory and autoimmune diseases. Thus, the development of new targeted drugs against AIM2 inflammasome would be important for the treatment of these diseases. However, since AIM2 inflammasome is an intracellular receptor, enforced internalization of both ligands and candidate molecules is necessary for the screening of AIM2-inflammasome-targeted molecules. We developed a reconstituted AIM2 inflammasome in a cell-free system with amplified luminescent proximity homogeneous assay (Alpha). Strong Alpha signal was detected upon incubation with poly-deoxyadenylic-deoxythymidylic acid, poly(dA:dT), whereas no Alpha signal was detected upon incubation with muramyl dipeptide, one of the NLR ligands of Nod2 ligand. The interaction between AIM2 and ASC was disrupted by an anti-human ASC monoclonal antibody, CRID3, a class of diarylsulfonylurea-containing compounds, and glycyrrhizin, a substance found in liquorice root. Thus, the reconstituted AIM2 inflammasome in a cell-free system is useful for screening AIM2-inflammasome-targeted therapeutic molecules. Copyright © 2015 Elsevier B.V. All rights reserved.

  3. Effects of the Commercial Flame Retardant Mixture DE-71 on Cytokine Production by Human Immune Cells.

    Science.gov (United States)

    Mynster Kronborg, Thit; Frohnert Hansen, Juliana; Nielsen, Claus Henrik; Ramhøj, Louise; Frederiksen, Marie; Vorkamp, Katrin; Feldt-Rasmussen, Ulla

    2016-01-01

    Although production of polybrominated diphenyl ethers (PBDEs) is now banned, release from existing products will continue for many years. The PBDEs are assumed to be neurotoxic and toxic to endocrine organs at low concentrations. Their effect on the immune system has not been investigated thoroughly. We aimed to investigate the influence of DE-71 on cytokine production by peripheral blood mononuclear cells (PBMCs) stimulated with Escherichia Coli lipopolysaccharide (LPS) or phytohaemagglutinin-L (PHA-L). PBMCs isolated from healthy donors were pre-incubated with DE-71 at various concentrations and subsequently incubated with the monocyte stimulator LPS, or the T-cell activator PHA-L. Interferon (IFN)-γ, interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-8, IL-10, tumor necrosis factor (TNF)-α, IL-17A, and IL-17F were quantified in the supernatants by Luminex kits. At non-cytotoxic concentrations (0.01-10 μg/mL), DE-71 significantly enhanced secretion of IL-1β, IL-6, CXCL8, IL-10, and TNF-α (pproduction by normal human PBMCs stimulated with LPS or PHA-L ex vivo.

  4. Systems-Biology Approaches to Discover Anti-Viral Effectors of the Human Innate Immune Response

    Directory of Open Access Journals (Sweden)

    Andreas F.R. Sommer

    2011-07-01

    Full Text Available Virus infections elicit an immediate innate response involving antiviral factors. The activities of some of these factors are, in turn, blocked by viral countermeasures. The ensuing battle between the host and the viruses is crucial for determining whether the virus establishes a foothold and/or induces adaptive immune responses. A comprehensive systems-level understanding of the repertoire of anti-viral effectors in the context of these immediate virus-host responses would provide significant advantages in devising novel strategies to interfere with the initial establishment of infections. Recent efforts to identify cellular factors in a comprehensive and unbiased manner, using genome-wide siRNA screens and other systems biology “omics” methodologies, have revealed several potential anti-viral effectors for viruses like Human immunodeficiency virus type 1 (HIV-1, Hepatitis C virus (HCV, West Nile virus (WNV, and influenza virus. This review describes the discovery of novel viral restriction factors and discusses how the integration of different methods in systems biology can be used to more comprehensively identify the intimate interactions of viruses and the cellular innate resistance.

  5. Immunocytochemical investigation of immune cells within human primary and permanent tooth pulp.

    Science.gov (United States)

    Rodd, H D; Boissonade, F M

    2006-01-01

    The aim of this study was to determine whether there are any differences in the number and distribution of immune cells within human primary and permanent tooth pulp, both in health and disease. The research took the form of a quantitative immunocytochemical study. One hundred and twenty-four mandibular first permanent molars and second primary molars were obtained from children requiring dental extractions under general anaesthesia. Following exodontia, 10-microm-thick frozen pulp sections were processed for indirect immunofluorescence. Triple-labelling regimes were employed using combinations of the following: (1) protein gene product 9.5, a general neuronal marker; (2) leucocyte common antigen (LCA); and (3) Ulex europaeus I lectin, a marker of vascular endothelium. Image analysis was then used to determine the percentage area of immunostaining for LCA. Leucocytes were significantly more abundant in the pulp horn and mid-coronal region of intact and carious primary teeth, as compared to permanent teeth (P < 0.05, anova). Both dentitions demonstrated the presence of well-localized inflammatory cell infiltrates and marked aborization of pulpal nerves in areas of dense leucocyte accumulation. Primary and permanent tooth pulps appear to have a similar potential to mount inflammatory responses to gross caries The management of the compromised primary tooth pulp needs to be reappraised in the light of these findings.

  6. Innate and adaptive immunity gene expression of human keratinocytes cultured of severe burn injury.

    Science.gov (United States)

    Noronha, Silvana Aparecida Alves Corrêa de; Noronha, Samuel Marcos Ribeiro de; Lanziani, Larissa Elias; Ferreira, Lydia Masako; Gragnani, Alfredo

    2014-01-01

    Evaluate the expression profile of genes related to Innate and Adaptive Immune System (IAIS) of human Primary Epidermal keratinocytes (hPEKP) of patients with severe burns. After obtaining viable fragments of skin with and without burning, culture hKEP was initiated by the enzymatic method using Dispase (Sigma-Aldrich). These cells were treated with Trizol(r) (Life Technologies) for extraction of total RNA. This was quantified and analyzed for purity for obtaining cDNA for the analysis of gene expression using specific IAIS PCR Arrays plates (SA Biosciences). After the analysis of gene expression we found that 63% of these genes were differentially expressed, of which 77% were repressed and 23% were hyper-regulated. Among these, the following genes (fold increase or decrease): IL8 (41), IL6 (32), TNF (-92), HLA-E (-86), LYS (-74), CCR6 (- 73), CD86 (-41) and HLA-A (-35). This study contributes to the understanding of the molecular mechanisms underlying wound infection caused by the burn. Furthermore, it may provide new strategies to restore normal expression of these genes and thereby change the healing process and improve clinical outcome.

  7. Thermostability of reconstituted newcastle disease virus strains at 36 ...

    African Journals Online (AJOL)

    Haemagglutination (HA) test was employed to determine the stability of HA titers of reconstituted form of Hitchner – B1 (B1), LaSota (L) and Komarov (K) strains of Newcastle Disease Vaccine (NDV) at 360c. The temperature treatment method was through incubation (in water bath) of the reconstituted vaccines at selected ...

  8. Stability of Beriplast P fibrin sealant: storage and reconstitution.

    Science.gov (United States)

    Eberhard, Ulrich; Broder, Martin; Witzke, Günther

    2006-04-26

    This study was performed to investigate the stability of Beriplast P fibrin sealant (FS) across a range of storage conditions, both pre- and post-reconstitution. Storage stability of the FS was evaluated during long-term refrigeration (24 months) with or without interim storage at elevated temperatures (40 degrees C for 1 week and 25 degrees C for 1 and 3 months). Stability of individual FS components was assessed by measuring: fibrinogen content, Factor XIII activity (FXIII), thrombin activity and aprotinin potency. The package integrity of each component was also checked (sterility testing, moisture content and pH). Storage stability was also evaluated by testing the reconstituted product for adhesion (tearing force testing after mixing the solutions) and sterility. Reconstitution stability was evaluated following 3-months' storage, for up to 50 h post-reconstitution using the same tests as for the storage stability investigations. Pre-defined specifications were met for fibrinogen content, Factor XIII activity, and thrombin activity, demonstrating storage stability. Package integrity and the functionality and sterility of the reconstituted product were confirmed throughout. Reconstitution stability was demonstrated for up to 50 h following reconstitution, in terms of both tearing force and sterility tests. In conclusion, the storage stability of Beriplast P was demonstrated over a range of 24-month storage schedules including interim exposure to elevated temperature, and the reconstituted product was stable for up to 50 h.

  9. Effects of blood transportation on human peripheral mononuclear cell yield, phenotype and function: implications for immune cell biobanking.

    Directory of Open Access Journals (Sweden)

    Anita Posevitz-Fejfár

    Full Text Available Human biospecimen collection, processing and preservation are rapidly emerging subjects providing essential support to clinical as well as basic researchers. Unlike collection of other biospecimens (e.g. DNA and serum, biobanking of viable immune cells, such as peripheral blood mononuclear cells (PBMC and/or isolated immune cell subsets is still in its infancy. While certain aspects of processing and freezing conditions have been studied in the past years, little is known about the effect of blood transportation on immune cell survival, phenotype and specific functions. However, especially for multicentric and cooperative projects it is vital to precisely know those effects. In this study we investigated the effect of blood shipping and pre-processing delay on immune cell phenotype and function both on cellular and subcellular levels. Peripheral blood was collected from healthy volunteers (n = 9: at a distal location (shipped overnight and in the central laboratory (processed immediately. PBMC were processed in the central laboratory and analyzed post-cryopreservation. We analyzed yield, major immune subset distribution, proliferative capacity of T cells, cytokine pattern and T-cell receptor signal transduction. Results show that overnight transportation of blood samples does not globally compromise T- cell subsets as they largely retain their phenotype and proliferative capacity. However, NK and B cell frequencies, the production of certain PBMC-derived cytokines and IL-6 mediated cytokine signaling pathway are altered due to transportation. Various control experiments have been carried out to compare issues related to shipping versus pre-processing delay on site. Our results suggest the implementation of appropriate controls when using multicenter logistics for blood transportation aiming at subsequent isolation of viable immune cells, e.g. in multicenter clinical trials or studies analyzing immune cells/subsets. One important conclusion might

  10. Influence of age, irradiation and humanization on NSG mouse phenotypes

    Directory of Open Access Journals (Sweden)

    Jaclyn S. Knibbe-Hollinger

    2015-10-01

    Full Text Available Humanized mice are frequently utilized in bench to bedside therapeutic tests to combat human infectious, cancerous and degenerative diseases. For the fields of hematology-oncology, regenerative medicine, and infectious diseases, the immune deficient mice have been used commonly in basic research efforts. Obstacles in true translational efforts abound, as the relationship between mouse and human cells in disease pathogenesis and therapeutic studies requires lengthy investigations. The interplay between human immunity and mouse biology proves ever more complicated when aging, irradiation, and human immune reconstitution are considered. All can affect a range of biochemical and behavioral functions. To such ends, we show age- and irradiation-dependent influences for the development of macrocytic hyper chromic anemia, myelodysplasia, blood protein reductions and body composition changes. Humanization contributes to hematologic abnormalities. Home cage behavior revealed day and dark cycle locomotion also influenced by human cell reconstitutions. Significant age-related day-to-day variability in movement, feeding and drinking behaviors were observed. We posit that this data serves to enable researchers to better design translational studies in this rapidly emerging field of mouse humanization.

  11. CSPG4-specific immunity and survival prolongation in dogs with oral malignant melanoma immunized with human CSPG4 DNA.

    Science.gov (United States)

    Riccardo, Federica; Iussich, Selina; Maniscalco, Lorella; Lorda Mayayo, Saray; La Rosa, Giuseppe; Arigoni, Maddalena; De Maria, Raffaella; Gattino, Francesca; Lanzardo, Stefania; Lardone, Elena; Martano, Marina; Morello, Emanuela; Prestigio, Simone; Fiore, Alessandra; Quaglino, Elena; Zabarino, Sara; Ferrone, Soldano; Buracco, Paolo; Cavallo, Federica

    2014-07-15

    Due to the many similarities with its human counterpart, canine malignant melanoma (cMM) is a valuable model in which to assess the efficacy of novel therapeutic strategies. The model is herein used to evaluate the immunogenicity, safety, and therapeutic efficacy of a human chondroitin sulfate proteoglycan-4 (hCSPG4) DNA-based vaccine. The fact that homology between hCSPG4 and cCSPG4 amino-acidic sequences stands at more than 80% provides the rationale for using an hCSPG4 DNA vaccine in the cMM model. Dogs with stage II-III surgically resected CSPG4-positive oral MM were subjected to monthly intramuscular plasmid administration, which was followed immediately by electroporation (electrovaccination) for at least 6, and up to 20, months. The immunogenicity, safety, and therapeutic efficacy of the vaccine have been evaluated. hCSPG4 electrovaccination caused no clinically relevant local or systemic side effects and resulted in significantly longer overall and disease-free survival times in 14 vaccinated dogs as compared with 13 nonvaccinated controls. All vaccinated dogs developed antibodies against both hCSPG4 and cCSPG4. Seven vaccinated dogs were also tested for a cCSPG4-specific T-cell response and only two gave a detectable interferon (IFN)γ response. Xenogeneic electrovaccination against CSPG4 is able to overcome host unresponsiveness to the "self" antigen and seems to be effective in treating cMM, laying the foundation for its translation to a human clinical setting. ©2014 American Association for Cancer Research.

  12. Immunosuppressive function of mesenchymal stem cells from human umbilical cord matrix in immune thrombocytopenia patients.

    Science.gov (United States)

    Ma, Li; Zhou, Zeping; Zhang, Donglei; Yang, Shaoguang; Wang, Jinhong; Xue, Feng; Yang, Yanhui; Yang, Renchi

    2012-05-01

    Human umbilical cord matrix/Wharton's jelly (hUC)-derived mesenchymal stem cells (MSC) have been shown to have marked therapeutic effects in a number of inflammatory diseases and autoimmune diseases in humans based on their potential for immunosuppression and their low immunogenicity. Currently, no data are available on the effectiveness of UC-MSC transplantation in immune thrombocytopenia (ITP) patients. It was the objective of this study to assess the effect of allogeneic UC-MSCs on ITP patients in vitro and in vivo. Peripheral blood mononuclear cells (PBMCs) and bone marrow mononuclear cells (BM-MNCs) from ITP patients and healthy controls were co-cultured with UC-MSCs for three days and seven days, respectively. Flow cytometry and ELISA were applied to assess the various parameters. In PBMCs from ITP patients, the proliferation of autoreactive T, B lymphocytes and destruction of autologous platelets were dramatically suppressed by UC-MSCs. UC-MSCs not only suppressed co-stimulatory molecules CD80, CD40L and FasL expression but also in shifting Th1/Th2/Treg cytokines profile in ITP patients. UC-MSCs obviously reversed the dysfunctions of megakaryocytes by promoting platelet production and decreasing the number of living megakaryocytes as well as early apoptosis. In addition, the level of thrombopoietin was increased significantly. Our clinical study showed that UC-MSCs play a role in alleviating refractory ITP by increasing platelet numbers. These findings suggested that UC-MSCs transplantation might be a potential therapy for ITP.

  13. Saturated fatty acids enhance TLR4 immune pathways in human trophoblasts.

    Science.gov (United States)

    Yang, Xiaohua; Haghiac, Maricela; Glazebrook, Patricia; Minium, Judi; Catalano, Patrick M; Hauguel-de Mouzon, Sylvie

    2015-09-01

    What are the effects of fatty acids on placental inflammatory cytokine with respect to toll-like receptor-4/nuclear factor-kappa B (TLR4/NF-kB)? Exogenous fatty acids induce a pro-inflammatory cytokine response in human placental cells in vitro via activation of TLR4 signaling pathways. The placenta is exposed to changes in circulating maternal fatty acid concentrations throughout pregnancy. Fatty acids are master regulators of innate immune pathways through recruitment of toll-like receptors and activation of cytokine synthesis. Trophoblast cells isolated from 14 normal term human placentas were incubated with long chain fatty acids (FA) of different carbon length and degree of saturation. The expression and secretion of interleukin-6 (IL-6), IL-8 and tumor necrosis factor-alpha (TNF-α) were measured by reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay. Antibodies against TLR4 ligand binding domain, downstream signaling and anti-p65 NFkB-inhibitor were used to characterize the pathways of FA action. General approach used primary human term trophoblast cell culture. Methods and end-points used real-time quantitative PCR, cytokine measurements, immunohistochemistry, western blots. The long chain saturated fatty acids, stearic and palmitic (PA), stimulated the synthesis as well as the release of TNF-α, IL-6 and IL-8 by trophoblast cells (2- to 6-fold, P acids did not modify cytokine expression significantly. Palmitate-induced inflammatory effects were mediated via TLR4 activation, NF-kB phosphorylation and nuclear translocation. TNF-α protein level was close to the limit of detection in the culture medium even when cells were cultured with PA. These mechanisms open the way to a better understanding of how changes in maternal lipid homeostasis may regulate placental inflammatory status. X.Y. was recipient of fellowship award from West China Second University Hospital, Sichuan University (NIH HD 22965-19). The authors have nothing

  14. The adaptive immune system promotes initiation of prostate carcinogenesis in a human c-Myc transgenic mouse model.

    Science.gov (United States)

    Melis, Monique H M; Nevedomskaya, Ekaterina; van Burgsteden, Johan; Cioni, Bianca; van Zeeburg, Hester J T; Song, Ji-Ying; Zevenhoven, John; Hawinkels, Lukas J A C; de Visser, Karin E; Bergman, Andries M

    2017-11-07

    Increasing evidence from epidemiological and pathological studies suggests a role of the immune system in the initiation and progression of multiple cancers, including prostate cancer. Reports on the contribution of the adaptive immune system are contradictive, since both suppression and acceleration of disease development have been reported. This study addresses the functional role of lymphocytes in prostate cancer development using a genetically engineered mouse model (GEMM) of human c-Myc driven prostate cancer (Hi-Myc mice) combined with B and T cell deficiency (RAG1 -/- mice). From a pre-cancerous stage on, Hi-Myc mice showed higher accumulation of immune cells in their prostates then wild-type mice, of which macrophages were the most abundant. The onset of invasive adenocarcinoma was delayed in Hi-MycRAG1 -/- compared to Hi-Myc mice and associated with decreased infiltration of leukocytes into the prostate. In addition, lower levels of the cytokines CXCL2, CCL5 and TGF-β1 were detected in Hi-MycRAG1 -/- compared to Hi-Myc mouse prostates. These results from a GEMM of prostate cancer provide new insights into the promoting role of the adaptive immune system in prostate cancer development. Our findings indicate that the endogenous adaptive immune system does not protect against de novo prostate carcinogenesis in Hi-Myc transgenic mice, but rather accelerates the formation of invasive adenocarcinomas. This may have implications for the development of novel treatment strategies.

  15. A potent adjuvant effect of a CD1d-binding NKT cell ligand in human immune system mice.

    Science.gov (United States)

    Li, Xiangming; Huang, Jing; Kaneko, Izumi; Zhang, Min; Iwanaga, Shiroh; Yuda, Masao; Tsuji, Moriya

    2017-01-01

    A CD1d-binding invariant natural killer T (iNKT)-cell stimulatory glycolipid, namely 7DW8-5, is shown to enhance the efficacy of radiation-attenuated sporozoites (RAS)-based malaria vaccine in mice. In the current study, we aim to determine whether 7DW8-5 can display a potent adjuvant effect in human immune system (HIS) mice. HIS-A2/hCD1d mice, which possess both functional human iNKT cells and CD8+ T cells, were generated by the transduction of NSG mice with adeno-associated virus serotype 9 expressing genes that encode human CD1d molecules and HLA-A*0201, followed by the engraftment of human hematopoietic stem cells. The magnitudes of human iNKT-cell response against 7DW8-5 and HLA-A*0201-restricted human CD8+ T-cell response against a human malaria antigen in HIS-A2/hCD1d mice were determined by using human CD1d tetramer and human HLA-A*0201 tetramer, respectively. We found that 7DW8-5 stimulates human iNKT cells in HIS-A2/hCD1d mice, as well as those derived from HIS-A2/hCD1d mice in vitro. We also found that 7DW8-5 significantly increases the level of a human malarial antigen-specific HLA-A*0201-restricted human CD8+ T-cell response in HIS-A2/hCD1d mice. Our study indicates that 7DW8-5 can display a potent adjuvant effect on RAS vaccine-induced anti-malarial immunity by augmenting malaria-specific human CD8+ T-cell response.

  16. Voluntary activation of the sympathetic nervous system and attenuation of the innate immune response in humans

    NARCIS (Netherlands)

    Kox, M.; Eijk, L.T.G.J. van; Zwaag, J.; Wildenberg, J. van den; Sweep, F.C.; Hoeven, J.G. van der; Pickkers, P.

    2014-01-01

    Excessive or persistent proinflammatory cytokine production plays a central role in autoimmune diseases. Acute activation of the sympathetic nervous system attenuates the innate immune response. However, both the autonomic nervous system and innate immune system are regarded as systems that cannot

  17. A review of the human vs. porcine female genital tract and associated immune system in the perspective of using minipigs as a model of human genital Chlamydia infection.

    Science.gov (United States)

    Lorenzen, Emma; Follmann, Frank; Jungersen, Gregers; Agerholm, Jørgen S

    2015-09-28

    Sexually transmitted diseases constitute major health issues and their prevention and treatment continue to challenge the health care systems worldwide. Animal models are essential for a deeper understanding of the diseases and the development of safe and protective vaccines. Currently a good predictive non-rodent model is needed for the study of genital chlamydia in women. The pig has become an increasingly popular model for human diseases due to its close similarities to humans. The aim of this review is to compare the porcine and human female genital tract and associated immune system in the perspective of genital Chlamydia infection. The comparison of women and sows has shown that despite some gross anatomical differences, the structures and proportion of layers undergoing cyclic alterations are very similar. Reproductive hormonal cycles are closely related, only showing a slight difference in cycle length and source of luteolysing hormone. The epithelium and functional layers of the endometrium show similar cyclic changes. The immune system in pigs is very similar to that of humans, even though pigs have a higher percentage of CD4(+)/CD8(+) double positive T cells. The genital immune system is also very similar in terms of the cyclic fluctuations in the mucosal antibody levels, but differs slightly regarding immune cell infiltration in the genital mucosa - predominantly due to the influx of neutrophils in the porcine endometrium during estrus. The vaginal flora in Göttingen Minipigs is not dominated by lactobacilli as in humans. The vaginal pH is around 7 in Göttingen Minipigs, compared to the more acidic vaginal pH around 3.5-5 in women. This review reveals important similarities between the human and porcine female reproductive tracts and proposes the pig as an advantageous supplementary model of human genital Chlamydia infection.

  18. immune response in human leishmania infections Respuesta inmune en infecciones humanas por Leishmania spp

    Directory of Open Access Journals (Sweden)

    Sara María Robledo Restrepo

    2000-03-01

    Full Text Available This review summarizes relevant information about the immune response triggered during leishmaniosis, a disease of great importance from the epidemiological point of view, since it is endemic in Colombia and other countries. We emphasize on human leishmaniosis; nevertheless, some important findings in the murine model are also mentioned. This information allows to conclude that Leishmania infection is a complex and coordinated process, which includes adhesion and entrance of the parasite into the host cells and its survival inside them. Events that mediate the infection process may influence its result in terms of elimination of the parasite or development of the disease, through induction or not of an effective specific immune response which involves host cell activation and parasite destruction. La presente revisión tiene como objetivo resumir la información más relevante acerca de la respuesta inmune que se desencadena durante la leishmaniosis, una enfermedad de gran importancia desde el punto de vista epidemiológico dado que es endémica en Colombia y otros países. Aunque la respuesta inmune en la leishmaniosis es un tema que se ha estudiado ampliamente en las infecciones por especies de Leishmania del Viejo Mundo, particularmente Leishmania major y Leishmania donovani y en el modelo murino, la presente revisión hace énfasis en la leishmaniosis humana. Algunos hallazgos importantes en el modelo murino también se mencionan. La información contenida en la revisión, en su mayoría, proviene de publicaciones derivadas de investigaciones, las cuales se seleccionaron con base en la calidad del trabajo realizado y en los aportes de sus resultados en el avance del conocimiento sobre las infecciones en humanos. La síntesis de la información seleccionada nos permite concluir que la infección por Leishmania es un proceso complejo y coordinado que incluye la adherencia y entrada del parásito a la célula hospedera y su posterior

  19. Immunotherapy: Shifting the Balance of Cell-Mediated Immunity and Suppression in Human Prostate Cancer

    International Nuclear Information System (INIS)

    Tucker, Jo A.; Jochems, Caroline; Gulley, James L.; Schlom, Jeffrey; Tsang, Kwong Y.

    2012-01-01

    Active immunotherapy is dependent on the ability of the immune system to recognize and respond to tumors. Despite overwhelming evidence to support a cell-mediated immune response to prostate cancer, it is insufficient to eradicate the disease. This is likely due to a high level of suppression at the tumor site from a variety of sources, including immunosuppressive cells. Immune cells entering the tumor microenvironment may be inhibited directly by the tumor, stromal cells or other immune cells that have been induced to adopt a suppressive phenotype. The resurgence of interest in immunotherapy following the approval of sipuleucel-T and ipilimumab by the Food and Drug Administration has brought about new strategies for overcoming tumor-mediated suppression and bolstering anti-tumor responses. Improved understanding of the immune response to prostate cancer can lead to new combination therapies, such as the use of vaccine with small molecule and checkpoint inhibitors or other immunotherapies

  20. Immunotherapy: Shifting the Balance of Cell-Mediated Immunity and Suppression in Human Prostate Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Tucker, Jo A.; Jochems, Caroline [Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 (United States); Gulley, James L. [Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 (United States); Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 (United States); Schlom, Jeffrey, E-mail: js141c@nih.gov; Tsang, Kwong Y. [Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 (United States)

    2012-12-11

    Active immunotherapy is dependent on the ability of the immune system to recognize and respond to tumors. Despite overwhelming evidence to support a cell-mediated immune response to prostate cancer, it is insufficient to eradicate the disease. This is likely due to a high level of suppression at the tumor site from a variety of sources, including immunosuppressive cells. Immune cells entering the tumor microenvironment may be inhibited directly by the tumor, stromal cells or other immune cells that have been induced to adopt a suppressive phenotype. The resurgence of interest in immunotherapy following the approval of sipuleucel-T and ipilimumab by the Food and Drug Administration has brought about new strategies for overcoming tumor-mediated suppression and bolstering anti-tumor responses. Improved understanding of the immune response to prostate cancer can lead to new combination therapies, such as the use of vaccine with small molecule and checkpoint inhibitors or other immunotherapies.

  1. Vaccination targeting human HER3 alters the phenotype of infiltrating T cells and responses to immune checkpoint inhibition.

    Science.gov (United States)

    Osada, Takuya; Morse, Michael A; Hobeika, Amy; Diniz, Marcio A; Gwin, William R; Hartman, Zachary; Wei, Junping; Guo, Hongtao; Yang, Xiao-Yi; Liu, Cong-Xiao; Kaneko, Kensuke; Broadwater, Gloria; Lyerly, H Kim

    2017-01-01

    Expression of human epidermal growth factor family member 3 (HER3), a critical heterodimerization partner with EGFR and HER2, promotes more aggressive biology in breast and other epithelial malignancies. As such, inhibiting HER3 could have broad applicability to the treatment of EGFR- and HER2-driven tumors. Although lack of a functional kinase domain limits the use of receptor tyrosine kinase inhibitors, HER3 contains antigenic targets for T cells and antibodies. Using novel human HER3 transgenic mouse models of breast cancer, we demonstrate that immunization with recombinant adenoviral vectors encoding full length human HER3 (Ad-HER3-FL) induces HER3-specific T cells and antibodies, alters the T cell infiltrate in tumors, and influences responses to immune checkpoint inhibitions. Both preventative and therapeutic Ad-HER3-FL immunization delayed tumor growth but were associated with both intratumoral PD-1 expressing CD8 + T cells and regulatory CD4 + T cell infiltrates. Immune checkpoint inhibition with either anti-PD-1 or anti-PD-L1 antibodies increased intratumoral CD8 + T cell infiltration and eliminated tumor following preventive vaccination with Ad-HER3-FL vaccine. The combination of dual PD-1/PD-L1 and CTLA4 blockade slowed the growth of tumor in response to Ad-HER3-FL in the therapeutic model. We conclude that HER3-targeting vaccines activate HER3-specific T cells and induce anti-HER3 specific antibodies, which alters the intratumoral T cell infiltrate and responses to immune checkpoint inhibition.

  2. Lactose in human breast milk an inducer of innate immunity with implications for a role in intestinal homeostasis.

    Science.gov (United States)

    Cederlund, Andreas; Kai-Larsen, Ylva; Printz, Gordana; Yoshio, Hiroyuki; Alvelius, Gunvor; Lagercrantz, Hugo; Strömberg, Roger; Jörnvall, Hans; Gudmundsson, Gudmundur H; Agerberth, Birgitta

    2013-01-01

    Postpartum, infants have not yet established a fully functional adaptive immune system and are at risk of acquiring infections. Hence, newborns are dependent on the innate immune system with its antimicrobial peptides (AMPs) and proteins expressed at epithelial surfaces. Several factors in breast milk are known to confer immune protection, but which the decisive factors are and through which manner they work is unknown. Here, we isolated an AMP-inducing factor from human milk and identified it by electrospray mass spectrometry and NMR to be lactose. It induces the gene (CAMP) that encodes the only human cathelicidin LL-37 in colonic epithelial cells in a dose- and time-dependent manner. The induction was suppressed by two different p38 antagonists, indicating an effect via the p38-dependent pathway. Lactose also induced CAMP in the colonic epithelial cell line T84 and in THP-1 monocytes and macrophages. It further exhibited a synergistic effect with butyrate and phenylbutyrate on CAMP induction. Together, these results suggest an additional function of lactose in innate immunity by upregulating gastrointestinal AMPs that may lead to protection of the neonatal gut against pathogens and regulation of the microbiota of the infant.

  3. Lactose in human breast milk an inducer of innate immunity with implications for a role in intestinal homeostasis.

    Directory of Open Access Journals (Sweden)

    Andreas Cederlund

    Full Text Available Postpartum, infants have not yet established a fully functional adaptive immune system and are at risk of acquiring infections. Hence, newborns are dependent on the innate immune system with its antimicrobial peptides (AMPs and proteins expressed at epithelial surfaces. Several factors in breast milk are known to confer immune protection, but which the decisive factors are and through which manner they work is unknown. Here, we isolated an AMP-inducing factor from human milk and identified it by electrospray mass spectrometry and NMR to be lactose. It induces the gene (CAMP that encodes the only human cathelicidin LL-37 in colonic epithelial cells in a dose- and time-dependent manner. The induction was suppressed by two different p38 antagonists, indicating an effect via the p38-dependent pathway. Lactose also induced CAMP in the colonic epithelial cell line T84 and in THP-1 monocytes and macrophages. It further exhibited a synergistic effect with butyrate and phenylbutyrate on CAMP induction. Together, these results suggest an additional function of lactose in innate immunity by upregulating gastrointestinal AMPs that may lead to protection of the neonatal gut against pathogens and regulation of the microbiota of the infant.

  4. Proteflazid® and local immunity in diseases caused by human papillomavirus, herpesvirus and mixed urogenital infections.

    Science.gov (United States)

    Kaminsky, Vjacheslav; Chernyshov, Viktor; Grynevych, Oleksandr; Benyuk, Vasil; Kornatskaya, Alla; Shalko, Miroslava; Usevich, Igor; Revenko, Oleg; Shepetko, Maxim; Solomakha, Ludmila

    2017-03-21

    Reporting of clinical trials results for Proteflazid® in the drug formulation suppositories and vaginal swabs soaked in the solution of the drug to the local immunity of the female reproductive tract. The aim of study was to examine the state of local immunity in the reproductive tract of women with sexually transmitted diseases caused by human papillomavirus, herpes viruses (Type 1, 2) and mixed infection (herpes viruses + chlamydia). The trials involved 216 women with viral sexually transmitted diseases: Cervical Dysplasia associated with papillomavirus infection (HPV) (Group 1); Herpes genitalis type 1 (HSV- 1) and type 2 (HSV-1) (Group 2); mixed infection - HSV-1, HSV-2 and chlamydia (Group 3). Treatment results have confirmed that Proteflazid® contributes to sustainable performance improvement of basic factors of local immunity - sIgA, lysozyme and complement component C3 in the cervical mucus for all three groups of women. Proteflazid® enhances level of local immunity markers (sIgA, lysozyme, C3 complement component) and improves their ratios. Also it intensifies anticontagious activity of mucosal protection and female reproductive system as whole, during treatment diseases caused by human papillomavirus, herpesvirus and mixed urogenital infections (herpesvirus and chlamydia).

  5. Lactose in Human Breast Milk an Inducer of Innate Immunity with Implications for a Role in Intestinal Homeostasis

    Science.gov (United States)

    Printz, Gordana; Yoshio, Hiroyuki; Alvelius, Gunvor; Lagercrantz, Hugo; Strömberg, Roger; Jörnvall, Hans; Gudmundsson, Gudmundur H.; Agerberth, Birgitta

    2013-01-01

    Postpartum, infants have not yet established a fully functional adaptive immune system and are at risk of acquiring infections. Hence, newborns are dependent on the innate immune system with its antimicrobial peptides (AMPs) and proteins expressed at epithelial surfaces. Several factors in breast milk are known to confer immune protection, but which the decisive factors are and through which manner they work is unknown. Here, we isolated an AMP-inducing factor from human milk and identified it by electrospray mass spectrometry and NMR to be lactose. It induces the gene (CAMP) that encodes the only human cathelicidin LL-37 in colonic epithelial cells in a dose- and time-dependent manner. The induction was suppressed by two different p38 antagonists, indicating an effect via the p38-dependent pathway. Lactose also induced CAMP in the colonic epithelial cell line T84 and in THP-1 monocytes and macrophages. It further exhibited a synergistic effect with butyrate and phenylbutyrate on CAMP induction. Together, these results suggest an additional function of lactose in innate immunity by upregulating gastrointestinal AMPs that may lead to protection of the neonatal gut against pathogens and regulation of the microbiota of the infant. PMID:23326523

  6. β-Glucan Size Controls Dectin-1-Mediated Immune Responses in Human Dendritic Cells by Regulating IL-1β Production

    Directory of Open Access Journals (Sweden)

    Matthew J. Elder

    2017-07-01

    Full Text Available Dectin-1/CLEC7A is a pattern recognition receptor that recognizes β-1,3 glucans, and its stimulation initiates signaling events characterized by the production of inflammatory cytokines from human dendritic cells (DCs required for antifungal immunity. β-glucans differ greatly in size, structure, and ability to activate effector immune responses from DC; as such, small particulate β-glucans are thought to be poor activators of innate immunity. We show that β-glucan particle size is a critical factor contributing to the secretion of cytokines from human DC; large β-glucan-stimulated DC generate significantly more IL-1β, IL-6, and IL-23 compared to those stimulated with the smaller β-glucans. In marked contrast, the secretion of TSLP and CCL22 were found to be insensitive to β-glucan particle size. Furthermore, we show that the capacity to induce phagocytosis, and the relative IL-1β production determined by β-glucan size, regulates the composition of the cytokine milieu generated from DC. This suggests that β-glucan particle size is critically important in orchestrating the nature of the immune response to fungi.

  7. Anti-proteinase 3 anti-neutrophil cytoplasm autoantibodies recapitulate systemic vasculitis in mice with a humanized immune system.

    Directory of Open Access Journals (Sweden)

    Mark A Little

    Full Text Available Evidence is lacking for direct pathogenicity of human anti-proteinase-3 (PR3 antibodies in development of systemic vasculitis and granulomatosis with polyangiitis (GPA, Wegener's granulomatosis. Progress in study of these antibodies in rodents has been hampered by lack of PR3 expression on murine neutrophils, and by different Fc-receptor affinities for IgG across species. Therefore, we tested whether human anti-PR3 antibodies can induce acute vasculitis in mice with a human immune system. Chimeric mice were generated by injecting human haematopoietic stem cells into irradiated NOD-scid-IL2Rγ⁻/⁻ mice. Matched chimera mice were treated with human IgG from patients with: anti-PR3 positive renal and lung vasculitis; patients with non-vasculitic renal disease; or healthy controls. Six-days later, 39% of anti-PR3 treated mice had haematuria, compared with none of controls. There was punctate bleeding on the surface of lungs of anti-PR3 treated animals, with histological evidence of vasculitis and haemorrhage. Anti-PR3 treated mice had mild pauci-immune proliferative glomerulonephritis, with infiltration of human and mouse leukocytes. In 3 mice (17% more severe glomerular injury was present. There were no glomerular changes in controls. Human IgG from patients with anti-PR3 autoantibodies is therefore pathogenic. This model of anti-PR3 antibody-mediated vasculitis may be useful in dissecting mechanisms of microvascular injury.

  8. Anti-proteinase 3 anti-neutrophil cytoplasm autoantibodies recapitulate systemic vasculitis in mice with a humanized immune system.

    LENUS (Irish Health Repository)

    Little, Mark A

    2012-01-01

    Evidence is lacking for direct pathogenicity of human anti-proteinase-3 (PR3) antibodies in development of systemic vasculitis and granulomatosis with polyangiitis (GPA, Wegener\\'s granulomatosis). Progress in study of these antibodies in rodents has been hampered by lack of PR3 expression on murine neutrophils, and by different Fc-receptor affinities for IgG across species. Therefore, we tested whether human anti-PR3 antibodies can induce acute vasculitis in mice with a human immune system. Chimeric mice were generated by injecting human haematopoietic stem cells into irradiated NOD-scid-IL2Rγ⁻\\/⁻ mice. Matched chimera mice were treated with human IgG from patients with: anti-PR3 positive renal and lung vasculitis; patients with non-vasculitic renal disease; or healthy controls. Six-days later, 39% of anti-PR3 treated mice had haematuria, compared with none of controls. There was punctate bleeding on the surface of lungs of anti-PR3 treated animals, with histological evidence of vasculitis and haemorrhage. Anti-PR3 treated mice had mild pauci-immune proliferative glomerulonephritis, with infiltration of human and mouse leukocytes. In 3 mice (17%) more severe glomerular injury was present. There were no glomerular changes in controls. Human IgG from patients with anti-PR3 autoantibodies is therefore pathogenic. This model of anti-PR3 antibody-mediated vasculitis may be useful in dissecting mechanisms of microvascular injury.

  9. Trivalent Human Papillomavirus (HPV) VLP vaccine covering HPV type 58 can elicit high level of humoral immunity but also induce immune interference among component types.

    Science.gov (United States)

    Zhang, Ting; Xu, Yufei; Qiao, Liang; Wang, Youchun; Wu, Xueling; Fan, Dongsheng; Peng, Qinglin; Xu, Xuemei

    2010-04-26

    Both Human Papillomavirus (HPV) type 16/18 bivalent vaccine and type 16/18/6/11 quadrivalent vaccine have been proved to be safe and effective, and licensed for public use. However, these two vaccines do not quite match the distribution of HPV types in China, Southeast Asia and Latin America, where HPV 58 is highly prevalent. Here we produced three types of virus-like particles (VLPs) in baculovirus expression system, formulated a trivalent vaccine containing HPV 16, 18, and 58 L1 VLPs and examined its in vitro neutralizing titers. This vaccine could induce high level and long-term humoral immunity against the component types. But immune interference was observed when comparing type specific neutralizing antibody levels induced by trivalent vaccine to those by corresponding monovalent vaccines. This kind of interference would become more obvious when formulating more types of VLPs into multivalent vaccines, but could be greatly overcome by decreasing the antigen dosage and adding a proper adjuvant. Copyright 2010 Elsevier Ltd. All rights reserved.

  10. Effect of traditional Chinese medicine for treating human immunodeficiency virus infections and acquired immune deficiency syndrome: Boosting immune and alleviating symptoms.

    Science.gov (United States)

    Zou, Wen; Wang, Jian; Liu, Ying

    2016-01-01

    To respond to the human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) epidemic in China, the integration of antiretroviral therapy (ART) and traditional Chinese medicine (TCM) has important implications in health outcomes, especially in China where the use of TCM is widespread. The National Free TCM Pilot Program for HIV Infected People began in 5 provinces (Henan, Hebei, Anhui, Hubei, and Guangdong) in 2004, and quickly scaled up to 19 provinces, autonomous regions, and municipalities in China including some places with high prevalence, 26,276 adults have been treated thus far. Usually, people with HIV infection seek TCM for four main reasons: to enhance immune function, to treat symptoms, to improve quality of life, and to reduce side effects related to medications. Evidences from randomized controlled clinical trials suggested some beneficial effects of use of traditional Chinese herbal medicine for HIV infections and AIDS. More proofs from large, well-designed, rigorous trials is needed to give firm support. Challenges include interaction between herbs and antiretroviral drugs, stigma and discrimination. The Free TCM Program has made considerable progress in providing the necessary alternative care and treatment for HIV-infected people in China, and has strong government support for continued improvement and expansion, establishing and improving a work mechanism integrating Chinese and Western medicines.

  11. Configuration management after design basis reconstitution

    International Nuclear Information System (INIS)

    Purcell, J.J.; Livingston, B.R.

    1991-01-01

    Over the last few years, Fort Calhoun station (FCS) has implemented a number of programs to enhance plant operability and readiness. The design basis document (DBD) reconstitution project was the cornerstone of this effort. Vendor manual upgrade, operating procedures upgrade, plant equipment data-base verification, equipment labeling, and warehousing improvements were also implemented as part of this improvement program. With the completion of these programs, plant documentation was current to the baselines established by each program, and a configuration management program (CMP) was established to maintain this level of accuracy throughout the remaining life of FCS. Change control throughout the organization has been reviewed and upgraded to ensure that all changes are evaluated for impact to the design bases

  12. Diversity of aging of the immune system classified in the cotton rat (Sigmodon hispidus) model of human infectious diseases.

    Science.gov (United States)

    Guichelaar, Teun; van Erp, Elisabeth A; Hoeboer, Jeroen; Smits, Noortje A M; van Els, Cécile A C M; Pieren, Daan K J; Luytjes, Willem

    2018-05-01

    Susceptibility and declined resistance to human pathogens like respiratory syncytial virus (RSV) at old age is well represented in the cotton rat (Sigmodon hispidus). Despite providing a preferred model of human infectious diseases, little is known about aging of its adaptive immune system. We aimed to define aging-related changes of the immune system of this species. Concomitantly, we asked whether the rate of immunological alterations may be stratified by physiological aberrations encountered during aging. With increasing age, cotton rats showed reduced frequencies of T cells, impaired induction of antibodies to RSV, higher incidence of aberrations of organs and signs of lipemia. Moreover, old animals expressed high biological heterogeneity, but the age-related reduction of T cell frequency was only observed in those specimens that displayed aberrant organs. Thus, cotton rats show age-related alterations of lymphocytes that can be classified by links with health status. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

  13. Survey of innate immune responses to Burkholderia pseudomallei in human blood identifies a central role for lipopolysaccharide.

    Directory of Open Access Journals (Sweden)

    Narisara Chantratita

    Full Text Available B. pseudomallei is a gram-negative bacterium that causes the tropical infection melioidosis. In northeast Thailand, mortality from melioidosis approaches 40%. As exemplified by the lipopolysaccharide-Toll-like receptor 4 interaction, innate immune responses to invading bacteria are precipitated by activation of host pathogen recognition receptors by pathogen associated molecular patterns. Human melioidosis is characterized by up-regulation of pathogen recognition receptors and pro-inflammatory cytokine release. In contrast to many gram-negative pathogens, however, the lipopolysaccharide of B. pseudomallei is considered only weakly inflammatory. We conducted a study in 300 healthy Thai subjects to investigate the ex vivo human blood response to various bacterial pathogen associated molecular patterns, including lipopolysaccharide from several bacteria, and to two heat-killed B. pseudomallei isolates. We measured cytokine levels after stimulation of fresh whole blood with a panel of stimuli. We found that age, sex, and white blood cell count modulate the innate immune response to B. pseudomallei. We further observed that, in comparison to other stimuli, the innate immune response to B. pseudomallei is most highly correlated with the response to lipopolysaccharide. The magnitude of cytokine responses induced by B. pseudomallei lipopolysaccharide was significantly greater than those induced by lipopolysaccharide from Escherichia coli and comparable to many responses induced by lipopolysaccharide from Salmonella minnesota despite lower amounts of lipid A in the B. pseudomallei lipopolysaccharide preparation. In human monocytes stimulated with B. pseudomallei, addition of polymyxin B or a TLR4/MD-2 neutralizing antibody inhibited the majority of TNF-α production. Challenging existing views, our data indicate that the innate immune response to B. pseudomallei in human blood is largely driven by lipopolysaccharide, and that the response to B

  14. Giving It Our Best Shot? Human Papillomavirus and Hepatitis B Virus Immunization Among Refugees, Massachusetts, 2011-2013.

    Science.gov (United States)

    Berman, Rachel Stein; Smock, Laura; Bair-Merritt, Megan H; Cochran, Jennifer; Geltman, Paul L

    2017-06-22

    The receipt rate of hepatitis B virus vaccine among adolescents in the United States is high, while the receipt rate of human papillomavirus vaccine is low. Rates have not been closely studied among refugees, whose home countries have high rates of disease caused by these viruses. We examined human papillomavirus and hepatitis B virus immunization rates among 2,269 refugees aged 9 to 26 years who resettled in Massachusetts from 2011 through 2013. This was a secondary analysis of data from their medical screenings. We used binary logistic regression to assess characteristics associated with immunization and bivariate analyses to compare refugee immunization rates with those of the general US population. Forty-five percent of US adolescents aged 13 to 17 years received 1 dose of human papillomavirus vaccine, compared with 68% of similarly aged refugees. Males (adjusted odds ratio [aOR], 0.62; 95% confidence interval [CI], 0.52-0.74), refugees older than 13 years (aOR, 0.74; 95% CI, 0.60-0.93), and refugees not from Sub-Saharan Africa (aOR, 0.74; 95% CI, 0.59-0.92) were less likely to receive human papillomavirus vaccine, while arrivals in 2012 through 2013 were more likely (aOR, 1.6; 95% CI, 1.3-1.9) than those arriving in 2011. Refugees older than 13 years were less likely to receive 2 doses of hepatitis B virus vaccine (aOR, 0.49; 95% CI, 0.37-0.63) than older refugees. Specialized post-arrival health assessment may improve refugees' immunization rates.

  15. Human Immunodeficiency Virus Type 1-Hepatitis C Virus Coinfection: Intraindividual Comparison of Cellular Immune Responses against Two Persistent Viruses

    OpenAIRE

    Lauer, Georg M.; Nguyen, Tam N.; Day, Cheryl L.; Robbins, Gregory K.; Flynn, Theresa; McGowan, Katherine; Rosenberg, Eric S.; Lucas, Michaela; Klenerman, Paul; Chung, Raymond T.; Walker, Bruce D.

    2002-01-01

    Both human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV) lead to chronic infection in a high percentage of persons, and an expanding epidemic of HIV-1-HCV coinfection has recently been identified. These individuals provide an opportunity for simultaneous assessment of immune responses to two viral infections associated with chronic plasma viremia. In this study we analyzed the breadth and magnitude of the CD8+- and CD4+-T-lymphocyte responses in 22 individuals infected wit...

  16. Effects of the Commercial Flame Retardant Mixture DE-71 on Cytokine Production by Human Immune Cells.

    Directory of Open Access Journals (Sweden)

    Thit Mynster Kronborg

    Full Text Available Although production of polybrominated diphenyl ethers (PBDEs is now banned, release from existing products will continue for many years. The PBDEs are assumed to be neurotoxic and toxic to endocrine organs at low concentrations. Their effect on the immune system has not been investigated thoroughly. We aimed to investigate the influence of DE-71 on cytokine production by peripheral blood mononuclear cells (PBMCs stimulated with Escherichia Coli lipopolysaccharide (LPS or phytohaemagglutinin-L (PHA-L.PBMCs isolated from healthy donors were pre-incubated with DE-71 at various concentrations and subsequently incubated with the monocyte stimulator LPS, or the T-cell activator PHA-L. Interferon (IFN-γ, interleukin (IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, tumor necrosis factor (TNF-α, IL-17A, and IL-17F were quantified in the supernatants by Luminex kits.At non-cytotoxic concentrations (0.01-10 μg/mL, DE-71 significantly enhanced secretion of IL-1β, IL-6, CXCL8, IL-10, and TNF-α (p<0.001-0.019; n = 6 from LPS-stimulated PBMCs. IFN-γ, TNF-α, IL-17A, and IL-17F (p = <0.001-0.043; n = 6 secretion were enhanced from PHA-L-stimulated PBMCs as well. Secretion of IL-1β, IL-2, IL-10, IL-8 and IL-6 was not significantly affected by DE-71.We demonstrate an enhancing effect of DE-71 on cytokine production by normal human PBMCs stimulated with LPS or PHA-L ex vivo.

  17. B-Cell and T-Cell Immune Responses to Experimental Helicobacter pylori Infection in Humans

    Science.gov (United States)

    Nurgalieva, Zhannat Z.; Conner, Margaret E.; Opekun, Antone R.; Zheng, Carl Q.; Elliott, Susan N.; Ernst, Peter B.; Osato, Michael; Estes, Mary K.; Graham, David Y.

    2005-01-01

    The acute antibody and T-cell immune response to Helicobacter pylori infection in humans has not been studied systematically. Serum from H. pylori-naive volunteers challenged with H. pylori and cured after 4 or 12 weeks was tested by enzyme-linked immunosorbent assays for anti-H. pylori-specific immunoglobulin M (IgM) and IgA established using bacterial lysates from homologous (the infecting strain) and heterologous H. pylori. Proteins recognized by IgM antibody were identified by mass spectrometry of immunoreactive bands separated by two-dimensional gel electrophoresis. Mucosal T-cell subsets (CD4, CD8, CD3, and CD30 cells) were assessed by immunohistochemistry. All 18 infected volunteers developed H. pylori-specific IgM responses to both homologous or heterologous H. pylori antigens. H. pylori antigens reacted with IgM antibody at 4 weeks postinfection. IgM Western blotting showed immunoreactivity of postinfection serum samples to multiple H. pylori proteins with molecular weights ranging between 9,000 (9K) to 150K with homologous strains but only a 70K band using heterologous antigens. Two-dimensional electrophoresis demonstrated that production of H. pylori-specific IgM antibodies was elicited by H. pylori flagellins A and B, urease B, ABC transporter binding protein, heat shock protein 70 (DnaK), and alkyl hydroperoxide reductase. Mucosal CD3, CD4, and CD8 T-cell numbers increased following infection. IgM antibody responses were detected to a range of homologous H. pylori antigens 2 to 4 weeks postchallenge. The majority of H. pylori proteins were those involved in motility and colonization and may represent targets for vaccine development. PMID:15845507

  18. Evaluation of the humoral immune response to human leukocyte antigens in Brazilian renal transplant candidates.

    Directory of Open Access Journals (Sweden)

    Patricia Keiko Saito

    Full Text Available Pre-transplant sensitization to human leukocyte antigens (HLA is a risk factor for graft failure. Studies of the immunological profile related to anti-HLA antibodies in Brazilian renal transplant candidates are few. In this study, we evaluated the humoral immune response to HLA antigens in 269 renal transplant candidates, in Paraná State, Brazil. The HLA typing was performed by the polymerase chain reaction sequence-specific oligonucleotide method (PCR-SSO combined with Luminex technology, using an SSO-LABType commercial kit (One Lambda, Inc., Canoga Park, CA, USA. The percentages of panel-reactive antibodies (PRA and the specificity of anti-HLA antibodies were determined using the LS1PRA and LS2PRA commercial kits (One Lambda, Inc.. The PRA-positive group consisted of 182 (67.7% patients, and the PRA-negative group of 87 (32.3% patients. The two groups differed significantly only with respect to gender. Females were the most sensitized. Among the 182 patients with PRA- positive, 62 (34.1% were positive for class I and negative for class II, 39 (21.4% were negative for class I and positive for class II, and 81 (44.5% were positive for both classes I and II. The HLA-A*02, A*24, A*01, B*44, B*35, B*15, DRB1*11, DRB1*04 and DRB1*03 allele groups were the most frequent. The specificities of anti-HLA antibodies were more frequent: A34, B57, Cw15, Cw16, DR51, DQ8 and DP14. This study documented the profile of anti-HLA antibodies in patients with chronic renal failure who were on waiting lists for an organ in Paraná, and found high sensitization to HLA antigens in the samples.

  19. Evaluation of the Humoral Immune Response to Human Leukocyte Antigens in Brazilian Renal Transplant Candidates

    Science.gov (United States)

    Saito, Patricia Keiko; Yamakawa, Roger Haruki; Aparecida, Erica Pereira; da Silva Júnior, Waldir Verissimo; Borelli, Sueli Donizete

    2014-01-01

    Pre-transplant sensitization to human leukocyte antigens (HLA) is a risk factor for graft failure. Studies of the immunological profile related to anti-HLA antibodies in Brazilian renal transplant candidates are few. In this study, we evaluated the humoral immune response to HLA antigens in 269 renal transplant candidates, in Paraná State, Brazil. The HLA typing was performed by the polymerase chain reaction sequence-specific oligonucleotide method (PCR-SSO) combined with Luminex technology, using an SSO-LABType commercial kit (One Lambda, Inc., Canoga Park, CA, USA). The percentages of panel-reactive antibodies (PRA) and the specificity of anti-HLA antibodies were determined using the LS1PRA and LS2PRA commercial kits (One Lambda, Inc.). The PRA-positive group consisted of 182 (67.7%) patients, and the PRA-negative group of 87 (32.3%) patients. The two groups differed significantly only with respect to gender. Females were the most sensitized. Among the 182 patients with PRA- positive, 62 (34.1%) were positive for class I and negative for class II, 39 (21.4%) were negative for class I and positive for class II, and 81 (44.5%) were positive for both classes I and II. The HLA-A*02, A*24, A*01, B*44, B*35, B*15, DRB1*11, DRB1*04 and DRB1*03 allele groups were the most frequent. The specificities of anti-HLA antibodies were more frequent: A34, B57, Cw15, Cw16, DR51, DQ8 and DP14. This study documented the profile of anti-HLA antibodies in patients with chronic renal failure who were on waiting lists for an organ in Paraná, and found high sensitization to HLA antigens in the samples. PMID:24927116

  20. Can measuring immunity to HIV during antiretroviral therapy (ART ...

    African Journals Online (AJOL)

    The vexing issue of whether the immune system can be reconstituted during HIV infection by supplying antiretroviral therapy (ART) has been a question asked about HIV-infected adults and children receiving therapy.1-9 Knowing that the immune system is sufficiently plastic in adults to show restoration of specific and ...

  1. Immune Components in Human Milk Are Associated with Early Infant Immunological Health Outcomes: A Prospective Three-Country Analysis.

    Science.gov (United States)

    Munblit, Daniel; Treneva, Marina; Peroni, Diego G; Colicino, Silvia; Chow, Li Yan; Dissanayeke, Shobana; Pampura, Alexander; Boner, Attilio L; Geddes, Donna T; Boyle, Robert J; Warner, John O

    2017-05-24

    The role of breastfeeding in improving allergy outcomes in early childhood is still unclear. Evidence suggests that immune mediators in human milk (HM) play a critical role in infant immune maturation as well as protection against atopy/allergy development. We investigated relationships between levels of immune mediators in colostrum and mature milk and infant outcomes in the first year of life. In a large prospective study of 398 pregnant/lactating women in the United Kingdom, Russia and Italy, colostrum and mature human milk (HM) samples were analysed for immune active molecules. Statistical analyses used models adjusting for the site of collection, colostrum collection time, parity and maternal atopic status. Preliminary univariate analysis showed detectable interleukin (IL) 2 and IL13 in HM to be associated with less eczema. This finding was further confirmed in multivariate analysis, with detectable HM IL13 showing protective effect OR 0.18 (95% CI 0.04-0.92). In contrast, a higher risk of eczema was associated with higher HM concentrations of transforming growth factor β (TGFβ) 2 OR 1.04 (95% CI 1.01-1.06) per ng/mL. Parental-reported food allergy was reported less often when IL13 was detectable in colostrum OR 0.10 (95% CI 0.01-0.83). HM hepatocyte growth factor (HGF) was protective for common cold incidence at 12 months OR 0.19 (95% CI 0.04-0.92) per ng/mL. Data from this study suggests that differences in the individual immune composition of HM may have an influence on early life infant health outcomes. Increased TGFβ2 levels in HM are associated with a higher incidence of reported eczema, with detectable IL13 in colostrum showing protective effects for food allergy and sensitization. HGF shows some protective effect on common cold incidence at one year of age. Future studies should be focused on maternal genotype, human milk microbiome and diet influence on human milk immune composition and both short- and long-term health outcomes in the infant.

  2. Evaluation of an In Vitro of Human Immune Activation Induced by Freeze-Thaw Tissue Damage

    National Research Council Canada - National Science Library

    DuBose, D

    2002-01-01

    In training and in combat, soldiers are under the constant threat of injury. Injury that results in tissue necrosis can activate the immune system and ultimately enhance disturbances in organ function...

  3. Studies of Cell-Mediated Immunity Against Immune Disorders Using Synthetic Peptides and Rotating Bioreactor System

    Science.gov (United States)

    Sastry, Jagannadha K.

    1997-01-01

    Our proposed experiments included: (1) immunzing mice with synthetic peptides; (2) preparing spleen and lymph node cells; (3) growing them under conventional conditions as well as in the rotatory vessel in appropriate medium reconstituting with synthetic peptides and/or cytokines as needed; and (4) comparing at regular time intervals the specific CTL activity as well as helper T-cell activity (in terms of both proliferative responses and cytokine production) using established procedures in my laboratory. We further proposed that once we demonstrated the merit of rotatory vessel technology to achieve desired results, these studies would be expanded to include immune cells from non-human primates (rhesus monkeys and chimpanzees) and also humans. We conducted a number of experiments to determine CTL induction by the synthetic peptides corresponding to antigenic proteins in HIV and HPV in different mouse strains that express MHC haplotypes H-2b or H-2d. We immunized mice with 100 ug of the synthetic peptide, suspended in sterile water, and emulsified in CFA (1:1). The immune lymph node cells obtained after 7 days were restimulated by culturing in T25 flask, HARV-10, or STLV-50, in the presence of the peptide at 20 ug/ml. The results from the 5'Cr-release assay consistently revealed complete abrogation of CTL activity of cells grown in the bioreactors (both HARV and STLV), while significant antigen-specific CTL activity was observed with cells cultured in tissue culture flasks. Thus, overall the data we generated in this study proved the usefulness of the NASA-developed developed technology for understanding the known immune deficiency during space travel. Additionally, this ex vivo microgravity technology since it mimics effectively the in vivo situation, it is also useful in understanding immune disorders in general. Thus, our proposed studies in TMC-NASA contract round II application benefit from data generated in this TMC-NASA contract round I study.

  4. MicroRNAs, Innate Immunity and Ventricular Rupture in Human Myocardial Infarction

    Directory of Open Access Journals (Sweden)

    Nina Zidar

    2011-01-01

    Full Text Available MicroRNAs are non-coding RNAs, functionioning as post-transcriptional regulators of gene expression. Some microRNAs have been demonstrated to play a role in regulation of innate immunity. After myocardial infarction (MI, innate immunity is activated leading to an acute inflammatory reaction. There is evidence that an intense inflammatory reaction might contribute to the development of ventricular rupture (VR after MI.

  5. Immune Status and Epidemiological Characteristics of Human Immunodeficiency Virus Seroconverters in Korea, 1999–2009

    OpenAIRE

    Wang, Jin-Sook; Kim, Na-young; Sim, Hyo Jung; Choi, Byeong-Sun; Kee, Mee-Kyung

    2012-01-01

    Objectives The detection of HIV seroconverters increased annually since HIV antigen/antibody testing kits have been available widely in South Korea. This study aimed to identify the epidemiological characteristics of HIV seroconverters and their immune level at HIV diagnosis. Method We analyzed the epidemiological and immunological characteristics of 341 HIV seroconverters among 6,008 HIV-diagnosed individuals from 1999 and 2009. The analysis of immune level and epidemiological factors of HIV...

  6. Absence of cytotoxic antibody to human immunodeficiency virus-infected cells in humans and its induction in animals after infection or immunization with purified envelope glycoprotein gp120

    International Nuclear Information System (INIS)

    Nara, P.L.; Robey, W.G.; Gonda, M.A.; Carter, S.G.; Fischinger, P.J.

    1987-01-01

    The presence of antibody-dependent complement-mediated cytotoxicity (ACC) was assessed in humans and chimpanzees, which are capable of infection with human immunodeficiency virus isolate HTLV-IIIb, and examined in the goat after immunization with the major viral glycoprotein (gp120) of HTLV-IIIb. In infected humans no antibody mediating ACC was observed regardless of the status of disease. Even healthy individuals with high-titer, broadly reactive, neutralizing antibodies has no ACC. In contrast, chimpanzees infected with HTLV-IIIb, from whom virus could be isolated, not only had neutralizing antibody but also antibodies broadly reactive in ACC, even against distantly related human immunodeficiency virus isolates, as well as against their own reisolated virus. In the goat, the gp120 of HTLV-IIIb induced a highly type-specific response as measured by both ACC and flow cytofluorometry of live infected H9 cells. Normal human cells were not subject to ACC by animal anti-HTLV-III gp120-specific sera. Induction of ACC and neutralizing antibody were closely correlated in the animal experimental models but not in humans. The presence of ACC in gp120-inoculated goats and HTLV-III-infected chimpanzees represent a qualitative difference that may be important in the quest for the elicitation of a protective immunity in humans

  7. A human type 5 adenovirus-based Trypanosoma cruzi therapeutic vaccine re-programs immune response and reverses chronic cardiomyopathy.

    Directory of Open Access Journals (Sweden)

    Isabela Resende Pereira

    2015-01-01

    Full Text Available Chagas disease (CD, caused by the protozoan Trypanosoma cruzi, is a prototypical neglected tropical disease. Specific immunity promotes acute phase survival. Nevertheless, one-third of CD patients develop chronic chagasic cardiomyopathy (CCC associated with parasite persistence and immunological unbalance. Currently, the therapeutic management of patients only mitigates CCC symptoms. Therefore, a vaccine arises as an alternative to stimulate protective immunity and thereby prevent, delay progression and even reverse CCC. We examined this hypothesis by vaccinating mice with replication-defective human Type 5 recombinant adenoviruses (rAd carrying sequences of amastigote surface protein-2 (rAdASP2 and trans-sialidase (rAdTS T. cr