Donor-Recipient Matching for KIR Genotypes Reduces Chronic GVHD and Missing Inhibitory KIR Ligands Protect against Relapse after Myeloablative, HLA Matched Hematopoietic Cell Transplantation.

Science.gov (United States)

Faridi, Rehan Mujeeb; Kemp, Taylor J; Dharmani-Khan, Poonam; Lewis, Victor; Tripathi, Gaurav; Rajalingam, Raja; Daly, Andrew; Berka, Noureddine; Storek, Jan; Masood Khan, Faisal

2016-01-01

Allogeneic hematopoietic cell transplantation (HCT) can be curative for many hematologic diseases. However, complications such as graft-versus-host disease (GVHD) and relapse of primary malignancy remain significant and are the leading causes of morbidity and mortality. Effects of killer Ig-like receptors (KIR)-influenced NK cells on HCT outcomes have been extensively pursued over the last decade. However, the relevance of the reported algorithms on HLA matched myeloablative HCT with rabbit antithymocyte globulin (ATG) is used for GVHD prophylaxis remains elusive. Here we examined the role of KIR and KIR-ligands of donor-recipient pairs in modifying the outcomes of ATG conditioned HLA matched sibling and unrelated donor HCT. The study cohort consisted of 281 HLA matched sibling and unrelated donor-recipient pairs of first allogeneic marrow or blood stem cell transplantation allocated into 'discovery' (135 pairs) and 'validation' (146 pairs) cohorts. High resolution HLA typing was obtained from the medical charts and KIR gene repertoires were obtained by a Luminex® based SSO method. All surviving patients were followed-up for a minimum of two years. KIR and HLA class I distributions of HCT pairs were stratified as per applicable definitions and were tested for their association with cause specific outcomes [acute GVHD grade II-IV (aGVHD), chronic GVHD needing systemic therapy (cGVHD) and relapse] using a multivariate competing risks regression model as well as with survival outcomes [relapse-free survival (RFS), cGVHD & relapse free survival (cGRFS) and overall survival (OS)] by multivariate Cox proportional hazards regression model. A significant association between KIR genotype mismatching (KIR-B/x donor into KIR-AA recipient or vice versa) and cGVHD was found in both discovery (p = 0.001; SHR = 2.78; 95%CI: 1.50-5.17) and validation cohorts (p = 0.005; SHR = 2.61; 95%CI: 1.33-5.11). High incidence of cGVHD associated with KIR genotype mismatching was applicable

Alternative allogeneic donor sources for transplantation for childhood diseases: unrelated cord blood and haploidentical family donors.

Science.gov (United States)

Cairo, Mitchell S; Rocha, Vanderson; Gluckman, Eliane; Hale, Gregory; Wagner, John

2008-01-01

Allogeneic stem cell transplantation has been demonstrated to be curative in a wide variety of pediatric malignant and nonmalignant diseases, and can be traced back over 50 years ago to the original report of Thomas et al. HLA matched sibling donors have been the gold standard for pediatric recipients requiring allogeneic donors for both nonmalignant and malignant conditions. However, only 25% of potential pediatric recipients possesses an HLA-matched sibling donor, and the frequency is even less in those with genetic nonmalignant conditions because of genetically affected other siblings within the family. Therefore, 75% to 90% of potential pediatric recipients require alternative allogeneic donor cells for treatment of their underlying conditions. Potential alternative allogeneic donor sources include unrelated cord blood donors, unrelated adult donors, and haploidentical family donors. In this article we review the experience of both unrelated cord blood donor and haploidentical family donor transplants in selected pediatric malignant and nonmalignant conditions.

The role of donor-recipient relationship in long-term outcomes of living donor renal transplantation.

Science.gov (United States)

Miles, Clifford D; Schaubel, Douglas E; Liu, Dandan; Port, Friedrich K; Rao, Panduranga S

2008-05-27

Graft failure related to acute and chronic rejection remains an important problem in transplantation. An association has been reported between microchimerism and the development of tolerance. Since it has been established that cells of fetal origin can be found in maternal tissues long after parturition, and cells of maternal origin may persist for years in offspring, we hypothesized that this fetal-maternal microchimerism may confer tolerance and thus less graft loss for kidneys transplanted between mothers and their offspring. We used data from the Scientific Registry of Transplant Recipients to compare death-censored graft survival among recipients of living-related renal transplants sharing at least one human leukocyte antigen (HLA) haplotype with their donor. A total of 23,064 such transplants were reported from 1995 to 2004. A Cox proportional hazards model was constructed to compare death-censored graft survival among the following donor-recipient pairings: child-to-mother, child-to-father, mother-to-child, father-to-child, 1-haplotype matched siblings, and HLA-identical siblings. HLA-identical sibling recipients had the best survival, but results for the child-to-father group were not significantly worse (hazard ratio=1.07, P=0.47). Mother-to-child transplants had the poorest graft survival (hazard ratio=2.61, P<0.0001). We found no evidence of tolerance to kidneys transplanted between mothers and offspring. Our analysis of 1-haplotype matched living-related renal transplants argues against tolerance to organs based on fetal-maternal microchimerism. Mechanistic studies examining the relationship between chimerism and immune sensitization would be useful to explore our results, and may contribute to a better understanding of tolerance.

Experiences of offspring searching for and contacting their donor siblings and donor.

Science.gov (United States)

Jadva, Vasanti; Freeman, Tabitha; Kramer, Wendy; Golombok, Susan

2010-04-01

This study investigates a new phenomenon whereby individuals conceived by donor insemination are searching for and contacting their donor and/or 'donor siblings' (i.e. donor offspring conceived by the same donor who are their genetic half siblings). On-line questionnaires were completed by members of the Donor Sibling Registry (DSR), a US-based registry that facilitates contact between donor conception families who share the same donor. Of the 165 donor offspring who completed the survey, 15% were searching for their donor siblings, 13% were searching for their donor, and 64% were searching for both. Differences were found according to family type and age of disclosure. Fewer offspring from heterosexual couple families had told their father about their search when compared with offspring from lesbian couple families who had told their co-parent. Offspring who had found out about their conception after age 18 were more likely to be searching for medical reasons, whereas those who had found out before age 18 tended to be searching out of curiosity. Some offspring had discovered large numbers of half siblings (maximum=13). The majority of offspring who had found their donor relations reported positive experiences and remained in regular contact with them. Copyright (c) 2010 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

The impact of HLA matching on long-term transplant outcome after allogeneic hematopoietic stem cell transplantation for CLL: a retrospective study from the EBMT registry

DEFF Research Database (Denmark)

Michallet, M; Sobh, M; Milligan, D

2010-01-01

We analyzed 368 chronic lymphocytic leukemia patients who underwent allogeneic hematopoietic stem cell transplantation reported to the EBMT registry between 1995 and 2007. There were 198 human leukocyte antigen (HLA)-identical siblings; among unrelated transplants, 31 were well matched in high...... worsened significantly when EBMT risk score increased. HLA matching had no significant impact on relapse (siblings: 24% (21-27); WMUD: 35% (26-44), P=0.11 and MM: 21% (18-24), P=0.81); alemtuzumab T-cell depletion and stem cell source (peripheral blood) were associated with an increased risk. Our findings...... support the use of WMUD as equivalent alternative to HLA-matched sibling donors for allogeneic HSCT in CLL, and justify the application of EBMT risk score in this disease....

Early onset of diabetes in the proband is the major determinant of risk in HLA DR3-DQ2/DR4-DQ8 siblings.

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Gillespie, Kathleen M; Aitken, Rachel J; Wilson, Isabel; Williams, Alistair J K; Bingley, Polly J

2014-03-01

Islet autoimmunity is initiated in infancy, and primary prevention trials require children at high genetic risk to be identified before autoantibodies appear. To inform screening strategies, we evaluated risks of autoimmunity and diabetes associated with HLA DR3-DQ2/DR4-DQ8 in U.K. families. Extended HLA haplotypes were determined in 2,134 siblings from the Bart's-Oxford Study followed to a median age of 22 years. Risks of diabetes and islet autoimmunity (more than two antibodies) were estimated by survival analysis. Of 138 informative DR3-DQ2/DR4-DQ8 siblings, 63% shared both haplotypes with their diabetic proband, 29% shared one, and 8% shared neither. In HLA-identical DR3-DQ2/DR4-DQ8 siblings, the cumulative risk of diabetes by age 15 was 17% (vs. 6% in those sharing one haplotype or none; P = 0.095). Risk varied, however, with the age at the onset of diabetes in the proband; the cumulative risk of autoimmunity and/or diabetes by age 15 was 61% in siblings of probands diagnosed when younger than 10 years old compared with only 4.7% in those diagnosed after age 10 years (P sibling risk. This suggests that non-HLA genes or epigenetic/environmental factors that accelerate the progression of type 1 diabetes in the proband strongly affect risk in siblings.

Criteria for selecting organ donors and recipients.

Science.gov (United States)

Michielsen, P

1990-11-01

As there is a world-wide shortage of organs for transplantation, the selection of the patients is more defined by the availability of transplantable organs than by the medical condition of the potential recipient. This shortage of cadaveric organs is mainly responsible for the use of living donors. With HLA identical sibling donors the results are better than with cadaveric organs, but the ethical problems are usually underestimated. For the parent-to-child donation, the HLA compatibility is less than what could be achieved with well-matched cadaveric donors. The use of genetically unrelated donors is unacceptable from the ethical as well as from the medical point of view. The short- and long-term risk of donation has been insufficiently documented. The experience with the introduction of an opting-out legislation in Belgium in 1987 demonstrates that the shortage of cadaveric organs can be overcome. Harmonization of the legislation is, however, necessary so as to achieve comparable organ retrieval rates between countries participating in organ-exchange organisations.

Intra HLA-D/DR region recombinant detected by primed lymphocyte typing (PLT)

DEFF Research Database (Denmark)

Jakobsen, B K; Kristensen, T; Lamm, L U

1983-01-01

The chromosome 6 markers, HLA-ABC, D, DR, MT, properdin factor Bf, and complement factors 2 (C2) and 5 (C4), were studied in three families, each of which included two HLA identical siblings, one or both of whom were known to be HLA-B: GLO recombinants. The families were also typed with primed...... lymphocyte typing (PLT) for HLA-D/DR region associated DP antigens. None of these studies gave evidence that the recombinations had occurred within the HLA region. Mixed leucocyte culture (MLC) tests within the families showed no detectable stimulation between the HLA identical siblings in two...

Moving Beyond HLA: A Review of nHLA Antibodies in Organ Transplantation

OpenAIRE

Sigdel, Tara K.; Sarwal, Minnie M.

2013-01-01

Given the finite graft life expectancy of HLA identical organ transplants and the recognition of humoral graft injury in the absence of donor directed anti-HLA antibodies, the clinical impact of antibodies against non-HLA (nHLA) antigens in transplant injury is being increasingly recognized. The recognition of the impact of nHLA antigen discrepancies between donor and recipient on transplant outcomes is timely given the advances in rapid and lower cost sequencing methods that can soon provide...

Being a haematopoietic stem cell donor for a sick sibling: Adult donors' experiences prior to donation.

Science.gov (United States)

Kisch, Annika; Bolmsjö, Ingrid; Lenhoff, Stig; Bengtsson, Mariette

2015-10-01

There is a lack of knowledge about sibling stem cell donors' experiences pre-donation and the waiting period before the donation might have been long. The donors and their corresponding sibling recipients were simultaneously included in two different interview studies. The results from the recipient study have been presented in a separate paper. The aim was to explore the experiences of being a stem cell donor for a sibling, prior to donation. Ten adult sibling donors were interviewed prior to stem cell donation. The interviews were digitally recorded, transcribed verbatim and subjected to qualitative content analysis. The main theme Being a cog in a big wheel describes the complex process of being a sibling donor prior to donation, covering a mixture of emotions and thoughts. The four subthemes Being available, Being anxious, Being concerned and Being obliged cover the various experiences. The sibling donors' experiences are influenced by the quality of the relationship with the sick sibling. Sibling stem cell donors go through a complex process once they have accidentally got involved in. They have been asked to become a donor; it was not a voluntary choice. In caring for sibling stem cell donors the nurses should be aware of the complexity of the process they experience and take into consideration their personal situation and needs. Providing optimal care for both sibling donors and their corresponding recipients is a challenge, and further improvement and exploration are needed. Copyright © 2015 Elsevier Ltd. All rights reserved.

Hematopoietic stem cell transplantation from non-sibling matched family donors for patients with thalassemia major in Jordan.

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Hussein, Ayad Ahmed; Al-Zaben, Abdulhadi; Khattab, Eman; Haroun, Anas; Frangoul, Haydar

2016-02-01

There are limited data on the outcome of patients with thalassemia receiving HSCT from non-sibling matched family donors. Of the 341 patients with thalassemia major that underwent donor search at our center from January 2003 to December 2011, 236 (69.2%) had fully matched family donor of which 28 patients (8.2%) had non-sibling matched family donors identified. We report on seven patients with a median age of eight yr (4-21) who underwent myeloablative (n = 4) or RIC (n = 3) HSCT. The median age of the donors was 33 yr (4-47), three were parents, two first cousins, one paternal uncle, and one paternal aunt. All patients achieved primary neutrophil and platelet engraftment at a median of 18 (13-20) and 16 days (11-20), respectively. One patient developed grade II acute GVHD, and two patients developed limited chronic GVHD. One patient experienced secondary GF requiring a second transplant. At a median follow-up of 69 months (7-110), all patients are alive and thalassemia free. Our data emphasize the need for extended family HLA typing for patients with thalassemia major in regions where there is high rate of consanguinity. Transplant from non-sibling matched family donor can result in excellent outcome. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Moving beyond HLA: a review of nHLA antibodies in organ transplantation.

Science.gov (United States)

Sigdel, Tara K; Sarwal, Minnie M

2013-11-01

Given the finite graft life expectancy of HLA identical organ transplants and the recognition of humoral graft injury in the absence of donor directed anti-HLA antibodies, the clinical impact of antibodies against non-HLA (nHLA) antigens in transplant injury is being increasingly recognized. The recognition of the impact of nHLA antigen discrepancies between donor and recipient on transplant outcomes is timely given the advances in rapid and lower cost sequencing methods that can soon provide complete maps of all recipient and donor HLA and nHLA mismatch data. In this review, we present a summary of recent reports evaluating the role of nHLA antibodies and their relevance to the field of organ transplantation. Copyright © 2013 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

Hematopoietic Stem Cell Transplantation Using Preimplantation Genetic Diagnosis and Human Leukocyte Antigen Typing for Human Leukocyte Antigen-Matched Sibling Donor: A Turkish Multicenter Study.

Science.gov (United States)

Kurekci, Emin; Küpesiz, Alphan; Anak, Sema; Öztürk, Gülyüz; Gürsel, Orhan; Aksoylar, Serap; Ileri, Talia; Kuşkonmaz, Barış; Eker, İbrahim; Cetin, Mualla; Tezcan Karasu, Gülsün; Kaya, Zühre; Fışgın, Tunç; Ertem, Mehmet; Kansoy, Savaş; Yeşilipek, Mehmet Akif

2017-05-01

Preimplantation genetic diagnosis involves the diagnosis of a genetic disorder in embryos obtained through in vitro fertilization, selection of healthy embryos, and transfer of the embryos to the mother's uterus. Preimplantation genetic diagnosis has been used not only to avoid the risk of having an affected child, but it also offers, using HLA matching, preselection of potential HLA-genoidentical healthy donor progeny for an affected sibling who requires bone marrow transplantation. Here, we share the hematopoietic stem cell transplantation results of 52 patients with different benign and malign hematological or metabolic diseases or immunodeficiencies whose donors were siblings born with this technique in Turkey since 2008. The median age of the patients' at the time of the transplantation was 8 years (range, 3 to 16 years) and the median age of the donors was 2 years (range, .5 to 6 years). The most common indication for HSCT was thalassemia major (42 of all patients, 80%). The stem cell source in all of the transplantations was bone marrow. In 37 of the transplantations, umbilical cord blood of the same donor was also used. In 50 of the 52 patients, full engraftment was achieved with a mean of 4.6 × 10 6 CD 34 + cells per kg of recipient weight. Ninety-six percent of the patients have been cured through hematopoietic stem cell transplantation without any complication. Primary engraftment failure was seen in only 2 patients with thalassemia major. All of the donors and the patients are alive with good health status. Preimplantation genetic diagnosis with HLA matching offers a life-saving chance for patients who need transplantation but lack an HLA genoidentical donor. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Comparable Outcomes after HLA-Matched Sibling and Alternative Donor Hematopoietic Cell Transplantation for Children with Fanconi Anemia and Severe Aplastic Anemia.

Science.gov (United States)

Ebens, Christen L; DeFor, Todd E; Tryon, Rebecca; Wagner, John E; MacMillan, Margaret L

2018-04-01

Fanconi anemia (FA)-associated severe aplastic anemia (SAA) requires allogeneic hematopoietic cell transplantation (HCT) for cure. With the evolution of conditioning regimens over time, outcomes of alternative donor HCT (AD-HCT) have improved dramatically. We compared outcomes of HLA-matched sibling donor HCT (MSD-HCT; n = 17) and AD-HCT (n = 57) performed for FA-associated SAA at a single institution between 2001 and 2016. Overall survival at 5 years was 94% for MSD-HCT versus 86% for AD-HCT, neutrophil engraftment was 100% versus 95%, platelet recovery was 100% versus 89%, grade II-IV acute graft-versus-host disease (GVHD) was 6% versus 12%, grade III-IV acute GVHD was 6% versus 4%, and chronic GVHD was 0 versus 7%, with no statistically significant differences by type of transplant. The use of UCB was associated with decreased rates of neutrophil recovery in AD-HCT and platelet recovery in both MSD-HCT and AD-HCT. A trend toward a higher serious infection density before day +100 post-HCT was observed in AD-HCT compared with MSD-HCT (P = .02). These data demonstrate that AD-HCT should be considered at the same time as MSD-HCT for patients with FA-associated SAA. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Preimplantation genetic diagnosis with HLA matching.

Science.gov (United States)

Rechitsky, Svetlana; Kuliev, Anver; Tur-Kaspa, Illan; Morris, Randy; Verlinsky, Yury

2004-08-01

Preimplantation genetic diagnosis (PGD) has recently been offered in combination with HLA typing, which allowed a successful haematopoietic reconstitution in affected siblings with Fanconi anaemia by transplantation of stem cells obtained from the HLA-matched offspring resulting from PGD. This study presents the results of the first PGD practical experience performed in a group of couples at risk for producing children with genetic disorders. These parents also requested preimplantation HLA typing for treating the affected children in the family, who required HLA-matched stem cell transplantation. Using a standard IVF procedure, oocytes or embryos were tested for causative gene mutations simultaneously with HLA alleles, selecting and transferring only those unaffected embryos, which were HLA matched to the affected siblings. The procedure was performed for patients with children affected by Fanconi anaemia (FANC) A and C, different thalassaemia mutations, Wiscott-Aldrich syndrome, X-linked adrenoleukodystrophy, X-linked hyperimmunoglobulin M syndrome and X-linked hypohidrotic ectodermal displasia with immune deficiency. Overall, 46 PGD cycles were performed for 26 couples, resulting in selection and transfer of 50 unaffected HLA-matched embryos in 33 cycles, yielding six HLA-matched clinical pregnancies and the birth of five unaffected HLA-matched children. Despite the controversy of PGD use for HLA typing, the data demonstrate the usefulness of this approach for at-risk couples, not only to avoid the birth of affected children with an inherited disease, but also for having unaffected children who may also be potential HLA-matched donors of stem cells for treatment of affected siblings.

Platelet transfusion refractoriness attributable to HLA antibodies produced by donor-derived cells after allogeneic bone marrow transplantation from one HLA-antigen-mismatched mother.

Science.gov (United States)

Hatakeyama, Naoki; Hori, Tsukasa; Yamamoto, Masaki; Inazawa, Natsuko; Iesato, Kotoe; Miyazaki, Toru; Ikeda, Hisami; Tsutsumi, Hiroyuki; Suzuki, Nobuhiro

2011-12-01

PTR is a serious problem in patients being treated for hematologic disorders. Two patients with acute leukemia developed PTR after allogeneic BMT from one HLA-antigen-mismatched mother attributable to HLA antibodies, which could not be detected in their serum before BMT. HLA antibodies, whose specificity resembled that of each patient, were detected in each donor's serum. Each donor had probably been immunized during pregnancy by their partner's HLA antigens expressed by the fetus, consequently, transplanted donor-derived cells provoked HLA antibodies in each recipient early after BMT, and those HLA antibodies induced PTR. If the mothers are selected as donors for their children, they should be tested for the presence of HLA antibodies. © 2010 John Wiley & Sons A/S.

Intra HLA-D/DR region recombinant detected by primed lymphocyte typing (PLT)

DEFF Research Database (Denmark)

Jakobsen, B K; Kristensen, T; Lamm, L U

1983-01-01

lymphocyte typing (PLT) for HLA-D/DR region associated DP antigens. None of these studies gave evidence that the recombinations had occurred within the HLA region. Mixed leucocyte culture (MLC) tests within the families showed no detectable stimulation between the HLA identical siblings in two......The chromosome 6 markers, HLA-ABC, D, DR, MT, properdin factor Bf, and complement factors 2 (C2) and 5 (C4), were studied in three families, each of which included two HLA identical siblings, one or both of whom were known to be HLA-B: GLO recombinants. The families were also typed with primed...... to reactive reagents. One of these (GHx), reacted with a determinant which segregated within the GG family as if child G was a paternal recombinant between the HLA-D, DR, DP, and C4 loci, on the one hand, and on the other hand one or more loci governing other HLA-D/DR region controlled lymphocyte activating...

In patients older than 55 years with AML in first CR, should we search for a matched unrelated donor when an old sibling donor is available?

DEFF Research Database (Denmark)

Peffault de Latour, R; Labopin, M; Cornelissen, J

2015-01-01

Allogeneic hematopoietic transplantation is increasingly used in patients aged 55 years or more with AML. The question of whether outcomes can be improved with an allele-level 8/8 HLA-matched unrelated donor (MUD) rather than an older HLA-matched sibling (MSD, more than 55 years) is still...... unanswered. We thus analyzed outcomes in 714 patients aged 55 years and older with AML in first CR (CR1) who received PBSCs after a reduced-intensity conditioning hematopoietic cell transplant from a MUD (n=310) or a MSD (n=404) in a recent period (2005-2010). The 3-year cumulative incidences (CIs) of non......-relapse mortality were 17% and 23% with MSD and MUD, respectively (P=0.17). The 3-year CIs of relapse were 37% and 30%, respectively (P=0.12), resulting in a 3-year CI of leukemia-free survival of 46% and 47%, respectively (P=0.51). The 3-year overall survival was 49% with both MSD and MUD. In conclusion, HLA...

Having a sibling as donor: patients' experiences immediately before allogeneic hematopoietic stem cell transplantation.

Science.gov (United States)

Kisch, Annika; Bolmsjö, Ingrid; Lenhoff, Stig; Bengtsson, Mariette

2014-08-01

Allogeneic hematopoietic stem cell transplantation (HSCT) offers a potential cure for a variety of diseases but is also associated with significant risks. With HSCT the donor is either a relative, most often a sibling, or an unrelated registry donor. The aim was to explore patients' experiences, immediately before transplantation, regarding having a sibling as donor. Ten adult patients with sibling donors were interviewed before admission for HSCT. The interviews were digitally recorded, transcribed verbatim and subjected to qualitative content analysis. The main theme Being in no man's land is a metaphor for the patients' complex situation with its mixture of emotions and thoughts prior to transplantation. The three subthemes Trust in the sibling donor, Concern about others and Loss of control cover the various experiences. The patient's experiences are influenced by their personal situation and the quality of the relationship with the sibling donor. While patients feel secure in having a sibling donor, they are dependent for their survival on the cell donation and feel responsible for the donor's safety during donation. These emotions intensify the patients' sense of dependency and loss of control. In caring for HSCT patients the nurses should be aware of the complexity of the patients' situation and keep in mind that having a sibling donor might imply extra pressure, including a sense of responsibility. Caring for both patients and sibling donors optimally is a challenge, which needs further improvement and exploration. Copyright © 2014 Elsevier Ltd. All rights reserved.

Impact of cyclophosphamide dose of conditioning on the outcome of allogeneic hematopoietic stem cell transplantation for aplastic anemia from human leukocyte antigen-identical sibling.

Science.gov (United States)

Mori, Takehiko; Koh, Hideo; Onishi, Yasushi; Kako, Shinichi; Onizuka, Makoto; Kanamori, Heiwa; Ozawa, Yukiyasu; Kato, Chiaki; Iida, Hiroatsu; Suzuki, Ritsuro; Ichinohe, Tatsuo; Kanda, Yoshinobu; Maeda, Tetsuo; Nakao, Shinji; Yamazaki, Hirohito

2016-04-01

The standard conditioning regimen in allogeneic hematopoietic stem cell transplantation (HSCT) for aplastic anemia from a human leukocyte antigen (HLA)-identical sibling has been high-dose cyclophosphamide (CY 200 mg/kg). In the present study, results for 203 patients with aplastic anemia aged 16 years or older who underwent allogeneic HSCT from HLA-identical siblings were retrospectively analyzed using the registry database of Japan Society for Hematopoietic Cell Transplantation. Conditioning regimens were defined as a (1) high-dose CY (200 mg/kg or greater)-based (n = 117); (2) reduced-dose CY (100 mg/kg or greater, but less than 200 mg/kg)-based (n = 38); and (3) low-dose CY (less than 100 mg/kg)-based (n = 48) regimen. Patient age and the proportion of patients receiving fludarabine were significantly higher in the reduced- and low-dose CY groups than the high-dose CY group. Engraftment was comparable among the groups. Five-year overall survival (OS) tended to be higher in the low-dose CY group [93.0 % (95 % CI 85.1-100.0 %)] than the high-dose CY [84.2 % (95 % CI 77.1-91.3 %)] or reduced-dose CY groups [83.8 % (95 % CI 71.8-95.8 %); P = 0.214]. Age-adjusted OS was higher in the low-dose CY group than the high- and reduced-dose CY groups with borderline significance (P = 0.067). These results suggest that CY dose can safely be reduced without increasing graft rejection by adding fludarabine in allogeneic HSCT for aplastic anemia from an HLA-identical sibling.

Donor-Shared Siblings or Genetic Strangers: New Families, Clans, and the Internet

Science.gov (United States)

Hertz, Rosanna; Mattes, Jane

2011-01-01

Donor-shared sibling families have recently emerged. Families who conceived using the same anonymous donor are locating one another through websites designed to match children with their biogenetic half-siblings. Based on a survey of 587 parents with donor-conceived children, we discovered that a growing number of unrelated parents whose children…

Reduced-Intensity Transplantation for Lymphomas Using Haploidentical Related Donors Versus HLA-Matched Sibling Donors: A Center for International Blood and Marrow Transplant Research Analysis

Science.gov (United States)

Ghosh, Nilanjan; Karmali, Reem; Rocha, Vanderson; Ahn, Kwang Woo; DiGilio, Alyssa; Hari, Parameswaran N.; Bachanova, Veronika; Bacher, Ulrike; Dahi, Parastoo; de Lima, Marcos; D’Souza, Anita; Fenske, Timothy S.; Ganguly, Siddhartha; Kharfan-Dabaja, Mohamed A.; Prestidge, Tim D.; Savani, Bipin N.; Smith, Sonali M.; Sureda, Anna M.; Waller, Edmund K.; Jaglowski, Samantha; Herrera, Alex F.; Armand, Philippe; Salit, Rachel B.; Wagner-Johnston, Nina D.; Fuchs, Ephraim; Bolaños-Meade, Javier

2016-01-01

Purpose Related donor haploidentical hematopoietic cell transplantation (Haplo-HCT) using post-transplantation cyclophosphamide (PT-Cy) is increasingly used in patients lacking HLA-matched sibling donors (MSD). We compared outcomes after Haplo-HCT using PT-Cy with MSD-HCT in patients with lymphoma, using the Center for International Blood and Marrow Transplant Research registry. Materials and Methods We evaluated 987 adult patients undergoing either Haplo-HCT (n = 180) or MSD-HCT (n = 807) following reduced-intensity conditioning regimens. The haploidentical group received graft-versus-host disease (GVHD) prophylaxis with PT-Cy with or without a calcineurin inhibitor and mycophenolate. The MSD group received calcineurin inhibitor–based GVHD prophylaxis. Results Median follow-up of survivors was 3 years. The 28-day neutrophil recovery was similar in the two groups (95% v 97%; P = .31). The 28-day platelet recovery was delayed in the haploidentical group compared with the MSD group (63% v 91%; P = .001). Cumulative incidence of grade II to IV acute GVHD at day 100 was similar between the two groups (27% v 25%; P = .84). Cumulative incidence of chronic GVHD at 1 year was significantly lower after Haplo-HCT (12% v 45%; P < .001), and this benefit was confirmed on multivariate analysis (relative risk, 0.21; 95% CI, 0.14 to 0.31; P < .001). For Haplo-HCT v MSD-HCT, 3-year rates of nonrelapse mortality (15% v 13%; P = .41), relapse/progression (37% v 40%; P = .51), progression-free survival (48% v 48%; P = .96), and overall survival (61% v 62%; P = .82) were similar. Multivariate analysis showed no significant difference between Haplo-HCT and MSD-HCT in terms of nonrelapse mortality (P = .06), progression/relapse (P = .10), progression-free survival (P = .83), and overall survival (P = .34). Conclusion Haplo-HCT with PT-Cy provides survival outcomes comparable to MSD-HCT, with a significantly lower risk of chronic GVHD. PMID:27269951

The role of siblings in identity development in adolescence and emerging adulthood.

Science.gov (United States)

Wong, Thessa M L; Branje, Susan J T; VanderValk, Inge E; Hawk, Skyler T; Meeus, Wim H J

2010-10-01

This study examined the role of siblings on identity formation in adolescence and emerging adulthood, using a three-wave longitudinal design. Measures of identity formation were filled out by 498 sibling dyads. Sibling effects differed as a function of age and gender configuration within the dyads. Controlled for age, earlier-born siblings reported the most advanced levels of identity formation, and later-born siblings the lowest. Positive relations between siblings' identity and changes in identity of respondents provided support for modeling processes between siblings. The identity of earlier-born same-sex siblings, in particular, tends to be important in influencing identity formation. Contrary to the expectations, differentiation processes between siblings did not appear to influence identity formation. It is apparent from this study that both the gender and birth order of siblings affect whether their own identity formation processes influence those of adolescents and emerging adults.

[Establishment of a novel HLA genotyping method for preimplantation genetic diagnonis using multiple displacement amplification-polymerase chain reaction-sequencing based technique].

Science.gov (United States)

Zhang, Yinfeng; Luo, Haining; Zhang, Yunshan

2015-12-01

To establish a novel HLA genotyping method for preimplantation genetic diagnonis (PGD) using multiple displacement amplification-polymerase chain reaction-sequencing based technique (MDA-PCR-SBT). Peripheral blood samples and 76 1PN, 2PN, 3PN discarded embryos from 9 couples were collected. The alleles of HLA-A, B, DR loci were detected from the MDA product with the PCR-SBT method. The HLA genotypes of the parental peripheral blood samples were analyzed with the same protocol. The genotypes of specific HLA region were evaluated for distinguishing the segregation of haplotypes among the family members, and primary HLA matching was performed between the embryos. The 76 embryos were subjected to MDA and 74 (97.4%) were successfully amplified. For the 34 embryos from the single blastomere group, the amplification rate was 94.1%, and for the 40 embryos in the two blastomeres group, the rate was 100%. The dropout rates for DQ allele and DR allele were 1.3% and 0, respectively. The positive rate for MDA in the single blastomere group was 100%, with the dropout rates for DQ allele and DR allele being 1.5% and 0, respectively. The positive rate of MDA for the two blastomere group was 100%, with the dropout rates for both DQ and DR alleles being 0. The recombination rate of fetal HLA was 20.2% (30/148). Due to the improper classification and abnormal fertilized embryos, the proportion of matched embryos HLA was 20.3% (15/74),which was lower than the theoretical value of 25%. PGD with HLA matching can facilitate creation of a HLA-identical donor (saviour child) for umbilical cord blood or bone marrow stem cells for its affected sibling with a genetic disease. Therefore, preimplantation HLA matching may provide a tool for couples desiring to conceive a potential donor progeny for transplantation for its sibling with a life-threatening disorder.

[Extending preimplantation genetic diagnosis to HLA typing: the French exception].

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Steffann, Julie; Frydman, Nelly; Burlet, Philippe; Gigarel, Nadine; Hesters, Laetitia; Kerbrat, Violaine; Lamazou, Frédéric; Munnich, Arnold; Frydman, René

2011-01-01

Umut-Talha, a "sibling savior", was born on 26 January 2011 at Beclère Hospital after embryo selection at the Paris preimplantation genetic diagnosis (PGD) center. His birth revived the controversy over "double PGD". This procedure, authorized in France since 2006, allows couples who already have a child with a serious, incurable genetic disease, to opt for PGD in order to select a healthy embryo that is HLA-matched to the affected sibling and who may thus serve as an ombilical cord blood donor. The procedure is particularly complex and the baby take-home rate is still very low. Double PGD is strictly regulated in France, and candidate couples must first receive individual authorization from the Biomedicine Agency. In our experience, these couples have a strong desire to have children, as reflected by the large number of prior spontaneous pregnancies (25% of couples). Likewise, most of these couples request embryo transfer even when there is no HLA-matched embryo, which accounts for more than half of embryo transfers. The controversy surrounding this practice has flared up again in recent weeks, over the concepts of "designer babies" and "double savior siblings" (the baby is selected to be free of the hereditary disease, and may also serve as a stem cell donor for the affected sibling).

Donor cytomegalovirus status influences the outcome of allogeneic stem cell transplant: a study by the European group for blood and marrow transplantation.

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Ljungman, Per; Brand, Ronald; Hoek, Jennifer; de la Camara, Rafael; Cordonnier, Catherine; Einsele, Hermann; Styczynski, Jan; Ward, Katherine N; Cesaro, Simone

2014-08-15

The use of a cytomegalovirus (CMV)-seronegative donor for a CMV-seronegative allogeneic hematopoietic stem cell transplant (HSCT) recipient is generally accepted. However, the importance of donor serostatus in CMV-seropositive patients is controversial. A total of 49 542 HSCT patients, 29 349 seropositive and 20 193 seronegative, were identified from the European Group for Blood and Marrow Transplantation database. Cox multivariate models were fitted to estimate the effect of donor CMV serological status on outcome. Seronegative patients receiving seropositive unrelated-donor grafts had decreased overall survival (hazard ratio [HR], 1.13; 95% confidence interval [CI], 1.06-1.21; P donors, whereas no difference was seen in patients receiving HLA-matched sibling grafts. Seropositive patients receiving grafts from seropositive unrelated donors had improved overall survival (HR, 0.92; 95% CI, .86-.98; P donors, if they had received myeloablative conditioning. This effect was absent when they received reduced-intensity conditioning. No effect was seen in patients grafted from HLA-identical sibling donors. The same association was found if the study was limited to patients receiving transplants from the year 2000 onward. We confirm the negative impact on overall survival if a CMV-seropositive unrelated donor is selected for a CMV-seronegative patient. For a CMV-seropositive patient, our data support selecting a CMV-seropositive donor if the patient receives a myeloablative conditioning regimen. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Establishing the role of pre-implantation genetic diagnosis with human leucocyte antigen typing: what place do "saviour siblings" have in paediatric transplantation?

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Samuel, G N; Strong, K A; Kerridge, I; Jordens, C F C; Ankeny, R A; Shaw, P J

2009-04-01

Not all children in need of a haematopoietic stem cell transplant have a suitable relative or unrelated donor available. Recently, in vitro fertilisation (IVF) with pre-implantation genetic diagnosis (PGD) for human leucocyte antigen (HLA) tissue typing has been used to selectively transfer an IVF embryo in order to produce a child who may provide umbilical cord blood for transplantation to an ill sibling. Such children are sometimes called "saviour siblings". To examine the published clinical and epidemiological evidence relevant to the use of this technology, with the aim of clarifying those situations where IVF and PGD for HLA typing should be discussed with parents of an ill child. A critical analysis of published literature on comparative studies of umbilical cord blood versus other sources of stem cells for transplantation; comparative studies of matched unrelated donor versus matched related donor transplantation; and the likelihood of finding an unrelated stem cell donor. IVF and PGD for HLA typing is only applicable when transplantation is non-urgent and parents are of reproductive age. Discussions regarding this technology may be appropriate where no suitable related or unrelated donor is available for a child requiring a transplant, or where no suitable related donor is available and transplantation is only likely to be entertained with a matched sibling donor. Discussion may also be considered in the management of any child lacking a matched related donor who requires a non-urgent transplant or may require a transplant in the future.

Comparison of matched sibling donors versus unrelated donors in allogeneic stem cell transplantation for primary refractory acute myeloid leukemia: a study on behalf of the Acute Leukemia Working Party of the EBMT

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Eolia Brissot

2017-06-01

Full Text Available Abstract Background Primary refractory acute myeloid leukemia (PRF-AML is associated with a dismal prognosis. Allogeneic stem cell transplantation (HSCT in active disease is an alternative therapeutic strategy. The increased availability of unrelated donors together with the significant reduction in transplant-related mortality in recent years have opened the possibility for transplantation to a larger number of patients with PRF-AML. Moreover, transplant from unrelated donors may be associated with stronger graft-mediated anti-leukemic effect in comparison to transplantations from HLA-matched sibling donor, which may be of importance in the setting of PRF-AML. Methods The current study aimed to address the issue of HSCT for PRF-AML and to compare the outcomes of HSCT from matched sibling donors (n = 660 versus unrelated donors (n = 381, for patients with PRF-AML between 2000 and 2013. The Kaplan-Meier estimator, the cumulative incidence function, and Cox proportional hazards regression models were used where appropriate. Results HSCT provide patients with PRF-AML a 2-year leukemia-free survival and overall survival of about 25 and 30%, respectively. In multivariate analysis, two predictive factors, cytogenetics and time from diagnosis to transplant, were associated with lower leukemia-free survival, whereas Karnofsky performance status at transplant ≥90% was associated with better leukemia-free survival (LFS. Concerning relapse incidence, cytogenetics and time from diagnosis to transplant were associated with increased relapse. Reduced intensity conditioning regimen was the only factor associated with lower non-relapse mortality. Conclusions HSCT was able to rescue about one quarter of the patients with PRF-AML. The donor type did not have any impact on PRF patients’ outcomes. In contrast, time to transplant was a major prognostic factor for LFS. For patients with PRF-AML who do not have a matched sibling donor, HSCT from an

Worse outcome and more chronic GVHD with peripheral blood progenitor cells than bone marrow in HLA-matched sibling donor transplants for young patients with severe acquired aplastic anemia.

NARCIS (Netherlands)

Schrezenmeier, H.; Passweg, J.R.; Marsh, J.C.; Bacigalupo, A.; Bredeson, C.N.; Bullorsky, E.; Camitta, B.M.; Champlin, R.E.; Gale, R.P.; Fuhrer, M.; Klein, J.P.; Locasciulli, A.; Oneto, R.; Schattenberg, A.V.M.B.; Socie, G.; Eapen, M.

2007-01-01

We analyzed the outcome of 692 patients with severe aplastic anemia (SAA) receiving transplants from HLA-matched siblings. A total of 134 grafts were peripheral blood progenitor cell (PBPC) grafts, and 558 were bone marrow (BM) grafts. Rates of hematopoietic recovery and grades 2 to 4 chronic

Risk and prevention of graft failure in patients with preexisting donor-specific HLA antibodies undergoing unmanipulated haploidentical SCT.

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Yoshihara, S; Maruya, E; Taniguchi, K; Kaida, K; Kato, R; Inoue, T; Fujioka, T; Tamaki, H; Ikegame, K; Okada, M; Soma, T; Hayashi, K; Fujii, N; Onuma, T; Kusunoki, Y; Saji, H; Ogawa, H

2012-04-01

A role of donor-specific HLA antibodies (DSA) in graft failure after SCT has been suggested, but the relevance of DSA in unmanipulated haploidentical SCT (haplo-SCT) remains unknown. We prospectively examined HLA antibodies using the Luminex-based single Ag assay for 79 adult patients undergoing unmanipulated haplo-SCT. Among them, 16 (20.2%) were HLA Ab-positive, including five patients with antibodies not corresponding to donor HLA Ags and 11 DSA-positive patients. Of the 11 DSA-positive patients, five received treatments to decrease DSA levels, including two, who received plasma exchange and rituximab, two who received platelet transfusions from healthy-related donors having DSA-corresponding HLA Ags and one who received bortezomib. Platelet transfusion was the most simple and effective treatment option for class I DSA. The cumulative incidence of neutrophil recovery was significantly lower in pretransplant (post-treatment) DSA-positive patients than in DSA-negative patients (61.9 vs 94.4%, P=0.026). Notably, three of five patients with high levels of DSA had graft failure. Donors should be selected on the basis of an evaluation of HLA antibodies. If haplo-SCT from donors with HLA Ags that correspond to high levels of DSA must be performed, then recipients should be treated for DSA to improve the chances of successful donor engraftment.

Effect of T-cell-epitope matching at HLA-DPB1 in recipients of unrelated-donor haemopoietic-cell transplantation: a retrospective study

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Fleischhauer, Katharina; Gooley, Theodore; Malkki, Mari; Bardy, Peter; Bignon, Jean-Denis; Dubois, Valérie; Horowitz, Mary M; Madrigal, J Alejandro; Morishima, Yasuo; Oudshoorn, Machteld; Ringden, Olle; Spellman, Stephen; Velardi, Andrea; Zino, Elisabetta; Petersdorf, Effie W

2013-01-01

Summary Background The risks after unrelated-donor haemopoietic-cell transplantation with matched HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQB1 alleles between donor and recipient (10/10 matched) can be decreased by selection of unrelated donors who also match for HLA-DPB1; however, such donors are difficult to find. Classification of HLA-DPB1 mismatches based on T-cell-epitope groups could identify mismatches that might be tolerated (permissive) and those that would increase risks (non-permissive) after transplantation. We did a retrospective study to compare outcomes between permissive and non-permissive HLA-DPB1 mismatches in unrelated-donor haemopoietic-cell transplantation. Methods HLA and clinical data for unrelated-donor transplantations submitted to the International Histocompatibility Working Group in haemopoietic-cell transplantation were analysed retrospectively. HLA-DPB1 T-cell-epitope groups were assigned according to a functional algorithm based on alloreactive T-cell crossreactivity patterns. Recipients and unrelated donors matching status were classified as HLA-DPB1 match, non-permissive HLA-DPB1 mismatch (those with mismatched T-cell-epitope groups), or permissive HLA-DPB1 mismatch (those with matched T-cell-epitope groups). The clinical outcomes assessed were overall mortality, non-relapse mortality, relapse, and severe (grade 3–4) acute graft-versus-host disease (aGvHD). Findings Of 8539 transplantations, 5428 (64%) were matched for ten of ten HLA alleles (HLA 10/10 matched) and 3111 (36%) for nine of ten alleles (HLA 9/10 matched). Of the group overall, 1719 (20%) were HLA-DPB1 matches, 2670 (31%) non-permissive HLA-DPB1 mismatches, and 4150 (49%) permissive HLA-DPB1 mismatches. In HLA 10/10-matched transplantations, non-permissive mismatches were associated with a significantly increased risk of overall mortality (hazard ratio [HR] 1·15, 95% CI 1·05–1·25; p=0·002), non-relapse mortality (1·28, 1·14–1·42; pKarolinska Institutet; and

Preimplantation HLA typing for stem cell transplantation treatment of hemoglobinopathies

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Anver Kuliev

2014-09-01

Full Text Available Preimplantation genetic diagnosis (PGD for HLA typing is steadily becoming an option for at risk couples with thalassemic children, requiring HLA matched bone marrow transplantation treatment. The paper presents the world’s largest PGD experience of 475 cases for over 2 dozens thalassemia mutations, resulting in birth of 132 unaffected children. A total of 146 cases were performed together with preimplantation HLA typing, resulting in detection and transfer of HLA matched unaffected embryos in 83 of them, yielding the birth of 16 HLA matched children, potential donors for their affected siblings. The presented experience of HLA matched stem cell transplantation for thalassemia, following PGD demonstrated a successful hematopoietic reconstitution both for younger and older patients. The data show that PGD is an efficient approach for HLA matched stem cell transplantation treatment for thalassemia.

A Modified Protocol with Improved Detection Rate for Mis-Matched Donor HLA from Low Quantities of DNA in Urine Samples from Kidney Graft Recipients.

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Janette Kwok

Full Text Available Urine from kidney transplant recipient has proven to be a viable source for donor DNA. However, an optimized protocol would be required to determine mis-matched donor HLA specificities in view of the scarcity of DNA obtained in some cases.In this study, fresh early morning urine specimens were obtained from 155 kidney transplant recipients with known donor HLA phenotype. DNA was extracted and typing of HLA-A, B and DRB1 loci by polymerase chain reaction-specific sequence primers was performed using tailor-made condition according to the concentration of extracted DNA.HLA typing of DNA extracted from urine revealed both recipient and donor HLA phenotypes, allowing the deduction of the unknown donor HLA and hence the degree of HLA mis-match. By adopting the modified procedures, mis-matched donor HLA phenotypes were successfully deduced in all of 35 tested urine samples at DNA quantities spanning the range of 620-24,000 ng.This urine-based method offers a promising and reliable non-invasive means for the identification of mis-matched donor HLA antigens in kidney transplant recipients with unknown donor HLA phenotype or otherwise inadequate donor information.

Through the eyes of young sibling donors: the hematopoietic stem cell donation experience.

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D'Auria, Jennifer P; Fitzgerald, Tania M; Presler, Cammie M; Kasow, Kimberly A

2015-01-01

This qualitative study used a grounded theory approach to explore how pediatric sibling donors of a successful hematopoietic stem cell transplantation conceptualized their donation experiences. Saving my sister's (or brother's) life describes the central phenomenon identified by this purposive sample of 8 sibling donors. Five themes captured their memories: being the perfect match, stepping up, worrying about the outcome, the waiting process, and sharing a special bond. Further research surrounding changes in relational issues will provide insight into inter-sibling support and the developmental course of the sibling relationship into adulthood when intensified by a health crisis. Copyright © 2015 Elsevier Inc. All rights reserved.

Selection of unrelated donors for bone marrow transplantation studied in rhesus monkeys

International Nuclear Information System (INIS)

Wagemaker, G.; Bekkum, D.W. van

Graft versus Host disease (GvHD) remains to be a severe limitation to a more general application of bone marrow transplantation. Clinically acceptable results are restricted to those potential recipients for which a major histocompatibility complex (MHC) identical sibling donor is available. At an average family size of 2 to 3 siblings, the frequency of such donors is not more than approximately 30%. This pre-clinical study in rhesus monkeys is directed at the selection of donors for recipients which lack an MHC identical sibling. (Auth.)

Improving the estimation of celiac disease sibling risk by non-HLA genes.

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Valentina Izzo

Full Text Available Celiac Disease (CD is a polygenic trait, and HLA genes explain less than half of the genetic variation. Through large GWAs more than 40 associated non-HLA genes were identified, but they give a small contribution to the heritability of the disease. The aim of this study is to improve the estimate of the CD risk in siblings, by adding to HLA a small set of non-HLA genes. One-hundred fifty-seven Italian families with a confirmed CD case and at least one other sib and both parents were recruited. Among 249 sibs, 29 developed CD in a 6 year follow-up period. All individuals were typed for HLA and 10 SNPs in non-HLA genes: CCR1/CCR3 (rs6441961, IL12A/SCHIP1 and IL12A (rs17810546 and rs9811792, TAGAP (rs1738074, RGS1 (rs2816316, LPP (rs1464510, OLIG3 (rs2327832, REL (rs842647, IL2/IL21 (rs6822844, SH2B3 (rs3184504. Three associated SNPs (in LPP, REL, and RGS1 genes were identified through the Transmission Disequilibrium Test and a Bayesian approach was used to assign a score (BS to each detected HLA+SNPs genotype combination. We then classified CD sibs as at low or at high risk if their BS was respectively < or ≥ median BS value within each HLA risk group. A larger number (72% of CD sibs showed a BS ≥ the median value and had a more than two fold higher OR than CD sibs with a BS value < the median (O.R = 2.53, p = 0.047. Our HLA+SNPs genotype classification, showed both a higher predictive negative value (95% vs 91% and diagnostic sensitivity (79% vs 45% than the HLA only. In conclusion, the estimate of the CD risk by HLA+SNPs approach, even if not applicable to prevention, could be a precious tool to improve the prediction of the disease in a cohort of first degree relatives, particularly in the low HLA risk groups.

[A comparative study of unrelated donor and matched-sibling donor allogeneic hematopoietic stem cell transplantation in children and adolescents with acquired severe aplastic anemia].

Science.gov (United States)

Zhou, J; Fu, Y W; Liang, L J; Wang, Q; Han, L J; Zu, Y L; Zhang, Yanli; Zhu, X H; Yu, F K; Fang, B J; Wei, X D; Song, Y P

2016-12-01

Objective: To evaluate the efficacy of unrelated donor allogeneic hematopoietic stem cell transplantation(URD allo-HSCT) for children and adolescents with severe aplastic anemia (SAA). Methods: Clinical data of 34 SAA children and adolescents undergoing allo-HSCT were retrospectively analyzed from October 2001 to October 2015. According to the source of donor, the patients were divided into matched sibling donor allo-HSCT group (MSD group) and unrelated donor group (URD group). The clinical outcome of SAA children and adolescents receiving URD allo-HSCT was assessed, and patients in MSD allo-HSCT group were enrolled as control at the same period. Results: The rate of hematopoietic reconstitution, the time of neutrophil and platelet engraftment, incidence of chimerism and graft rejection between two groups were not statistically different.The incidence of acute graft-versus-host disease (GVHD) in URD group was significantly higher than that in MSD group [42.9%(6/14) vs 10.5%(2/19), P =0.047]. The incidence of grade Ⅱ-Ⅳ acute GVHD and chronic GVHD in URD were higher than those in MSD group [21.4%(3/14) vs 5.3%(1/19), P =0.288; 35.7%(5/14) vs 5.3%(1/19), P =0.062, respectively], yet without significant difference between two groups. Other transplant-related complications including pulmonary complications, hemorrhagic cystitis, incidence of EBV and CMV reactivation and venous occlusive disease were comparable with two regimens. Estimated 5-years overall survival (OS) rate and disease free survival (DFS) rate were not statistically significant between URD group and MSD group [(84.4±6.6)% vs (89.4±7.1)%, (82.5±5.4)% vs (82.1±4.3)%; P =0.766, P =0.884, respectively]. Conclusions: By multivariate analysis, the outcome of URD allo-HSCT in SAA children and adolescent is similar to MSD allo-HSCT. It could be an alternative option as the first-line treatment for SAA children and adolescents without HLA matched sibling donors.

Donor-Specific Anti-HLA Antibodies in Huntington's Disease Recipients of Human Fetal Striatal Grafts.

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Porfirio, Berardino; Paganini, Marco; Mazzanti, Benedetta; Bagnoli, Silvia; Bucciantini, Sandra; Ghelli, Elena; Nacmias, Benedetta; Putignano, Anna Laura; Rombolà, Giovanni; Saccardi, Riccardo; Lombardini, Letizia; Di Lorenzo, Nicola; Vannelli, Gabriella B; Gallina, Pasquale

2015-01-01

Fetal grafting in a human diseased brain was thought to be less immunogenic than other solid organ transplants, hence the minor impact on the efficacy of the transplant. How much prophylactic immune protection is required for neural allotransplantation is also debated. High-sensitive anti-HLA antibody screening in this field has never been reported. Sixteen patients with Huntington's disease underwent human fetal striatal transplantation in the frame of an open-label observational trial, which is being carried out at Florence University. All patients had both brain hemispheres grafted in two separate robotic-stereotactic procedures. The trial started in February 2006 with the first graft to the first patient (R1). R16 was given his second graft on March 2011. All patients received triple immunosuppressive treatment. Pre- and posttransplant sera were analyzed for the presence of anti-HLA antibodies using the multiplexed microsphere-based suspension array Luminex xMAP technology. Median follow-up was 38.5 months (range 13-85). Six patients developed anti-HLA antibodies, which turned out to be donor specific. Alloimmunization occurred in a time window of 0-49 months after the first neurosurgical procedure. The immunogenic determinants were non-self-epitopes from mismatched HLA antigens. These determinants were both public epitopes shared by two or more HLA molecules and private epitopes unique to individual HLA molecules. One patient had non-donor-specific anti-HLA antibodies in her pretransplant serum sample, possibly due to previous sensitization events. Although the clinical significance of donor-specific antibodies is far from being established, particularly in the setting of neuronal transplantation, these findings underline the need of careful pre- and posttransplant immunogenetic evaluation of patients with intracerebral grafts.

Alternative Donor Graft Sources for Adults with Hematologic Malignancies: A Donor for All Patients in 2017!

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Kindwall-Keller, Tamila L; Ballen, Karen K

2017-09-01

Hematopoietic stem cell transplant (HSCT) is potentially curative for a wide variety of malignant diseases, including acute and leukemias, lymphoma, and myelodysplasia. Choice of a stem cell donor is dependent on donor availability, donor compatibility and health, recipient disease type, and recipient condition. Current sources of stem cell donation for HSCT are matched sibling donors (MSDs), matched unrelated donors (MUDs), 1-antigen mismatched unrelated donors (MMUDs), haploidentical donors (haplo), and umbilical cord blood (UCB) units. Historically, preferred donors for HSCT have been human leukocyte antigen (HLA)-matched sibling donors; however, only about 30% of U.S. patients will have a MSD available. The majority of patients referred for HSCT will require an alternative donor graft: MUD, MMUD, UCB, or haplo. The likelihood of finding a MUD varies depending on the ethnicity of the recipient. White Caucasians of European descent have the greatest chance of finding a MUD. Chances of finding a MUD are significantly less for African-American or Hispanic recipients due to HLA polymorphisms. Therefore, MMUD, UCB, and haplo donor graft sources expand the donor pool for recipients who do not have a MSD or MUD available. Given the variety of different donor stem cell sources available today, nearly every patient who needs an allogeneic HSCT has a potential donor in 2017. All transplant-eligible patients with hematologic malignancies should be evaluated by a transplant center to determine if HSCT is a viable treatment option for their underlying disease process. The goal of this review is to increase the awareness of oncology practitioners to the availability of alternative donor stem cell transplants for patients with hematologic malignancies. Despite new agents, stem cell transplant remains the only curative therapy for many patients with acute and chronic leukemia, myelodysplasia, and lymphoma. Given the variety of different donor stem cell sources available today

Haplótipos HLA mais freqüentes em doadores voluntários de medula óssea de Curitiba, Paraná

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Bicalho Maria G.

2002-01-01

Full Text Available Bone Marrow Transplant (BMT is a therapy used to treat patients with hematological diseases. The success of the transplant relies on a HLA match between host and donor. The HLA is located in the Major Histocompatibility Complex in the 6p12.3 region of the chromosome 6. The HLA gene products are involved in the immunomodulation of the immune response due to their function of presenting peptides to the T cells. The HLA genes are the most polymorphic in humans and the most relevant genetic marker for clinical transplants and are largely used in population studies. The knowledge of the HLA-A, HLA-B and HLA-DR haplotype frequencies of bone marrow donors is an important tool when a patient needs an identical HLA donor, and there are few population studies similar to this in Brazil. The HLA typing was performed in the LIGH of the UFPR by the PCR-SSP technique. The most common haplotypes among the population studied were HLA-A*01B*08DR*03, HLA-A*29B*44DR*07 and HLA-A*03B*07DR*15. The search of a Brazilian patient for an identical HLA donor is usually hopeless and the understanding of the HLA frequencies permits a real foreknowledge of the success of this search. Success depends on the eventual registration of the perfect donor in the national centers of bone marrow donation. Aiming to increase the perspectives of patients who need a BMT, the evaluation of the HLA frequencies and the enhancement of the national registrations of bone marrow donors are crucial for the accomplishment of this objective.

Familial Hodgkin lymphoma: pediatric onset in three out of five siblings

DEFF Research Database (Denmark)

Kamper, Peter; Kjeldsen, Eigil; Clausen, Niels

2005-01-01

Introduction: This is a report on FHL describing a family with five children of whom three were HLA class I genotype identical. Within a period of six years, these three siblings (one girl and two boys) were diagnosed with Epstein-Barr virus (EBV)-positive Hodgkin lymphoma (HL). Methods: In......-situ hybridisation for EBV-encoded small nuclear RNAs 1 and 2 (EBER-ISH) was performed by standard non-isotopic technique. Germline mutation analysis was performed on peripheral blood lymphocytes. Results: Two of the siblings were diagnosed at age 12, the other at age 5. All three cases were localised at diagnosis i...... on peripheral blood samples of all family members (the five siblings and their parents) did not reveal germline mutations. None of the children had overt immunodeficiency or autoimmune disease. Conclusions: Genetic factors may be involved in HL. In fact, FHL cases may share HLA haplotypes and siblings...

The Risk of Transplant Failure With HLA Mismatch in First Adult Kidney Allografts From Deceased Donors.

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Williams, Robert C; Opelz, Gerhard; McGarvey, Chelsea J; Weil, E Jennifer; Chakkera, Harini A

2016-05-01

Since the beginning of the technology, there has been active debate about the role of human leucocyte antigen (HLA) matching in kidney allograft survival. Recent studies have reported diminishing importance of HLA matching, which have, in turn, been challenged by reports that suggest the continuing importance of these loci. Given the controversies, we examined the effect of HLA compatibility on kidney allograft survival by studying all first adult kidney transplants in the United States from a deceased donor. Using the United Network for Organ Sharing data, we identified first deceased donor kidney transplants between October 1, 1987, and December 31, 2013. Recipients were classified by their number of HLA mismatches. Cox multivariate regression analyses adjusting for recipient and donor transplant characteristics were performed to determine the impact of HLA compatibility on kidney allograft survival. Study cohort included 189 141 first adult kidney alone transplants, with a total of 994 558 years of kidney allograft follow-up time. Analyses adjusted for recipient and donor characteristics demonstrated a 13% higher risk (hazard ratio, 1.13; 95% confidence interval, 1.06-1.21) with 1 mismatch and a 64% higher risk (hazard ratio, 1.64, 95% confidence interval, 1.56-1.73) with 6 mismatches. Dividing the mismatch categories into 27 ordered permutations, and testing their 57 within mismatch category differences, demonstrated that all but 1 were equal, independent of locus. A significant linear relationship of hazard ratios was associated with HLA mismatch and affects allograft survival even during the recent periods of increasing success in renal transplantation.

Haematopoietic transplants combining a single unrelated cord blood unit and mobilized haematopoietic stem cells from an adult HLA-mismatched third party donor. Comparable results to transplants from HLA-identical related donors in adults with acute leukaemia and myelodysplastic syndromes.

Science.gov (United States)

Sebrango, Ana; Vicuña, Isabel; de Laiglesia, Almudena; Millán, Isabel; Bautista, Guiomar; Martín-Donaire, Trinidad; Regidor, Carmen; Cabrera, Rafael; Fernandez, Manuel N

2010-06-01

We describe results of the strategy, developed by our group, of co-infusion of mobilized haematopoietic stem cells as a support for single-unit unrelated cord blood transplant (dual CB/TPD-MHSC transplants) for treatment of haematological malignancies in adults, and a comparative analysis of results obtained using this strategy and transplants performed with mobilized haematopoietic stem cells from related HLA-identical donors (RTD) for treatment of adults with acute leukaemia and myelodysplastic syndromes. Our data show that the dual CB/TPD-MHSC transplant strategy results in periods of post-transplant neutropenia, final rates of full donor chimerism and transplant-related mortality rates comparable to those of the RTD. Final survival outcomes are comparable in adults transplanted because of acute leukaemia, with different incidences of the complications that most influence these: a higher incidence of infections related to late recovery of protective immunity dependent on T cell functions, and a lower incidence of serious acute graft-versus-host disease and relapses. Recent advances in cord blood transplant techniques allow allogeneic haematopoietic stem cell transplantation (HSCT) to be a viable option for almost every patient who may benefit from this therapeutic approach. Development of innovative strategies to improve the post-transplant recovery of T cells function is currently the main challenge to further improving the possibilities of unrelated cord blood transplantation. Copyright © 2010 Elsevier Ltd. All rights reserved.

HLA polymorphism in Sudanese renal donors

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Ameer M Dafalla

2011-01-01

Full Text Available The main objective of this study is to provide a database for renal transplantation in Sudan and to determine the HLA antigens and haplotype frequencies (HFs in the study subjects. HLA typing was performed using the complement-dependant lymphocytotoxicity test in 250 unrelated healthy individuals selected as donors in the Sudanese Renal Transplantation Program. Considerable polymorphism was observed at each locus; A2 (0.28, A30 (0.12, A3 (0.09, A24 (0.09, A1 (0.09, and A68 (0.06 were the most frequent antigens in the A locus, while B51 (0.092, B41 (0.081, B39 (0.078, B57 (0.060, B35 (0.068, B 50 (0.053 and B 52 (0.051 were the most common B locus antigens. DR13 (0.444 and DR15 (0.160 showed the highest antigen frequencies (AFs in the DR locus. In the DQ locus, DQ1 showed the highest gene frequency (0.498, while DQ2 and DQ3 AFs were (0.185 and (0.238, respectively. The most common HLA-A and -B haplotypes in positive linkage disequilibrium were A24, B38; A1, B7; and A3, B52. The common HLA-A and -B HFs in positive linkage disequilibrium in the main three tribe-stocks of the study subjects (Gaalia, Nile Nubian and Johyna were A24, B38 for Gaalia; A24, B38 and A2, B7 for Johyna; and A2, B64 and A3, B53 for Nile Nubian. These results suggest that both class I and class II polymorphisms of the study subjects depict considerable heterogeneity, which reflects recent admixture of this group with neighboring Arabs and African populations.

Preceding immunosuppressive therapy with antithymocyte globulin and ciclosporin increases the incidence of graft rejection in children with aplastic anaemia who underwent allogeneic bone marrow transplantation from HLA-identical siblings.

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Kobayashi, Ryoji; Yabe, Hiromasa; Hara, Junichi; Morimoto, Akira; Tsuchida, Masahiro; Mugishima, Hideo; Ohara, Akira; Tsukimoto, Ichiro; Kato, Koji; Kigasawa, Hisato; Tabuchi, Ken; Nakahata, Tatsutoshi; Ohga, Shoichi; Kojima, Seiji

2006-12-01

The incidence of graft rejection was determined in 66 children with acquired aplastic anaemia (AA) following bone marrow transplantation (BMT) from a related donor. Eleven of 65 evaluable patients experienced either early or late rejection. Multivariate analysis identified previous immunosuppressive therapy with antithymocyte-globulin (ATG) and ciclosporin (CsA) as a risk factor for graft rejection (relative risk: 16.6, P = 0.001). Patients who received ATG and CsA had a significantly lower probability of failure-free survival than those who did not (69.7 +/- 6.2% vs. 87.9 +/- 8.0%, P = 0.044). These results suggest that BMT should be instituted immediately in children with severe AA who have human leucocyte antigen-identical siblings.

Donor Selection for Allogenic Hemopoietic Stem Cell Transplantation: Clinical and Ethical Considerations

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Irene Riezzo

2017-01-01

Full Text Available Allogenic hematopoietic progenitor cell transplantation (allo-HSCT is an established treatment for many diseases. Stem cells may be obtained from different sources: mobilized peripheral blood stem cells, bone marrow, and umbilical cord blood. The progress in transplantation procedures, the establishment of experienced transplant centres, and the creation of unrelated adult donor registries and cord blood banks gave those without an human leucocyte antigen- (HLA- identical sibling donor the opportunity to find a donor and cord blood units worldwide. HSCT imposes operative cautions so that the entire donation/transplantation procedure is safe for both donors and recipients; it carries with it significant clinical, moral, and ethical concerns, mostly when donors are minors. The following points have been stressed: the donation should be excluded when excessive risks for the donor are reasonable, donors must receive an accurate information regarding eventual adverse events and health burden for the donors themselves, a valid consent is required, and the recipient’s risks must be outweighed by the expected benefits. The issue of conflict of interest, when the same physician has the responsibility for both donor selection and recipient care, is highlighted as well as the need of an adequate insurance protection for all the parties involved.

The Risk of Transplant Failure With HLA Mismatch in First Adult Kidney Allografts 2: Living Donors, Summary, Guide

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Williams, Robert C.; Opelz, Gerhard; Weil, E. Jennifer; McGarvey, Chelsea J.; Chakkera, Harini A.

2017-01-01

Background Allografts from living donors survive longer than those from deceased donors but the role of HLA mismatching in living kidney donation is still in question. We examined the effect of HLA compatibility on kidney allograft survival from living donors by studying all first adult kidney transplants performed in the United States over 25 years. Methods Using the United Network for Organ Sharing data, we identified first kidney transplants between October 1, 1987, and December 31, 2013. ...

Presentation of human minor histocompatibility antigens by HLA-B35 and HLA-B38 molecules

International Nuclear Information System (INIS)

Yamamoto, Junji; Kariyone, Ai; Kano, Kyoichi; Takiguchi, Masafumi; Akiyama, Nobuo

1990-01-01

Cytotoxic T lymphocyte (CTL) clones specific for human minor histocompatibility antigens (hmHAs) were produced from a patient who had been grafted with the kidneys from his mother and two HLA-identical sisters. Of eight CTL clones generated, four recognized an hmHA (hmHA-1) expressed on cells from the mother and sister 3 (second donor); two recognized another antigen (hmHA-2) on cells from the father, sister (third donor), and sister 3; and the remaining two clones recognized still another antigen (hmHA-3) on cells from the father and sister 3. Panel studies revealed that CTL recognition of hmHA-1 was restricted by HLA-B35 and that of hmHA-2 and hmHA-3 was restricted by HLA-B38. The HLA-B35 restriction of the hmHA-1 -specific CTL clones was substantiated by the fact that they killed HLA-A null/HLA-B null Hmy2CIR targets transfected with HLA-B35 but not HLA-B51, -Bw52, or -Bw53 transfected Hmy2CIR targets. These data demonstrated that the five amino acids substitutions on the α 1 domain between HLA-B35 and -Bw53, which are associated with Bw4/Bw6 epitopes, play a critical role in the relationship of hmHA-1 to HLA-B35 molecules. The fact that the hmHA-1-specific CTLs failed to kill Hmy2CIR cells expressing HLA-B35/51 chimeric molecules composed of the α 1 domain of HLA-B35 and other domains of HLA-B51 indicated that eight residues on the α 2 domain also affect the interaction of hmHA-1 and the HLA-B35 molecules

PBSCT is associated with poorer survival and increased chronic GvHD than BMT in Japanese paediatric patients with acute leukaemia and an HLA-matched sibling donor.

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Shinzato, Aki; Tabuchi, Ken; Atsuta, Yoshiko; Inoue, Masami; Inagaki, Jiro; Yabe, Hiromasa; Koh, Katsuyoshi; Kato, Koji; Ohta, Hideaki; Kigasawa, Hisato; Kitoh, Toshiyuki; Ogawa, Atsushi; Takahashi, Yoshiyuki; Sasahara, Yoji; Kato, Shun-Ichi; Adachi, Souichi

2013-09-01

Peripheral blood stem cells (PBSC) may be used as an alternative to bone marrow (BM) for allogeneic transplantation. Since peripheral blood stem cell bank from unrelated volunteer donor has been started in Japan, use of PBSC allografts may be increased. Therefore we surveyed the outcomes of Japanese leukemia children after PBSC and BM transplantation. This retrospective study compared the outcomes of 661 children (0-18 years) with acute lymphoblastic leukaemia (ALL) or acute myeloid leukaemia (AML) who received their first allogeneic peripheral blood stem cell transplantation (PBSCT; n = 90) or bone marrow transplantation (BMT; n = 571) from HLA-matched siblings between January 1996 and December 2007. Neutrophil recovery was faster after PBSCT than after BMT (ALL: P vs. 9.9%, P = 0.0066; AML: 41.6% vs. 11.1%, P vs. 57.1%, P = 0.0257). The 5-year overall survival (OS) was lower after PBSCT than after BMT for ALL (42.4% vs. 63.7%, P = 0.0032) and AML (49.8% vs. 71.8%, P = 0.0163). Multivariate analysis revealed the use of PBSC was a significant risk factor for DFS and OS. PBSCT and BMT did not differ in relapse rate, acute GvHD for ALL and AML, or in DFS for AML. PBSC allografts in Japanese children engraft faster but are associated with poorer survival and increased chronic GvHD. Copyright © 2013 Wiley Periodicals, Inc.

Avaliação do percentual de compatibilidade HLA entre membros da mesma família para pacientes à espera de transplante de medula óssea em Santa Catarina, Brasil Evaluation of the percentage of HLA compatibility between members of the same family for patients awaiting bone marrow transplantation in the state of Santa Catarina, Brazil

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Carine Meinerz

2008-10-01

Full Text Available O transplante de medula óssea (TMO é uma terapia especial utilizada para tratar pacientes com doenças hematológicas e certas alterações genéticas. Para que um transplante seja bem sucedido, é necessário, entre outros fatores, que haja compatibilidade para moléculas codificadas pelos genes HLA. Em geral, os transplantes de melhor prognóstico são aqueles realizados entre irmãos HLA idênticos. Este trabalho tem por objetivo avaliar o percentual de compatibilidade de doadores de medula óssea (MO nas famílias de pacientes que necessitam de TMO no estado de Santa Catarina. A coleta dos dados foi realizada no arquivo do Laboratório de Imunogenética do Hemocentro de Santa Catarina (Hemosc, compreendendo o período de 2000 a 2007. Foram totalizados 469 casos de pacientes à espera de TMO. Para estes, foram triados 2.463 possíveis doadores aparentados. Destes, 49,8% eram irmãos dos pacientes. Houve compatibilidade com algum membro da família do paciente em 213 (45,4% casos, sendo que 99% das compatibilidades foram estabelecidas entre irmãos, 0,7% com mães e 0,3% com tios dos pacientes. Avaliando-se os doadores, obteve-se um total de 1.230 irmãos tipificados para doação, dos quais 296 (24,06% apresentaram compatibilidade com o paciente para o qual realizaram a tipificação. Os dados encontrados neste estudo mostram que a possibilidade de que seja encontrado um doador compatível para TMO dentro da família do paciente, em Santa Catarina, é bastante promissora, principalmente entre irmãos do paciente.Bone marrow transplantation (BMT is a special therapy used to treat patients with hematological diseases and certain genetic disorders. For a transplant to be successful, it is necessary, among others factors, to have compatibility of the molecules coded by HLA genes. In general, the best prognosis for BMT is obtained with HLA-identical siblings. The aim of this work was to evaluate the percentage of compatibility between patients

Probability of Finding Marrow Unrelated Donor (MUD) for an Indian patient in a Multi-national Human Leukocyte Antigen (HLA) Registry.

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Tiwari, Aseem K; Bhati-Kushwaha, Himakshi; Kukreja, Pooja; Mishra, Vikash C; Tyagi, Neetu; Sharma, Ashish; Raina, Vimarsh

2015-06-01

With an increase in the number of transplants happening globally, hematopoietic stem cells (HSC) transplantation from matched unrelated donor (MUD) has begun. The increasing trend of MUD transplants across countries has been largely facilitated with the conspicuous growth of volunteer HSC donor noted in the last decade i.e. 8 million HSC donors in 2002 to more than 22 million in 2013 registered in 71 member registries of the Bone Marrow Donor Worldwide (BMDW). Some populations of the world are still very poorly represented in these registries. Since, the chances of successful engraftment and disease free survival are directly proportional to the HLA compatibility between the recipient and the prospective donor, the diversity of the HLA system at the antigenic and allelic level and the heterogeneity of HLA data of the registered donors has a bearing on the probability of finding a volunteer unrelated HSC donor for patients from such populations. In the present study 126 patients were identified suffering from hematological diseases requiring MUD transplant. Their HLA typing was performed and search was done using BMDW database. The search results for these Indian patients in the multinational registry as well as in the Indian Registries were analyzed using mean, range, standard deviation and finally evaluated in terms of probability for finding matched donor (MUD). Total Asian population is only 11 % in the BMDW making it difficult to find a MUD for an Asian patient. The current study supports this, experimentally; revealing that the probability of finding an allele match for an Indian patient in the multinational Human Leukocyte Antigen (HLA) registries is 16 % and a dismal 0.008 % in the Indian registries (donors in Indian registries is just 33,678 as compared to 22.5 million in BMDW). This greatly, emphasizes on enhancing the number of Indian donors in Indian and multi-national registries.

Genetic diversity through human leukocyte antigen typing in end-stage renal disease patients and prospective donors of North India

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Mohit Chowdhry

2016-01-01

Full Text Available As the incidence of end-stage renal disease (ESRD is rapidly increasing, the demand for dialysis and transplantation has dramatically increased, which has led to concerns about the availability and equitable allocation of kidneys for transplantation. The distribution of HLA-A, B and DR alleles in 148 renal transplant recipients and 191 live related prospective donors from 2009 to 2010 were analyzed. Allele frequencies and haplotype frequencies were calculated in recipients and donors. The prospective donors were further analyzed on the basis of their relationship to the patients and according to the sex ratio. A significant female preponderance was noted in the prospective donor population, most of whom were either siblings or parents of the recipients. On the contrary, the recipient population predominantly comprised of males. The most frequent HLA-A, HLA-B, HLA-DRB1 alleles in renal transplant patients were HLA-AFNx0111, AFNx0102, AFNx0101, AFNx0124; HLA-BFNx0135, BFNx0140, BFNx0144, BFNx0115, BFNx0152, and HLA-DRB1FNx0115, DRB1FNx0107, DRB1FNx0113, DRB1FNx0111 respectively. The most frequent HLA-A, HLA-B, HLA-DRB1 alleles in prospective donors were HLA-AFNx0102, AFNx0111, AFNx0133, AFNx0124; HLA-BFNx0135, BFNx0144, BFNx0140, BFNx0115 and HLA-DRB1FNx0115, DRB1FNx0107, DRB1FNx0111, DRB1FNx0113 respectively. AFNx0111-BFNx0135, AFNx0102-DRB1FNx0115, BFNx0140-DRB1FNx0115 were the most common HLA A-B , HLA A-DR, HLA B-DR haplotypes respectively in renal transplant patients, whereas, AFNx0111-BFNx0135, AFNx0111-DRB1FNx0115, BFNx0144-DRB1FNx0107 were the most common haplotypes in renal donors. In three locus haplotype, HLA-AFNx0102-BFNx0140-DRB1FNx0115 was the most frequent haplotype in patients, whereas, in prospective renal donors HLA-AFNx0133-BFNx0144-DRB1FNx0107 was the most frequent haplotype.

Sibling differentiation, identity development, and the lateral dimension of psychic life.

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Vivona, Jeanine M

2007-01-01

The lateral dimension of psychic life, lived through relationships with siblings and their substitutes, is structured around a distinct psychic challenge: to find one's unique place in a world of similar others. Like the challenge that structures the vertical parent-child dimension, the lateral challenge is fraught with conflict and ambivalence; its resolution imbues psychic structure. That resolution may be accomplished through a process of differentiation, an active and unconscious process of identity development by which a child amplifies differences with siblings and minimizes similarities. Differentiation from siblings serves to mitigate interpersonal rivalry with them and to ease internal conflict associated with the lateral dimension. Three clinical examples are offered to illustrate the operation of sibling differentiation and its costs, particularly in terms of constricted identity and attenuated relationships with siblings and peers. Differentiation as a process of becoming what the other is not has been eclipsed by identification in psychoanalytic theories of identity development. Yet differentiation is a common strategy for resolving the primary rivalries and conflicts of the lateral dimension, and has unique developmental and clinical implications.

DIFFERENTIAL IMPACT OF HLA-A, HLA-B AND HLA-DR COMPATIBILITY ON THE RENAL ALLOGRAFT SURVIVAL

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V. Y. Abramov

2012-01-01

Full Text Available We studied the long-term results of 532 deceased donor kidney transplantations to investigate the impact of HLA match on the survival of renal allograft. All transplants were performed in our center in 1996–2009 and moni- tored prospectively for 1–14 years. We found, the survival of 58 kidneys grafted with 0–2 mismatch for HLA- ABDR to be significantly better (Plogrank = 0,016 than the survival of the kidneys grafted with 3–6 HLA-ABDR mismatch. The full compatibility for HLA-A (n = 75 did not influence the long-term survival (Plogrank = 0,48. The absence of HLA-DR mismatch had a beneficial effect for survival of 68 kidneys (Plogrank = 0,07. Eighteen cases with the full HLA-B compatibility between graft and recipient demonstrated excellent long-term survival (Plogrank = 0,007. HLA-B compatibility influenced significantly (P = 0,042 the survival of transplanted kidney in the Cox regression model adjusted for donor and recipient age, panel-reactive antibody level, re-transplant, and immunosuppression protocol. The data obtained support the conclusion, that HLA compatibility should be one of the criteria of deceased donor kidney allocation. 

Sibling recognition and the development of identity: intersubjective consequences of sibling differentiation in the sister relationship.

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Vivona, Jeanine M

2013-01-01

Identity is, among other things, a means to adapt to the others around whom one must fit. Psychoanalytic theory has highlighted ways in which the child fits in by emulating important others, especially through identification. Alternately, the child may fit into the family and around important others through differentiation, an unconscious process that involves developing or accentuating qualities and desires in oneself that are expressly different from the perceived qualities of another person and simultaneously suppressing qualities and desires that are perceived as similar. With two clinical vignettes centered on the sister relationship, the author demonstrates that recognition of identity differences that result from sibling differentiation carries special significance in the sibling relationship and simultaneously poses particular intersubjective challenges. To the extent that the spotlight of sibling recognition delimits the lateral space one may occupy, repeatedly frustrated desires for sibling recognition may have enduring consequences for one's sense of self-worth and expectations of relationships with peers and partners.

Outcomes after HLA-matched sibling transplantation or chemotherapy in children with B-precursor acute lymphoblastic leukemia in a second remission: a collaborative study of the Children's Oncology Group and the Center for International Blood and Marrow Transplant Research.

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Eapen, Mary; Raetz, Elizabeth; Zhang, Mei-Jie; Muehlenbein, Catherine; Devidas, Meenakshi; Abshire, Thomas; Billett, Amy; Homans, Alan; Camitta, Bruce; Carroll, William L; Davies, Stella M

2006-06-15

The best treatment approach for children with B-precursor acute lymphoblastic leukemia (ALL) in second clinical remission (CR) after a marrow relapse is controversial. To address this question, we compared outcomes in 188 patients enrolled in chemotherapy trials and 186 HLA-matched sibling transplants, treated between 1991 and 1997. Groups were similar except that chemotherapy recipients were younger (median age, 5 versus 8 years) and less likely to have combined marrow and extramedullary relapse (19% versus 30%). To adjust for time-to-transplant bias, treatment outcomes were compared using left-truncated Cox regression models. The relative efficacy of chemotherapy and transplantation depended on time from diagnosis to first relapse and the transplant conditioning regimen used. For children with early first relapse (children with a late first relapse (> or = 36 months), risks of second relapse were similar after TBI-containing regimens and chemotherapy (RR, 0.92; 95% CI, 0.49-1.70, P = .78). These data support HLA-matched sibling donor transplantation using a TBI-containing regimen in second CR for children with ALL and early relapse.

Graft failure following bone marrow transplantation for severe aplastic anemia risk factors and treatment results

NARCIS (Netherlands)

Champlin, R.E.; Horowitz, M.M.; Bekkum, D.W. van; Camitta, B.M. Elfenbein, G.E.; Gale, R.P.; Gluckman, E.; Good, R.A.; Rimm, A.A. Rozman, C.; Speck, B. Bortin, M.M

1989-01-01

Graft failure was analyzed in 625 patients receiving allogeneic bone marrow transplants from HLA-identical sibling donors as treatment for severe aplastic anemia. Sixty-eight (11%) had no or only transient engraftment. Second bone marrow transplants were successful in achieving extended survival in

Analysis of the results of allogeneic hematopoietic stem cell transplantation depending on HLA matching of the unrelated donor / recipient pair

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Ye. V. Kuzmich

2015-01-01

Full Text Available HLA matching of the donor / recipient pair is a major factor associated with the outcome of allogeneic stem cell transplantation. In the presentstudy we analyzed the risk of severe acute graft-versus-host disease, graft failure, 2.year overall survival of the patients after allogeneic stem cell transplantation depending on HLA matching of the unrelated donor / recipient pair.

[The impact of HLA haplotype and alleles mismatches of donor-recipient pairs on outcome of haploidentical hematopoietic stem cell transplantation with a third part cord blood unit].

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Zhu, W J; He, J; Bao, X J; Yuan, X N; Li, Y; Xue, S L; Pan, Z J; Chen, J; Wu, D P

2016-07-01

To analyze allele mismatches of HLA- A, - B, - C, - DRB1, - DQB1 and haplotype mismatch of donor- recipient pairs on the outcome of haploidentical transplantation combined with a third part cord blood unit. 230 pairs of donor-recipient were performed HLA-A, B, C, DRB1, DQB1 typing using SBT and SSOP methods from January 2012 to December 2014. Pairs were divided into HLA- 5/10、6/10、7/10 and ≥8/10 groups according to HLA- A, B, C and DRB1 highresolution typing and matched degrees, the 3-year probability of overall survival (OS) for each group were 48.7%, 59.3%, 71.1%, 38.3% (P=0.068) respectively. HLA-6/10 matched group associated with significant favorable effect on OS compared with HLA- 5/10 matched one (P=0.041).When the HLA class I antigen matched on the recipient and donor, improved OS and event free survival (EFS) in HLA- 6/10 matched group than in HLA-5/10 matched one (P=0.017,P=0.088), especially in single HLA-A loci allele matched one (P=0.013,P=0.013), were observed. As to the third part cord blood unit, sharing the same haplotype with the recipient-donor pairs produced better platelet recovery than the misfit one (95.3%vs 86.2%,P= 0.007), similar result was found in terms of neutrophil recovery (98.8%vs 96.1% ,P=0.022). HLA locus mismatch and haplotype mismatch of the donor and recipient should be useful for selection of the most optimum donor. Co- infused of an unrelated cord blood unit sharing the same haplotype with the recipient-donor pairs could improve hematopoietic recovery.

BAT2 and BAT3 polymorphisms as novel genetic risk factors for rejection after HLA-related SCT.

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Piras, Ignazio Stefano; Angius, Andrea; Andreani, Marco; Testi, Manuela; Lucarelli, Guido; Floris, Matteo; Marktel, Sarah; Ciceri, Fabio; La Nasa, Giorgio; Fleischhauer, Katharina; Roncarolo, Maria Grazia; Bulfone, Alessandro; Gregori, Silvia; Bacchetta, Rosa

2014-11-01

The genetic background of donor and recipient is an important factor determining the outcome of allogeneic hematopoietic SCT (allo-HSCT). We applied whole-genome analysis to investigate genetic variants-other than HLA class I and II-associated with negative outcome after HLA-identical sibling allo-HSCT in a cohort of 110 β-Thalassemic patients. We identified two single-nucleotide polymorphisms (SNPs) in BAT2 (A/G) and BAT3 (T/C) genes, SNP rs11538264 and SNP rs10484558, both located in the HLA class III region, in strong linkage disequilibrium between each other (R(2)=0.92). When considered as single SNP, none of them reached a significant association with graft rejection (nominal P<0.00001 for BAT2 SNP rs11538264, and P<0.0001 for BAT3 SNP rs10484558), whereas the BAT2/BAT3 A/C haplotype was present at significantly higher frequency in patients who rejected as compared to those with functional graft (30.0% vs 2.6%, nominal P=1.15 × 10(-8); and adjusted P=0.0071). The BAT2/BAT3 polymorphisms and specifically the A/C haplotype may represent a novel immunogenetic factor associated with graft rejection in patients undergoing allo-HSCT.

Three-dimensional structure discrepancy between HLA alleles for effective prediction of aGVHD severity and optimal selection of recipient-donor pairs: a proof-of-concept study.

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Han, Hongxing; Yuan, Fang; Sun, Yuying; Liu, Jinfeng; Liu, Shuguang; Luo, Yuan; Liang, Fei; Liu, Nan; Long, Juan; Zhao, Xiao; Kong, Fanhua; Xi, Yongzhi

2015-11-24

The optimal selection of recipient-donor pair and accurate prediction of acute graft-versus-host disease (aGVHD) severity are always the two most crucial works in allogeneic hematopoietic stem cell transplantation (allo-HSCT), which currently rests mostly with HLA compatibility, the most polymorphic loci in the human genome, in clinic. Thus, there is an urgent need for a rapid and reliable quantitative system for optimal recipient-donor pairs selection and accurate prediction of aGVHD severity prior to allo-HSCT. For these reasons, we have developed a new selection/prediction system for optimal recipient-donor selection and effective prediction of aGVHD severity based on HLA three-dimensional (3D) structure modeling (HLA-TDSM) discrepancy, and applied this system in a pilot randomized clinical allo-HSCT study. The 37 patient-donor pairs in the study were typed at low- and high-resolution levels for HLA-A/-B/-DRB1/-DQB1 loci. HLA-TDSM system covering the 10000 alleles in HLA class I and II consists of the revised local and coordinate root-mean-square deviation (RMSD) values for each locus. Its accuracy and reliability were confirmed using stably transfected Hmy2.CIR-HLA-B cells, TCR Vβ gene scan, and antigen-specific alloreactive cytotoxic lymphocytes. Based on the preliminary results, we theoretically defined all HLA acceptable versus unacceptable mismatched alleles. More importantly, HLA-TDSM enabled a successful retrospective verification and prospective prediction for aGVHD severity in a pilot randomized clinical allo-HSCT study of 32 recipient-donor transplant pairs. There was a strong direct correlation between single/total revised RMSD and aGVHD severity (92% in retrospective group vs 95% in prospective group). These results seem to be closely related to the 3D structure discrepancy of mismatched HLA-alleles, but not the number or loci of mismatched HLA-alleles. Our data first provide the proof-of-concept that HLA-TDSM is essential for optimal selection of

Dynamical System Modeling to Simulate Donor T Cell Response to Whole Exome Sequencing-Derived Recipient Peptides Demonstrates Different Alloreactivity Potential in HLA-Matched and -Mismatched Donor-Recipient Pairs.

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Abdul Razzaq, Badar; Scalora, Allison; Koparde, Vishal N; Meier, Jeremy; Mahmood, Musa; Salman, Salman; Jameson-Lee, Max; Serrano, Myrna G; Sheth, Nihar; Voelkner, Mark; Kobulnicky, David J; Roberts, Catherine H; Ferreira-Gonzalez, Andrea; Manjili, Masoud H; Buck, Gregory A; Neale, Michael C; Toor, Amir A

2016-05-01

Immune reconstitution kinetics and subsequent clinical outcomes in HLA-matched recipients of allogeneic stem cell transplantation (SCT) are variable and difficult to predict. Considering SCT as a dynamical system may allow sequence differences across the exomes of the transplant donors and recipients to be used to simulate an alloreactive T cell response, which may allow better clinical outcome prediction. To accomplish this, whole exome sequencing was performed on 34 HLA-matched SCT donor-recipient pairs (DRPs) and the nucleotide sequence differences translated to peptides. The binding affinity of the peptides to the relevant HLA in each DRP was determined. The resulting array of peptide-HLA binding affinity values in each patient was considered as an operator modifying a hypothetical T cell repertoire vector, in which each T cell clone proliferates in accordance with the logistic equation of growth. Using an iterating system of matrices, each simulated T cell clone's growth was calculated with the steady-state population being proportional to the magnitude of the binding affinity of the driving HLA-peptide complex. Incorporating competition between T cell clones responding to different HLA-peptide complexes reproduces a number of features of clinically observed T cell clonal repertoire in the simulated repertoire, including sigmoidal growth kinetics of individual T cell clones and overall repertoire, Power Law clonal frequency distribution, increase in repertoire complexity over time with increasing clonal diversity, and alteration of clonal dominance when a different antigen array is encountered, such as in SCT. The simulated, alloreactive T cell repertoire was markedly different in HLA-matched DRPs. The patterns were differentiated by rate of growth and steady-state magnitude of the simulated T cell repertoire and demonstrate a possible correlation with survival. In conclusion, exome wide sequence differences in DRPs may allow simulation of donor alloreactive T

Discovery of the rare HLA-B*39:77 allele in an unrelated Taiwanese bone marrow stem cell donor using the sequence-based typing method.

Science.gov (United States)

Yang, K L; Lee, S K; Lin, P Y

2013-08-01

We detected a rare HLA-B locus allele, B*39:77, in a Taiwanese unrelated marrow stem cell donor in our routine HLA sequence-based typing (SBT) exercise for a possible haematopoietic stem cell donation. In exons 2, 3 and 4, the DNA sequence of B*39:77 is identical to the sequence of B*39:01:01:01 except one nucleotide at nucleotide position 733 (G->A) in exon 4. The nucleotide variation caused one amino acid alteration at residue 221 (Gly->Ser). B*39:77 was probably derived from a nucleotide substitution event involving B*39:01:01:01. The probable HLA-A, -B, -C, -DRB1 and -DQB1 haplotype in association with B*39:77 may be deduced as A*02:01-B*39:77-C*07:02-DRB1*08:03-DQB1*06:01. Our discovery of B*39:77 in Taiwanese adds further polymorphism of B*39 variants in Taiwanese population. © 2013 John Wiley & Sons Ltd.

Reduced-intensity conditioning regimen using low-dose total body irradiation before allogeneic transplant for hematologic malignancies: Experience from the European Group for Blood and Marrow Transplantation

International Nuclear Information System (INIS)

Belkacemi, Yazid; Labopin, Myriam; Hennequin, Christophe; Hoffstetter, Sylvette; Mungai, Raffaello; Wygoda, Marc; Lundell, Marie; Finke, Jurgen; Aktinson, Chris; Lorchel, Frederic; Durdux, Catherine; Basara, Nadezda

2007-01-01

Purpose: The high rate of toxicity is the limitation of myelobalative regimens before allogeneic transplantation. A reduced intensity regimen can allow engraftment of stem cells and subsequent transfer of immune cells for the induction of a graft-vs.-tumor reaction. Methods and Materials: The data from 130 patients (80 males and 50 females) treated between 1998 and 2003 for various hematologic malignancies were analyzed. The median patient age was 50 years (range, 3-72 years). Allogeneic transplantation using peripheral blood or bone marrow, or both, was performed in 104 (82%), 22 (17%), and 4 (3%) patients, respectively, from HLA identical sibling donors (n = 93, 72%), matched unrelated donors (n = 23, 18%), mismatched related donors (4%), or mismatched unrelated donors (6%). Total body irradiation (TBI) at a dose of 2 Gy delivered in one fraction was given to 101 patients (78%), and a total dose of 4-6 Gy was given in 29 (22%) patients. The median dose rate was 14.3 cGy/min (range, 6-16.4). Results: After a median follow-up period of 20 months (range, 1-62 months), engraftment was obtained in 122 patients (94%). Acute graft-vs.-host disease of Grade 2 or worse was observed in 37% of patients. Multivariate analysis showed three favorable independent factors for event-free survival: HLA identical sibling donor (p < 0.0001; relative risk [RR], 0.15), complete remission (p < 0.0001; RR, 3.08), and female donor to male patient (p = 0.006; RR 2.43). For relapse, the two favorable prognostic factors were complete remission (p < 0.0001, RR 0.11) and HLA identical sibling donor (p = 0.0007; RR 3.59). Conclusions: In this multicenter study, we confirmed high rates of engraftment and chimerism after the reduced intensity regimen. Our results are comparable to those previously reported. Radiation parameters seem to have no impact on outcome. However, the lack of a statistically significant difference in terms of dose rate may have been due, in part, to the small population

Assignment of C1q-binding HLA antibodies as unacceptable HLA antigens avoids positive CDC-crossmatches prior to transplantation of deceased donor organs.

Science.gov (United States)

Juhl, David; Marget, Matthias; Hallensleben, Michael; Görg, Siegfried; Ziemann, Malte

2017-03-01

Soon, a virtual crossmatch shall replace the complement-dependent cytotoxicity (CDC) allocation crossmatch in the Eurotransplant region. To prevent positive CDC-crossmatches in the recipient centre, careful definition of unacceptable antigens is necessary. For highly sensitized patients, this is difficult by CDC alone. Assignment of all antibodies detected by sensitive assays, however, could prevent organ allocation. To assess the usefulness of the Luminex C1q-assay to prevent positive CDC-crossmatches, all CDC-crossmatches performed prior to deceased kidney transplantation in a 16-month-period were reviewed. Sera causing positive crossmatches were investigated by the C1q-assay. 31 out of 1432 crossmatches (2.2%) were positive. Sera involved in 26 positive crossmatches were available. C1q-binding donor-specific antibodies were detected in 19 sera (73.1%). The other sera were from recipients without any HLA antibodies detectable by CDC or common solid phase assays. Three patients had known Non-HLA antibodies causing positive CDC-results. Four crossmatches were only weak positive. Therefore, avoidance of donors with HLA antigens against whom C1q-binding antibodies were detected would have prevented all positive crossmatches due to HLA antibodies. Provided that all HLA specificities against which antibodies are detected by the Luminex C1q-assay are considered as unacceptable antigens, CDC-crossmatches prior to transplantation might safely be omitted in many patients. They should be maintained in highly immunized patients, however, for whom assignment of all C1q-positive antibodies as unacceptable antigens could lead to a significant delay or even prevention of transplantation. Copyright © 2017 Elsevier B.V. All rights reserved.

Sequential studies of cell inhibition of host fibroblasts in 51 patients given HLA-identical marrow grafts

International Nuclear Information System (INIS)

Tsoi, M.-S.; Storb, R.; Weiden, P.; Santos, E.; Kopecky, K.J.; Thomas, E.D.

1982-01-01

Thirty-four patients with leukemia, two with lymphoma and 15 with aplastic anemia, were studied sequentially between 33 and 666 days after treatment with high-dose cyclophosphamide and/or total body irradiation and marrow transplantation from HLA-identical siblings. Peripheral blood mononuclear cells from patients and normals were tested for cell inhibition (CI) of cultured skin fibroblasts from patients and donors or unrelated individuals using the microcytotoxicity assay. In addition, blocking of Cl by factors in patient serum was studied. Twenty patients were tested three or more times during the first year, 15 patients were studied twice and 16 patients once. Results showed that during the first 2 mo postgrafting, mononuclear cells from 45% of the patients had neither Cl nor blocking activities, 50% had Cl and serum blocking, and 5% had Cl without blocking. As time after transplatation elapsed, the percentage of patients without Cl gradually increased, whereas the percentage of patients with Cl with or without blocking decreased. At the end of 1 yr, 89% of the patients showed neither Cl nor blocking compared with 11% who showed Cl and blocking. This trend was significant (p < 0.005). The results were in agreement with our previus conclusion that serum-blocking factors were not important in the maintenance of the stable chimeric state. Early after grafting, there was a suggestive correlation (p < 0.08) between the in vitro finding of Cl of host fibroblasts by chimeric cells and the in vivo finding of acute graft-vs-host disease. However, there was no evidence that presence or absence of serum-blocking factors early after grafting was correlated with presence or absence of graft-vs-host disease

GVHD after HLA-matched sibling BMT or PBSCT: Comparison of North American Caucasian and Japanese Populations

Science.gov (United States)

Kanda, Junya; Brazauskas, Ruta; Hu, Zhen-Huan; Kuwatsuka, Yachiyo; Nagafuji, Koji; Kanamori, Heiwa; Kanda, Yoshinobu; Miyamura, Koichi; Murata, Makoto; Fukuda, Takahiro; Sakamaki, Hisashi; Kimura, Fumihiko; Seo, Sachiko; Aljurf, Mahmoud; Yoshimi, Ayami; Milone, Giuseppe; Wood, William A; Ustun, Celalettin; Hashimi, Shahrukh; Pasquini, Marcelo; Bonfim, Carmem; Dalal, Jignesh; Hahn, Theresa; Atsuta, Yoshiko; Saber, Wael

2016-01-01

The risk of acute graft-versus-host disease (GVHD) after HLA-matched sibling bone marrow (BM) transplantation is lower in Japanese than in Caucasian patients. However, race may have differential effect on GVHD dependent on the graft source. North American Caucasian and Japanese patients receiving their first allogeneic BM or peripheral blood stem cell (PBSC) transplantations from an HLA-matched sibling for leukemia were eligible. BM was used in 13% and 53% of Caucasian and Japanese patients, respectively. In multivariate analysis, the interaction term between race and graft source was not significant in any of the models, indicating that graft source does not affect the impact of race on outcomes. The risk of grades III–IV acute GVHD was significantly lower in Japanese than in Caucasian patients (hazard ratio (HR) 0.74, 95% confidence interval (CI) 0.57–0.96), which resulted in lower risk of non-relapse mortality in Japanese patients (HR 0.69, 95% CI 0.54–0.89). The risk of relapse was also lower in this group. Lower risk of non-relapse mortality and relapse resulted in lower overall mortality rates among Japanese patients. In conclusion, irrespective of graft source, the risk of severe acute GVHD is lower in Japanese patients, which results in lower risk of non-relapse mortality. PMID:26762681

Crossing the Ts by case-story “Exploring moral distress in potential sibling stem cell donors"

DEFF Research Database (Denmark)

Kaltoft, Mette Kjer

Crossing the Ts by Exploring moral distress in potential sibling stem cell donors [1] Mette Kjer Kaltoft, Ph.d student, MPH, RN, Health Visitor University of Southern Denmark and Sydney School of Public Health Background: Catalysts aiming to reduce the burden of malignant disease by integrating...... off the benefits and harms specific to each stakeholder-context may increase live and posthumous donations without inflicting preventable harm. Reference: [1] Exploring moral distress in potential sibling stem cell donors, Nursing Ethics 20(2) 178-188, 2012 Begley A, Virtual University of Uganda......-type-test’) for enhanced decision quality and reduction of harm. Methods: A *case-story of siblings of a sick brother needing live donation is presented within an interactive model for prescriptive translation using a diagram and multi-criteria decision-analytic approach. Actual or projected results: You can see each...

HLA-DQ Mismatching and Kidney Transplant Outcomes.

Science.gov (United States)

Leeaphorn, Napat; Pena, Jeremy Ryan A; Thamcharoen, Natanong; Khankin, Eliyahu V; Pavlakis, Martha; Cardarelli, Francesca

2018-05-07

Recent evidence suggests that HLA epitope-mismatching at HLA-DQ loci is associated with the development of anti-DQ donor-specific antibodies and adverse graft outcomes. However, the clinical significance of broad antigen HLA-DQ mismatching for graft outcomes is not well examined. Using the United Network Organ Sharing/the Organ Procurement and Transplantation Network (UNOS/OPTN) data, patients with primary kidney transplants performed between 2005 and 2014 were included. Patients were classified as having either zero HLA-DQ mismatches, or one or two HLA-DQ mismatches. Primary outcomes were death-censored graft survival and incidence of acute rejection. A total of 93,782 patients were included. Of these, 22,730 (24%) and 71,052 (76%) received zero and one or two HLA-DQ mismatched kidneys, respectively. After adjusting for variables including HLA-ABDR, HLA-DQ mismatching was associated with a higher risk of graft loss in living kidney donor recipients with an adjusted hazard ratio (HR) of 1.18 (95% confidence interval [95% CI], 1.07 to 1.30; P HLA-DQ mismatching was associated with a higher risk of graft loss in deceased kidney donor recipients with cold ischemic time ≤17 hours (HR, 1.12; 95% CI, 1.02 to 1.27; P =0.002), but not in deceased kidney donor recipients with cold ischemic time >17 hours (HR, 0.97; 95% CI, 0.88 to 1.06; P =0.49) ( P value for interaction HLA-DQ mismatched kidneys had a higher incidence of acute rejection at 1 year, with adjusted odds ratios of 1.13 (95% CI, 1.03 to 1.23; P transplant recipients. Specific donor-DQ mismatches seemed to be associated with the risk of acute rejection and graft failure, whereas others did not. HLA-DQ mismatching is associated with lower graft survival independent of HLA-ABDR in living donor kidney transplants and deceased donor kidney transplants with cold ischemia time ≤17 hours, and a higher 1-year risk of acute rejection in living and deceased donor kidney transplants. Copyright © 2018 by the American

The role of HLA antibodies in allogeneic SCT: is the 'type-and-screen' strategy necessary not only for blood type but also for HLA?

Science.gov (United States)

Yoshihara, S; Taniguchi, K; Ogawa, H; Saji, H

2012-12-01

The role of HLA antibodies in SCT has drawn increasing attention because of the significantly increased number of patients who receive HLA-mismatched SCT, including cord blood transplantation, haploidentical SCT and unrelated SCT. Technical advancements in the methods of HLA Ab testing have realized rapid, accurate and objective identification, as well as quantification of specific HLA antibodies. Recent clinical studies have suggested that the presence of donor-specific HLA antibodies (DSA) in patients is associated with graft failure in HLA-mismatched SCT when the above-listed stem cell sources are used and results in different impacts. Of note, most of the 'HLA-matched' unrelated SCT actually involve HLA mismatches in HLA-DP and the presence of antibodies against this locus has been reported to be associated with graft failure. Thus, HLA Ab should be examined as a work-up for all patients who undergo SCT from 'alternative donors.' The simplest route for preventing HLA Ab-mediated graft failure in Ab-positive patients is to avoid donors who possess the target Ag of HLA antibodies. If SCT from such donors must be performed, treatment for DSA before SCT may improve the chances of successful donor engraftment.

Open-Identity Sperm Donation: How Does Offering Donor-Identifying Information Relate to Donor-Conceived Offspring's Wishes and Needs?

Science.gov (United States)

Ravelingien, An; Provoost, Veerle; Pennings, Guido

2015-09-01

Over the past years, a growing number of countries have legislated open-identity donation, in which donor-conceived offspring are given access to the donor's identity once the child has reached maturity. It is held that donor anonymity creates identity problems for such children similar to the "genealogical bewilderment" described within the adoption context. The study of the social and psychological effects of open-identity donation is still very much in its infancy, but what has been left unquestioned is whether (and to what extent) offering access to the donor's name and address is an adequate response to such effects. This study has two goals: First, we aim to provide a systematic review of the reasons why donor-conceived (DC) offspring want to know the identity of their sperm donor. Second, we examine to what extent the provision of donor-identifying information can satisfy the reasons mentioned. The most important motivations appear to be: (1) to avoid medical risks and consanguineous relationships; (2) to satisfy curiosity; (3) to learn more about the self or to complete one's identity; (4) to learn more about what kind of person the donor is (biographical information, why he donated, etc.); (5) to form a relationship with the donor and/or his family; and (6) to learn about one's ancestry/genealogy. Our analysis shows that for nearly all of these reasons access to the donor's identity is not necessary. In those cases where it is, moreover, donor identification is not sufficient. What is really needed is (extended) contact with the donor, rather than the mere provision of his name.

The impact of HLA matching on long-term transplant outcome after allogeneic hematopoietic stem cell transplantation for CLL: a retrospective study from the EBMT registry.

NARCIS (Netherlands)

Michallet, M.; Sobh, M.; Milligan, D.; Morisset, S.; Niederwieser, D.; Koza, V.; Ruutu, T.; Russell, N.H.; Verdonck, L.; Dhedin, N.; Vitek, A.; Boogaerts, M.; Vindelov, L.; Finke, J.; Dubois, V.; Biezen, A. van; Brand, R.; Witte, T.J.M. de; Dreger, P.

2010-01-01

We analyzed 368 chronic lymphocytic leukemia patients who underwent allogeneic hematopoietic stem cell transplantation reported to the EBMT registry between 1995 and 2007. There were 198 human leukocyte antigen (HLA)-identical siblings; among unrelated transplants, 31 were well matched in high

Analysis of HLA-A, HLA-B, HLA-DRB1 allelic, genotypic, and haplotypic frequencies in colombian population

OpenAIRE

Yazmin Rocío Árias-Murillo; Miguel Ángel Castro-Jiménez; María Fernanda Ríos-Espinosa; Juan Javier López-Rivera; Sandra Johanna Echeverry-Coral; Oscar Martínez-Nieto

2010-01-01

Introduction: The high polymorphism of the HLA system allows its typification to be used as valuable tool in establishing association to various illnesses, immune and genetic profiles; it also provides a guide to identifying compatibility among donors and receptors of organs transplants. Objective: To establish HLA-A, HLA-B, and HLA.DRB1 allele, genotype and haplotype frequencies among patients treated at Clinica Colsanitas SA. Methods: 561 patients coming from different regions in Col...

Role of HLA in Hematopoietic Stem Cell Transplantation

Directory of Open Access Journals (Sweden)

Meerim Park

2012-01-01

Full Text Available The selection of hematopoietic stem cell transplantation (HSCT donors includes a rigorous assessment of the availability and human leukocyte antigen (HLA match status of donors. HLA plays a critical role in HSCT, but its involvement in HSCT is constantly in flux because of changing technologies and variations in clinical transplantation results. The increased availability of HSCT through the use of HLA-mismatched related and unrelated donors is feasible with a more complete understanding of permissible HLA mismatches and the role of killer-cell immunoglobulin-like receptor (KIR genes in HSCT. The influence of nongenetic factors on the tolerability of HLA mismatching has recently become evident, demonstrating a need for the integration of both genetic and nongenetic variables in donor selection.

CMV Serostatus of Donor-Recipient Pairs Influences the Risk of CMV Infection/Reactivation in HSCT Patients

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Emilia Jaskula

2012-01-01

Full Text Available CMV donor/recipient serostatus was analyzed in 200 patients allografted in our institution from unrelated (122 patients donors and 78 sibling donors in the years 2002–2011 in relation to posttransplant complications. On a group basis independently of the CMV serostatus of donor-recipient pairs sibling transplantations and those from unrelated donors that matched 10/10 at allele level had a similar rate of CMV reactivation (17/78 versus 19/71, P=ns. The rate of CMV reactivation/infection was higher in patients grafted from donors accepted at the lower level of matching than 10/10 (18/38 versus 36/149, P=0.008. The incidence of aGvHD followed frequencies of CMV reactivation in the tested groups, being 40/156 and 25/44 in patients grafted from sibling or unrelated donors that 10/10 matched and in those grafted from donors taht HLA mismatched, respectively (P=0.001. Regarding the rate of reactivation in both groups seropositive patients receiving a transplant from seronegative donors had more frequently CMV reactivation as compared to those with another donor-recipient matching CMV serostatus constellation (22/43 versus 32/143, P=0<0.001. Multivariate analysis revealed that seropositivity of recipients with concomitant seronegativity of donors plays an independent role in the CMV reactivation/infection (OR=2.669, P=0.037; OR=5.322, P=0.078; OR=23.034, P=0.023 for optimally matched and mismatched patients and the whole group of patients, resp..

In Silico Derivation of HLA-Specific Alloreactivity Potential from Whole Exome Sequencing of Stem Cell Transplant Donors and Recipients: Understanding the Quantitative Immunobiology of Allogeneic Transplantation

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Max eJameson-Lee

2014-11-01

Full Text Available Donor T cell mediated graft versus host effects (GVH may result from the aggregate alloreactivity to minor histocompatibility antigens (mHA presented by the HLA molecules in each donor-recipient pair undergoing stem cell transplantation (SCT. Whole exome sequencing has previously demonstrated a large number of nonsynonymous single nucleotide polymorphisms (SNP present in HLA-matched recipients of SCT donors (GVH direction. The nucleotide sequence flanking each of these SNPs was obtained and the amino acid sequence determined. All the possible nonameric-peptides incorporating the variant amino acid resulting from these SNPs were interrogated in-silico for their likelihood to be presented by the HLA class I molecules using the Immune Epitope Database stabilized matrix method (SMM and NetMHCpan algorithms. The SMM algorithm predicted that a median of 18,396 peptides weakly bound HLA class I molecules in individual SCT recipients, and 2,254 peptides displayed strong binding. A similar library of presented peptides was identified when the data was interrogated using the NetMHCpan algorithm. The bioinformatic algorithm presented here demonstrates that there may be a high level of mHA variation in HLA-matched individuals, constituting an HLA-specific alloreactivity potential.

The impact of HLA matching on long-term transplant outcome after allogeneic hematopoietic stem cell transplantation for CLL: a retrospective study from the EBMT registry

DEFF Research Database (Denmark)

Michallet, M; Sobh, M; Milligan, D

2010-01-01

We analyzed 368 chronic lymphocytic leukemia patients who underwent allogeneic hematopoietic stem cell transplantation reported to the EBMT registry between 1995 and 2007. There were 198 human leukocyte antigen (HLA)-identical siblings; among unrelated transplants, 31 were well matched in high re...

Production of human anti-HLA monoclonal antibodies

Energy Technology Data Exchange (ETDEWEB)

Walker, M.C.; Mercier, F.; Roger, J.; Varin, M.

1986-03-01

Only 40% of the several hundred anti-HLA murine monoclonal antibodies (MAbs) that have been made detect HLA-A,B,C or DR specificities previously defined by human alloantisera, the range of recognized specificities is very narrow, and few of the MAbs have proven useful as tissue typing reagents. In hopes of obtaining HLA typing reagents, the authors are developing a protocol for the production of human anti-HLA MAbs from HLA-antigen (Ag) immunized peripheral blood B cells of volunteering renal patients, immunized to one or more HLA Ags through therapeutic blood transfusions. A simple enrichment of the donor B cells has not been sufficient for anti-HLA MAb production, the authors are currently delineating the conditions necessary for increasing the number of HLA-specific donor B cells by in vitro stimulation with cells expressing the HLA Ag to which the B cell donor is immunized. For the production of MAbs, the stimulated B cells are transformed with Epstein-Barr virus and subsequently fused with KR-4 lymphoblastoid cells. Hybridomas are selected by HAT and Ouabain. Supernatants are screened for anti-HLA activity against lymphocyte targets expressing the original immunizing HLA Ag by complement mediated /sup 51/Cr release assay. Antibody specificity is determined by the complement-dependent microcytotoxicity test used for HLA typing.

[Results of hematopoietic stem cell transplantation in hemoglobinopathies: thalassemia major and sickle cell disease].

Science.gov (United States)

Hladun, R; Elorza, I; Olivé, T; Dapena, J L; Llort, A; Sánchez de Toledo, J; Díaz de Heredia, C

2013-08-01

The prevalence of hemoglobinopathies in Spain is increasing as a result of immigration. Thalassemia major presents with chronic hemolytic anemia that requires regular red blood cell transfusions within the first year of life. Patients with sickle cell disease suffer from chronic anemia, vasculopathy and progressive damage in almost any organ. There is decreased life expectancy in both conditions. Allogeneic hematopoietic stem cell transplantation represents the only potentially curative option. Seventeen patients (fourteen thalassemia major, and three sickle cell disease) underwent allogeneic hematopoietic stem cell transplantations. In the thalassemia group, nine donors were HLA-geno-identical siblings, two were partially matched related donors (one HLA allele mismatch), and three unrelated donors. All three patients with sickle cell disease were transplanted from HLA-geno-identical siblings. The source of stem cells was bone marrow in sixteen cases. Median patient age at transplant was six years (range: 1-16) in the thalassemia group, and twelve years (range: 8-15) in the sickle cell disease group. The graft was successful in all patients. Secondary graft rejection was observed in two thalassemia patients rendering them dependent on blood transfusions. Complete chimerism was observed in thirteen patients and, although mixed chimerism occurred in two, with all of them showing normal hemoglobin levels after transplantation and not requiring further transfusion support. Patients affected by sickle cell disease did not present with new vaso-occlusive crises, and stabilization of pulmonary and neurological function was observed. Chronic graft-versus-host disease was detected in three patients affected by thalassemia, and hypogonadotrophic hypogonadism in five patients. We conclude that for thalassemia major and sickle cell disease, allogenic hematopoietic stem cell transplantation from HLA-geno-identical siblings offers a high probability of complication-free survival

Addition of exogenous cytokines in mixed lymphocyte culture for selecting related donors for bone marrow transplantation

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Jeane Eliete Laguila Visentainer

Full Text Available CONTEXT: Mixed lymphocyte culturing has led to conflicting opinions regarding the selection of donors for bone marrow transplantation. The association between a positive mixed lymphocyte culture and the development of graft-versus-host disease (GVHD is unclear. The use of exogenous cytokines in mixed lymphocyte cultures could be an alternative for increasing the sensitivity of culture tests. OBJECTIVE: To increase the sensitivity of mixed lymphocyte cultures between donor and recipient human leukocyte antigen (HLA identical siblings, using exogenous cytokines, in order to predict post-transplantation GVHD and/or rejection. TYPE OF STUDY: Prospective study. SETTING: Bone Marrow Transplantation Unit, Universidade Estadual de Campinas. PARTICIPANTS: Seventeen patients with hematological malignancies and their respective donors selected for bone marrow transplantation procedures. PROCEDURES: Standard and modified mixed lymphocyte culturing by cytokine supplementation was carried out using donor and recipient cells typed for HLA. MAIN MEASUREMENTS: Autologous and allogenic responses in mixed lymphocyte cultures after the addition of IL-4 or IL-2. RESULTS: In comparison with the standard method, average responses in the modified mixed lymphocyte cultures increased by a factor of 2.0 using IL-4 (p < 0.001 and 6.4 using IL-2 (p < 0.001, for autologous donor culture responses. For donor-versus-recipient culture responses, the increase was by a factor of 1.9 using IL-4 (p < 0.001 and 4.1 using IL-2 (p < 0.001. For donor-versus-unrelated culture responses, no significant increase was observed using IL-4, and a mean response inhibition of 20% was observed using IL-2 (p < 0.001. Neither of the cytokines produced a significant difference in the unrelated control versus recipient cell responses. CONCLUSION: IL-4 supplementation was the best for increasing the mixed lymphocyte culture sensitivity. However, IL-4 also increased autologous responses, albeit less

Clinical presentations of 23 half-siblings from a mosaic neurofibromatosis type 1 sperm donor.

Science.gov (United States)

Ejerskov, C; Farholt, S; Skovby, F; Vestergaard, E M; Haagerup, A

2016-03-01

The Danish sperm donor number 7042 has fathered several offspring with neurofibromatosis type 1 (NF1) worldwide. NF1 is caused by loss-of-function mutations in the NF1 gene and more than 1000 NF1 mutations are identified. Analysis of the donor sperm demonstrated gonosomal mosaicism with an intragenic deletion involving exons 15-29 in the NF1 gene. At the two Danish reference centres for NF1 patients, we evaluated 23 half-siblings from the donor. Nine were diagnosed with NF1. The severity grade of NF1 progressed from minimal to mild/moderate within 3 years of follow-up. The NF1 phenotype shows great variability in intra- and inter-family expressivity and to date only two NF1 genotype-phenotype correlations have been established. This rare possibility of a long-term follow-up of a cohort of half-siblings with NF1 makes further studies including phenotypic variability and search for modifier genes possible. To achieve this goal, we have initiated The International Donor 7042 NF1 Offspring Registry. Research facilitated via this registry may reveal important new knowledge of clinical characteristics and prognostics for the specific NF1 genotype and thereby contribute to future individualised targeted clinical follow-up and treatment. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Measuring Ambiguity in HLA Typing Methods

Science.gov (United States)

Madbouly, Abeer; Freeman, John; Maiers, Martin

2012-01-01

In hematopoietic stem cell transplantation, donor selection is based primarily on matching donor and patient HLA genes. These genes are highly polymorphic and their typing can result in exact allele assignment at each gene (the resolution at which patients and donors are matched), but it can also result in a set of ambiguous assignments, depending on the typing methodology used. To facilitate rapid identification of matched donors, registries employ statistical algorithms to infer HLA alleles from ambiguous genotypes. Linkage disequilibrium information encapsulated in haplotype frequencies is used to facilitate prediction of the most likely haplotype assignment. An HLA typing with less ambiguity produces fewer high-probability haplotypes and a more reliable prediction. We estimated ambiguity for several HLA typing methods across four continental populations using an information theory-based measure, Shannon's entropy. We used allele and haplotype frequencies to calculate entropy for different sets of 1,000 subjects with simulated HLA typing. Using allele frequencies we calculated an average entropy in Caucasians of 1.65 for serology, 1.06 for allele family level, 0.49 for a 2002-era SSO kit, and 0.076 for single-pass SBT. When using haplotype frequencies in entropy calculations, we found average entropies of 0.72 for serology, 0.73 for allele family level, 0.05 for SSO, and 0.002 for single-pass SBT. Application of haplotype frequencies further reduces HLA typing ambiguity. We also estimated expected confirmatory typing mismatch rates for simulated subjects. In a hypothetical registry with all donors typed using the same method, the entropy values based on haplotype frequencies correspond to confirmatory typing mismatch rates of 1.31% for SSO versus only 0.08% for SBT. Intermediate-resolution single-pass SBT contains the least ambiguity of the methods we evaluated and therefore the most certainty in allele prediction. The presented measure objectively evaluates HLA

Measuring ambiguity in HLA typing methods.

Directory of Open Access Journals (Sweden)

Vanja Paunić

Full Text Available In hematopoietic stem cell transplantation, donor selection is based primarily on matching donor and patient HLA genes. These genes are highly polymorphic and their typing can result in exact allele assignment at each gene (the resolution at which patients and donors are matched, but it can also result in a set of ambiguous assignments, depending on the typing methodology used. To facilitate rapid identification of matched donors, registries employ statistical algorithms to infer HLA alleles from ambiguous genotypes. Linkage disequilibrium information encapsulated in haplotype frequencies is used to facilitate prediction of the most likely haplotype assignment. An HLA typing with less ambiguity produces fewer high-probability haplotypes and a more reliable prediction. We estimated ambiguity for several HLA typing methods across four continental populations using an information theory-based measure, Shannon's entropy. We used allele and haplotype frequencies to calculate entropy for different sets of 1,000 subjects with simulated HLA typing. Using allele frequencies we calculated an average entropy in Caucasians of 1.65 for serology, 1.06 for allele family level, 0.49 for a 2002-era SSO kit, and 0.076 for single-pass SBT. When using haplotype frequencies in entropy calculations, we found average entropies of 0.72 for serology, 0.73 for allele family level, 0.05 for SSO, and 0.002 for single-pass SBT. Application of haplotype frequencies further reduces HLA typing ambiguity. We also estimated expected confirmatory typing mismatch rates for simulated subjects. In a hypothetical registry with all donors typed using the same method, the entropy values based on haplotype frequencies correspond to confirmatory typing mismatch rates of 1.31% for SSO versus only 0.08% for SBT. Intermediate-resolution single-pass SBT contains the least ambiguity of the methods we evaluated and therefore the most certainty in allele prediction. The presented measure

Mobilized peripheral blood stem cells compared with bone marrow from HLA-identical siblings for reduced-intensity conditioning transplantation in acute myeloid leukemia in complete remission

DEFF Research Database (Denmark)

Nagler, Arnon; Labopin, Myriam; Shimoni, Avichai

2012-01-01

Reduced-intensity conditioning (RIC)-alloSCT is increasingly used for acute myelogenous leukemia. Limited data are available for the comparison of peripheral blood stem cells with bone marrow for RIC-alloSCT. We used the European Group for Blood and Marrow Transplantation (EBMT) ALWP data...... to compare the outcome of mobilized peripheral blood stem cells (PBSC) (n = 1430) vs. bone marrow (BM) (n = 107) for acute myelogenous leukemia (AML) patients with complete remission that underwent RIC-alloSCT from compatible sibling donors. The leukemia features, the disease status, and the time from...

2012 annual literature review of donor-specific HLA antibodies after organ transplantation.

Science.gov (United States)

Kaneku, Hugo

2012-01-01

From the articles reviewed in the present chapter, we observed: 1. The frequency of de novo donor-specific human leukocyte antigen (HLA) antibodies (DSA) detection in different organs is very similar: ranging between 15% and 23% in kidney, 23% in pancreas, and 18% in intestinal transplant patients. Apparently, all organs can elicit humoral responses after transplantation at comparable rates. 2. Although rates of de novo DSA formation after kidney transplantation are very similar across different centers--between 15% and 23%--, the mean time to the first detection of de novo DSA is markedly variable between centers (from 8 months to 4 years). Some differences found in the studies that may account for this could be the age of patients (studies including pediatric patients tend to show longer time to DSA detection compared to studies only including adults patients), patients' race, and maintenance immunosuppression regimens. 3. In most organs, alloantibodies against class II HLA--and especially against HLA-DQ antigens--are the most common DSA detected. This finding supports previous studies, but the explanation remains unclear. Poor HLA-DQ matching, paucity of class II HLA antigen expression on cell surface, and technical factors related to the detection of these antibodies (mean fluorescence intensity cutoff, multiple beads with the same antigen, denatured protein on single antigen beads) are some of the potential explanations that need further investigation. 4. Recent focus on histological changes during rejection in the presence of DSA that are independent of C4d deposition may change how antibody-mediated rejection is diagnosed in the near future. 5. More studies are looking into the importance of DSA in non-kidney transplants and now evidence shows that DSA may not only affect survival and rejection rates, but may also be associated with organ-specific lesions like fibrosis and biliary complications in livers or capillaritis in lungs.

Impact of donor-specific HLA antibodies in transplantation, a review of the literature published in the last three years.

Science.gov (United States)

Kaneku, Hugo

2010-01-01

This chapter summarizes some of the recent findings published on the role in organ transplantation of HLA antibodies, and--more important--donor-specific HLA antibodies. The negative impact of both, preformed and de novo DSA is now better recognized in recipients of kidney, heart, lung, liver, pancreas, islet cells and bone marrow transplants. An appropriate design of a schedule to monitor HLA antibodies may identify patients at higher risk for immunological events earlier and allow interventions to avoid later graft loss. The value of strategies like preemptive treatment of antibodies and the use of new agents like bortezomib and eculizumab are of interest and need further investigation.

Non-HLA antibodies post-transplantation: clinical relevance and treatment in solid organ transplantation.

Science.gov (United States)

Dragun, Duska; Hegner, Bjorn

2009-01-01

Antibodies and B cells are increasingly recognized as major modulators of allograft function and survival. Improved immunohistochemical and serologic diagnostic procedures have been developed to monitor antibody responses against HLA antigens during the last decade. Acute and chronic allograft rejection can occur in HLA-identical sibling transplants implicating the importance of immune response against non-HLA targets. Non-HLA anti-bodies may occur as alloantiboides, yet they seem to be predominantly autoantibodies. Antigenic targets of non-HLA antibodies described thus far include various minor histocompatibility antigens, vascular receptors, adhesion molecules, and intermediate filaments. Non-HLA antibodies may function as complement- and non-complement-fixing antibodies and they may induce a wide variety of allograft injuries, reflecting the complexity of their acute and chronic actions. Refined approaches considering the subtle mechanistic differences in the individual antibody responses directed against non-HLA antigens may help to define patients at particular risk for irreversible acute or chronic allograft injuries and improve over-all outcomes. We attempted to summarize the current state of research, development in diagnostic and therapeutic strategies, and to address some emerging problems in the area of humoral response against non-HLA antigens beyond ABO blood group and MHC class I chain-related gene A and B (MICA and MICB) antigens in solid organ transplantation. Copyright (c) 2009 S. Karger AG, Basel.

HLA Match Likelihoods for Hematopoietic Stem-Cell Grafts in the U.S. Registry

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Gragert, Loren; Eapen, Mary; Williams, Eric; Freeman, John; Spellman, Stephen; Baitty, Robert; Hartzman, Robert; Rizzo, J. Douglas; Horowitz, Mary; Confer, Dennis; Maiers, Martin

2018-01-01

Background Hematopoietic stem-cell transplantation (HSCT) is a potentially lifesaving therapy for several blood cancers and other diseases. For patients without a suitable related HLA-matched donor, unrelated-donor registries of adult volunteers and banked umbilical cord–blood units, such as the Be the Match Registry operated by the National Marrow Donor Program (NMDP), provide potential sources of donors. Our goal in the present study was to measure the likelihood of finding a suitable donor in the U.S. registry. Methods Using human HLA data from the NMDP donor and cord-blood-unit registry, we built population-based genetic models for 21 U.S. racial and ethnic groups to predict the likelihood of identifying a suitable donor (either an adult donor or a cord-blood unit) for patients in each group. The models incorporated the degree of HLA matching, adult-donor availability (i.e., ability to donate), and cord-blood-unit cell dose. Results Our models indicated that most candidates for HSCT will have a suitable (HLA-matched or minimally mismatched) adult donor. However, many patients will not have an optimal adult donor — that is, a donor who is matched at high resolution at HLA-A, HLA-B, HLA-C, and HLA-DRB1. The likelihood of finding an optimal donor varies among racial and ethnic groups, with the highest probability among whites of European descent, at 75%, and the lowest probability among blacks of South or Central American descent, at 16%. Likelihoods for other groups are intermediate. Few patients will have an optimal cord-blood unit — that is, one matched at the antigen level at HLA-A and HLA-B and matched at high resolution at HLA-DRB1. However, cord-blood units mismatched at one or two HLA loci are available for almost all patients younger than 20 years of age and for more than 80% of patients 20 years of age or older, regardless of racial and ethnic background. Conclusions Most patients likely to benefit from HSCT will have a donor. Public investment in

Application of High-Throughput Next-Generation Sequencing for HLA Typing on Buccal Extracted DNA: Results from over 10,000 Donor Recruitment Samples.

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Yin, Yuxin; Lan, James H; Nguyen, David; Valenzuela, Nicole; Takemura, Ping; Bolon, Yung-Tsi; Springer, Brianna; Saito, Katsuyuki; Zheng, Ying; Hague, Tim; Pasztor, Agnes; Horvath, Gyorgy; Rigo, Krisztina; Reed, Elaine F; Zhang, Qiuheng

2016-01-01

Unambiguous HLA typing is important in hematopoietic stem cell transplantation (HSCT), HLA disease association studies, and solid organ transplantation. However, current molecular typing methods only interrogate the antigen recognition site (ARS) of HLA genes, resulting in many cis-trans ambiguities that require additional typing methods to resolve. Here we report high-resolution HLA typing of 10,063 National Marrow Donor Program (NMDP) registry donors using long-range PCR by next generation sequencing (NGS) approach on buccal swab DNA. Multiplex long-range PCR primers amplified the full-length of HLA class I genes (A, B, C) from promotor to 3' UTR. Class II genes (DRB1, DQB1) were amplified from exon 2 through part of exon 4. PCR amplicons were pooled and sheared using Covaris fragmentation. Library preparation was performed using the Illumina TruSeq Nano kit on the Beckman FX automated platform. Each sample was tagged with a unique barcode, followed by 2×250 bp paired-end sequencing on the Illumina MiSeq. HLA typing was assigned using Omixon Twin software that combines two independent computational algorithms to ensure high confidence in allele calling. Consensus sequence and typing results were reported in Histoimmunogenetics Markup Language (HML) format. All homozygous alleles were confirmed by Luminex SSO typing and exon novelties were confirmed by Sanger sequencing. Using this automated workflow, over 10,063 NMDP registry donors were successfully typed under high-resolution by NGS. Despite known challenges of nucleic acid degradation and low DNA concentration commonly associated with buccal-based specimens, 97.8% of samples were successfully amplified using long-range PCR. Among these, 98.2% were successfully reported by NGS, with an accuracy rate of 99.84% in an independent blind Quality Control audit performed by the NDMP. In this study, NGS-HLA typing identified 23 null alleles (0.023%), 92 rare alleles (0.091%) and 42 exon novelties (0.042%). Long

Application of High-Throughput Next-Generation Sequencing for HLA Typing on Buccal Extracted DNA: Results from over 10,000 Donor Recruitment Samples.

Directory of Open Access Journals (Sweden)

Yuxin Yin

Full Text Available Unambiguous HLA typing is important in hematopoietic stem cell transplantation (HSCT, HLA disease association studies, and solid organ transplantation. However, current molecular typing methods only interrogate the antigen recognition site (ARS of HLA genes, resulting in many cis-trans ambiguities that require additional typing methods to resolve. Here we report high-resolution HLA typing of 10,063 National Marrow Donor Program (NMDP registry donors using long-range PCR by next generation sequencing (NGS approach on buccal swab DNA.Multiplex long-range PCR primers amplified the full-length of HLA class I genes (A, B, C from promotor to 3' UTR. Class II genes (DRB1, DQB1 were amplified from exon 2 through part of exon 4. PCR amplicons were pooled and sheared using Covaris fragmentation. Library preparation was performed using the Illumina TruSeq Nano kit on the Beckman FX automated platform. Each sample was tagged with a unique barcode, followed by 2×250 bp paired-end sequencing on the Illumina MiSeq. HLA typing was assigned using Omixon Twin software that combines two independent computational algorithms to ensure high confidence in allele calling. Consensus sequence and typing results were reported in Histoimmunogenetics Markup Language (HML format. All homozygous alleles were confirmed by Luminex SSO typing and exon novelties were confirmed by Sanger sequencing.Using this automated workflow, over 10,063 NMDP registry donors were successfully typed under high-resolution by NGS. Despite known challenges of nucleic acid degradation and low DNA concentration commonly associated with buccal-based specimens, 97.8% of samples were successfully amplified using long-range PCR. Among these, 98.2% were successfully reported by NGS, with an accuracy rate of 99.84% in an independent blind Quality Control audit performed by the NDMP. In this study, NGS-HLA typing identified 23 null alleles (0.023%, 92 rare alleles (0.091% and 42 exon novelties (0.042%.Long

Renal artery aneurysm in hand-assisted laparoscopic donor nephrectomy: case report.

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Maciel, R F; Branco, A J; Branco, A W; Guterres, J C; Silva, A E; Ramos, L B; Rost, C; Vieira, C A; Cicogna, P E S; Daudt, C A; Deboni, L M; Vieira, M A; Luz, H A; Vieira, J A

2003-12-01

We report a living donor who underwent laparoscopic nephrectomy using a hand-assisted device (HALD). At preoperative arteriography the donor showed a renal artery aneurysm. The patient was a 37-year-old female, 166 cm height, white, weighing 87 kg, HLA identical to the recipient. HALD was indicated due to the better visualization of renal pedicle and greater security in an obese patient. Renal artery aneurysm is a rare condition, with many possible complications. The method proved to be adequate and safe for donor nephrectomy, despite a renal artery aneurysm.

Successful Renal Transplantation Across HLA Barrier: Report from India.

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Aggarwal, G; Tiwari, A K; Dorwal, P; Chauhan, R; Arora, D; Dara, R C; Kher, V

2017-01-01

Organ donors are sometimes found "unsuitable" due to the presence of donor-specific anti-HLA antibodies in the recipient. In recent years, improved desensitization protocols have successfully helped to overcome HLA incompatibility hurdle. We present three cases where optimum desensitization was achieved in patients with the donor-specific anti-HLA antibody (DSA) leading to successful renal transplantation. All patient-donor pair underwent HLA typing, complement dependent cytotoxicity crossmatch (CDC-XM), flow cytometry XM (FC-XM), and panel reactive antibody. If any of the three tests was positive, single antigen bead assay was performed to determine the specificity of the anti-HLA antibody (s). Patients with DSA were offered organ-swap or anti-HLA antibody desensitization followed by transplantation. Desensitization protocol consisted of single dose rituximab and cascade plasmapheresis (CP) along with standard triple immunosuppression. The target DSA mean fluorescence index (MFI) was HLA DSA, who did not find a suitable match in organ swap program, consented to anti-HLA antibody desensitization, followed by transplantation. Mean pre-desensitization antibody MFI was 1740 (1422-2280). Mean number of CP required to achieve the target MFI was 2.3 (2-3). All the three patients are on regular follow-up and have normal renal function test at a mean follow-up of 8 months. This report underlines successful application of desensitization protocol leading to successful HLA-antibody incompatible renal transplants and their continued normal renal functions.

HLA-inferred extended haplotype disparity level is more relevant than the level of HLA mismatch alone for the patients survival and GvHD in T cell-replate hematopoietic stem cell transplantation from unrelated donor.

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Nowak, Jacek; Nestorowicz, Klaudia; Graczyk-Pol, Elzbieta; Mika-Witkowska, Renata; Rogatko-Koros, Marta; Jaskula, Emilia; Koscinska, Katarzyna; Madej, Sylwia; Tomaszewska, Agnieszka; Nasilowska-Adamska, Barbara; Szczepinski, Andrzej; Halaburda, Kazimierz; Dybko, Jaroslaw; Kuliczkowski, Kazimierz; Czerw, Tomasz; Giebel, Sebastian; Holowiecki, Jerzy; Baranska, Malgorzata; Pieczonka, Anna; Wachowiak, Jacek; Czyz, Anna; Gil, Lidia; Lojko-Dankowska, Anna; Komarnicki, Mieczyslaw; Bieniaszewska, Maria; Kucharska, Agnieszka; Hellmann, Andrzej; Gronkowska, Anna; Jedrzejczak, Wieslaw W; Markiewicz, Miroslaw; Koclega, Anna; Kyrcz-Krzemien, Slawomira; Mielcarek, Monika; Kalwak, Krzysztof; Styczynski, Jan; Wysocki, Mariusz; Drabko, Katarzyna; Wojcik, Beata; Kowalczyk, Jerzy; Gozdzik, Jolanta; Pawliczak, Daria; Gwozdowicz, Slawomir; Dziopa, Joanna; Szlendak, Urszula; Witkowska, Agnieszka; Zubala, Marta; Gawron, Agnieszka; Warzocha, Krzysztof; Lange, Andrzej

2018-06-01

Serious risks in unrelated hematopoietic stem cell transplantation (HSCT) including graft versus host disease (GvHD) and mortality are associated with HLA disparity between donor and recipient. The increased risks might be dependent on disparity in not-routinely-tested multiple polymorphisms in genetically dense MHC region, being organized in combinations of two extended MHC haplotypes (Ehp). We assessed the clinical role of donor-recipient Ehp disparity levels in N = 889 patients by the population-based detection of HLA allele phase mismatch. We found increased GvHD incidences and mortality rates with increasing Ehp mismatch level even with the same HLA mismatch level. In multivariate analysis HLA mismatch levels were excluded from models and Ehp disparity level remained independent prognostic factor for high grade acute GvHD (p = 0.000037, HR = 10.68, 95%CI 5.50-32.5) and extended chronic GvHD (p < 0.000001, HR = 15.51, CI95% 5.36-44.8). In group with single HLA mismatch, patients with double Ehp disparity had worse 5-year overall survival (45% vs. 56%, p = 0.00065, HR = 4.05, CI95% 1.69-9.71) and non-relapse mortality (40% vs. 31%, p = 0.00037, HR = 5.63, CI95% 2.04-15.5) than patients with single Ehp disparity. We conclude that Ehp-linked factors contribute to the high morbidity and mortality in recipients given HLA-mismatched unrelated transplant and Ehp matching should be considered in clinical HSCT. Copyright © 2018. Published by Elsevier Inc.

Data mining of mental health issues of non-bone marrow donor siblings.

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Takita, Morihito; Tanaka, Yuji; Kodama, Yuko; Murashige, Naoko; Hatanaka, Nobuyo; Kishi, Yukiko; Matsumura, Tomoko; Ohsawa, Yukio; Kami, Masahiro

2011-07-20

Allogenic hematopoietic stem cell transplantation is a curative treatment for patients with advanced hematologic malignancies. However, the long-term mental health issues of siblings who were not selected as donors (non-donor siblings, NDS) in the transplantation have not been well assessed. Data mining is useful in discovering new findings from a large, multidisciplinary data set and the Scenario Map analysis is a novel approach which allows extracting keywords linking different conditions/events from text data of interviews even when the keywords appeared infrequently. The aim of this study is to assess mental health issues on NDSs and to find helpful keywords for the clinical follow-up using a Scenario Map analysis. A 47-year-old woman whose younger sister had undergone allogenic hematopoietic stem cell transplantation 20 years earlier was interviewed as a NDS. The text data from the interview transcriptions was analyzed using Scenario Mapping. Four clusters of words and six keywords were identified. Upon review of the word clusters and keywords, both the subject and researchers noticed that the subject has had mental health issues since the disease onset to date with being a NDS. The issues have been alleviated by her family. This single subject study suggested the advantages of data mining in clinical follow-up for mental health issues of patients and/or their families.

Successful renal transplantation across HLA barrier: Report from India

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G Aggarwal

2017-01-01

Full Text Available Organ donors are sometimes found “unsuitable” due to the presence of donor-specific anti-HLA antibodies in the recipient. In recent years, improved desensitization protocols have successfully helped to overcome HLA incompatibility hurdle. We present three cases where optimum desensitization was achieved in patients with the donor-specific anti-HLA antibody (DSA leading to successful renal transplantation. All patient–donor pair underwent HLA typing, complement dependent cytotoxicity crossmatch (CDC-XM, flow cytometry XM (FC-XM, and panel reactive antibody. If any of the three tests was positive, single antigen bead assay was performed to determine the specificity of the anti-HLA antibody (s. Patients with DSA were offered organ-swap or anti-HLA antibody desensitization followed by transplantation. Desensitization protocol consisted of single dose rituximab and cascade plasmapheresis (CP along with standard triple immunosuppression. The target DSA mean fluorescence index (MFI was <500, along with negative CDC-XM and FC-XM for both T- and B-cells. Three patients with anti-HLA DSA, who did not find a suitable match in organ swap program, consented to anti-HLA antibody desensitization, followed by transplantation. Mean pre-desensitization antibody MFI was 1740 (1422–2280. Mean number of CP required to achieve the target MFI was 2.3 (2–3. All the three patients are on regular follow-up and have normal renal function test at a mean follow-up of 8 months. This report underlines successful application of desensitization protocol leading to successful HLA-antibody incompatible renal transplants and their continued normal renal functions.

Ethnic differences in HLA antigens in Chilean donors and recipients: data from the National Renal Transplantation Program.

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Droguett, M A; Beltran, R; Ardiles, R; Raddatz, N; Labraña, C; Arenas, A; Flores, J; Alruiz, P; Mezzano, S; Ardiles, L

2008-11-01

To describe HLA antigen distribution, looking for possible markers of renal disease in Mapuche and non-Mapuche people in the renal transplantation program, we reviewed data from 1297 histocompatibility studies of the Chilean national renal transplantation program (421 donors and 876 recipients), performed between 2000 and 2005. Mapuche people were classified according to their family surnames. The most frequent antigens found among the total Chilean population were A2 (48%), A19 (33%), B16 (33%), B35 (26%), DR4 (38%), and DR6 (28%), without significant differences between donors and recipients. Among the 114 individuals (9%) classified as Mapuche, the most frequent antigens were A28 (49%), A2 (44%), B16 (63%), B35 (24%), DR4 (48%), and DR8 (30%), with A28/B16/DR4 as the most common haplotype. In contrast, A28, B16, DR4, and DR8 were significantly more frequent in Mapuche compared with non-Mapuche people. B8 was significantly more frequent in Mapuche recipients than in non-Mapuche recipients and Mapuche donors. The higher frequency of some HLA antigens in Mapuche people was confirmed, possibly corresponding to ethnic markers. The special concentration of B8 among Mapuche recipients might represent a genetic factor predisposing to chronic renal disease in this human group.

Establishment of HLA-DR4 transgenic mice for the identification of CD4+ T cell epitopes of tumor-associated antigens.

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Junji Yatsuda

Full Text Available Reports have shown that activation of tumor-specific CD4(+ helper T (Th cells is crucial for effective anti-tumor immunity and identification of Th-cell epitopes is critical for peptide vaccine-based cancer immunotherapy. Although computer algorithms are available to predict peptides with high binding affinity to a specific HLA class II molecule, the ability of those peptides to induce Th-cell responses must be evaluated. We have established HLA-DR4 (HLA-DRA*01:01/HLA-DRB1*04:05 transgenic mice (Tgm, since this HLA-DR allele is most frequent (13.6% in Japanese population, to evaluate HLA-DR4-restricted Th-cell responses to tumor-associated antigen (TAA-derived peptides predicted to bind to HLA-DR4. To avoid weak binding between mouse CD4 and HLA-DR4, Tgm were designed to express chimeric HLA-DR4/I-E(d, where I-E(d α1 and β1 domains were replaced with those from HLA-DR4. Th cells isolated from Tgm immunized with adjuvant and HLA-DR4-binding cytomegalovirus-derived peptide proliferated when stimulated with peptide-pulsed HLA-DR4-transduced mouse L cells, indicating chimeric HLA-DR4/I-E(d has equivalent antigen presenting capacity to HLA-DR4. Immunization with CDCA155-78 peptide, a computer algorithm-predicted HLA-DR4-binding peptide derived from TAA CDCA1, successfully induced Th-cell responses in Tgm, while immunization of HLA-DR4-binding Wilms' tumor 1 antigen-derived peptide with identical amino acid sequence to mouse ortholog failed. This was overcome by using peptide-pulsed syngeneic bone marrow-derived dendritic cells (BM-DC followed by immunization with peptide/CFA booster. BM-DC-based immunization of KIF20A494-517 peptide from another TAA KIF20A, with an almost identical HLA-binding core amino acid sequence to mouse ortholog, successfully induced Th-cell responses in Tgm. Notably, both CDCA155-78 and KIF20A494-517 peptides induced human Th-cell responses in PBMCs from HLA-DR4-positive donors. Finally, an HLA-DR4 binding DEPDC1191

Therapeutic preparations of IVIg contain naturally occurring anti-HLA-E antibodies that react with HLA-Ia (HLA-A/-B/-Cw) alleles.

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Ravindranath, Mepur H; Terasaki, Paul I; Pham, Tho; Jucaud, Vadim; Kawakita, Satoru

2013-03-14

The US Food and Drug Administration approved intravenous immunoglobulin (IVIg), extracted from the plasma of thousands of blood donors, for removing HLA antibodies (Abs) in highly sensitized patients awaiting organ transplants. Since the blood of healthy individuals has HLA Abs, we tested different IVIg preparations for reactivity to HLA single antigen Luminex beads. All preparations showed high levels of HLA-Ia and -Ib reactivity. Since normal nonalloimmunized males have natural antibodies to the heavy chains (HCs) of HLA antigens, the preparations were then tested against iBeads coated only with intact HLA antigens. All IVIg preparations varied in level of antibody reactivity to intact HLA antigens. We raised monoclonal Abs against HLA-E that mimicked IVIg's HLA-Ia and HLA-Ib reactivity but reacted only to HLA-I HCs. Inhibition experiments with synthetic peptides showed that HLA-E shares epitopes with HLA-Ia alleles. Importantly, depleting anti-HLA-E Abs from IVIg totally eliminated the HLA-Ia reactivity of IVIg. Since anti-HLA-E mAbs react with HLA-Ia, they might be useful in suppressing HLA antibody production, similar to the way anti-RhD Abs suppress production. At the same time, anti-HLA-E mAb, which reacts only to HLA-I HCs, is unlikely to produce transfusion-related acute lung injury, in contrast to antibodies reacting to intact-HLA.

Determination of HLA-A, -B and -DRB1 polymorphism in brain dead organ donors representative of the Colombian general population, 2007-2014

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Yazmin Rocío Arias

2017-06-01

Conclusions: This study provides information on the allelic distribution of HLA class I and II in organ donors from the six regions in which Colombia is structurally divided to provide transplant services.

Impact of donor-specific anti-HLA antibodies on graft failure and survival after reduced intensity conditioning-unrelated cord blood transplantation: a Eurocord, Société Francophone d'Histocompatibilité et d'Immunogénétique (SFHI) and Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC) analysis.

Science.gov (United States)

Ruggeri, Annalisa; Rocha, Vanderson; Masson, Emeline; Labopin, Myriam; Cunha, Renato; Absi, Lena; Boudifa, Ali; Coeffic, Brigitte; Devys, Anne; De Matteis, Muriel; Dubois, Valérie; Hanau, Daniel; Hau, Françoise; Jollet, Isabelle; Masson, Dominique; Pedron, Beatrice; Perrier, Pascale; Picard, Christophe; Ramouneau-Pigot, Annie; Volt, Fernanda; Charron, Dominique; Gluckman, Eliane; Loiseau, Pascale

2013-07-01

Graft failure is a major complication after unrelated cord blood transplantation. Presence of HLA-antibodies before cord blood transplantation may impact graft failure. To analyze the effect of anti-HLA antibodies on unrelated cord blood transplantation outcomes, we analyzed 294 unrelated cord blood transplant recipients after reduced intensity conditioning regimen. The majority of the patients (82%) were transplanted for malignancies, 60% with double-unrelated cord blood transplant, 63% were HLA mismatched. Retrospectively, pre-unrelated cord blood transplant serum was tested for HLA-Ab using Luminex™ platform. Results were interpreted as mean fluorescence intensity (MFI) against donor-specific mismatch. Among 62 recipients (23%) who had anti-HLA antibodies before unrelated cord blood transplant, 14 patients had donor specific anti-HLA antibodies (DSA) (7 were donor-specific anti-HLA antibodies for single unrelated cord blood transplant and 7 for double unrelated cord blood transplant). Donor specific anti-HLA antibodies threshold ranged from 1620-17629 of mean fluorescence intensity (MFI). Cumulative incidence of Day-60 neutrophil engraftment was 76%: 44% for recipients with donor specific anti-HLA antibodies and 81% in those without donor specific anti-HLA antibodies (P=0.006). The cumulative incidence of 1-year transplant related mortality was 46% in patients with donor specific anti-HLA antibodies and 32% in those without antibodies (P=0.06). The presence of donor specific anti-HLA antibodies was associated with a trend for decreased survival rate (42% vs. 29%; P=0.07). Donor specific anti-HLA antibody in recipients of unrelated cord blood transplant is associated with graft failure and decreased survival. Patient's screening for donor specific anti-HLA antibodies before unrelated cord blood transplantation is recommended before choosing an HLA mismatched cord blood unit. Whenever possible it is important to avoid selecting a unit for which the patient has

Total lymphoid irradiation preceding bone marrow transplantation for chronic myeloid leukaemia

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James, N D; Apperley, J F; Kam, K C; Mackinnon, S; Goldman, J M; Goolden, A W.G.; Sikora, K [Royal Postgraduate Medical School, London (UK)

1989-03-01

Between August 1985 and October 1987 35 patients with chronic myeloid leukaemia (CML) were treated by high dose chemotherapy, total body irradiation (TBI) (1000 or 1200 cGy, n=31) and total lymphoid irradiation (TLI) (800 or 600 cGy, n=35) preceding allogeneic bone marrow transplantation (BMT). Both TBI and TLI were given at 200 cGy/fraction. Twenty-three patients had HLA-identical sibling donors, nine patients had HLA-matched but unrelated donors, and three partially HLA-mismatched donors. Twenty-two patients received T-cell depleted marrow. TLI did not add greatly to the toxicity. Four patients had recurrent leukaemia before engraftment was evaluable. The other 31 patients engrafted and no graft failed. Twenty-two patients survive at a median time from transplant of 305 days (range 81-586 days). Fourteen have no evidence of disease; eight have or had only cytogenetic evidence of leukaemia. It is concluded that addition of TLI to pretransplant immunosuppression increases the probability of reliable engraftment in patients receiving T-cell depleted marrow. This is not associated with significantly increased toxicity. (author).

Total lymphoid irradiation preceding bone marrow transplantation for chronic myeloid leukaemia

International Nuclear Information System (INIS)

James, N.D.; Apperley, J.F.; Kam, K.C.; Mackinnon, S.; Goldman, J.M.; Goolden, A.W.G.; Sikora, K.

1989-01-01

Between August 1985 and October 1987 35 patients with chronic myeloid leukaemia (CML) were treated by high dose chemotherapy, total body irradiation (TBI) (1000 or 1200 cGy, n=31) and total lymphoid irradiation (TLI) (800 or 600 cGy, n=35) preceding allogeneic bone marrow transplantation (BMT). Both TBI and TLI were given at 200 cGy/fraction. Twenty-three patients had HLA-identical sibling donors, nine patients had HLA-matched but unrelated donors, and three partially HLA-mismatched donors. Twenty-two patients received T-cell depleted marrow. TLI did not add greatly to the toxicity. Four patients had recurrent leukaemia before engraftment was evaluable. The other 31 patients engrafted and no graft failed. Twenty-two patients survive at a median time from transplant of 305 days (range 81-586 days). Fourteen have no evidence of disease; eight have or had only cytogenetic evidence of leukaemia. It is concluded that addition of TLI to pretransplant immunosuppression increases the probability of reliable engraftment in patients receiving T-cell depleted marrow. This is not associated with significantly increased toxicity. (author)

The role of amino acid electron-donor/acceptor atoms in host-cell binding peptides is associated with their 3D structure and HLA-binding capacity in sterile malarial immunity induction

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Patarroyo, Manuel E., E-mail: mepatarr@mail.com [Fundacion Instituto de Inmunologia de Colombia (FIDIC), Bogota (Colombia); Universidad Nacional de Colombia, Bogota (Colombia); Almonacid, Hannia; Moreno-Vranich, Armando [Fundacion Instituto de Inmunologia de Colombia (FIDIC), Bogota (Colombia)

2012-01-20

Highlights: Black-Right-Pointing-Pointer Fundamental residues located in some HABPs are associated with their 3D structure. Black-Right-Pointing-Pointer Electron-donor atoms present in {beta}-turn, random, distorted {alpha}-helix structures. Black-Right-Pointing-Pointer Electron-donor atoms bound to HLA-DR53. Black-Right-Pointing-Pointer Electron-acceptor atoms present in regular {alpha}-helix structure bound to HLA-DR52. -- Abstract: Plasmodium falciparum malaria continues being one of the parasitic diseases causing the highest worldwide mortality due to the parasite's multiple evasion mechanisms, such as immunological silence. Membrane and organelle proteins are used during invasion for interactions mediated by high binding ability peptides (HABPs); these have amino acids which establish hydrogen bonds between them in some of their critical binding residues. Immunisation assays in the Aotus model using HABPs whose critical residues had been modified have revealed a conformational change thereby enabling a protection-inducing response. This has improved fitting within HLA-DR{beta}1{sup Asterisk-Operator} molecules where amino acid electron-donor atoms present in {beta}-turn, random or distorted {alpha}-helix structures preferentially bound to HLA-DR53 molecules, whilst HABPs having amino acid electron-acceptor atoms present in regular {alpha}-helix structure bound to HLA-DR52. This data has great implications for vaccine development.

Should pediatric patients wait for HLA-DR-matched renal transplants?

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Gritsch, H A; Veale, J L; Leichtman, A B; Guidinger, M K; Magee, J C; McDonald, R A; Harmon, W E; Delmonico, F L; Ettenger, R B; Cecka, J M

2008-10-01

Graft survival rates from deceased donors aged 35 years or less among all primary pediatric kidney transplant recipients in the United States between 1996 and 2004 were retrospectively examined to determine the effect of HLA-DR mismatches on graft survival. Zero HLA-DR-mismatched kidneys had statistically comparable 5-year graft survival (71%), to 1-DR-mismatched kidneys (69%) and 2-DR-mismatched kidneys (71%). When compared to donors less than 35 years of age, the relative rate of allograft failure was 1.32 (p = 0.0326) for donor age greater than or equal to age 35. There was no statistical increase in the odds of developing a panel-reactive antibody (PRA) greater than 30% at the time of second waitlisting, based upon the degree of HLA-A, -B or -DR mismatch of the first transplant, nor was there a 'dose effect' when more HLA antigens were mismatched between the donor and recipient. Therefore, pediatric transplant programs should utilize the recently implemented Organ Procurement and Transplantation Network's (OPTN)allocation policy, which prioritizes pediatric recipients to receive kidneys from deceased donors less than 35 years of age, and should not turn down such kidney offers to wait for a better HLA-DR-matched kidney.

HLA Mismatching Strategies for Solid Organ Transplantation – A Balancing Act

Science.gov (United States)

Zachary, Andrea A.; Leffell, Mary S.

2016-01-01

HLA matching provides numerous benefits in organ transplantation including better graft function, fewer rejection episodes, longer graft survival, and the possibility of reduced immunosuppression. Mismatches are attended by more frequent rejection episodes that require increased immunosuppression that, in turn, can increase the risk of infection and malignancy. HLA mismatches also incur the risk of sensitization, which can reduce the opportunity and increase waiting time for a subsequent transplant. However, other factors such as donor age, donor type, and immunosuppression protocol, can affect the benefit derived from matching. Furthermore, finding a well-matched donor may not be possible for all patients and usually prolongs waiting time. Strategies to optimize transplantation for patients without a well-matched donor should take into account the immunologic barrier represented by different mismatches: what are the least immunogenic mismatches considering the patient’s HLA phenotype; should repeated mismatches be avoided; is the patient sensitized to HLA and, if so, what are the strengths of the patient’s antibodies? This information can then be used to define the HLA type of an immunologically optimal donor and the probability of such a donor occurring. A probability that is considered to be too low may require expanding the donor population through paired donation or modifying what is acceptable, which may require employing treatment to overcome immunologic barriers such as increased immunosuppression or desensitization. Thus, transplantation must strike a balance between the risk associated with waiting for the optimal donor and the risk associated with a less than optimal donor. PMID:28003816

Utility of HLA Antibody Testing in Kidney Transplantation

Science.gov (United States)

Konvalinka, Ana

2015-01-01

HLA antigens are polymorphic proteins expressed on donor kidney allograft endothelium and are critical targets for recipient immune recognition. HLA antibodies are risk factors for acute and chronic rejection and allograft loss. Solid-phase immunoassays for HLA antibody detection represent a major advance in sensitivity and specificity over cell-based methods and are widely used in organ allocation and pretransplant risk assessment. Post-transplant, development of de novo donor–specific HLA antibodies and/or increase in donor-specific antibodies from pretransplant levels are associated with adverse outcomes. Although single antigen bead assays have allowed sensitive detection of recipient HLA antibodies and their specificities, a number of interpretive considerations must be appreciated to understand test results in clinical and research contexts. This review, which is especially relevant for clinicians caring for transplant patients, discusses the technical aspects of single antigen bead assays, emphasizes their quantitative limitations, and explores the utility of HLA antibody testing in identifying and managing important pre- and post-transplant clinical outcomes. PMID:25804279

Indirect recognition of HLA epitopes in solid organ transplantation

NARCIS (Netherlands)

Geneugelijk, C.C.A.

2017-01-01

Alloreactivity due to HLA mismatches between donor and recipient remains the major limiting factor in successful graft outcome after solid organ transplantation. However, the immunogenicity of individual HLA mismatches is highly variable. Therefore, epitope-based HLA matching may be a sophisticated

HLA-C incompatibilities in allogeneic unrelated hematopoietic stem cell transplantation

Directory of Open Access Journals (Sweden)

Jean-Marie eTIERCY

2014-05-01

Full Text Available An increasingly larger fraction of patients with hematological diseases are treated by hematopoietic stem cells transplantation (HSCT from HLA matched unrelated donors. Polymorphism of HLA genes represent a major barrier to HSCT because HLA-A,B,C and DRB1 incompatibilities confer a higher risk of aGVHD and mortality. Although >22 million volunteer HLA-typed donors are available worldwide, still a significant number of patients do not find a highly matched HSC donor. Because of the large haplotypic diversity in HLA-B-C associations, incompatibilities occur most frequently at HLA-C, so that unrelated donors with a single HLA-C mismatch often represent the only possible choice. The ratio of HLA-C-mismatched HSCT over the total number of transplants varies from 15-30%, as determined in 12 multicenter studies. Six multicenter studies involving >1800 patients have reported a 21-43% increase in mortality risk. By using in vitro cellular assays a large heterogeneity in T-cell allorecognition has been observed. Yet the permissiveness of individual HLA-C mismatches remains poorly defined. It could be linked to the position and nature of the mismatched residues on HLA-C molecules, but also to variability in the expression levels of the mismatched alleles. The permissive C*03:03-03:04 mismatch is caracterized by full compatibility at residues 9, 97, 99, 116, 152, 156 and 163 reported to be key positions influencing T-cell allorecognition. With a single difference in these key residues the C*07:01-07:02 mismatch might also be considered by analogy as permissive. High variability of HLA-C expression as determined by quantitative RT-PCR has been observed within individual allotypes and shows some correlation with A-B-C-DRB1 haplotypes. Thus in addition to the position of mismatched amino acid residues, expression level of patient’s mismatched HLA-C allotype might influence T-cell allorecognition, with patient's low expression-C alleles representing possible

Charting improvements in US registry HLA typing ambiguity using a typing resolution score.

Science.gov (United States)

Paunić, Vanja; Gragert, Loren; Schneider, Joel; Müller, Carlheinz; Maiers, Martin

2016-07-01

Unrelated stem cell registries have been collecting HLA typing of volunteer bone marrow donors for over 25years. Donor selection for hematopoietic stem cell transplantation is based primarily on matching the alleles of donors and patients at five polymorphic HLA loci. As HLA typing technologies have continually advanced since the beginnings of stem cell transplantation, registries have accrued typings of varied HLA typing ambiguity. We present a new typing resolution score (TRS), based on the likelihood of self-match, that allows the systematic comparison of HLA typings across different methods, data sets and populations. We apply the TRS to chart improvement in HLA typing within the Be The Match Registry of the United States from the initiation of DNA-based HLA typing to the current state of high-resolution typing using next-generation sequencing technologies. In addition, we present a publicly available online tool for evaluation of any given HLA typing. This TRS objectively evaluates HLA typing methods and can help define standards for acceptable recruitment HLA typing. Copyright © 2016 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

HLA Matching at the Eplet Level Protects Against Chronic Lung Allograft Dysfunction.

Science.gov (United States)

Walton, D C; Hiho, S J; Cantwell, L S; Diviney, M B; Wright, S T; Snell, G I; Paraskeva, M A; Westall, G P

2016-09-01

Donor selection in lung transplantation (LTx) is historically based upon clinical urgency, ABO compatibility, and donor size. HLA matching is not routinely considered; however, the presence or later development of anti-HLA antibodies is associated with poorer outcomes, particularly chronic lung allograft dysfunction (CLAD). Using eplet mismatches, we aimed to determine whether donor/recipient HLA incompatibility was a significant predictor of CLAD. One hundred seventy-five LTx undertaken at the Alfred Hospital between 2008 and 2012 met criteria. Post-LTx monitoring was continued for at least 12 months, or until patient death. HLA typing was performed by sequence-based typing and Luminex sequence-specific oligonucleotide. Using HLAMatchmaker, eplet mismatches between each donor/recipient pairing were analyzed and correlated against incidences of CLAD. HLA-DRB1/3/4/5+DQA/B eplet mismatch was a significant predictor of CLAD (hazard ratio [HR] 3.77, 95% confidence interval [CI]: 1.71-8.29 p HLA-DRB1/3/4/5 + DQA/B eplet mismatch was shown to significantly predict RAS (HR 8.3, 95% CI: 2.46-27.97 p HLA-A/B eplet mismatch was shown not to be a significant predictor when analyzed independently but did provide additional stratification of results. This study illustrates the importance of epitope immunogenicity in defining donor-recipient immune compatibility in LTx. © Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.

Comparative analysis of unrelated cord blood transplantation and HLA-matched sibling hematopoietic stem cell transplantation in children with high-risk or advanced acute leukemia.

Science.gov (United States)

Zheng, Changcheng; Zhu, Xiaoyu; Tang, Baolin; Yao, Wen; Song, Kaidi; Tong, Juan; Geng, Liangquan; Liu, Huilan; Sun, Zimin

2015-03-01

The aim of this report was to present a clinical comparison of unrelated cord blood transplantation (CBT) and human leukocyte antigen (HLA)-matched sibling allogeneic peripheral blood stem cell or bone marrow transplantation (allo-PBSCT/BMT) in children with high-risk or advanced acute leukemia. A total of 115 consecutive pediatric patients received unrelated CBT (n = 90) or sibling allo-PBSCT/BMT (n = 25) between 2000 and 2012. Neutrophil and platelet recovery were significantly delayed after CBT compared to allo-PBSCT/BMT. There was no difference in the incidence of acute graft-versus-host disease (GVHD) or chronic GVHD between the two groups. The cumulative incidence of transplant-related mortality (TRM) was higher in the CBT group than in the allo-PBSCT/BMT group (32.5 vs 12.8 %) (p = 0.03). The cumulative incidence of relapse was 13.1 % after CBT, which was significantly lower than that of after allo-PBSCT/BMT (45.3 %) (p = 0.015). The overall survival (OS) and leukemia-free survival (LFS) in the CBT group were similar to those of the allo-PBSCT/BMT group; however, for acute myeloid leukemia (AML) patients, the 5-year LFS in the CBT group was slightly better than the allo-PBSCT/BMT group (55.7 % for CBT and 32.7 % for allo-PBSCT/BMT) (p = 0.08). Our comparisons suggest that for high-risk or advanced childhood acute leukemia, unrelated CBT has a higher TRM and similar long-term survival, but better antileukemia effect than HLA-matched sibling PBSCT/BMT. New strategies and better supportive care are required to decrease the TRM of CBT.

Long- and short-term outcomes in renal allografts with deceased donors: A large recipient and donor genome-wide association study.

Science.gov (United States)

Hernandez-Fuentes, Maria P; Franklin, Christopher; Rebollo-Mesa, Irene; Mollon, Jennifer; Delaney, Florence; Perucha, Esperanza; Stapleton, Caragh; Borrows, Richard; Byrne, Catherine; Cavalleri, Gianpiero; Clarke, Brendan; Clatworthy, Menna; Feehally, John; Fuggle, Susan; Gagliano, Sarah A; Griffin, Sian; Hammad, Abdul; Higgins, Robert; Jardine, Alan; Keogan, Mary; Leach, Timothy; MacPhee, Iain; Mark, Patrick B; Marsh, James; Maxwell, Peter; McKane, William; McLean, Adam; Newstead, Charles; Augustine, Titus; Phelan, Paul; Powis, Steve; Rowe, Peter; Sheerin, Neil; Solomon, Ellen; Stephens, Henry; Thuraisingham, Raj; Trembath, Richard; Topham, Peter; Vaughan, Robert; Sacks, Steven H; Conlon, Peter; Opelz, Gerhard; Soranzo, Nicole; Weale, Michael E; Lord, Graham M

2018-02-01

Improvements in immunosuppression have modified short-term survival of deceased-donor allografts, but not their rate of long-term failure. Mismatches between donor and recipient HLA play an important role in the acute and chronic allogeneic immune response against the graft. Perfect matching at clinically relevant HLA loci does not obviate the need for immunosuppression, suggesting that additional genetic variation plays a critical role in both short- and long-term graft outcomes. By combining patient data and samples from supranational cohorts across the United Kingdom and European Union, we performed the first large-scale genome-wide association study analyzing both donor and recipient DNA in 2094 complete renal transplant-pairs with replication in 5866 complete pairs. We studied deceased-donor grafts allocated on the basis of preferential HLA matching, which provided some control for HLA genetic effects. No strong donor or recipient genetic effects contributing to long- or short-term allograft survival were found outside the HLA region. We discuss the implications for future research and clinical application. © 2018 The Authors. American Journal of Transplantation published by Wiley Periodicals, Inc. on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.

T-cell depleted haploidentical three loci mismatched bone-marrow and peripheral blood stem cell transplantation in acute leukaemia patients

International Nuclear Information System (INIS)

Aristei, C.; Aversa, F.; Panizza, B.M.; Perrucci, E.; Barone, V.; Marafioti, L.; Raymondi, C.; Terenzi, A.; Martelli, M.F.; Latini, P.

1996-01-01

Objectives: Allogeneic bone-marrow transplantation (BMT) is an established treatment for many haematological malignancies. Unfortunately, most patients lack an HLA geno typically identical sibling and require an alternative donor, such as an HLA-haploidentical mismatched related donor, an HLA phenotypically matched or partially mismatched unrelated donor or an HLA-similar cord blood stem cell donor. However, these types of BMT increase the risk of graft-versus-host disease (GvHD), graft failure, delayed immuno reconstitution and fatal infection that observed after a sibling matched donor. Many centers are exploring the possibility of using donors other than matched sibling. Our approach has been to employ T-cell depleted mismatched haploidentical familial donor BMT to solve the problem of GvHD, a highly immuno- and myelo-suppressive conditioning regimen to reduce the incidence of graft failure and relapse, a graft inoculum plus G-CSF donor mobilized peripheral blood stem cells (PBSC) to overcome the host-versus-graft barrier. Patients and methods: Thirty-six patients (25 male, 11 female; median age 22 years, range 2-51) were treated with an allogeneic T-depleted haploidentical three loci mismatched bone-marrow and G-CSF mobilized PBSC transplantation from a familiar donor (18 siblings, 17 parents and 1 cousin) between March 1993 and June 1995. All had high-risk or advanced stage acute myeloid (12) or acute lymphoid (24) leukaemia; 18 were in haematological complete remission (CR) and 18 in chemo resistant relapse. Patients were conditioned with 8 Gy single dose TBI administered on day -5 at an instantaneous dose-rate of 13.4-31.7 cGy/min/midplane and average of 6.7-12.12 cGy/min/midplane. Shields were used to reduce the lung dose to 7 Gy in the first 23 cases and to 6 Gy in the last 13. 10 mg/Kg thiotepa were administered on day -4, 5 mg/Kg rabbit ATG from day -4 to day -1, 60 or 50 mg/Kg/cyclophosphamide on days -3 and -2. Bone-marrow and PBSC were infused on day

Unrelated Hematopoietic Stem Cell Donor Matching Probability and Search Algorithm

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J.-M. Tiercy

2012-01-01

Full Text Available In transplantation of hematopoietic stem cells (HSCs from unrelated donors a high HLA compatibility level decreases the risk of acute graft-versus-host disease and mortality. The diversity of the HLA system at the allelic and haplotypic level and the heterogeneity of HLA typing data of the registered donors render the search process a complex task. This paper summarizes our experience with a search algorithm that includes at the start of the search a probability estimate (high/intermediate/low to identify a HLA-A, B, C, DRB1, DQB1-compatible donor (a 10/10 match. Based on 2002–2011 searches about 30% of patients have a high, 30% an intermediate, and 40% a low probability search. Search success rate and duration are presented and discussed in light of the experience of other centers. Overall a 9-10/10 matched HSC donor can now be identified for 60–80% of patients of European descent. For high probability searches donors can be selected on the basis of DPB1-matching with an estimated success rate of >40%. For low probability searches there is no consensus on which HLA incompatibilities are more permissive, although HLA-DQB1 mismatches are generally considered as acceptable. Models for the discrimination of more detrimental mismatches based on specific amino acid residues rather than specific HLA alleles are presented.

Immunogenicity of Anti-HLA Antibodies in Pancreas and Islet Transplantation.

Science.gov (United States)

Chaigne, Benjamin; Geneugelijk, Kirsten; Bédat, Benoît; Ahmed, Mohamed Alibashe; Hönger, Gideon; De Seigneux, Sophie; Demuylder-Mischler, Sandrine; Berney, Thierry; Spierings, Eric; Ferrari-Lacraz, Sylvie; Villard, Jean

2016-11-01

The aim of the current study was to characterize the anti-HLA antibodies before and after pancreatic islet or pancreas transplantation. We assessed the risk of anti-donor-specific antibody (DSA) sensitization in a single-center, retrospective clinical study at Geneva University Hospital. Data regarding clinical characteristics, graft outcome, HLA mismatch, donor HLA immunogenicity, and anti-HLA antibody characteristics were collected. Between January 2008 and July 2014, 18 patients received islet transplants, and 26 patients received a pancreas transplant. Eleven out of 18 patients (61.1%) in the islet group and 12 out of 26 patients (46.2%) in the pancreas group had anti-HLA antibodies. Six patients (33.3%) developed DSAs against HLA of the islets, and 10 patients (38.4%) developed DSAs against HLA of the pancreas. Most of the DSAs were at a low level. Several parameters such as gender, number of times cells were transplanted, HLA mismatch, eplet mismatch and PIRCHE-II numbers, rejection, and infection were analyzed. Only the number of PIRCHE-II was associated with the development of anti-HLA class II de novo DSAs. Overall, the development of de novo DSAs did not influence graft survival as estimated by insulin independence. Our results indicated that pretransplant DSAs at low levels do not restrict islet or pancreas transplantation [especially islet transplantation (27.8% vs. 15.4.%)]. De novo DSAs do occur at a similar rate in both pancreas and islet transplant recipients (mainly of class II), and the immunogenicity of donor HLA is a parameter that should be taken into consideration. When combined with an immunosuppressive regimen and close follow-up, development of low levels of DSAs was not found to result in reduced graft survival or graft function in the current study.

Rejection of a kidney transplant does not always lead to priming of cytotoxic T cells against mismatched donor HLA class I antigens

NARCIS (Netherlands)

van Kampen, C. A.; Versteeg-van der Voort Maarschalk, M. F.; Roelen, D. L.; ten Berge, I. J.; Claas, F. H.

2001-01-01

BACKGROUND: Previous studies showed that graft rejection is often associated with the presence of primed cytotoxic T cells (CTLs) with a high avidity for donor cells. Similar high avidity CTLs have been found in individuals who have formed IgG anti-HLA antibodies. The presence of such CTLs to a

HLA typing: Conventional techniques v. next-generation sequencing ...

African Journals Online (AJOL)

Background. The large number of population-specific polymorphisms present in the HLA complex in the South African (SA) population reduces the probability of finding an adequate HLA-matched donor for individuals in need of an unrelated haematopoietic stem cell transplantation (HSCT). Next-generation sequencing ...

The Core of Sibling Stem Cell Donation - A Grounded Theory Study.

Science.gov (United States)

Kisch, Annika M; Forsberg, Anna

2017-01-01

There is a lack of theoretical framework supporting stem cell transplant nurses in their assessment, judgment and caring interventions of sibling stem cell donors. The purpose of this study was to explore sibling stem cell donors' main concerns and how they deal with them before and after donation. Ten healthy sibling donors, 5 men and 5 women, with a median age of 54 years were included in this study when they were due to donate stem cells to a brother or sister. Data were collected prospectively on three occasions (before the donation and three and twelve months after it) through in-depth interviews, which were recorded and transcribed verbatim for analysis by the Grounded Theory method according to Charmaz. This study describes the efforts of the ten donors to fulfil their duty as a sibling by doing what they considered necessary in order to help. Their efforts were summarised in a process wherein the grounded theory generated three main categories; Prepare, Promote and Preserve. A clear path of transition leading to fulfilment is evident, starting before the donation and continuing for one year afterwards. Being a sibling stem cell donor means doing what you have to do to fulfil your duty and if possible, saving the life of a seriously ill brother or sister. The relationship between the siblings is strengthened by the donation process. Sibling stem cell donation appears to be about fulfilment and the theoretical framework may support clinicians in their evaluation and support of donors.

Tandem autologous-allo-SCT is feasible in patients with high-risk relapsed non-Hodgkin's lymphoma.

Science.gov (United States)

Crocchiolo, R; Castagna, L; Fürst, S; El-Cheikh, J; Faucher, C; Oudin, C; Granata, A; Bouabdallah, R; Coso, D; Chabannon, C; Balzarotti, M; Santoro, A; Blaise, D

2013-02-01

Allo-SCT is used to exploit GVL effect in high-risk relapsed non-Hodgkin's lymphoma (NHL). Here, we retrospectively analyzed 34 high-risk NHL patients who underwent auto-SCT followed closely by reduced-intensity allo-SCT ('tandem auto-allo') from January 2002 to November 2010. The search for an allogeneic donor was started at the beginning of salvage regimen. Median patients' age was 47 (27-68) years; histotypes were: diffuse large B-cell n=5, follicular n=14, transformed follicular n=4, mantle-cell n=5, plasmocytoid lymphoma n=1, anaplastic large T-cell n=2, peripheral T-cell n=3. Donors were HLA-identical siblings (n=29) or 10/10-matched unrelated individuals (n=5). Median interval between auto-SCT and allo-SCT was 77 days (36-197). At a median follow-up of 46 (8-108) months since allo-SCT, 5-year OS is 77% (61-93) and PFS is 68% (51-85). Disease relapse or progression occurred in six patients, 100-day TRM was 0%, 2-year TRM incidence was 6%. In conclusion, tandem transplantation is feasible in high-risk NHL patients having a HLA-identical donor. This approach could represent a suitable therapeutic option for those patients with high-risk NHL potentially benefitting from further therapy after auto-SCT. Donor searches should be started promptly whenever such an approach is chosen.

HLA-A2 reactive antibodies in a patient who types as HLA-A2: The importance of high resolution typing and epitope-based antibody analysis.

Science.gov (United States)

Hahn, A B; Bravo-Egana, V; Jackstadt, J L; Conti, D J; Duquesnoy, R J

2015-06-01

This report describes a case of a highly sensitized patient who had serum antibodies reacting with HLA-A2 but whose phenotype included HLA-A2. The determination of HLA mismatch acceptability at the antigen level was problematic, but high-resolution HLA typing information and epitope-based antibody specificity analysis based on the nonself-self paradigm of HLA epitope immunogenicity have provided a solution. This case supports the concept that HLA typing at the allele level offers a better approach to identifying suitable donors for sensitized patients. Copyright © 2015 Elsevier B.V. All rights reserved.

High-sensitivity HLA typing by Saturated Tiling Capture Sequencing (STC-Seq).

Science.gov (United States)

Jiao, Yang; Li, Ran; Wu, Chao; Ding, Yibin; Liu, Yanning; Jia, Danmei; Wang, Lifeng; Xu, Xiang; Zhu, Jing; Zheng, Min; Jia, Junling

2018-01-15

Highly polymorphic human leukocyte antigen (HLA) genes are responsible for fine-tuning the adaptive immune system. High-resolution HLA typing is important for the treatment of autoimmune and infectious diseases. Additionally, it is routinely performed for identifying matched donors in transplantation medicine. Although many HLA typing approaches have been developed, the complexity, low-efficiency and high-cost of current HLA-typing assays limit their application in population-based high-throughput HLA typing for donors, which is required for creating large-scale databases for transplantation and precision medicine. Here, we present a cost-efficient Saturated Tiling Capture Sequencing (STC-Seq) approach to capturing 14 HLA class I and II genes. The highly efficient capture (an approximately 23,000-fold enrichment) of these genes allows for simplified allele calling. Tests on five genes (HLA-A/B/C/DRB1/DQB1) from 31 human samples and 351 datasets using STC-Seq showed results that were 98% consistent with the known two sets of digitals (field1 and field2) genotypes. Additionally, STC can capture genomic DNA fragments longer than 3 kb from HLA loci, making the library compatible with the third-generation sequencing. STC-Seq is a highly accurate and cost-efficient method for HLA typing which can be used to facilitate the establishment of population-based HLA databases for the precision and transplantation medicine.

HLA-B8 association with late-stage melanoma – an immunological lesson?

Directory of Open Access Journals (Sweden)

Andersen Mads

2006-03-01

Full Text Available Abstract Background Differences in HLA allele frequencies between the diseased and healthy populations may signify efficient immune responses, a notion that has been successfully tested for infectious diseases or for association with genetic elements involved in a distinct type of immunity. This retrospective study is intended to detect differences in MHC class I carrier frequencies of advanced melanoma patients compared to healthy bone marrow donors. Methods The HLA-A and -B carrier frequencies of 748 stage IV melanoma patients retrieved from serotyping at 6 different centers in Germany were compared using a chi-square test to 13,386 fully HLA typed bone marrow donors registered in the German national bone marrow donor registry. Results The comparison of HLA carrier frequencies in advanced cancer patients with healthy bone marrow donors revealed a significant decrease in HLA-B8 carrier frequencies, which was also apparent in patients with advanced disease compared to patients with loco-regional disease. Conclusion The data suggest that protective immune responses restricted to distinct MHC class I molecules may be operational in a subset of melanoma patients, which is the prerequisite for a large scale screen for the corresponding epitopes. Alternatively, the known association of the ancestral haplotype HLA-A1, -B8 and -DR3 with genetic elements such as distinct TNF-α alleles might have a protective effect on disease progression. In any case, identification of the cause of protection within this patient subset might lead to a significant improvement in the efficacy of current immunotherapeutic approaches.

The UNOS renal transplant registry.

Science.gov (United States)

Cecka, J M

2001-01-01

The shortage of cadaver kidneys relative to increasing demand for transplantation has lead to a remarkable rise in transplantation from living donors. Based upon data reported to UNOS, the number of living donor kidneys transplanted in 2000 (5,106) nearly equaled the number of cadaver kidneys from preferred donors aged 6-50. HLA-mismatched siblings, offspring, spouses and other genetically unrelated donors accounted for nearly 80% of increased living donor transplantation during 1994-2000. Despite the increased use of poorly HLA-matched living donor kidneys, the actuarial 10-year graft survival rates for transplants between 1988-2000 were clustered between 53-57% for HLA-mismatched living donor grafts, except for offspring-to-parent transplants (49%) when the recipients were generally older. The 10-year survival rate for 96,053 cadaver grafts was 38% during the same period. The 5-year graft survival rates for more recent (1996-2000) cadaver donor transplants were 66%, 62% and 56% for recipients of first, second and multiple grafts, respectively (p < 0.001). The comparable results among recipients of living donor kidneys were 67%, 66% and 59% (p = ns). The 5-year graft survival rates for HLA-matched first grafts were 7% higher than those for HLA-mismatched transplants when the kidney was from a living or cadaver donor. HLA-identical sibling transplants provided the best long-term graft survival (85% at 5 years and a 32 year half-life). Even with improved crossmatch tests and stronger immunosuppression, sensitization was associated with 8% lower graft survival at 5 years and with a higher rate of late graft loss among first cadaver kidney recipients. Sensitization also was associated with an increase in delayed graft function from 22% of unsensitized first transplant recipients to as much as 36% among multiply retransplanted patients. Recipient race was a key factor in long-term graft survival of both living and cadaver donor kidneys. The rate of late graft loss was

Alternative donor transplantation--"mixing and matching": the role of combined cord blood and haplo-identical donor transplantation (haplo-cord SCT) as a treatment strategy for patients lacking standard donors?

Science.gov (United States)

Liu, Hongtao; van Besien, Koen

2015-03-01

In the past decade, haplo-cord stem cell transplantation (SCT) using myeloablative or reduced intensive conditioning regimens has been shown to result in reliable and fast engraftment of neutrophils and platelets comparable to HLA-matched donors and much faster than after cord stem cell transplant. Haplo-cord SCT also has a low incidence of early non-relapse mortality, low incidences of acute and chronic graft-vs-host disease (GVHD), and excellent graft-vs-leukemia (GVL) effects. Favorable long-term outcomes for high-risk patients with hematologic malignancies have been reported, including older patients. Haplo-cord SCT will likely overcome the limitations of cell dose during cord stem cell selection and might significantly expand the use of cord stem cell transplant in the adult population. The comparable survival outcomes of matched related donor (MRD), matched unrelated donor (MUD), and haplo-cord stem cell transplant strongly argue that haplo-cord SCT should be considered as effective alternative stem cell transplant for high-risk patients lacking standard donors. Further improvement in supportive care and incorporation of a better understanding of the human fetal immune development into the haplo-cord SCT are required to further improve this strategy.

In vitro generation of Epstein-Barr virus-specific cytotoxic T cells in patients receiving haplo-identical allogeneic stem cell transplantation.

Science.gov (United States)

Musk, P; Szmania, S; Galloway, A T; Johnson, K; Scott, A; Guttman, S; Bridges, K; Bruorton, M; Gatlin, J; Garcia, J V; Lamb, L; Chiang, K Y; Spencer, T; Henslee-Downey, J; van Rhee, F

2001-01-01

Use of a partially mismatched related donor (PMRD) is an option for patients who require allogeneic transplantation but do not have a matched sibling or unrelated donor. Epstein-Barr virus (EBV)-induced lymphoma is a major cause of mortality after PMRD transplantation. In this study, we present a clinical grade culture system for donor-derived EBV-specific cytotoxic T cells (CTLs) that do not recognize haplo-identical recipient cells. The EBV-specific CTLs were tested for cytolytic specificity and other functional properties, including ability to transgress into tissues, propensity for apoptosis, degree of clonality, stability of dominant T-cell clones, and Tc and Th phenotypes. The EBV-specific CTLs were routinely expanded to greater than 80 x 10(6) over a period of 5 weeks, which is sufficient for clinical application. A CD8+ phenotype predominated, and the CTLs were highly specific for donor lymphoblastoid cell lines (LCLs) without killing of recipient targets or K562. Vbeta spectratyping showed an oligoclonal population that was stable on prolonged culture. The EBV-specific CTLs were activated (D-related human leukocyte antigen [HLA-DR+], L-selectin+/-) and of memory phenotype (CD45RO+). Expression of the integrin VLA-4 suggested that these CTLs could adhere to endothelium and migrate into tissues. The Bcl-2 message was upregulated, which may protect the CTLs from the apoptosis. The first demonstration of overexpression of bcl-2 in human memory CTLs. In addition, we show that lymphoblastoid cell lines used to generate CTLs are readily genetically modified with recombinant lentivirus, indicating that genetically engineered antigen presentation is feasible.

Peptide immunisation of HLA-DR-transgenic mice permits the identification of a novel HLA-DRbeta1*0101- and HLA-DRbeta1*0401-restricted epitope from p53.

Science.gov (United States)

Rojas, José Manuel; McArdle, Stephanie E B; Horton, Roger B V; Bell, Matthew; Mian, Shahid; Li, Geng; Ali, Selman A; Rees, Robert C

2005-03-01

Because of the central role of CD4(+) T cells in antitumour immunity, the identification of the MHC class II-restricted peptides to which CD4(+) T cells respond has become a priority of tumour immunologists. Here, we describe a strategy permitting us to rapidly determine the immunogenicity of candidate HLA-DR-restricted peptides using peptide immunisation of HLA-DR-transgenic mice, followed by assessment of the response in vitro. This strategy was successfully applied to the reported haemaglutinin influenza peptide HA(307-319), and then extended to three candidate HLA-DR-restricted p53 peptides predicted by the evidence-based algorithm SYFPEITHI to bind to HLA-DRbeta1*0101 (HLA-DR1) and HLA-DRbeta1*0401 (HLA-DR4) molecules. One of these peptides, p53(108-122), consistently induced responses in HLA-DR1- and in HLA-DR4-transgenic mice. Moreover, this peptide was naturally processed by dendritic cells (DCs), and induced specific proliferation in the splenocytes of mice immunised with p53 cDNA, demonstrating that immune responses could be naturally mounted to the peptide. Furthermore, p53(108-122) peptide was also immunogenic in HLA-DR1 and HLA-DR4 healthy donors. Thus, the use of this transgenic model permitted the identification of a novel HLA-DR-restricted epitope from p53 and constitutes an attractive approach for the rapid identification of novel immunogenic MHC class II-restricted peptides from tumour antigens, which can ultimately be incorporated in immunotherapeutic protocols.

HLA-DQA1 and HLA-DQB1 in Celiac disease predisposition: practical implications of the HLA molecular typing

Directory of Open Access Journals (Sweden)

Megiorni Francesca

2012-10-01

Full Text Available Abstract Celiac disease (CD is a multifactorial disorder with an estimated prevalence in Europe and USA of 1:100 and a female:male ratio of approximately 2:1. The disorder has a multifactorial etiology in which the triggering environmental factor, the gluten, and the main genetic factors, Human Leukocyte Antigen (HLA-DQA1 and HLA-DQB1 loci, are well known. About 90-95% of CD patients carry DQ2.5 heterodimers, encoded by DQA1*05 and DQB1*02 alleles both in cis or in trans configuration, and DQ8 molecules, encoded by DQB1*03:02 generally in combination with DQA1*03 variant. Less frequently, CD occurs in individuals positive for the DQ2.x heterodimers (DQA1≠*05 and DQB1*02 and very rarely in patients negative for these DQ predisposing markers. HLA molecular typing for Celiac disease is, therefore, a genetic test with a negative predictive value. Nevertheless, it is an important tool able to discriminate individuals genetically susceptible to CD, especially in at-risk groups such as first-degree relatives (parents, siblings and offspring of patients and in presence of autoimmune conditions (type 1 diabetes, thyroiditis, multiple sclerosis or specific genetic disorders (Down, Turner or Williams syndromes.

Identity Processes and Parent-Child and Sibling Relationships in Adolescence : A Five-Wave Multi-Informant Longitudinal Study

NARCIS (Netherlands)

Crocetti, Elisabetta; Branje, Susan; Rubini, Monica; Koot, Hans M.; Meeus, Wim

The purpose of this study was to examine reciprocal associations between identity processes (commitment, in-depth exploration, and reconsideration of commitment) and dimensions (support, negative interaction, and power) of maternal, paternal, and sibling relationships. A total of 497 Dutch families

Identity Processes and Parent–Child and Sibling Relationships in Adolescence : A Five-Wave Multi-Informant Longitudinal Study

NARCIS (Netherlands)

Crocetti, Elisabetta; Branje, Susan J. T.; Rubini, Monica; Koot, Hans M.; Meeus, Wim H J

2017-01-01

The purpose of this study was to examine reciprocal associations between identity processes (commitment, in-depth exploration, and reconsideration of commitment) and dimensions (support, negative interaction, and power) of maternal, paternal, and sibling relationships. A total of 497 Dutch families

Identity processes and parent-child and sibling relationships in adolescence : A five-wave multi-informant longitudinal study

NARCIS (Netherlands)

Crocetti, E; Branje, S; Rubini, M; Koot, H; Meeus, W.H.J.

2017-01-01

The purpose of this study was to examine reciprocal associations between identity processes (commitment, in-depth exploration, and reconsideration of commitment) and dimensions (support, negative interaction, and power) of maternal, paternal, and sibling relationships. A total of 497 Dutch families

The Core of Sibling Stem Cell Donation – A Grounded Theory Study

Science.gov (United States)

Kisch, Annika M; Forsberg, Anna

2017-01-01

Background: There is a lack of theoretical framework supporting stem cell transplant nurses in their assessment, judgment and caring interventions of sibling stem cell donors. Objective: The purpose of this study was to explore sibling stem cell donors’ main concerns and how they deal with them before and after donation. Method: Ten healthy sibling donors, 5 men and 5 women, with a median age of 54 years were included in this study when they were due to donate stem cells to a brother or sister. Data were collected prospectively on three occasions (before the donation and three and twelve months after it) through in-depth interviews, which were recorded and transcribed verbatim for analysis by the Grounded Theory method according to Charmaz. Results: This study describes the efforts of the ten donors to fulfil their duty as a sibling by doing what they considered necessary in order to help. Their efforts were summarised in a process wherein the grounded theory generated three main categories; Prepare, Promote and Preserve. A clear path of transition leading to fulfilment is evident, starting before the donation and continuing for one year afterwards. Conclusions: Being a sibling stem cell donor means doing what you have to do to fulfil your duty and if possible, saving the life of a seriously ill brother or sister. The relationship between the siblings is strengthened by the donation process. Sibling stem cell donation appears to be about fulfilment and the theoretical framework may support clinicians in their evaluation and support of donors. PMID:28839511

The heterogeneous HLA genetic makeup of the Swiss population.

Science.gov (United States)

Buhler, Stéphane; Nunes, José Manuel; Nicoloso, Grazia; Tiercy, Jean-Marie; Sanchez-Mazas, Alicia

2012-01-01

This study aims at investigating the HLA molecular variation across Switzerland in order to determine possible regional differences, which would be highly relevant to several purposes: optimizing donor recruitment strategies in hematopoietic stem cell transplantation (HSCT), providing reliable reference data in HLA and disease association studies, and understanding the population genetic background(s) of this culturally heterogeneous country. HLA molecular data of more than 20,000 HSCT donors from 9-13 recruitment centers of the whole country were analyzed. Allele and haplotype frequencies were estimated by using new computer tools adapted to the heterogeneity and ambiguity of the data. Non-parametric and resampling statistical tests were performed to assess Hardy-Weinberg equilibrium, selective neutrality and linkage disequilibrium among different loci, both in each recruitment center and in the whole national registry. Genetic variation was explored through genetic distance and hierarchical analysis of variance taking into account both geographic and linguistic subdivisions in Switzerland. The results indicate a heterogeneous genetic makeup of the Swiss population: first, allele frequencies estimated on the whole national registry strongly deviate from Hardy-Weinberg equilibrium, by contrast with the results obtained for individual centers; second, a pronounced differentiation is observed for Ticino, Graubünden, and, to a lesser extent, Wallis, suggesting that the Alps represent(ed) a barrier to gene flow; finally, although cultural (linguistic) boundaries do not represent a main genetic differentiation factor in Switzerland, the genetic relatedness between population from south-eastern Switzerland and Italy agrees with historical and linguistic data. Overall, this study justifies the maintenance of a decentralized donor recruitment structure in Switzerland allowing increasing the genetic diversity of the national--and hence global--donor registry. It also

Impact of HLA Diversity on Donor Selection in Organ and Stem Cell Transplantation

OpenAIRE

Tiercy Jean-Marie; Claas Frans

2013-01-01

The human major histocompatibility complex is a multigene system encoding polymorphic human leucocyte antigens (HLA) that present peptides derived from pathogens to the immune system. The high diversity of HLA alleles and haplotypes in the worldwide populations represents a major barrier to organ and allogeneic hematopoietic stem cell transplantation because HLA incompatibilities are efficiently recognized by T and B lymphocytes. In organ transplantation pre transplant anti HLA antibodies nee...

A genomic study on distribution of human leukocyte antigen (HLA-A and HLA-B alleles in Lak population of Iran

Directory of Open Access Journals (Sweden)

Farhad Shahsavar

2017-03-01

Full Text Available Anthropological studies based on the highly polymorphic gene, human leukocyte antigen (HLA, provide useful information for bone marrow donor registry, forensic medicine, disease association studies, as well as infertility treatment, designing peptide vaccines against tumors, and infectious or autoimmune diseases. The aim of this study was to determine HLA-A and HLA-B allele frequencies in 100 unrelated Lak/lᴂk/individuals from Lorestan province of Iran. Finally, we compared the results with that previously described in Iranian population. Commercial HLA-Type kits from BAG (Lich, Germany company were used for determination of the HLA-A and HLA-B allele frequencies in genomic DNA, based on polymerase chain reaction with sequence specific primer (PCR-SSP assay. The differences between the populations in distribution of HLA-A and HLA-B alleles were estimated by chi-squared test with Yate's correction. The most frequent HLA-A alleles were *24 (20%, *02 (18%, *03 (12% and *11 (10%, and the most frequent HLA-B alleles were *35 (24%, *51 (16%, *18 (6% and *38 (6% in Lak population. HLA-A*66 (1%, *74(1% and HLA-B*48 (1%, *55(1% were the least observed frequencies in Lak population. Our results based on HLA-A and HLA-B allele frequencies showed that Lak population possesses the previously reported general features of Iranians but still with unique.

Deciphering allogeneic antibody response against native and denatured HLA epitopes in organ transplantation.

Science.gov (United States)

Visentin, Jonathan; Guidicelli, Gwendaline; Moreau, Jean-François; Lee, Jar-How; Taupin, Jean-Luc

2015-07-01

Anti-HLA donor-specific antibodies are deleterious for organ transplant survival. Class I HLA donor-specific antibodies are identified by using the Luminex single antigen beads (LSAB) assay, which also detects anti-denatured HLA antibodies (anti-dHLAs). Anti-dHLAs are thought to be unable to recognize native HLA (nHLA) on the cell surface and therefore to be clinically irrelevant. Acid denaturation of nHLA on LSAB allows anti-dHLAs to be discriminated from anti-nHLAs. We previously defined a threshold for the ratio between mean fluorescence intensity against acid-treated (D for denaturation) and nontreated (N) LSAB, D ≥ 1.2 N identifying the anti-dHLAs. However, some anti-dHLAs remained able to bind nHLA on lymphocytes in flow cytometry crossmatches, and some anti-nHLAs conserved significant reactivity toward acid-treated LSAB. After depleting serum anti-nHLA reactivity with HLA-typed cells, we analyzed the residual LSAB reactivity toward nontreated and acid-treated LSABs, and then evaluated the ability of antibodies to recognize nHLA alleles individually. We observed that sera can contain mixtures of anti-nHLAs and anti-dHLAs, or anti-nHLAs recognizing acid-resistant epitopes, all possibly targeting the same allele(s). Therefore, the anti-HLA antibody response can be highly complex and subtle, as is the accurate identification of pathogenic anti-HLA antibodies in human serum. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Complex preimplantation genetic diagnosis for beta-thalassaemia, sideroblastic anaemia, and human leukocyte antigen (HLA)-typing.

Science.gov (United States)

Kakourou, Georgia; Vrettou, Christina; Kattamis, Antonis; Destouni, Aspasia; Poulou, Myrto; Moutafi, Maria; Kokkali, Georgia; Pantos, Konstantinos; Davies, Stephen; Kitsiou-Tzeli, Sophia; Kanavakis, Emmanuel; Traeger-Synodinos, Joanne

2016-01-01

Preimplantation genetic diagnosis (PGD) to select histocompatible siblings to facilitate curative haematopoeitic stem-cell transplantation (HSCT) is now an acceptable option in the absence of an available human leukocyte antigen (HLA) compatible donor. We describe a case where the couple who requested HLA-PGD, were both carriers of two serious haematological diseases, beta-thalassaemia and sideroblastic anaemia. Their daughter, affected with sideroblastic anaemia, was programmed to have HSCT. A multiplex-fluorescent-touchdown-PCR protocol was optimized for the simultaneous amplification of: the two HBB-gene mutated regions (c.118C> T, c.25-26delAA), four short tandem repeats (STRs) in chr11p15.5 linked to the HBB gene, the SLC25A38 gene mutation (c.726C > T), two STRs in chr3p22.1 linked to the SLC25A38 gene, plus eleven informative STRs for HLA-haplotyping (chr6p22.1-21.3). This was followed by real-time nested PCR and high-resolution melting analysis (HRMA) for the detection of HBB and SLC25A38 gene mutations, as well as the analysis of all STRs on an automatic genetic analyzer (sequencer). The couple completed four clinical in vitro fertilization (IVF)/PGD cycles. At least one matched unaffected embryo was identified and transferred in each cycle. A twin pregnancy was established in the fourth PGD cycle and genotyping results at all loci were confirmed by prenatal diagnosis. Two healthy baby girls were delivered at week 38 of pregnancy. The need to exclude two familial disorders for HLA-PGD is rarely encountered. The methodological approach described here is fast, accurate, clinically-validated, and of relatively low cost.

HLA-C and guttate psoriasis.

Science.gov (United States)

Mallon, E; Bunce, M; Savoie, H; Rowe, A; Newson, R; Gotch, F; Bunker, C B

2000-12-01

Psoriasis is a heterogeneous disease in its clinical expression. Both genetic and environmental factors are thought to contribute to the pathogenesis of the inflammatory and hyperproliferative components of the typical skin lesions. Predisposing genetic influences include associations with human leucocyte antigens (HLA) of which that with HLA-Cw6 is the strongest. Guttate psoriasis is a specific clinical manifestation of psoriasis frequently associated with group A beta-haemolytic streptococcal throat infection. We set out to determine whether further clinical subdivision of psoriasis is associated with tighter correlation with HLA-C alleles. We determined the HLA-C locus genotype of 29 caucasian patients with guttate psoriasis presenting consecutively with guttate psoriasis associated with a history of a sore throat and/or an antistreptolysin O titre > 200 IU mL-1. Polymerase chain reaction typing using sequence-specific primers was used to detect all known HLA-C alleles. These data were compared with a control population of 604 random caucasian cadaver donors. All patients (100%) with guttate psoriasis carried the Cw*0602 allele compared with 20% of the control population (odds ratio = infinity; 95% confidence limits 25.00-infinity; Pcorrected < 0.0000002). This result is consistent with HLA-Cw*0602 playing a part directly in the pathogenesis of guttate psoriasis.

Nyretransplantation med levende donor

DEFF Research Database (Denmark)

Kamper, A L; Løkkegaard, H; Rasmussen, F

2000-01-01

In recent years transplantation from living donors has accounted for 25-30% of all kidney transplants in Denmark corresponding to 40-45 per year. Most of these living donors are parents or siblings, although internationally an increasing number are unrelated donors. Donor nephrectomy is associate...... in cadaver transplantation. The ethical and psychological aspects related to transplantation from a living donor are complex and need to be carefully evaluated when this treatment is offered to the patients....

The Perfect Storm: HLA Antibodies, Complement, FcγRs and Endothelium in Transplant Rejection

OpenAIRE

Thomas, Kimberly A.; Valenzuela, Nicole M.; Reed, Elaine F.

2015-01-01

The pathophysiology of antibody-mediated rejection (AMR) in solid organ transplants is multi-faceted and predominantly caused by antibodies directed against polymorphic donor human leukocyte antigens (HLA). Despite the clearly detrimental impact of HLA antibodies (HLA-Ab) on graft function and survival, the prevention, diagnosis and treatment of AMR remain a challenge. Histological manifestations of AMR reflect signatures of HLA-Ab-triggered injury, specifically endothelial changes, recipient...

Soluble HLA-G and HLA-E Levels in Bone Marrow Plasma Samples Are Related to Disease Stage in Neuroblastoma Patients

Directory of Open Access Journals (Sweden)

Fabio Morandi

2016-01-01

Full Text Available The role of nonclassical HLA-class Ib molecules HLA-G and HLA-E in the progression of Neuroblastoma (NB, the most common pediatric extracranial solid tumor, has been characterized in the last years. Since BM infiltration by NB cells is an adverse prognostic factor, we have here analyzed for the first time the concentration of soluble (sHLA-G and HLA-E in bone marrow (BM plasma samples from NB patients at diagnosis and healthy donors. sHLA-G and sHLA-E are present in BM plasma samples, and their levels were similar between NB patients and controls, thus suggesting that these molecules are physiologically released by resident or stromal BM cell populations. This hypothesis was supported by the finding that sHLA-G and sHLA-E levels did not correlate with BM infiltration and other adverse prognostic factors (MYCN amplification and age at diagnosis. In contrast, BM plasma levels of both molecules were higher in patients with metastatic disease than in patients with localized NB, thus suggesting that concentration of these molecules might be correlated with disease progression. The prognostic role of sHLA-G and sHLA-E concentration in the BM plasma for NB patients will be evaluated in future studies, by analyzing the clinical outcome of the same NB patients at follow-up.

Human leukocyte antigen (HLA)-G during pregnancy part II

DEFF Research Database (Denmark)

Dahl, Mette; Klitkou, Louise; Christiansen, Ole B

2015-01-01

plasma samples from gestational week 20 and at term, as well as in fetal umbilical cord blood samples. This is the first large study simultaneously performing HLA-G genotyping of mother and offspring and measuring sHLA-G in both maternal and umbilical cord blood. The results showed that increasing...... miscarriage. Levels of soluble HLA-G (sHLA-G) in blood plasma from non-pregnant donors seem to be associated with these polymorphisms. In the current study, we have genotyped 246 mothers and their offspring for HLA-G polymorphisms in the 3'-untranslated region (3'UTR) and measured sHLA-G in maternal blood...... numbers of 14bp ins (rs66554220) alleles in the mother-child genotype combinations were associated with higher maternal sHLA-G levels at term when restricting the analysis to 14bp ins/del heterozygous mothers (p=0.015). Furthermore, increasing numbers of 14InsG haplotypes (14bp ins/del and +3142C/G (rs...

Outcome of children with acute leukemia given HLA-haploidentical HSCT after αβ T-cell and B-cell depletion.

Science.gov (United States)

Locatelli, Franco; Merli, Pietro; Pagliara, Daria; Li Pira, Giuseppina; Falco, Michela; Pende, Daniela; Rondelli, Roberto; Lucarelli, Barbarella; Brescia, Letizia Pomponia; Masetti, Riccardo; Milano, Giuseppe Maria; Bertaina, Valentina; Algeri, Mattia; Pinto, Rita Maria; Strocchio, Luisa; Meazza, Raffaella; Grapulin, Lavinia; Handgretinger, Rupert; Moretta, Alessandro; Bertaina, Alice; Moretta, Lorenzo

2017-08-03

Allogeneic hematopoietic stem cell transplantation (HSCT) from an HLA-haploidentical relative (haplo-HSCT) is a suitable option for children with acute leukemia (AL) either relapsed or at high-risk of treatment failure. We developed a novel method of graft manipulation based on negative depletion of αβ T and B cells and conducted a prospective trial evaluating the outcome of children with AL transplanted with this approach. Eighty AL children, transplanted between September 2011 and September 2014, were enrolled in the trial. All children were given a fully myeloablative preparative regimen. Anti-T-lymphocyte globulin from day -5 to -3 was used for preventing graft rejection and graft-versus-host disease (GVHD); no patient received any posttransplantation GVHD prophylaxis. Two children experienced primary graft failure. The cumulative incidence of skin-only, grade 1-2 acute GVHD was 30%; no patient developed extensive chronic GVHD. Four patients died, the cumulative incidence of nonrelapse mortality being 5%, whereas 19 relapsed, resulting in a 24% cumulative incidence of relapse. With a median follow-up of 46 months for surviving patients, the 5-year probability of chronic GVHD-free, relapse-free survival (GRFS) is 71%. Total body irradiation-containing preparative regimen was the only variable favorably influencing relapse incidence and GRFS. The outcomes of these 80 patients are comparable to those of 41 and 51 children given transplantation from an HLA-identical sibling or a 10/10 allelic-matched unrelated donor in the same period. These data indicate that haplo-HSCT after αβ T- and B-cell depletion represents a competitive alternative for children with AL in need of urgent allograft. This trial was registered at www.clinicaltrials.gov as #NCT01810120. © 2017 by The American Society of Hematology.

Granulocyte Colony-stimulating Factor-primed Bone Marrow: An Excellent Stem-cell Source for Transplantation in Acute Myelocytic Leukemia and Chronic Myelocytic Leukemia

Directory of Open Access Journals (Sweden)

Yuhang Li

2015-01-01

Full Text Available Background: Steady-state bone marrow (SS-BM and granulocyte colony-stimulating growth factor-primed BM/peripheral blood stem-cell (G-BM/G-PBSC are the main stem-cell sources used in allogeneic hematopoietic stem-cell transplantation. Here, we evaluated the treatment effects of SS-BM and G-BM/G-PBSC in human leucocyte antigen (HLA-identical sibling transplantation. Methods: A total of 226 patients (acute myelogenous leukemia-complete remission 1, chronic myelogenous leukemia-chronic phase 1 received SS-BM, G-BM, or G-PBSC from an HLA-identical sibling. Clinical outcomes (graft-versus-host disease [GVHD], overall survival, transplant-related mortality [TRM], and leukemia-free survival [LFS] were analyzed. Results: When compared to SS-BM, G-BM gave faster recovery time to neutrophil or platelet (P 0.05. Conclusions: G-CSF-primed bone marrow shared the advantages of G-PBSC and SS-BM. We conclude that G-BM is an excellent stem-cell source that may be preferable to G-PBSC or SS-BM in patients receiving HLA-identical sibling hematopoietic stem-cell transplantation.

Chimerism representing both paternal alleles detected by HLA typing before kidney transplantation

DEFF Research Database (Denmark)

Christiansen, Mette; Petersen, Mikkel Steen; Møller, Bjarne Kuno

2014-01-01

trisomy 6p or by chimerism. Flow cytometric analysis, employing antibodies specific for the two paternal HLA-A alleles, clearly showed two distinct populations of cells: 83% expressing HLA-A11 and 12% expressing HLA-A2, suggesting a paternal chimerism. We are studying these cell populations to possibly...... identify the mechanism behind this rather unusual paternally derived chimerism. This exceptional case illustrates that careful scrutiny of HLA-typing results may produce atypical conclusions. Clinically, the father is considered the best donor based on immunogenetics....

Association study between HLA-DRB, HLA-DQA1, HLA-DQB1 and breast cancer in Iranian women

Directory of Open Access Journals (Sweden)

Amirzargar AA

2010-11-01

Full Text Available "n Normal 0 false false false EN-US X-NONE AR-SA MicrosoftInternetExplorer4 /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-qformat:yes; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Calibri","sans-serif"; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"Times New Roman"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:Arial; mso-bidi-theme-font:minor-bidi;} Background: Based on the reports, high frequency of special alleles of HLA class II genes might be associated with susceptibility to or protective from a particular cancer. These alleles might vary depending on the geographical region. Here we investigate the association between alleles of HLA class II genes and breast cancer in Iranian women."n"nMethods: 100 patients with pathologically proved breast cancer who referred to Cancer Institute, Tehran University of Medical Sciences in Tehran, Iran, were divided to two groups based on ages (40 years old and less/ or more than 40 years old and were randomly selected and compared with a group of 80 healthy blood donor subjects. HLA class II alleles were determined by amplification of DNA with polymerase chain reaction (PCR method followed by HLA-typing using sequence-specific primer (SSP for each allele."n"nResults: The most frequent alleles in the DR and DQ regions in group 1 (40 years old and less in comparison with control group were HLA-DQA1*0301 (p=0.002 and HLA-DQB1*0302 (p>0.05. In contrast HLA-DQA1*0505 (p=0.004 had significantly lower frequency in this group compared with control group. Patients of group two (more than 40 years old had a higher frequencies of HLA

Origin of Azeris (Iran) according to HLA genes

African Journals Online (AJOL)

toshiba

2017-10-17

Oct 17, 2017 ... ... Complutense, School of Medicine, Madrid Regional Blood Center, Madrid, ... between donor and receptor in organ transplantation and several HLA alleles ..... adverse reactions, according to the presence of frequent HLA ...

Influence of HLA-D/DR antigen disparity in CTL generation in vitro

International Nuclear Information System (INIS)

Johnsen, H.E.; Madsen, M.; Mossin, J.; Kristensen, T.

1983-01-01

This report describes the influence of HLA-D/-DR antigen disparity upon the level of cytotoxicity in allogeneic in vitro cultures. Allogeneic cultures, between unrelated HLA-D/-DR full house donors, tested in CML gave three different levels of cytotoxicity, termed weak, intermediate and strong cytotoxicity. HLA-D/-DR compatibility predicts weak cytotoxicity and two HLA-B antigen incompatibility predicts strong cytotoxicity. On the contrary, HLA-A antigens have no major influence upon the strength of cytotoxicity. Accepting that the MLC/CML reaction is an in vitro parallel to the in vivo transplantation of allogeneic tissue, the observations are in accordance with the results of HLA-D/-DR matching for graft survival in human renal transplantation. (author)

The HLA Dictionary 2001: A Summary of HLA-A, -B, -C, -DRB1/3/4/5, -DQB1 Alleles and Their Association with Serologically Defined HLA-A, -B, -C, -DR and -DQ Antigens

National Research Council Canada - National Science Library

Schreuder, G

2001-01-01

...) the National Marrow Donor Program (NMDP) and individual laboratories. In addition a listing is provided of alleles which are expressed as antigens with serologic reaction patterns that differ from the well-established HLA specificities...

HLA-DR-expressing cells and T-lymphocytes in sural nerve biopsies

DEFF Research Database (Denmark)

Schrøder, H D; Olsson, T; Solders, G

1988-01-01

was confirmed. HLA-DR expression was found in all biopsies and thus was not restricted to any particular type of neuropathy. The HLA-DR expression appeared to correlate with severity and activity of the neuropathy. HLA-DR-expressing macrophages wrapping myelinated fibers were prominent in primary demyelinating......Thirty-five sural nerve biopsies were stained immunohistochemically for HLA-DR antigen. HLA-DR was expressed on nonmyelinating Schwann cells, macrophages, vascular endothelium, and perineurium. By means of double immunofluorescence staining the identity of the HLA-DR presenting structures...

Interplay between immune responses to HLA and non-HLA self-antigens in allograft rejection.

Science.gov (United States)

Angaswamy, Nataraju; Tiriveedhi, Venkataswarup; Sarma, Nayan J; Subramanian, Vijay; Klein, Christina; Wellen, Jason; Shenoy, Surendra; Chapman, William C; Mohanakumar, T

2013-11-01

Recent studies strongly suggest an increasing role for immune responses against self-antigens (Ags) which are not encoded by the major histocompatibility complex in the immunopathogenesis of allograft rejection. Although, improved surgical techniques coupled with improved methods to detect and avoid sensitization against donor human leukocyte antigen (HLA) have improved the immediate and short term function of transplanted organs. However, acute and chronic rejection still remains a vexing problem for the long term function of the transplanted organ. Immediately following organ transplantation, several factors both immune and non immune mechanisms lead to the development of local inflammatory milieu which sets the stage for allograft rejection. Traditionally, development of antibodies (Abs) against mismatched donor HLA have been implicated in the development of Ab mediated rejection. However, recent studies from our laboratory and others have demonstrated that development of humoral and cellular immune responses against non-HLA self-Ags may contribute in the pathogenesis of allograft rejection. There are reports demonstrating that immune responses to self-Ags especially Abs to the self-Ags as well as cellular immune responses especially through IL17 has significant pro-fibrotic properties leading to chronic allograft failure. This review summarizes recent studies demonstrating the role for immune responses to self-Ags in allograft immunity leading to rejection as well as present recent evidence suggesting there is interplay between allo- and autoimmunity leading to allograft dysfunction. Copyright © 2013 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

Desensitization protocol enabling pediatric crossmatch-positive renal transplantation: successful HLA-antibody-incompatible renal transplantation of two highly sensitized children.

Science.gov (United States)

Adamusiak, Anna M; Stojanovic, Jelena; Shaw, Olivia; Vaughan, Robert; Sebire, Neil J; Drage, Martin; Kessaris, Nicos; Marks, Stephen D; Mamode, Nizam

2017-02-01

Renal transplantation improves quality of life (QoL) and survival in children requiring renal replacement therapy (RRT). Sensitization with development of a broad-spectrum of anti-HLA antibodies as a result of previous transplantation or after receiving blood products is an increasing problem. There are no published reports of desensitization protocols in children allowing renal transplantation from HLA-antibody-incompatible living donors. We adopted our well-established adult desensitization protocol for this purpose and undertook HLA antibody-incompatible living donor renal transplants in two children: a 14-year-old girl and a 13-year-old boy. After 2 and 1.5 years of follow-up, respectively, both patients have stable renal allograft function despite a rise in donor-specific antibodies in one case. HLA-incompatible transplantation should be considered in selected cases for sensitized children.

Survival of allografts from bone marrow donors in temporary dog radiation chimeras

International Nuclear Information System (INIS)

Vriesendorp, H.M.

Complete radiation chimeras accept indefinitely a skin or a kidney graft from the bone marrow (BM) donor. The advantages of this method of inducing graft acceptance are that it does not require the use of toxic post-operative immunosuppressive agents and that the immune reactivity against antigens other than the ones carried by the BM donor remains intact. The disadvantages of this approach are that supralethal total body irradiation (TBI) causes toxicity and that allogeneic BM cells can cause lethal Graft versus Host reactions. Attempts were made to diminish the significance of these disadvantages by using lower dose TBI and giving fewer BM cells. It is shown that, in dogs, 7.5 Gy TBI followed by 4 X 10 8 BM cells.kg -1 body weight of a DLA identical sibling leads to the development of complete radiation chimeras. The exclusive presence of donor type haemopoiesis can be demonstrated by determinations of 'informative' genetic markers, i.e., markers that show different genotypes in donor and recipient. (Auth.)

Hyperfractionated total body irradiation for T-depleted HLA identical bone marrow transplants

International Nuclear Information System (INIS)

Latini, P.; Checcaglini, F.; Maranzano, E.; Aristei, C.; Panizza, B.M.; Gobbi, G.; Raymondi, C.; Aversa, F.; Martelli, M.F.

1988-01-01

Twenty patients suffering from malignant hemopathies (mean age 31.7 years) were given hyperfractionated total body irradiation (TBI) as conditioning for T-depleted HLA identical allogeneic bone marrow transplantation. At an average of 12 months (range of 4.5-22 months) follow-up there were two cases of early death and two cases (11%) of rejection. There were no cases of acute or chronic graft versus host disease nor cases of interstitial pneumonitis. The average time for durable engraftment was 22 days. Disease-free survival at 12 months was 65%. To improve the results and further reduce the percent of rejection, the authors propose intensifying the immunosuppressive conditioning by increasing the cyclophosphamide dose and that of TBI so that a total dose of 1560 cGy is reached. 35 refs.; 1 figure

Bone marrow transplantation from genetically HLA-nonidentical donors in children with fatal inherited disorders excluding severe combined immunodeficiencies: use of two monoclonal antibodies to prevent graft rejection.

Science.gov (United States)

Jabado, N; Le Deist, F; Cant, A; De Graeff-Meeders, E R; Fasth, A; Morgan, G; Vellodi, A; Hale, G; Bujan, W; Thomas, C; Cavazzana-Calvo, M; Wijdenes, J; Fischer, A

1996-09-01

For children with life-threatening inborn errors of metabolism without a matched related bone marrow donor, transplantation from an HLA genetically nonidentical donor is the only therapeutic option. To reduce the high risk of graft rejection in this setting without increasing the conditioning regimen, a protocol based on the infusion of an antiadhesion antibody directed against the CD11a (leukocyte function-associated antigen 1 [LFA-1]) molecule was performed by the European Bone Marrow Transplantation-European Society for Immunodeficiency group with promising results. To optimize engraftment, and thereby survival, further, the additional blockade of a second important leukocyte adhesion and signalization pathway mediated by the CD2 and LFA-3 interaction was attempted in a multicenter protocol conducted by the European Bone Marrow Transplantation-European Society for Immunodeficiency group. Results of this study (ie, engraftment and survival) were compared with a historical control group that received the anti-LFA-1 antibody alone. Factors that may have affected engraftment and survival were also considered in this study. Forty-four children with inborn errors, including inherited immunodeficiencies (excluding severe combined immunodeficiencies), Chédiak-Higashi syndrome, familial hemophagocytic lymphohistiocytosis, and malignant osteopetrosis, received bone marrow from HLA-nonidentical related donors or from HLA-identical unrelated donors at 13 European centers between August 1990 and June 1993. Bone marrow was depleted of T cells by use of either erythrocyte (E) rosetting or monoclonal antibodies (MoAbs) to prevent graft-versus-host disease. The conditioning regimen consisted of busulfan and cyclophosphamide for all patients plus etoposide for patients with osteopetrosis, familial hemophagocytic lymphohistiocytosis, and Chédiak-Higashi syndrome. Infusions of MoAbs specific for the CD11a and the CD2 molecules were started 4 and 3 days, respectively, before and

High risk of graft failure in patients with anti-HLA antibodies undergoing haploidentical stem-cell transplantation.

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Ciurea, Stefan O; de Lima, Marcos; Cano, Pedro; Korbling, Martin; Giralt, Sergio; Shpall, Elizabeth J; Wang, Xuemei; Thall, Peter F; Champlin, Richard E; Fernandez-Vina, Marcelo

2009-10-27

BACKGROUND.: Although donor-specific anti-human leukocyte antigen (HLA) antibodies (DSA) have been implicated in graft rejection in solid organ transplantation, their role in hematopoietic stem-cell transplantation remains unclear. METHODS.: To address the hypothesis that the presence of DSA contributes to the development graft failure, we tested 24 consecutive patients for the presence of anti-HLA antibodies determined by a sensitive and specific solid-phase/single-antigen assay. The study included a total of 28 haploidentical transplants, each with 2 to 5 HLA allele mismatches, at a single institution, from September 2005 to August 2008. RESULTS.: DSA were detected in five patients (21%). Three of four (75%) patients with DSA before the first transplant failed to engraft, compared with 1 of 20 (5%) without DSA (P=0.008). All four patients who experienced primary graft failure had second haploidentical transplants. One patient developed a second graft failure with persistent high DSA levels, whereas three engrafted, two of them in the absence of DSA. No other known factors that could negatively influence engraftment were associated with the development of graft failure in these patients. CONCLUSIONS.: These results suggest that donor-specific anti-HLA antibodies are associated with a high rate of graft rejection in patients undergoing haploidentical stem-cell transplantation. Anti-HLA sensitization should be evaluated routinely in hematopoietic stem-cell transplantation with HLA mismatched donors.

The Genotype of the Donor for the (GTn Polymorphism in the Promoter/Enhancer of FOXP3 Is Associated with the Development of Severe Acute GVHD but Does Not Affect the GVL Effect after Myeloablative HLA-Identical Allogeneic Stem Cell Transplantation.

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Víctor Noriega

Full Text Available The FOXP3 gene encodes for a protein (Foxp3 involved in the development and functional activity of regulatory T cells (CD4+/CD25+/Foxp3+, which exert regulatory and suppressive roles over the immune system. After allogeneic stem cell transplantation, regulatory T cells are known to mitigate graft versus host disease while probably maintaining a graft versus leukemia effect. Short alleles (≤(GT15 for the (GTn polymorphism in the promoter/enhancer of FOXP3 are associated with a higher expression of FOXP3, and hypothetically with an increase of regulatory T cell activity. This polymorphism has been related to the development of auto- or alloimmune conditions including type 1 diabetes or graft rejection in renal transplant recipients. However, its impact in the allo-transplant setting has not been analyzed. In the present study, which includes 252 myeloablative HLA-identical allo-transplants, multivariate analysis revealed a lower incidence of grade III-IV acute graft versus host disease (GVHD in patients transplanted from donors harboring short alleles (OR = 0.26, CI 0.08-0.82, p = 0.021; without affecting chronic GVHD or graft versus leukemia effect, since cumulative incidence of relapse, event free survival and overall survival rates are similar in both groups of patients.

Comparison of long-term outcomes between spousal transplants and other living unrelated donor transplants: single-center experience.

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Yoon, Hye Eun; Song, Joon Chang; Hyoung, Bok Jin; Hwang, Hyeon Seok; Lee, So Young; Jeon, Youn Joo; Park, Sun Cheol; Choi, Bum Soon; Kim, Yong Soo; Moon, In Sung; Yang, Chul Woo

2009-01-01

The greater use of living unrelated donors (LUDs) as kidney donors is a worldwide trend in the current era of organ shortage, and spouses are an important source of LUDs. This study was to compare the long-term outcomes of spousal donor grafts with other LUD grafts. Among 445 LUD grafts, 77 were spouses and 368 were other LUDs. The clinical characteristics and long-term survival rates for spousal transplants were compared with those for other LUD transplants, and risk factors affecting graft survival were assessed. Spousal donors had a significantly higher average number of human leukocyte antigen (HLA) mismatches (4.2 vs. 3.4, p HLA mismatching, the spousal donor type or donor age did not affect the graft survival. Renal transplants from spousal donors show similar long-term outcomes to those from better HLA-matched and younger LUDs. (c) 2009 S. Karger AG, Basel.

Nonmyeloablative HLA-matched sibling allogeneic hematopoietic stem cell transplantation for severe sickle cell phenotype.

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Hsieh, Matthew M; Fitzhugh, Courtney D; Weitzel, R Patrick; Link, Mary E; Coles, Wynona A; Zhao, Xiongce; Rodgers, Griffin P; Powell, Jonathan D; Tisdale, John F

2014-07-02

Myeloablative allogeneic hematopoietic stem cell transplantation (HSCT) is curative for children with severe sickle cell disease, but toxicity may be prohibitive for adults. Nonmyeloablative transplantation has been attempted with degrees of preparative regimen intensity, but graft rejection and graft-vs-host disease remain significant. To determine the efficacy, safety, and outcome on end-organ function with this low-intensity regimen for sickle cell phenotype with or without thalassemia. From July 16, 2004, to October 25, 2013, 30 patients aged 16-65 years with severe disease enrolled in this nonmyeloablative transplant study, consisting of alemtuzumab (1 mg/kg in divided doses), total-body irradiation (300 cGy), sirolimus, and infusion of unmanipulated filgrastim mobilized peripheral blood stem cells (5.5-31.7 × 10(6) cells/kg) from human leukocyte antigen-matched siblings. The primary end point was treatment success at 1 year after the transplant, defined as a full donor-type hemoglobin for patients with sickle cell disease and transfusion independence for patients with thalassemia. The secondary end points were the level of donor leukocyte chimerism; incidence of acute and chronic graft-vs-host disease; and sickle cell-thalassemia disease-free survival, immunologic recovery, and changes in organ function, assessed by annual brain imaging, pulmonary function, echocardiographic image, and laboratory testing. Twenty-nine patients survived a median 3.4 years (range, 1-8.6), with no nonrelapse mortality. One patient died from intracranial bleeding after relapse. As of October 25, 2013, 26 patients (87%) had long-term stable donor engraftment without acute or chronic graft-vs-host disease. The mean donor T-cell level was 48% (95% CI, 34%-62%); the myeloid chimerism levels, 86% (95% CI, 70%-100%). Fifteen engrafted patients discontinued immunosuppression medication with continued stable donor chimerism and no graft-vs-host disease. The normalized hemoglobin and

Sibling deidentification in the clinic: devil vs. angel.

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Schachter, F F

1985-09-01

A four-member family structure consisting of two siblings contrasting in personality (sibling deidentification) and each identified with a different parent (split-parent identification) was recently reported (15). In well-functioning families, this tetrad or quadrangle is wide-spread in the first pair of siblings in the family and tends to be more common in same-sex pairs, suggesting that sibling deidentification is designed to mitigate the relatively intense sibling rivalry characteristic of these pairs and hence to maintain family harmony. In this collated case report, deidentification is found to follow the same pattern in 39 clinic first pairs. However, contrasting attributes are varied and nonevaluative in nonclinic pairs but mainly "good-bad" in clinic pairs, with polarization extreme. Results suggest that nonclinic siblings negotiate their identity (being) much as they negotiate about possessions (having) and that negotiations are blocked in clinic pairs, freezing mythic devil or angel identity. Intervention is directed at dislodging this block.

HLA engineering of human pluripotent stem cells.

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Riolobos, Laura; Hirata, Roli K; Turtle, Cameron J; Wang, Pei-Rong; Gornalusse, German G; Zavajlevski, Maja; Riddell, Stanley R; Russell, David W

2013-06-01

The clinical use of human pluripotent stem cells and their derivatives is limited by the rejection of transplanted cells due to differences in their human leukocyte antigen (HLA) genes. This has led to the proposed use of histocompatible, patient-specific stem cells; however, the preparation of many different stem cell lines for clinical use is a daunting task. Here, we develop two distinct genetic engineering approaches that address this problem. First, we use a combination of gene targeting and mitotic recombination to derive HLA-homozygous embryonic stem cell (ESC) subclones from an HLA-heterozygous parental line. A small bank of HLA-homozygous stem cells with common haplotypes would match a significant proportion of the population. Second, we derive HLA class I-negative cells by targeted disruption of both alleles of the Beta-2 Microglobulin (B2M) gene in ESCs. Mixed leukocyte reactions and peptide-specific HLA-restricted CD8(+) T cell responses were reduced in class I-negative cells that had undergone differentiation in embryoid bodies. These B2M(-/-) ESCs could act as universal donor cells in applications where the transplanted cells do not express HLA class II genes. Both approaches used adeno-associated virus (AAV) vectors for efficient gene targeting in the absence of potentially genotoxic nucleases, and produced pluripotent, transgene-free cell lines.

HLA Engineering of Human Pluripotent Stem Cells

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Riolobos, Laura; Hirata, Roli K; Turtle, Cameron J; Wang, Pei-Rong; Gornalusse, German G; Zavajlevski, Maja; Riddell, Stanley R; Russell, David W

2013-01-01

The clinical use of human pluripotent stem cells and their derivatives is limited by the rejection of transplanted cells due to differences in their human leukocyte antigen (HLA) genes. This has led to the proposed use of histocompatible, patient-specific stem cells; however, the preparation of many different stem cell lines for clinical use is a daunting task. Here, we develop two distinct genetic engineering approaches that address this problem. First, we use a combination of gene targeting and mitotic recombination to derive HLA-homozygous embryonic stem cell (ESC) subclones from an HLA-heterozygous parental line. A small bank of HLA-homozygous stem cells with common haplotypes would match a significant proportion of the population. Second, we derive HLA class I–negative cells by targeted disruption of both alleles of the Beta-2 Microglobulin (B2M) gene in ESCs. Mixed leukocyte reactions and peptide-specific HLA-restricted CD8+ T cell responses were reduced in class I–negative cells that had undergone differentiation in embryoid bodies. These B2M−/− ESCs could act as universal donor cells in applications where the transplanted cells do not express HLA class II genes. Both approaches used adeno-associated virus (AAV) vectors for efficient gene targeting in the absence of potentially genotoxic nucleases, and produced pluripotent, transgene-free cell lines. PMID:23629003

HLA-C is necessary for optimal human immunodeficiency virus type 1 infection of human peripheral blood CD4 lymphocytes.

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Baroni, Miriam; Matucci, Andrea; Scarlatti, Gabriella; Soprana, Elisa; Rossolillo, Paola; Lopalco, Lucia; Zipeto, Donato; Siccardi, Antonio G; De Santis, Claudio

2010-01-01

The hypothesis that open conformers of HLA-C on target cells might directly exert an effect on their infectability by human immunodeficiency virus (HIV) has been suggested previously. This was tested by exploiting the peculiar specificity of monoclonal antibody (mAb) L31 for HLA-C open conformers to show that normal levels of Env-driven fusion were restored in HLA-C transfectants of a major histocompatibility complex-deleted (fusion-incompetent) cell line. The physiological relevance of this finding is now confirmed in this report, where small interfering RNA (siRNA) technology was used to silence HLA-C expression in peripheral blood lymphocytes (PBLs) from 11 healthy donors. Infectability by HIV (strains IIIB and Bal and primary isolates) was significantly reduced (P=0.016) in silenced cells compared with cells that maintained HLA-C expression in 10 of the 11 PBL donors. Normal infectability was resumed, together with HLA-C expression, when the effect of siRNA interference waned after several days in culture. Additional confirmation of the HLA-C effect was obtained in several assays employing HLA-C-positive and -negative cell lines, a number of HIV strains and also pseudoviruses. In particular, viruses pseudotyped with env genes from HIV strains AC10 and QH0692.42 were assayed on siRNA-silenced lymphocytes from three healthy donors: the differences in infection with pseudoviruses were even higher than those observed in infections with normal viruses.

Seleção de doador de medula óssea ou sangue periférico Bone marrow or peripheral blood donor selection

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Noemi F. Pereira

2010-05-01

Full Text Available A compatibilidade HLA é o fator mais valorizado na escolha do doador de medula óssea voluntário, preconizando-se a realização de HLA de alta resolução nos locos HLA-A,B,C, DRB1 e DQB1. Tem sido dado preferência para o doador com consanguinidade alélica 8x8 (A,B,C, DRB1. Na presença de incompatibilidade na classe-I sugere-se a busca de doador com compatibilidade DQB1 (9x10. Já as incompatibilidades dos locos DPB1 não constituem critério de exclusão de doador, exceto quando existir presença de anticorpo contra o loco HLA-DP do doador.The HLA system is considered the most important factor in choosing a volunteer bone marrow donor with the recommendation of performing high resolution HLA tests for the HLA-A, B, C, DRB1 and DQB1 loci. A preference has been given for donor 8x8 (A, B, C, DRB1 allele matching. In the presence of class-I incompatibility a search for DQB1 (9x10 donor compatibility is suggested. The incompatibility of the DPB1 locus does not constitute exclusion of the donor, except when there is the presence of antibodies against the HLA-DP locus of the donor.

Superior outcome using cyclosporin A alone versus cyclosporin A plus methotrexate for post-transplant immunosuppression in children with acute leukemia undergoing sibling hematopoietic stem cell transplantation.

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Weiss, Melissa; Steinbach, Daniel; Zintl, Felix; Beck, James; Gruhn, Bernd

2015-06-01

The outcome of cyclosporin A (CSA) alone (n = 19) as graft-versus-host disease (GVHD) prophylaxis was compared to that of CSA combined with methotrexate (MTX) (n = 43) in children with acute leukemia who underwent hematopoietic stem cell transplantation. All respective donors were HLA-identical siblings. All patients received CSA at a dose of 3 mg/kg/day starting on day -1. A CSA level of 80-130 ng/ml was aimed for. The 43 patients in the historical control were given an additional 10 mg/m(2) dosage of MTX on days 1, 3, 6, and 11. Patients who received CSA alone had a significantly reduced cumulative incidence of relapse (5 vs. 40 %; p = 0.002), a significantly increased 5-year event-free survival (84 vs. 35 %; p = 0.001), and a significantly increased 5-year overall survival (84 vs. 42 %; p = 0.004). The incidence of acute GVHD grade II-IV and chronic GVHD in patients in the CSA group was equivalent to the CSA+MTX group (26 vs. 19 %; p = 0.440, and 32 vs. 23 %; p = 0.428). In conclusion, post-transplant immunosuppression consisting of CSA alone is well tolerated and may contribute to a superior outcome.

[COMPARATIVE STUDY ON THE SECRET OF THE DONOR'S IDENTITY OF DONATED GAMETES].

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Tisseyre, Sandrine

2015-07-01

French law lies down a principle of anonymity of donated gametes. This principle is ignored by English law. Moreover, English law has established, few years ago, the contrary principle: the one of transparency of the donor's identity. This study of English law reports this evolution and its consequences.

An Anti-C1s Monoclonal, TNT003, Inhibits Complement Activation Induced by Antibodies Against HLA.

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Thomas, K A; Valenzuela, N M; Gjertson, D; Mulder, A; Fishbein, M C; Parry, G C; Panicker, S; Reed, E F

2015-08-01

Antibody-mediated rejection (AMR) of solid organ transplants (SOT) is characterized by damage triggered by donor-specific antibodies (DSA) binding donor Class I and II HLA (HLA-I and HLA-II) expressed on endothelial cells. While F(ab')2 portions of DSA cause cellular activation and proliferation, Fc regions activate the classical complement cascade, resulting in complement deposition and leukocyte recruitment, both hallmark features of AMR. We characterized the ability of an anti-C1s monoclonal antibody, TNT003, to inhibit HLA antibody (HLA-Ab)-induced complement activation. Complement deposition induced by HLA-Ab was evaluated using novel cell- and bead-based assays. Human aortic endothelial cells (HAEC) were cultured with HLA-Ab and human complement; production of activated complement proteins was measured by flow cytometry. Additionally, C3d deposition was measured on single antigen beads (SAB) mixed with HLA-Ab and human complement. TNT003 inhibited HLA-Ab mediated complement deposition on HAEC in a concentration-dependent manner; C3a, C4a and C5a anaphylatoxin production was also diminished by TNT003. Finally, TNT003 blocked C3d deposition induced by Class I (HLAI-Ab)- and Class II (HLAII-Ab)-specific antibodies on SAB. These data suggest TNT003 may be useful for modulating the effects of DSA, as TNT003 inhibits complement deposition and split product formation generated by HLA-I/II-Ab in vitro. © 2015 The Authors. American Journal of Transplantation Published by Wiley Periodicals, Inc.

Allorecognition of HLA-C mismatches by CD8+ T cells in hematopoietic stem cell transplantation is a complex interplay between mismatched peptide binding region residues, HLA-C expression and HLA-DPB1 disparities

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Florence Bettens

2016-12-01

Full Text Available HLA-C locus mismatches are the most frequent class I disparities in unrelated hematopoietic stem cell transplantation (HSCT and have a detrimental impact on clinical outcome. Recently, a few retrospective clinical studies have reported some variability in the immunogenicity of HLA-C incompatibilities. To get better insight into presumably permissive HLA-C mismatches we have developed a one-way in vitro mixed lymphocyte reaction (MLR assay allowing to quantify activated CD56-CD137+CD8+ lymphocytes in HLA-C incompatible combinations. T cell-mediated alloresponses were correlated with genetic markers such as HLA-C mRNA expression and the number of amino acid mismatches in the α1/α2 domains (peptide binding region. Because of the high rate of HLA-DPB1 incompatibilities in HLA-A, B, C, DRB1 and DQB1 matched unrelated HSCT patient/donor pairs, the impact of HLA-DPB1 mismatching, a potential bystander of CD4+ T cell activation, was also considered. Heterogeneous alloresponses were measured in 63 HLA-C mismatched pairs with a positive assay in 52% of the combinations (2.3-18.6% activated CTLs, representing 24 different HLA-A~B~DRB1~DQB1 haplotypes. There was no correlation between measured alloresponses and mRNA expression of the mismatched HLA-C alleles. The HLA-C*03:03/03:04 mismatch did not induce any positive alloresponse in 5 MLRs. We also identified HLA-C*02:02 and HLA-C*06:02 as mismatched alleles with lower immunogenicity, and HLA-C*14:02 as a more immunogenic mismatch. A difference of at least 10 amino acid residues known to impact peptide/TCR binding and a bystander HLA-DPB1 incompatibility had a significant impact on CTL alloreactivity (p=0.021. The same HLA-C mismatch, when recognized by two different responders with the same HLA haplotypes, was recognized differently, emphasizing the role of the T-cell repertoire of responding cells. In conclusion, mismatched HLA-C alleles differing by10 or more amino acids in the peptide/TCR binding

Distinct Biomarker Profiles in Ex Vivo T Cell Depletion Graft Manipulation Strategies: CD34+ Selection versus CD3+/19+ Depletion in Matched Sibling Allogeneic Peripheral Blood Stem Cell Transplantation.

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Cantilena, Caroline R; Ito, Sawa; Tian, Xin; Jain, Prachi; Chinian, Fariba; Anandi, Prathima; Keyvanfar, Keyvan; Draper, Debbie; Koklanaris, Eleftheria; Hauffe, Sara; Superata, Jeanine; Stroncek, David; Muranski, Pawel; Barrett, A John; Battiwalla, Minoo

2018-03-01

Various approaches have been developed for ex vivo T cell depletion in allogeneic stem cell transplantation to prevent graft-versus-host disease (GVHD). Direct comparisons of T cell depletion strategies have not been well studied, however. We evaluated cellular and plasma biomarkers in 2 different graft manipulation strategies, CD3 + CD19 + cell depletion (CD3/19D) versus CD34 + selection (CD34S), and their associations with clinical outcomes. Identical conditions, including the myeloablative preparative regimen, HLA-identical sibling donor, GVHD prophylaxis, and graft source, were used in the 2 cohorts. Major clinical outcomes were similar in the 2 groups in terms of overall survival, nonrelapse mortality, and cumulative incidence of relapse; however, the cumulative incidence of acute GVHD trended to be higher in the CD3/19D cohort compared with the CD34S cohort. A distinct biomarker profile was noted in the CD3/19D cohort: higher levels of ST2, impaired Helios - FoxP3 + Treg reconstitution, and rapid reconstitution of naïve, Th2, and Th17 CD4 cells in the early post-transplantation period. In vitro graft replication studies confirmed that CD3/19D disproportionately depleted Tregs and other CD4 subset repertoires in the graft. This study confirms the utility of biomarker monitoring, which can be directly correlated with biological consequences and possible future therapeutic indications. Published by Elsevier Inc.

Protecting the interests of the child bone marrow donor.

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Terry, Louise M; Campbell, Anne

2004-01-01

At a time when designer babies have been created to act as cord blood donors to sick siblings, ethical debate has focused predominantly on the extent to which it is acceptable to create one human being to assist another. However, children are frequently used this way, by their families and doctors who extract their bone marrow, to try to save the life of another, usually a sibling. With any life-threatening illness, there is the possibility that the urgency of the sick sibling's need means that the short-term welfare of the donor child receives less attention than it should by parents and doctors. This article suggests ways to protect the interests of such children and empower them within the decision-making process and concludes that the drive to save life must be tempered by recognition of the intrinsic worth of donor children and their rights not to be exploited.

Hematopoietic stem cell transplantation for acquired aplastic anemia

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Georges, George E.; Storb, Rainer

2016-01-01

Purpose of review There has been steady improvement in outcomes with allogeneic bone marrow transplantation (BMT) for severe aplastic anemia (SAA), due to progress in optimization of the conditioning regimens, donor hematopoietic cell source and supportive care. Here we review recently published data that highlight the improvements and current issues in the treatment of SAA. Recent findings Approximately one-third of AA patients treated with immune suppression therapy (IST) have acquired mutations in myeloid cancer candidate genes. Because of the greater probability for eventual failure of IST, human leukocyte antigen (HLA)-matched sibling donor BMT is the first-line of treatment for SAA. HLA-matched unrelated donor (URD) BMT is generally recommended for patients who have failed IST. However, in younger patients for whom a 10/10-HLA-allele matched URD can be rapidly identified, there is a strong rationale to proceed with URD BMT as first-line therapy. HLA-haploidentical BMT using post-transplant cyclophosphamide (PT-CY) conditioning regimens, is now a reasonable second-line treatment for patients who failed IST. Summary Improved outcomes have led to an increased first-line role of BMT for treatment of SAA. The optimal cell source from an HLA-matched donor is bone marrow. Additional studies are needed to determine the optimal conditioning regimen for HLA-haploidentical donors. PMID:27607445

Can Non-HLA Single Nucleotide Polymorphisms Help Stratify Risk in TrialNet Relatives at Risk for Type 1 Diabetes?

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Steck, Andrea K; Xu, Ping; Geyer, Susan; Redondo, Maria J; Antinozzi, Peter; Wentworth, John M; Sosenko, Jay; Onengut-Gumuscu, Suna; Chen, Wei-Min; Rich, Stephen S; Pugliese, Alberto

2017-08-01

Genome-wide association studies identified >50 type 1 diabetes (T1D) associated non-human leukocyte antigens (non-HLA) loci. The purpose of this study was to assess the contribution of non-HLA single nucleotide polymorphisms (SNPs) to risk of disease progression. The TrialNet Pathway to Prevention Study follows relatives of T1D patients for development of autoantibodies (Abs) and T1D. Using the Immunochip, we analyzed 53 diabetes-associated, non-HLA SNPs in 1016 Ab-positive, at-risk non-Hispanic white relatives. Effect of SNPs on the development of multiple Abs and T1D. Cox proportional analyses included all substantial non-HLA SNPs, HLA genotypes, relationship to proband, sex, age at initial screening, initial Ab type, and number. Factors involved in progression from single to multiple Abs included age at screening, relationship to proband, HLA genotypes, and rs3087243 (cytotoxic T lymphocyte antigen-4). Significant factors for diabetes progression included age at screening, Ab number, HLA genotypes, rs6476839 [GLIS family zinc finger 3 (GLIS3)], and rs3184504 [SH2B adaptor protein 3 (SH2B3)]. When glucose area under the curve (AUC) was included, factors involved in disease progression included glucose AUC, age at screening, Ab number, relationship to proband, HLA genotypes, rs6476839 (GLIS3), and rs7221109 (CCR7). In stratified analyses by age, glucose AUC, age at screening, sibling, HLA genotypes, rs6476839 (GLIS3), and rs4900384 (C14orf64) were significantly associated with progression to diabetes in participants <12 years old, whereas glucose AUC, sibling, rs3184504 (SH2B3), and rs4900384 (C14orf64) were significant in those ≥12. In conclusion, we identified five non-HLA SNPs associated with increased risk of progression from Ab positivity to disease that may improve risk stratification for prevention trials. Copyright © 2017 by the Endocrine Society

Gene Map of the HLA Region, Graves' Disease and Hashimoto Thyroiditis, and Hematopoietic Stem Cell Transplantation.

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Sasazuki, Takehiko; Inoko, Hidetoshi; Morishima, Satoko; Morishima, Yasuo

2016-01-01

The human leukocyte antigen (HLA) genomic region spanning about 4 Mb is the most gene dense and the polymorphic stretches in the human genome. A total of the 269 loci were identified, including 145 protein coding genes mostly important for immunity and 50 noncoding RNAs (ncRNAs). Biological function of these ncRNAs remains unknown, becoming hot spot in the studies of HLA-associated diseases. The genomic diversity analysis in the HLA region facilitated by next-generation sequencing will pave the way to molecular understanding of linkage disequilibrium structure, population diversity, histocompatibility in transplantation, and associations with autoimmune diseases. The 4-digit DNA genotyping of HLA for six HLA loci, HLA-A through DP, in the patients with Graves' disease (GD) and Hashimoto thyroiditis (HT) identified six susceptible and three resistant HLA alleles. Their epistatic interactions in controlling the development of these diseases are shown. Four susceptible and one resistant HLA alleles are shared by GD and HT. Two HLA alleles associated with GD or HT control the titers of autoantibodies to thyroid antigens. All these observations led us to propose a new model for the development of GD and HT. Hematopoietic stem cell transplantation from unrelated donor (UR-HSCT) provides a natural experiment to elucidate the role of allogenic HLA molecules in immune response. Large cohort studies using HLA allele and clinical outcome data have elucidated that (1) HLA locus, allele, and haplotype mismatches between donor and patient, (2) specific amino acid substitution at specific positions of HLA molecules, and (3) ethnic background are all responsible for the immunological events related to UR-HSCT including acute graft-versus-host disease (GVHD), chronic GVHD, graft-versus-leukemia (GvL) effect, and graft failure. © 2016 Elsevier Inc. All rights reserved.

Outcomes of peripheral blood stem cell transplantation patients from HLA-mismatched unrelated donor with antithymocyte globulin (ATG)-Thymoglobulin versus ATG-Fresenius: a single-center study.

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Huang, Wenrong; Zhao, Xiaoli; Tian, Yamin; Cao, Tingting; Li, Yanfen; Liu, Zhanxiang; Jing, Yu; Wang, Shuhong; Gao, Chunji; Yu, Li

2015-02-01

Although antithymocyte globulin (ATG) had been widely used in hematopoietic stem cell transplantation from unrelated donor due to its ability to prevent acute and chronic graft-versus-host disease (GVHD), the comparative efficacy and safety of ATG-Thymoglobulin (ATG-T) and ATG-Fresenius (ATG-F) in patients undergoing HLA-mismatched allogeneic peripheral blood stem cell transplantation from unrelated donors (UR-PBSCT) has not been evaluated. Retrospective analysis of patients who underwent HLA-mismatched UR-PBSCT between January 2003 and December 2013 and received pre-transplant ATG-T at a total dose of 10 mg/kg or ATG-F at a total dose of 20 mg/kg was performed. Patients who received ATG-T (n = 23) or ATG-F (n = 28) had similar baseline demographic, disease, and transplant characteristics. There were no significant between-groups differences in the probability of acute GVHD (P = 0.721) and chronic GVHD (P = 0.439). ATG-F was associated with nonsignificant trends toward higher disease-free survival at 3-year follow-up compared with ATG-T (45.7 ± 11.1 vs 61.3 ± 9.7 %, respectively, P = 0.07). A significantly greater proportion of ATG-T patients experienced high fever than ATG-F patients (P < 0.01) during ATG infusion. There was no difference in the rate of infection between the two treatment groups. There were less adverse effects comparing ATG-F with ATG-T. ATG-T at a total dose of 10 mg/kg and ATG-F at a total dose of 20 mg/kg had a similar clinical outcome in the setting of HLA-mismatched UR-PBSCT.

[Preimplantation genetic diagnosis in order to choose a saviour sibling].

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Shenfield, F

2005-10-01

Preimplantation genetic diagnosis with HLA matching in order to bring about the birth of a saviour sibling is not mere instrumentalisation of the future child, as long as the post natal test is used and the future child will be looked after with the same love and care as if he/she had not been selected as well for the purpose.

Tensions among siblings in parent care.

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Lashewicz, Bonnie; Keating, Norah

2009-06-01

From a place of "genealogical equivalence" as children of their parents, siblings spend a lifetime developing separate identities. As parents near the end of their lives, issues of sibling equivalence are renegotiated in the face of equal obligations to provide care and equal entitlement to parent assets. In this paper, we hypothesize how unresolved issues of rivalry for parent affection/attention among siblings may be reasserted when parents need care. Data are drawn from a project about how parent care and assets are shared. In-depth interviews with three sibling groups experiencing conflict over sharing parent care and assets along with six Canadian legal case portrayals of disputes among siblings over how parent care and assets were shared are examined. Findings are that disputes occur when siblings perceive others as dominating parent care and assets through tactics such as separating the parent from other siblings and preventing other siblings from being engaged in decisions about care and assets. Discussion is focused on paradoxes faced by siblings given expectations for equity in parent relationships alongside perceived pre-eminence in care and asset decisions.

The Emerging Importance of Non-HLA Autoantibodies in Kidney Transplant Complications

OpenAIRE

Cardinal, Héloise; Dieudé, Mélanie; Hébert, Marie-Josée

2016-01-01

Antibodies that are specific to organ donor HLA have been involved in the majority of cases of antibody-mediated rejection in solid organ transplant recipients. However, recent data show that production of non-HLA autoantibodies can occur before transplant in the form of natural autoantibodies. In contrast to HLAs, which are constitutively expressed on the cell surface of the allograft endothelium, autoantigens are usually cryptic. Tissue damage associated with ischemia-reperfusion, vascular ...

HLA matching and the United Network for Organ Sharing Allocation System: impact of HLA matching on African-American recipients of cadaveric kidney transplants.

Science.gov (United States)

Rebellato, Lorita M; Arnold, Angelo N; Bozik, Karen M; Haisch, Carl E

2002-12-15

A recent proposal supports the elimination of allocation points for human leukocyte antigen (HLA) mismatches (MM) in cadaveric kidney transplantation. The intent is to increase access for some racial groups that might be disadvantaged by the representation of race-specific HLA in a largely white donor pool. We report our experience from two transplant centers that serve a large African American (AA) patient population. All cadaveric transplants into AA recipients from 1994 to 2000 (n=162) were included in a retrospective review. Superior graft survival was observed in AA recipients of 0 MM transplants. When induction therapy was used, the graft survival at 3 years for the human leukocyte antigen (HLA)-BDR MM grades given allocation points (0,1,2 MM) was 82% versus only 49% for BDR MM grades not given points (3,4 MM: =0.0022). Our collective experience demonstrates that AA patients having HLA-BDR MM grades given allocation points had better graft survival. Removing points for HLA from the national allocation system may result in significantly poorer outcome in AA kidney recipients.

HLA-DP and bone marrow transplantation: DP-incompatibility and severe acute graft versus host disease

DEFF Research Database (Denmark)

Ødum, Niels; Platz, P; Jakobsen, B K

1987-01-01

Thirteen recipients of HLA-haploidentical, DR compatible bone marrow (BM) and the corresponding BM donors were HLA-DP typed using primed lymphocyte typing (PLT). Severe acute GVHD (greater than or equal to grade 2) developed within 3 months after BM-transplantation in all of eight recipients of DP...... a role as transplantation antigens....

Donor-Derived Myeloid Sarcoma in Two Kidney Transplant Recipients from a Single Donor

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Amudha Palanisamy

2015-01-01

Full Text Available We report the rare occurrence of donor-derived myeloid sarcoma in two kidney transplant patients who received organs from a single deceased donor. There was no evidence of preexisting hematologic malignancy in the donor at the time of organ recovery. Both recipients developed leukemic involvement that appeared to be limited to the transplanted organ. Fluorescence in situ hybridization (FISH and molecular genotyping analyses confirmed that the malignant cells were of donor origin in each patient. Allograft nephrectomy and immediate withdrawal of immunosuppression were performed in both cases; systemic chemotherapy was subsequently administered to one patient. Both recipients were in remission at least one year following the diagnosis of donor-derived myeloid sarcoma. These cases suggest that restoration of the immune system after withdrawal of immunosuppressive therapy and allograft nephrectomy may be sufficient to control HLA-mismatched donor-derived myeloid sarcoma without systemic involvement.

Epitopes recognized by CBV4 responding T cells: effect of type 1 diabetes and associated HLA-DR-DQ haplotypes

International Nuclear Information System (INIS)

Marttila, Jane; Hyoety, Heikki; Naentoe-Salonen, Kirsti; Simell, Olli; Ilonen, Jorma

2004-01-01

The present study aimed at characterizing the epitopes recognized by coxsackievirus B4 (CBV4)-specific T-cell lines established from 23 children with type 1 diabetes (T1D) and 29 healthy children with T1D risk-associated HLA genotypes. Responsiveness to VP1 region was dependent on the specific infection history as 55% of the T-cell lines from donors with neutralizing antibodies to CBV serotypes responded to VP1 peptides compared to none of the T-cell lines from other donors (P = 0.01). The pattern of recognized peptides was dependent of the HLA genotype. Forty-two percent of the T-cell lines from donors carrying the HLA-(DR4)-DQB1*0302 haplotype responded to VP1 peptides 71-80 compared to none of the T-cell lines from donors without this haplotype (P = 0.02). No evidence for the existence of diabetes-specific epitopes was found. Only few epitopes were exclusive recognized by T cells from diabetic children, and in each case only one or two T-cell lines were responding

Birth order and sibling sex ratio of children and adolescents referred to a gender identity service.

Science.gov (United States)

Vanderlaan, Doug P; Blanchard, Ray; Wood, Hayley; Zucker, Kenneth J

2014-01-01

In adult male samples, homosexuality is associated with a preponderance of older brothers (i.e., the fraternal birth order effect). In several studies comparing gender dysphoric youth, who are likely to be homosexual in adulthood, to clinical or non-clinical control groups, the findings have been consistent with the fraternal birth order effect in males; however, less is known about unique sibship characteristics of gender dysphoric females. The current study investigated birth order and sibling sex ratio in a large sample of children and adolescents referred to the same Gender Identity Service (N = 768). Probands were classified as heterosexual males, homosexual males, or homosexual females based on clinical diagnostic information. Groups differed significantly in age and sibship size, and homosexual females were significantly more likely to be only children. Subsequent analyses controlled for age and for sibship size. Compared to heterosexual males, homosexual males had a significant preponderance of older brothers and homosexual females had a significant preponderance of older sisters. Similarly, the older sibling sex ratio of homosexual males showed a significant excess of brothers whereas that of homosexual females showed a significant excess of sisters. Like previous studies of gender dysphoric youth and adults, these findings were consistent with the fraternal birth order effect. In addition, the greater frequency of only children and elevated numbers of older sisters among the homosexual female group adds to a small literature on sibship characteristics of potential relevance to the development of gender identity and sexual orientation in females.

Identification of an elaborate NK-specific system regulating HLA-C expression.

Directory of Open Access Journals (Sweden)

Hongchuan Li

2018-01-01

Full Text Available The HLA-C gene appears to have evolved in higher primates to serve as a dominant source of ligands for the KIR2D family of inhibitory MHC class I receptors. The expression of NK cell-intrinsic MHC class I has been shown to regulate the murine Ly49 family of MHC class I receptors due to the interaction of these receptors with NK cell MHC in cis. However, cis interactions have not been demonstrated for the human KIR and HLA proteins. We report the discovery of an elaborate NK cell-specific system regulating HLA-C expression, indicating an important role for HLA-C in the development and function of NK cells. A large array of alternative transcripts with differences in intron/exon content are generated from an upstream NK-specific HLA-C promoter, and exon content varies between HLA-C alleles due to SNPs in splice donor/acceptor sites. Skipping of the first coding exon of HLA-C generates a subset of untranslatable mRNAs, and the proportion of untranslatable HLA-C mRNA decreases as NK cells mature, correlating with increased protein expression by mature NK cells. Polymorphism in a key Ets-binding site of the NK promoter has generated HLA-C alleles that lack significant promoter activity, resulting in reduced HLA-C expression and increased functional activity. The NK-intrinsic regulation of HLA-C thus represents a novel mechanism controlling the lytic activity of NK cells during development.

Granulocyte-mobilized bone marrow.

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Arcese, William; De Angelis, Gottardo; Cerretti, Raffaella

2012-11-01

In the last few years, mobilized peripheral blood has overcome bone marrow as a graft source, but, despite the evidence of a more rapid engraftment, the incidence of chronic graft-versus-host disease is significantly higher with, consequently, more transplant-related mortality on the long follow-up. Overall, the posttransplant outcome of mobilized peripheral blood recipients is similar to that of patients who are bone marrow grafted. More recently, the use of bone marrow after granulocyte colony-stimulating factor (G-CSF) donor priming has been introduced in the transplant practice. Herein, we review biological acquisitions and clinical results on the use of G-CSF-primed bone marrow as a source of hematopoietic stem cells (HSC) for allogeneic stem cell transplantation. G-CSF the increases the HSC compartment and exerts an intense immunoregulatory effect on marrow T-cells resulting in the shift from Th1 to Th2 phenotype with higher production of anti-inflammatory cytokines. The potential advantages of these biological effects have been translated in the clinical practice by using G-CSF primed unmanipulated bone marrow in the setting of transplant from human leukocyte antigen (HLA)-haploidentical donor with highly encouraging results. For patients lacking an HLA-identical sibling, the transplant of G-CSF primed unmanipulated bone marrow from a haploidentical donor combined with an intense in-vivo immunosuppression is a valid alternative achieving results that are well comparable with those reported for umbilical cord blood, HLA-matched unrelated peripheral blood/bone marrow or T-cell-depleted haploidentical transplant.

Strategies to work with HLA data in human populations for histocompatibility, clinical transplantation, epidemiology and population genetics: HLA-NET methodological recommendations.

Science.gov (United States)

Sanchez-Mazas, A; Vidan-Jeras, B; Nunes, J M; Fischer, G; Little, A-M; Bekmane, U; Buhler, S; Buus, S; Claas, F H J; Dormoy, A; Dubois, V; Eglite, E; Eliaou, J F; Gonzalez-Galarza, F; Grubic, Z; Ivanova, M; Lie, B; Ligeiro, D; Lokki, M L; da Silva, B Martins; Martorell, J; Mendonça, D; Middleton, D; Voniatis, D Papioannou; Papasteriades, C; Poli, F; Riccio, M E; Vlachou, M Spyropoulou; Sulcebe, G; Tonks, S; Nevessignsky, M Toungouz; Vangenot, C; van Walraven, A-M; Tiercy, J-M

2012-12-01

HLA-NET (a European COST Action) aims at networking researchers working in bone marrow transplantation, epidemiology and population genetics to improve the molecular characterization of the HLA genetic diversity of human populations, with an expected strong impact on both public health and fundamental research. Such improvements involve finding consensual strategies to characterize human populations and samples and report HLA molecular typings and ambiguities; proposing user-friendly access to databases and computer tools and defining minimal requirements related to ethical aspects. The overall outcome is the provision of population genetic characterizations and comparisons in a standard way by all interested laboratories. This article reports the recommendations of four working groups (WG1-4) of the HLA-NET network at the mid-term of its activities. WG1 (Population definitions and sampling strategies for population genetics' analyses) recommends avoiding outdated racial classifications and population names (e.g. 'Caucasian') and using instead geographic and/or cultural (e.g. linguistic) criteria to describe human populations (e.g. 'pan-European'). A standard 'HLA-NET POPULATION DATA QUESTIONNAIRE' has been finalized and is available for the whole HLA community. WG2 (HLA typing standards for population genetics analyses) recommends retaining maximal information when reporting HLA typing results. Rather than using the National Marrow Donor Program coding system, all ambiguities should be provided by listing all allele pairs required to explain each genotype, according to the formats proposed in 'HLA-NET GUIDELINES FOR REPORTING HLA TYPINGS'. The group also suggests taking into account a preliminary list of alleles defined by polymorphisms outside the peptide-binding sites that may affect population genetic statistics because of significant frequencies. WG3 (Bioinformatic strategies for HLA population data storage and analysis) recommends the use of programs capable

Identification of HLA Class I Misreads/Dropouts Using Serological Typing, in Comparison with DNA-based Typing.

Science.gov (United States)

Tipu, Hamid Nawaz; Bashir, Muhammad Mukarram; Noman, Muhammad

2016-10-01

Serology and DNA techniques are employed for Human Leukocyte Antigen (HLA) typing in different transplant centers. Results may not always correlate well and may need retyping with different technique. All the patients (with aplastic anemia, thalassemia, and immunodeficiency) and their donors, requiring HLA typing for bone marrow transplant were enrolled in the study. Serological HLA typing was done by complement-dependent lymphocytotoxicity while DNA-based typing was done with sequence specific primers (SSP). Serology identified 167 HLA A and 165 HLA B antigens while SSP in same samples identified 181 HLA A and 184 HLA B alleles. A11 and B51 were the commonest antigens/alleles by both methods. There were a total of 21 misreads and 32 dropouts on serology, for both HLA A and B loci with HLA A32, B52 and B61 being the most ambiguous antigens. Inherent limitations of serological techniques warrant careful interpretation or use of DNA-based methods for resolution of ambiguous typing.

Homozygous HLA-C1 is Associated with Reduced Risk of Relapse after HLA-Matched Transplantation in Patients with Myeloid Leukemia.

Science.gov (United States)

Arima, Nobuyoshi; Kanda, Junya; Tanaka, Junji; Yabe, Toshio; Morishima, Yasuo; Kim, Sung-Won; Najima, Yuho; Ozawa, Yukiyasu; Eto, Tetsuya; Kanamori, Heiwa; Mori, Takehiko; Kobayashi, Naoki; Kondo, Tadakazu; Nakamae, Hirohisa; Uchida, Naoyuki; Inoue, Masami; Fukuda, Takahiro; Ichinohe, Tatsuo; Atsuta, Yoshiko; Kanda, Yoshinobu

2018-04-01

Natural killer (NK) cells assume graft-versus-leukemia alloreactivity after hematopoietic stem cell transplantation (HSCT) through their inhibitory killer cell immunoglobulin-like receptors (KIRs). KIR2D family members recognize HLA-C alleles with Asn80 (HLA-C1) or Lys80 (HLA-C2). The predominance of HLA-C1 over HLA-C2 and the frequent presence of KIR2DL1 are characteristic of Japanese people. We compared clinical outcomes among homozygous HLA-C1 (HLA-C1/C1) patients and heterozygous HLA-C1/C2 patients who underwent HLA-matched HSCT for hematologic malignancies by assessing the data of 10,638 patients from the Japanese national registry. HLA-C1/C1 recipients had a lower rate of relapse than HLA-C1/C2 recipients after transplantation for acute myelogenous leukemia (AML) (hazard ratio [HR], .79; P = .006) and chronic myelogenous leukemia (CML) (HR, .48; P = .025), but not for acute lymphoblastic leukemia (HR, 1.36), lymphoma (HR, .97), or low-grade myelodysplastic syndrome (HR, 1.40). We then grouped AML and CML patients together and divided them into several subgroups. Advantages of HLA-C1/C1 recipients over HLA-C1/C2 recipients regarding relapse were observed irrespective of donor relation (related: HR, .79, P = .069; unrelated: HR, .77, P = .022), preparative regimen (myeloablative: HR, .79, P = .014; reduced intensity: HR, .73, P = .084), and occurrence of acute graft-versus-host disease (yes: HR, .70, P = .122; no, HR .71, P = .026) or cytomegalovirus reactivation (reactivated: HR .67,P = .054; nonreactivated: HR .71, P = .033); however, these advantages were not observed in recipients with a delay in achieving complete chimerism (HR, 1.06). The advantage of decreasing relapse and extending relapse-free survival of C1/1 over C1/2 KIR-ligand status was most pronounced in T cell-depleted HSCT (HR, .27; P < .001 and HR, .30; P = .002, respectively) and in children age <15 years (HR, .29; P < .001 and HR .31; P�

EpHLA: an innovative and user-friendly software automating the HLAMatchmaker algorithm for antibody analysis.

Science.gov (United States)

Sousa, Luiz Cláudio Demes da Mata; Filho, Herton Luiz Alves Sales; Von Glehn, Cristina de Queiroz Carrascosa; da Silva, Adalberto Socorro; Neto, Pedro de Alcântara dos Santos; de Castro, José Adail Fonseca; do Monte, Semíramis Jamil Hadad

2011-12-01

The global challenge for solid organ transplantation programs is to distribute organs to the highly sensitized recipients. The purpose of this work is to describe and test the functionality of the EpHLA software, a program that automates the analysis of acceptable and unacceptable HLA epitopes on the basis of the HLAMatchmaker algorithm. HLAMatchmaker considers small configurations of polymorphic residues referred to as eplets as essential components of HLA-epitopes. Currently, the analyses require the creation of temporary files and the manual cut and paste of laboratory tests results between electronic spreadsheets, which is time-consuming and prone to administrative errors. The EpHLA software was developed in Object Pascal programming language and uses the HLAMatchmaker algorithm to generate histocompatibility reports. The automated generation of reports requires the integration of files containing the results of laboratory tests (HLA typing, anti-HLA antibody signature) and public data banks (NMDP, IMGT). The integration and the access to this data were accomplished by means of the framework called eDAFramework. The eDAFramework was developed in Object Pascal and PHP and it provides data access functionalities for software developed in these languages. The tool functionality was successfully tested in comparison to actual, manually derived reports of patients from a renal transplantation program with related donors. We successfully developed software, which enables the automated definition of the epitope specificities of HLA antibodies. This new tool will benefit the management of recipient/donor pairs selection for highly sensitized patients. Copyright © 2011 Elsevier B.V. All rights reserved.

Effect of antithymocyte globulin source on outcomes of bone marrow transplantation for severe aplastic anemia.

Science.gov (United States)

Kekre, Natasha; Zhang, Ying; Zhang, Mei-Jie; Carreras, Jeanette; Ahmed, Parvez; Anderlini, Paolo; Atta, Elias Hallack; Ayas, Mouhab; Boelens, Jaap Jan; Bonfim, Carmem; Deeg, H Joachim; Kapoor, Neena; Lee, Jong-Wook; Nakamura, Ryotaro; Pulsipher, Michael A; Eapen, Mary; Antin, Joseph H

2017-07-01

For treatment of severe aplastic anemia, immunosuppressive therapy with horse antithymocyte globulin results in superior response and survival compared with rabbit antithymocyte globulin. This relative benefit may be different in the setting of transplantation as rabbit antithymocyte globulin results in more profound immunosuppression. We analyzed 833 severe aplastic anemia transplants between 2008 and 2013 using human leukocyte antigen (HLA)-matched siblings (n=546) or unrelated donors (n=287) who received antithymocyte globulin as part of their conditioning regimen and bone marrow graft. There were no differences in hematopoietic recovery by type of antithymocyte globulin. Among recipients of HLA-matched sibling transplants, day 100 incidence of acute (17% versus 6%, P aplastic anemia. Copyright© 2017 Ferrata Storti Foundation.

Sibling influences on childhood development.

Science.gov (United States)

Dunn, J

1988-03-01

To summarize the main points concerning sibling influence: 1. That siblings play a causal role in the development of aggressive behavior, in children's style of conflict behavior and in cooperative fantasy play is strongly suggested by recent research. 2. Marked problems in the sibling relationship are indicative of other problems, but a causal role for siblings is not established, other than for aggressive behavior. 3. Family factors are closely involved in the quality of sibling relationships--and thus in sibling influence, namely differential parental behavior, and the emotional climate of the family. That is, it is important not to consider the sibling relationship in isolation from other family relationships. 4. Studies of families under stress indicate heightened importance of these family factors. 5. It is likely, but not yet established, that later-born siblings are influenced by first-born in socio-cognitive development and gender identity. 6. Finally it should be noted that an important theme in current research on siblings is a concern with the question of why siblings develop to be so different from one another. It has been shown that the major source of environmental influence on the development of individual differences is within-family rather than between-family differences in experience (Plomin & Daniels, 1987). The different experiences each sibling may have within their relationship is one potential source of such differential environmental influence. Thus documenting the influence of siblings upon each other takes on added significance: By clarifying the extent and nature of this influence we will gain not only useful clinical information but illumination on a developmental principle of very general significance.

Creatinine and cytokines plasma levels related to HLA compatibility in kidney transplant patients

Directory of Open Access Journals (Sweden)

Lorraine V. Alves

2015-10-01

Full Text Available ABSTRACTIntroduction:The success of kidney transplantation depends on prevention of organ rejection by the recipient’s immune system, which recognizes alloantigens present in transplanted tissue. Human leukocyte antigen (HLA typing is one of the tests used in pre-renal transplantation and represents one of the most important factors for a successful procedure.Objective:The present study evaluated creatinine and cytokines plasma levels in kidney transplant patients according to pre-transplant HLA typing.Methods:We assessed 40 renal transplanted patients selected in two transplant centers in Belo Horizonte (MG.Results:Patients were distributed into three groups according to HLA compatibility and, through statistical analysis, the group with more than three matches (H3 was found to have significantly lower post-transplant creatinine levels, compared to groups with three or fewer matches (H2 and H1, respectively. The median plasma levels of cytokines interleukin 6 (IL-6, tumor necrosis factor alpha (TNF-α, and interleukin 10 (IL-10 were evaluated according to the number of matches. Pro-inflammatory cytokines (IL-6 and TNF-α were significantly higher in groups with lower HLA compatibility. On the other hand, the regulatory cytokine IL-10 had significantly higher plasma levels in the group with greater compatibility between donor and recipient.Conclusion:These findings allow us to infer that pre-transplant HLA typing of donors and recipients can influence post-transplant renal graft function and may contribute to the development and choice of new treatment strategies.

Combination of Complement-Dependent Cytotoxicity and Relative Fluorescent Quantification of HLA Length Polymorphisms Facilitates the Detection of a Loss of Heterozygosity

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Klaus Witter

2014-01-01

Full Text Available Loss of heterozygosity (LOH is a common event in malignant cells. In this work we introduce a new approach to identify patients with loss of heterozygosity in the HLA region either at first diagnosis or after HLA mismatched allogeneic HSCT. Diagnosis of LOH requires a high purity of recipient target cells. FACS is time consuming and also frequently prevented by rather nonspecific or unknown immune phenotype. The approach for recipient cell enrichment is based on HLA targeted complement-dependent cytotoxicity (CDC. Relative fluorescent quantification (RFQ analysis of HLA intron length polymorphisms then allows analysis of HLA heterozygosity. The approach is exemplified in recent clinical cases illustrating the detection of an acquired allele loss. As illustrated in one case with DPB1, distinct HLA loci in donor and patient were sufficient for both proof of donor cell removal and evaluation of allele loss in the patient's leukemic cells. Results were confirmed using HLA-B RFQ analysis and leukemia-associated aberrant immunophenotype (LAIP based cell sort. Both results confirmed suspected loss of HLA heterozygosity. Our approach complements or substitutes for FACS-based cell enrichment; hence it may be further developed as novel routine diagnostic tool. This allows rapid recipient cell purification and testing for loss of HLA heterozygosity before and after allogeneic HSCT in easily accessible peripheral blood samples.

Parents' contributions to the narrative identity of offspring of donor-assisted conception.

Science.gov (United States)

Kirkman, Maggie

2003-12-01

Donated sperm, eggs, and embryos are an increasing feature of assisted reproduction; people conceived in this way have different genetic and social histories. Although most offspring of donor-assisted conception are ignorant of their genetic history, recipient parents must negotiate increasing demand for full disclosure to offspring. This paper illustrates some of the reasons parents give for not telling their children, underlines the experience of many parents of being uncertain of how to go about telling, presents information from some parents who have endeavoured to be open with their children about conception from very early childhood, and discusses implications for the narrative identity of offspring of donor-assisted conception. Recipient parents (n=55) and offspring (12) from Australia; Canada, US, England, and Argentina were interviewed and subsequently consulted about the development of their narrative accounts and the way in which these have been interpreted. Parental narratives were found to be located along a continuum, broadly encompassing: (1). Parents who intend to exclude donor-assisted conception from the narratives they construct for their children, (2). parents who are uncertain about what they want to do, or confused about the best way to disclose and discuss donor conception with their children and (3). those have incorporated the donor in their children's narratives from the beginning. From interviews with offspring and on the basis of human rights issues and the increasing salience of genetic knowledge, it is concluded that disclosure to offspring before adolescence should be encouraged.

A Kidney Graft Survival Calculator that Accounts for Mismatches in Age, Sex, HLA, and Body Size.

Science.gov (United States)

Ashby, Valarie B; Leichtman, Alan B; Rees, Michael A; Song, Peter X-K; Bray, Mathieu; Wang, Wen; Kalbfleisch, John D

2017-07-07

Outcomes for transplants from living unrelated donors are of particular interest in kidney paired donation (KPD) programs where exchanges can be arranged between incompatible donor-recipient pairs or chains created from nondirected/altruistic donors. Using Scientific Registry of Transplant Recipients data, we analyzed 232,705 recipients of kidney-alone transplants from 1998 to 2012. Graft failure rates were estimated using Cox models for recipients of kidney transplants from living unrelated, living related, and deceased donors. Models were adjusted for year of transplant and donor and recipient characteristics, with particular attention to mismatches in age, sex, human leukocyte antigens (HLA), body size, and weight. The dependence of graft failure on increasing donor age was less pronounced for living-donor than for deceased-donor transplants. Male donor-to-male recipient transplants had lower graft failure, particularly better than female to male (5%-13% lower risk). HLA mismatch was important in all donor types. Obesity of both the recipient (8%-18% higher risk) and donor (5%-11% higher risk) was associated with higher graft loss, as were donor-recipient weight ratios of transplants where both parties were of similar weight (9%-12% higher risk). These models are used to create a calculator of estimated graft survival for living donors. This calculator provides useful information to donors, candidates, and physicians of estimated outcomes and potentially in allowing candidates to choose among several living donors. It may also help inform candidates with compatible donors on the advisability of joining a KPD program. Copyright © 2017 by the American Society of Nephrology.

Quantification of transplant-derived circulating cell-free DNA in absence of a donor genotype.

Science.gov (United States)

Sharon, Eilon; Shi, Hao; Kharbanda, Sandhya; Koh, Winston; Martin, Lance R; Khush, Kiran K; Valantine, Hannah; Pritchard, Jonathan K; De Vlaminck, Iwijn

2017-08-01

Quantification of cell-free DNA (cfDNA) in circulating blood derived from a transplanted organ is a powerful approach to monitoring post-transplant injury. Genome transplant dynamics (GTD) quantifies donor-derived cfDNA (dd-cfDNA) by taking advantage of single-nucleotide polymorphisms (SNPs) distributed across the genome to discriminate donor and recipient DNA molecules. In its current implementation, GTD requires genotyping of both the transplant recipient and donor. However, in practice, donor genotype information is often unavailable. Here, we address this issue by developing an algorithm that estimates dd-cfDNA levels in the absence of a donor genotype. Our algorithm predicts heart and lung allograft rejection with an accuracy that is similar to conventional GTD. We furthermore refined the algorithm to handle closely related recipients and donors, a scenario that is common in bone marrow and kidney transplantation. We show that it is possible to estimate dd-cfDNA in bone marrow transplant patients that are unrelated or that are siblings of the donors, using a hidden Markov model (HMM) of identity-by-descent (IBD) states along the genome. Last, we demonstrate that comparing dd-cfDNA to the proportion of donor DNA in white blood cells can differentiate between relapse and the onset of graft-versus-host disease (GVHD). These methods alleviate some of the barriers to the implementation of GTD, which will further widen its clinical application.

Birth order and sibling sex ratio of children and adolescents referred to a gender identity service.

Directory of Open Access Journals (Sweden)

Doug P Vanderlaan

Full Text Available In adult male samples, homosexuality is associated with a preponderance of older brothers (i.e., the fraternal birth order effect. In several studies comparing gender dysphoric youth, who are likely to be homosexual in adulthood, to clinical or non-clinical control groups, the findings have been consistent with the fraternal birth order effect in males; however, less is known about unique sibship characteristics of gender dysphoric females. The current study investigated birth order and sibling sex ratio in a large sample of children and adolescents referred to the same Gender Identity Service (N = 768. Probands were classified as heterosexual males, homosexual males, or homosexual females based on clinical diagnostic information. Groups differed significantly in age and sibship size, and homosexual females were significantly more likely to be only children. Subsequent analyses controlled for age and for sibship size. Compared to heterosexual males, homosexual males had a significant preponderance of older brothers and homosexual females had a significant preponderance of older sisters. Similarly, the older sibling sex ratio of homosexual males showed a significant excess of brothers whereas that of homosexual females showed a significant excess of sisters. Like previous studies of gender dysphoric youth and adults, these findings were consistent with the fraternal birth order effect. In addition, the greater frequency of only children and elevated numbers of older sisters among the homosexual female group adds to a small literature on sibship characteristics of potential relevance to the development of gender identity and sexual orientation in females.

Human Leukocyte Antigen-A, B, C, DRB1, and DQB1 Allele and Haplotype Frequencies in a Subset of 237 Donors in the South African Bone Marrow Registry

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Mqondisi Tshabalala

2018-01-01

Full Text Available Human leukocyte antigen- (HLA- A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 allele and haplotype frequencies were studied in a subset of 237 volunteer bone marrow donors registered at the South African Bone Marrow Registry (SABMR. Hapl-o-Mat software was used to compute allele and haplotype frequencies from individuals typed at various resolutions, with some alleles in multiple allele code (MAC format. Four hundred and thirty-eight HLA-A, 235 HLA-B, 234 HLA-DRB1, 41 HLA-DQB1, and 29 HLA-C alleles are reported. The most frequent alleles were A∗02:02g (0.096, B∗07:02g (0.082, C∗07:02g (0.180, DQB1∗06:02 (0.157, and DRB1∗15:01 (0.072. The most common haplotype was A∗03:01g~B∗07:02g~C∗07:02g~DQB1∗06:02~DRB1∗15:01 (0.067, which has also been reported in other populations. Deviations from Hardy-Weinberg equilibrium were observed in A, B, and DRB1 loci, with C~DQB1 being the only locus pair in linkage disequilibrium. This study describes allele and haplotype frequencies from a subset of donors registered at SABMR, the only active bone marrow donor registry in Africa. Although the sample size was small, our results form a key resource for future population studies, disease association studies, and donor recruitment strategies.

The perfect storm: HLA antibodies, complement, FcγRs, and endothelium in transplant rejection.

Science.gov (United States)

Thomas, Kimberly A; Valenzuela, Nicole M; Reed, Elaine F

2015-05-01

The pathophysiology of antibody-mediated rejection (AMR) in solid organ transplants is multifaceted and predominantly caused by antibodies directed against polymorphic donor human leukocyte antigens (HLAs). Despite the clearly detrimental impact of HLA antibodies (HLA-Abs) on graft function and survival, the prevention, diagnosis, and treatment of AMR remain a challenge. The histological manifestations of AMR reflect the signatures of HLA-Ab-triggered injury, specifically endothelial changes, recipient leukocytic infiltrate, and complement deposition. We review the interconnected mechanisms of HLA-Ab-mediated injury that might synergize in a 'perfect storm' of inflammation. Characterization of antibody features that are critical for effector functions may help to identify HLA-Abs that are more likely to cause rejection. We also highlight recent advances that may pave the way for new, more effective therapies. Copyright © 2015 Elsevier Ltd. All rights reserved.

Clinical outcomes of ABO- and HLA-incompatible kidney transplantation: a nationwide cohort study.

Science.gov (United States)

Ko, Eun Jeong; Yu, Ji Hyun; Yang, Chul Woo; Chung, Byung Ha

2017-12-01

This was a nationwide cohort study to investigate the impact of anti-A/B and donor-specific anti-HLA (HLA-DSA) antibodies on the clinical outcomes in kidney transplant recipients (KTRs). We classified a total of 1964 KTRs into four groups: transplants from ABO-incompatible donors (ABOi, n = 248); transplants in recipients with HLA-DSA (HLAi, n = 144); transplants from combined ABOi and HLAi donors (ABOi + HLAi, n = 31); and a control group for whom neither ABOi nor HLAi was applicable (CONT, n = 1541). We compared the incidence of biopsy-proven acute rejection (BPAR), allograft and patient survival rates. The incidence of BPAR was higher in the HLAi and ABOi + HLAi groups relative to the CONT group; in contrast, it was not higher in the ABOi group. Death-censored graft survival rates did not differ across the four groups. However, relative to the CONT group, patient survival rate was reduced in the ABOi and ABOi + HLAi groups, and with infection being the most common cause of death. Further, multivariable analysis revealed that desensitization therapy because of ABOi or HLAi was independent risk factors for patient mortality. HLAi was a more important risk factor for BPAR compared with ABOi. However, pretransplant desensitization therapy for either ABOi or HLAi significantly increased the risk of infection-related mortality. © 2017 Steunstichting ESOT.

Marrow donor registry and cord blood bank in Taiwan.

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Lee, Tsung Dao

2002-08-01

Unrelated Bone marrow transplant was initiated thirty years ago. Though there are over millions of donors registered with the bone marrow registries worldwide, Asian patients rarely find a match with all these donors. Tzu Chi Marrow Donor Registry was established to meet this need. It has become the largest Asian marrow donor registry in the world. With the introduction of high technology to test the HLA of the donors and recipients, the success rate of bone marrow transplant is greatly improved among Asian countries. 50% of blood disease Asian patients who cannot find a bone marrow matched donor will be complemented by the establishment of cord blood banks in Taiwan.

Modeling coverage gaps in haplotype frequencies via Bayesian inference to improve stem cell donor selection.

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Louzoun, Yoram; Alter, Idan; Gragert, Loren; Albrecht, Mark; Maiers, Martin

2018-05-01

Regardless of sampling depth, accurate genotype imputation is limited in regions of high polymorphism which often have a heavy-tailed haplotype frequency distribution. Many rare haplotypes are thus unobserved. Statistical methods to improve imputation by extending reference haplotype distributions using linkage disequilibrium patterns that relate allele and haplotype frequencies have not yet been explored. In the field of unrelated stem cell transplantation, imputation of highly polymorphic human leukocyte antigen (HLA) genes has an important application in identifying the best-matched stem cell donor when searching large registries totaling over 28,000,000 donors worldwide. Despite these large registry sizes, a significant proportion of searched patients present novel HLA haplotypes. Supporting this observation, HLA population genetic models have indicated that many extant HLA haplotypes remain unobserved. The absent haplotypes are a significant cause of error in haplotype matching. We have applied a Bayesian inference methodology for extending haplotype frequency distributions, using a model where new haplotypes are created by recombination of observed alleles. Applications of this joint probability model offer significant improvement in frequency distribution estimates over the best existing alternative methods, as we illustrate using five-locus HLA frequency data from the National Marrow Donor Program registry. Transplant matching algorithms and disease association studies involving phasing and imputation of rare variants may benefit from this statistical inference framework.

Strategies to work with HLA data in human populations for histocompatibility, clinical transplantation, epidemiology and population genetics

DEFF Research Database (Denmark)

Sanchez-Mazas, A; Vidan-Jeras, B; Nunes, J M

2012-01-01

QUESTIONNAIRE' has been finalized and is available for the whole HLA community. WG2 (HLA typing standards for population genetics analyses) recommends retaining maximal information when reporting HLA typing results. Rather than using the National Marrow Donor Program coding system, all ambiguities should...... and fundamental research. Such improvements involve finding consensual strategies to characterize human populations and samples and report HLA molecular typings and ambiguities; proposing user-friendly access to databases and computer tools and defining minimal requirements related to ethical aspects. The overall......-Weinberg equilibrium and selective neutrality on data containing any number and kind of ambiguities. WG4 (Ethical issues) proposes to adopt thorough general principles for any HLA population study to ensure that it conforms to (inter)national legislation or recommendations/guidelines. All HLA-NET guidelines and tools...

HLA-E-expressing pluripotent stem cells escape allogeneic responses and lysis by NK cells.

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Gornalusse, Germán G; Hirata, Roli K; Funk, Sarah E; Riolobos, Laura; Lopes, Vanda S; Manske, Gabriel; Prunkard, Donna; Colunga, Aric G; Hanafi, Laïla-Aïcha; Clegg, Dennis O; Turtle, Cameron; Russell, David W

2017-08-01

Polymorphisms in the human leukocyte antigen (HLA) class I genes can cause the rejection of pluripotent stem cell (PSC)-derived products in allogeneic recipients. Disruption of the Beta-2 Microglobulin (B2M) gene eliminates surface expression of all class I molecules, but leaves the cells vulnerable to lysis by natural killer (NK) cells. Here we show that this 'missing-self' response can be prevented by forced expression of minimally polymorphic HLA-E molecules. We use adeno-associated virus (AAV)-mediated gene editing to knock in HLA-E genes at the B2M locus in human PSCs in a manner that confers inducible, regulated, surface expression of HLA-E single-chain dimers (fused to B2M) or trimers (fused to B2M and a peptide antigen), without surface expression of HLA-A, B or C. These HLA-engineered PSCs and their differentiated derivatives are not recognized as allogeneic by CD8 + T cells, do not bind anti-HLA antibodies and are resistant to NK-mediated lysis. Our approach provides a potential source of universal donor cells for applications where the differentiated derivatives lack HLA class II expression.

HLA-E-expressing pluripotent stem cells escape allogeneic responses and lysis by NK cells

Science.gov (United States)

Gornalusse, Germán G.; Hirata, Roli K.; Funk, Sarah; Riolobos, Laura; Lopes, Vanda S.; Manske, Gabriel; Prunkard, Donna; Colunga, Aric G.; Hanafi, Laïla-Aïcha; Clegg, Dennis O.; Turtle, Cameron; Russell, David W.

2017-01-01

Polymorphisms in the human leukocyte antigen (HLA) class I genes can cause the rejection of pluripotent stem cell (PSC)-derived products in allogeneic recipients. Disruption of the Beta-2 Microglobulin (B2M) gene eliminates surface expression of all class I molecules, but leaves the cells vulnerable to lysis by natural killer (NK) cells. Here we show that this ‘missing self’ response can be prevented by forced expression of minimally polymorphic HLA-E molecules. We use adeno-associated virus (AAV)-mediated gene editing to knock in HLA-E genes at the B2M locus in human PSCs in a manner that confers inducible, regulated, surface expression of HLA-E single-chain dimers (fused to B2M) or trimers (fused to B2M and a peptide antigen), without surface expression of HLA-A, B or C. These HLA-engineered PSCs and their differentiated derivatives are not recognized as allogeneic by CD8+ T cells, do not bind anti-HLA antibodies, and are resistant to NK-mediated lysis. Our approach provides a potential source of universal donor cells for applications where the differentiated derivatives lack HLA class II expression. PMID:28504668

HLA diversity in the 1000 genomes dataset.

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Pierre-Antoine Gourraud

Full Text Available The 1000 Genomes Project aims to provide a deep characterization of human genome sequence variation by sequencing at a level that should allow the genome-wide detection of most variants with frequencies as low as 1%. However, in the major histocompatibility complex (MHC, only the top 10 most frequent haplotypes are in the 1% frequency range whereas thousands of haplotypes are present at lower frequencies. Given the limitation of both the coverage and the read length of the sequences generated by the 1000 Genomes Project, the highly variable positions that define HLA alleles may be difficult to identify. We used classical Sanger sequencing techniques to type the HLA-A, HLA-B, HLA-C, HLA-DRB1 and HLA-DQB1 genes in the available 1000 Genomes samples and combined the results with the 103,310 variants in the MHC region genotyped by the 1000 Genomes Project. Using pairwise identity-by-descent distances between individuals and principal component analysis, we established the relationship between ancestry and genetic diversity in the MHC region. As expected, both the MHC variants and the HLA phenotype can identify the major ancestry lineage, informed mainly by the most frequent HLA haplotypes. To some extent, regions of the genome with similar genetic or similar recombination rate have similar properties. An MHC-centric analysis underlines departures between the ancestral background of the MHC and the genome-wide picture. Our analysis of linkage disequilibrium (LD decay in these samples suggests that overestimation of pairwise LD occurs due to a limited sampling of the MHC diversity. This collection of HLA-specific MHC variants, available on the dbMHC portal, is a valuable resource for future analyses of the role of MHC in population and disease studies.

Analysis of Luminex-based algorithms to define unacceptable HLA antibodies in CDC-crossmatch negative kidney transplant recipients.

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Zecher, Daniel; Bach, Christian; Preiss, Adrian; Staudner, Christoph; Utpatel, Kirsten; Evert, Matthias; Jung, Bettina; Bergler, Tobias; Böger, Carsten A; Spriewald, Bernd M; Banas, Bernhard

2018-02-20

HLA-specific antibodies detected by solid phase assays are increasingly used to define unacceptable HLA antigen mismatches (UAM) prior to renal transplantation. The accuracy of this approach is unclear. Day of transplant sera from 211 CDC-crossmatch-negative patients were retrospectively analyzed for donor-specific anti-HLA antibodies (DSA) using Luminex technology. HLA were defined as UAM if DSA had mean fluorescence intensity above (I) 3000 (patients retransplanted and those with DSA against HLA class I and II) or 5000 (all other patients), (II) 5000 for HLA A, B and DR and 10,000 for HLA DQ or (III) 10,000 (all HLA). We then studied the accuracy of these algorithms to identify patients with antibody-mediated rejection (AMR) and graft loss. UAM were also determined in 256 transplant candidates and virtual panel-reactive antibody (vPRA) levels calculated. At transplantation, 67/211 patients had DSA. Of these, 31 (algorithm I), 24 (II) and 17 (III) had UAM. 9 (I and II) and 8 (III) of 11 early AMR episodes and 7 (I), 6 (II) and 5 (III) of 9 graft losses occurred in UAM-positive patients during 4.9 years of follow-up. Algorithms (I) and (II) identified patients with persistently lower GFR even in the absence of overt AMR. 23-33% of waiting list patients had UAM with median vPRA of 69.2-79.1%. Algorithms (I) and (II) had comparable efficacy but were superior to (III) in identifying at-risk patients at an acceptable false positive rate. However, Luminex-defined UAM significantly restrict the donor pool of affected patients, which might prolong waiting time.

Familial concordance of phenotype and microbial variation among siblings with CF.

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Picard, Elie; Aviram, Micha; Yahav, Yaakov; Rivlin, Joseph; Blau, Hanna; Bentur, Lea; Avital, Avraham; Villa, Yael; Schwartz, Shepard; Kerem, Batsheva; Kerem, Eitan

2004-10-01

The clinical spectrum of cystic fibrosis (CF) is influenced by the cystic fibrosis transmembrane conductance regulator (CFTR) genotype. However, variable courses of the disease were demonstrated among patients with identical genotypes. Since siblings share identical CFTR mutations and environmental factors, they can serve as a model to assess the effect of modifier genes on disease expression, and also to evaluate cross-infection. The aim of this study was to compare disease expression among siblings with CF. All sibling pairs treated at 7 CF centers in Israel were included in the study. Data were collected from patients' medical charts. Fifty families with at least 2 siblings were identified. As expected, the second-born sibling was diagnosed at an earlier age compared to the first-born. The mode of CF presentation at diagnosis showed significant familial concordance. In the families where the first sibling presented with gastrointestinal manifestations, 79% of the second siblings also presented with gastrointestinal manifestations. When gastrointestinal manifestations were absent in the first sibling, only 12% of the second siblings presented with gastrointestinal manifestations (P sibling presented with respiratory symptoms, 60% of the second siblings presented with the similar symptoms. However, when the first sibling presented without respiratory symptoms, only 12% of the second siblings presented with respiratory symptoms (P sibling had MI, 8 (80%) of the subsequent siblings had MI. On the other hand, in the 39 families where the first-born sibling did not have MI, only 2 (5%) subsequent siblings had MI (P siblings. P. aeruginosa grew from sputum in 89% of our study patients. When P. aeruginosa was isolated from the first-born patient, 91% of the second siblings were also positive for P. aeruginosa, whereas when the initial sibling was not a carrier of P. aeruginosa, only 50% of subsequent siblings were positive (P sibling than in the first for the two

What Unrelated Hematopoietic Stem Cell Transplantation in Thalassemia Taught us about Transplant Immunogenetics

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La Nasa, Giorgio; Vacca, Adriana; Littera, Roberto; Piras, Eugenia; Orru, Sandro; Greco, Marianna; Carcassi, Carlo; Caocci, Giovanni

2016-01-01

Although the past few decades have shown an improvement in the survival and complication-free survival rates in patients with beta-thalassemia major and gene therapy is already at an advanced stage of experimentation, hematopoietic stem cell transplantation (HSCT) continues to be the only effective and realistic approach to the cure of this chronic non-malignant disease. Historically, human leukocyte antigen (HLA)-matched siblings have been the preferred source of donor cells owing to superior outcomes compared with HSCT from other sources. Nowadays, the availability of an international network of voluntary stem cell donor registries and cord blood banks has significantly increased the odds of finding a suitable HLA matched donor. Stringent immunogenetic criteria for donor selection have made it possible to achieve overall survival (OS) and thalassemia-free survival (TFS) rates comparable to those of sibling transplants. However, acute and chronic graft-versus-host disease (GVHD) remains the most important complication in unrelated HSCT in thalassemia, leading to significant rates of morbidity and mortality for a chronic non-malignant disease. A careful immunogenetic assessment of donors and recipients makes it possible to individualize appropriate strategies for its prevention and management. This review provides an overview of recent insights about immunogenetic factors involved in GVHD, which seem to have a potential role in the outcome of transplantation for thalassemia. PMID:27872728

WHAT UNRELATED HEMATOPOIETIC STEM CELL TRANSPLANTATION IN THALASSEMIA TAUGHT US ABOUT TRANSPLANT IMMUNOGENETICS.

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Giorgio La Nasa

2016-10-01

Full Text Available Abstract Although the past few decades have shown an improvement in the survival and complication-free survival rates in patients with beta-thalassemia major and gene therapy is already at an advanced stage of experimentation, hematopoietic stem cell transplantation (HSCT continues to be the only effective and realistic approach to the cure of this chronic non-malignant disease. Historically, human leukocyte antigen (HLA-matched siblings have been the preferred source of donor cells owing to superior outcomes compared with HSCT from other sources. Nowadays, the availability of an international network of voluntary stem cell donor registries and cordon blood banks has significantly increased the odds of finding a suitable HLA matched donor. Stringent immunogenetic criteria for donor selection have made it possible to achieve overall survival (OS and thalassemia-free survival (TFS rates comparable to those of sibling transplants. However, acute and chronic graft-versus-host disease (GVHD remains the most important complication in unrelated HSCT in thalassemia, leading to considerable rates of morbidity and mortality for a chronic non-malignant disease. A careful immunogenetic assessment of donors and recipients makes it possible to individuate appropriate strategies for its prevention and management. This review provides an overview on recent insights about immunogenetic factors involved in GVHD, which seem to have a potential role in the outcome of transplantation for thalassemia.

Significant Association of HLA-DQ5 with Autoimmune Hepatitis in Taiwan

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Lok-Beng Koay

2007-12-01

Full Text Available Genetic predisposition is known to be an important etiopathogenic factor of autoimmune hepatitis (AIH. HLA antigens associated with AIH have been well studied in Western countries and Japan, but there is no HLA typing data of AIH patients in Taiwan. We therefore investigated HLA phenotypes and their association with AIH patients and compared the results with those of normal subjects and patients with chronic liver disease. Group 1 consisted of 22 AIH patients. All were born in Taiwan with no history of blood transfusion. Group 2 consisted of 19 chronic liver disease patients. Group 3 consisted of 81 unrelated healthy subjects who were normal blood donors. All three groups were tested for HLA phenotypes (HLAA, B, C, DR, DQ using the polymerase chain reaction—sequence specific probe method. The statistical method used was Fisher's exact test. We found that HLA-DQ5 was significantly more frequent in the AIH group compared to the control group (RR, 2.03; p = 0.034. Low frequency of A1 (n = 2/22, B8 (n = 1/22 and DR3 (n = 0/22 were noted compared to results from the West; only HLA-DR4 showed a higher rate in our AIH patients (n = 8/22. This is a preliminary report of our study of HLA antigens in AIH patients. Further investigation to characterize AIH patients into HLA allelic subgroups is being done.

National Marrow Donor Program. HLA Typing for Bone Marrow Transplantation

Science.gov (United States)

2014-11-30

suggestion that low CFU doses were associated with delayed engraftment by day 28, but the effect disappeared by days 45 and 60 post transplant... chromosome 6, and non-HLA genetic factors may all influence the suitability and success of allogeneic stem cell transplants. The largest body of data...receptors (KIR) that specifically interact with MHC class I molecules. Genes encoding for these Ig-like ligands are found on chromosome 19. The

Permanent, lowered HLA class I expression using lentivirus vectors with shRNA constructs: Averting cytotoxicity by alloreactive T lymphocytes.

Science.gov (United States)

Haga, K; Lemp, N A; Logg, C R; Nagashima, J; Faure-Kumar, E; Gomez, G G; Kruse, C A; Mendez, R; Stripecke, R; Kasahara, N; Kasahara, N A; Cicciarelli, J C

2006-12-01

Transplantation of many tissues requires histocompatibility matching of human leukocyte antigens (HLA) to prevent graft rejection, to reduce the level of immunosuppression needed to maintain graft survival, and to minimize the risk of graft-versus-host disease, particularly in the case of bone marrow transplantation. However, recent advances in fields of gene delivery and genetic regulation technologies have opened the possibility of engineering grafts that display reduced levels of HLA expression. Suppression of HLA expression could help to overcome the limitations imposed by extensive HLA polymorphisms that restrict the availability of suitable donors, necessitate the maintenance of large donor registries, and complicate the logistics of procuring and delivering matched tissues and organs to the recipient. Accordingly, we investigated whether knockdown of HLA by RNA interference (RNAi), a ubiquitous regulatory system that can efficiently and selectively inhibit the expression of specific gene products, would enable allogeneic cells to evade immune recognition. For efficient and stable delivery of short hairpin-type RNAi constructs (shRNA), we employed lentivirus-based gene transfer vectors, which provide a delivery system that can achieve integration into genomic DNA, thereby permanently modifying transduced graft cells. Our results show that lentivirus-mediated delivery of shRNA targeting pan-Class I and allele-specific HLA can achieve efficient and dose-dependent reduction in surface expression of HLA in human cells, associated with enhanced resistance to alloreactive T lymphocyte-mediated cytotoxicity, while avoiding MHC-non-restricted killing. We hypothesize that RNAi-induced silencing of HLA expression has the potential to create histocompatibility-enhanced, and, eventually, perhaps "universally" compatible cellular grafts.

Quantification of transplant-derived circulating cell-free DNA in absence of a donor genotype.

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Eilon Sharon

2017-08-01

Full Text Available Quantification of cell-free DNA (cfDNA in circulating blood derived from a transplanted organ is a powerful approach to monitoring post-transplant injury. Genome transplant dynamics (GTD quantifies donor-derived cfDNA (dd-cfDNA by taking advantage of single-nucleotide polymorphisms (SNPs distributed across the genome to discriminate donor and recipient DNA molecules. In its current implementation, GTD requires genotyping of both the transplant recipient and donor. However, in practice, donor genotype information is often unavailable. Here, we address this issue by developing an algorithm that estimates dd-cfDNA levels in the absence of a donor genotype. Our algorithm predicts heart and lung allograft rejection with an accuracy that is similar to conventional GTD. We furthermore refined the algorithm to handle closely related recipients and donors, a scenario that is common in bone marrow and kidney transplantation. We show that it is possible to estimate dd-cfDNA in bone marrow transplant patients that are unrelated or that are siblings of the donors, using a hidden Markov model (HMM of identity-by-descent (IBD states along the genome. Last, we demonstrate that comparing dd-cfDNA to the proportion of donor DNA in white blood cells can differentiate between relapse and the onset of graft-versus-host disease (GVHD. These methods alleviate some of the barriers to the implementation of GTD, which will further widen its clinical application.

Unrelated alternative donor transplantation for severe acquired aplastic anemia: a study from the French Society of Bone Marrow Transplantation and Cell Therapies and the EBMT Severe Aplastic Anemia Working Party.

Science.gov (United States)

Devillier, Raynier; Dalle, Jean-Hugues; Kulasekararaj, Austin; D'aveni, Maud; Clément, Laurence; Chybicka, Alicja; Vigouroux, Stéphane; Chevallier, Patrice; Koh, Mickey; Bertrand, Yves; Michallet, Mauricette; Zecca, Marco; Yakoub-Agha, Ibrahim; Cahn, Jean-Yves; Ljungman, Per; Bernard, Marc; Loiseau, Pascale; Dubois, Valérie; Maury, Sébastien; Socié, Gérard; Dufour, Carlo; Peffault de Latour, Regis

2016-07-01

Unrelated allogeneic transplantation for severe aplastic anemia is a treatment option after immunosuppressive treatment failure in the absence of a matched sibling donor. Age, delay between disease diagnosis and transplantation, and HLA matching are the key factors in transplantation decisions, but their combined impact on patient outcomes remains unclear. Using the French Society of Bone Marrow Transplantation and Cell Therapies registry, we analyzed all consecutive patients (n=139) who underwent a first allogeneic transplantation for idiopathic severe aplastic anemia from an unrelated donor between 2000 and 2012. In an adjusted multivariate model, age over 30 years (Hazard Ratio=2.39; P=0.011), time from diagnosis to transplantation over 12 months (Hazard Ratio=2.18; P=0.027) and the use of a 9/10 mismatched unrelated donor (Hazard Ratio=2.14; P=0.036) were independent risk factors that significantly worsened overall survival. Accordingly, we built a predictive score using these three parameters, considering patients at low (zero or one risk factors, n=94) or high (two or three risk factors, n=45) risk. High-risk patients had significantly shorter survival (Hazard Ratio=3.04; Paplastic anemia. Copyright© Ferrata Storti Foundation.

Transfusion-related acute lung injury (TRALI in two thalassaemia patients caused by the same multiparous blood donor

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George J Kontoghiorghes

2017-10-01

Full Text Available Two separate episodes of transfusion-related acute lung injury (TRALI in thalassaemia patients caused by red blood cell transfusions from the same multiparous blood donor are reported. Both cases had the same symptomatology and occurred 10-60 minutes of transfusion. The patients presented dyspnea, sweating, fatigue, dizziness, fever, and sense of losing consciousness. The chest x-ray showed a pulmonary oedema-like picture with both lungs filled with fluid. The patients were treated in the intensive therapy unit. They were weaned off the ventilator and discharged following hospitalization 7 and 9 days respectively. The TRALI syndrome was diagnosed to be associated with HLA-specific donor antibodies against mismatched HLA-antigens of the transfused patients. Haemovigilance improvements are essential for reducing the morbidity and mortality in transfused patients. Blood from multiparous donors should be tested for the presence of IgG HLA-Class I and –Class II antibodies before being transfused in thalassaemia and other chronically transfused patients.

Targeting the Immunogenetic Diseases with the Appropriate HLA Molecular Typing: Critical Appraisal on 2666 Patients Typed in One Single Centre

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M. Guarene

2013-01-01

Full Text Available We compared the immunogenetic data from 2666 patients affected by HLA-related autoimmune diseases with those from 4389 ethnically matched controls (3157 cord blood donors CBD, 1232 adult bone marrow donors BMD, to verify the appropriateness of HLA typing requests received in the past decade. The frequency of HLA-B*27 phenotype was 10.50% in 724 ankylosing spondylitis, 16.80% in 125 uveitis (3.41% BMD, 4.24% CBD, P<0.0001; HLA-B*51 allele was 15.57% in 212 Behçet’s disease (12.91% BMD, 9.88% CBD, P<0.0001; the HLA-DRB1-rheumatoid arthritis (RA shared epitope was 13.72% in 554 RA (10.85% BMD, 13.48% CBD, P=0.016; the carriers of almost one of HLA-DQB1 susceptibility alleles were 84.91% in 795 celiac disease (CD and 59.37% in 256 insulin-dependent diabetes mellitus (IDDM (46.06% in 875 CBD, 42.75% in 662 BMD P<0.0001. Overall, our results show that the HLA marker frequencies were higher in patients than controls, but lower than expected from the literature data (excluding CD and IDDM and demonstrate that, in complex immunogenetic conditions, a substantial number of genetic analyses are redundant and inappropriate, burdening to the public health costs. For this reason, we suggest the Italian Scientific Society of Immunogenetics to establish guidelines to improve the appropriateness of typing requests.

[Sibling relations between individuation and attachment: attempt at a conceptualization].

Science.gov (United States)

Seiffge-Krenke, I

2001-01-01

Although sibling relationships can be considered as one of the most durable and intensive relationships, not much research in developmental psychology and family research has been done on this issue. The strong focus on parents, more specifically on mothers, stood in the way of adequate conceptualization and understanding of the function and contribution of siblings to individual development and family interaction. In this contribution a conceptualization of sibling relationships is presented. Siblings as objects of aggressive and sexual feelings as well as the function of siblings in the family system, for example, as parentification and negative identity is emphasized. In addition, the different qualities of sibling relationships, for example, envy, rivalry, similarity, and difference, are emphasized. The function of siblings as love objects is stressed, and the role of siblings as support as well as teaching object is illustrated. Finally, it is emphasized that, similar to relationships between parents and child, the quality of sibling relationships changed over time and leads, for example, to a detachment between sibling relationships during adolescence.

Post-Transplant Cyclophosphamide and Tacrolimus-Mycophenolate Mofetil Combination Prevents Graft-versus-Host Disease in Allogeneic Peripheral Blood Hematopoietic Cell Transplantation from HLA-Matched Donors.

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Carnevale-Schianca, Fabrizio; Caravelli, Daniela; Gallo, Susanna; Coha, Valentina; D'Ambrosio, Lorenzo; Vassallo, Elena; Fizzotti, Marco; Nesi, Francesca; Gioeni, Luisa; Berger, Massimo; Polo, Alessandra; Gammaitoni, Loretta; Becco, Paolo; Giraudo, Lidia; Mangioni, Monica; Sangiolo, Dario; Grignani, Giovanni; Rota-Scalabrini, Delia; Sottile, Antonino; Fagioli, Franca; Aglietta, Massimo

2017-03-01

Allogeneic hematopoietic cell transplant (HCT) remains the only curative therapy for many hematologic malignancies but it is limited by high nonrelapse mortality (NRM), primarily from unpredictable control of graft-versus-host disease (GVHD). Recently, post-transplant cyclophosphamide demonstrated improved GVHD control in allogeneic bone marrow HCT. Here we explore cyclophosphamide in allogeneic peripheral blood stem cell transplantation (alloPBSCT). Patients with high-risk hematologic malignancies received alloPBSCT from HLA-matched unrelated/related donors. GVHD prophylaxis included combination post-HCT cyclophosphamide 50 mg/kg (days +3 and +4) and tacrolimus/mofetil mycophenolate (T/MMF) (day +5 forward). The primary objective was the cumulative incidence of acute and chronic GVHD. Between March 2011 and May 2015, 35 consecutive patients received the proposed regimen. MMF was stopped in all patients at day +28; the median discontinuation of tacrolimus was day +113. Acute and chronic GVHD cumulative incidences were 17% and 7%, respectively, with no grade IV GVHD events, only 2 patients requiring chronic GVHD immunosuppression control, and no deaths from GVHD. Two-year NRM, overall survival, event-free survival, and chronic GVHD event-free survival rates were 3%, 77%, 54%, and 49%, respectively. The graft-versus-tumor effect was maintained as 5 of 15 patients (33%) who received HCT with evidence of disease experienced further disease response. A post-transplant cyclophosphamide + T/MMF combination strategy effectively prevented acute and chronic GVHD after alloPBSCT from HLA-matched donors and achieved an unprecedented low NRM without losing efficacy in disease control or impaired development of the graft-versus-tumor effect. This trial is registered at clinicaltrials.gov as NCT02300571. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Bone marrow transplantation in patients with Thalassemia

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Ghavamzadeh A

1993-05-01

Full Text Available During April, 1991 and September, 1993, eighteen patients with major thalassemia admitted to Shariati BMT center. Seventeen patients were transplanted were from HLA identical siblings and one from. his HLA identical father. Eleven of the donors were the known cases of minor thalassemia. The range of patients' age was within 3-10 years (with the average of 5 years and 11 months. Among them, seven patients were male and eleven were female. As the other international BMT centers, we classified our patients into three classes. Our criteria for this classification were hepatomegaly, ferretin, and liver fibrous; 60% of our patients were put in class I and 40% in class II. All of our patients revealed a GVHD (severe graft vs. host disease three weeks post-BMT as pruritus, diarrhea, and skin erythema especially in hands and feet. Two of the patients showed severe GVHD. One of the patients had chimerism after BMT. Although one year after BMT has passed, the patients is still depended on blood transfusion. One patient, despite graft rejection, died nine months post-BMT; another one died after +70 due to GVHD. During 2.5 years, the overall graft survival rate was 88% in our center

Living unrelated donor kidney transplantation: A fourteen-year experience

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Ignjatović Ljiljana

2010-01-01

Full Text Available Background. In countries without a national organization for retrieval and distribution of organs of the deceased donors, problem of organ shortage is still not resolved. In order to increase the number of kidney transplantations we started with the program of living unrelated - spousal donors. The aim of this study was to compare treatment outcome and renal graft function in patients receiving the graft from spousal and those receiving ghe graft from living related donors. Method. We retrospectively identified 14 patients who received renal allograft from spousal donors between 1996 and 2009 (group I. The control group consisted of 14 patients who got graft from related donor retrieved from the database and matched than with respect to sex, age, kidney disease, immunological and viral pretransplant status, the initial method of the end stage renal disease treatment and ABO compatibility. In the follow-up period of 41 ± 38 months we recorded immunosuppressive therapy, surgical complications, episodes of acute rejection, CMV infection and graft function, assessed by serum creatinine levels at the beginning and in the end of the follow-up period. All patients had pretransplant negative cross-match. In ABO incompatible patients pretransplant isoagglutinine titer was zero. Results. The patients with a spousal donor had worse HLA matching. There were no significant differences between the groups in surgical, infective, immunological complications and graft function. Two patients from the group I returned to hemodialysis after 82 and 22 months due to serious comorbidities. Conclusion. In spite of the worse HLA matching, graft survival and function of renal grafts from spousal donors were as good as those retrieved from related donors.

Expression of a Chimeric Antigen Receptor Specific for Donor HLA Class I Enhances the Potency of Human Regulatory T Cells in Preventing Human Skin Transplant Rejection.

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Boardman, D A; Philippeos, C; Fruhwirth, G O; Ibrahim, M A A; Hannen, R F; Cooper, D; Marelli-Berg, F M; Watt, F M; Lechler, R I; Maher, J; Smyth, L A; Lombardi, G

2017-04-01

Regulatory T cell (Treg) therapy using recipient-derived Tregs expanded ex vivo is currently being investigated clinically by us and others as a means of reducing allograft rejection following organ transplantation. Data from animal models has demonstrated that adoptive transfer of allospecific Tregs offers greater protection from graft rejection compared to polyclonal Tregs. Chimeric antigen receptors (CAR) are clinically translatable synthetic fusion proteins that can redirect the specificity of T cells toward designated antigens. We used CAR technology to redirect human polyclonal Tregs toward donor-MHC class I molecules, which are ubiquitously expressed in allografts. Two novel HLA-A2-specific CARs were engineered: one comprising a CD28-CD3ζ signaling domain (CAR) and one lacking an intracellular signaling domain (ΔCAR). CAR Tregs were specifically activated and significantly more suppressive than polyclonal or ΔCAR Tregs in the presence of HLA-A2, without eliciting cytotoxic activity. Furthermore, CAR and ΔCAR Tregs preferentially transmigrated across HLA-A2-expressing endothelial cell monolayers. In a human skin xenograft transplant model, adoptive transfer of CAR Tregs alleviated the alloimmune-mediated skin injury caused by transferring allogeneic peripheral blood mononuclear cells more effectively than polyclonal Tregs. Our results demonstrated that the use of CAR technology is a clinically applicable refinement of Treg therapy for organ transplantation. © 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.

The availability of full match sibling donors and feasibility of allogeneic bone marrow transplantation in Brazil

Directory of Open Access Journals (Sweden)

Eid K.A.B.

2003-01-01

Full Text Available The feasibility of allogeneic bone marrow transplantation (alloBMT in a developing country has not yet been demonstrated. Many adverse factors including social and economic limitations may reduce the overall results of this complex and expensive procedure. Our objective was to characterize the most important clinical, social and economic features of candidates for transplantation and their potential donors as well as the influence of these factors on overall survival in a retrospective and exploratory analysis at a university hospital. From July 1993 to July 2001, candidates for BMT were referred to the Bone Marrow Transplantation Unit by Hematology and Oncology Centers from several regions of Brazil. A total of 1138 patients were referred to us as candidates for alloBMT. Median age was 25 years (range: 2 months-60 years, 684 (60.1% were males and 454 (39.9% were females. The clinical indications were severe aplastic anemia and hematological malignancies. From the total of 1138 patients, 923 had HLA-typing; 497/923 (53.8% candidates had full match donors; 352/1138 (30.8% were eligible for alloBMT. Only 235 of 352 (66.7% were transplanted. Schooling was 1st to 8th grade for 123/235 (52.3%; monthly family income ranged from US$60 (7% to more than US$400 (36%. Overall survival for patients with chronic myeloid leukemia, severe aplastic anemia and acute myeloid leukemia was 58, 60 and 30%, respectively. Thus, overall survival rates for the most frequent hematological diseases were similar to those reported in the International Registry, except for acute myeloid leukemia. This descriptive and exploratory analysis suggests the feasibility of alloBMT in a developing country like Brazil.

HLA-DQA1 typing in Danes by two polymerase chain reaction (PCR) based methods

DEFF Research Database (Denmark)

Cowland, J B; Madsen, H O; Morling, N

1995-01-01

(ASA) method, which together recognise eight alleles. In 146 unrelated Danish individuals, the HLA-DQA1 alleles were in Hardy-Weinberg equilibrium. For identity testing, the power of discrimination (PD) of HLA-DQA1 was 0.932 with the RDB method and 0.942 with the PCR-RFLP/ASA method. For paternity...

Response to 'A relational approach to Saviour Siblings?' by Selgelid.

Science.gov (United States)

Taylor-Sands, Michelle

2016-10-01

In his concise argument, 'A relational approach to saviour siblings?', Selgelid reiterates some of the arguments raised in the author meets critics discussion of my book, Saviour Siblings In this response, I highlight an important misunderstanding in one of the arguments put forward by Selgelid, which forms the basis of a large portion of his analysis. Contrary to what Selgelid contends, I do not use the deafness case in my discussion of the non-identity problem to contend that the case of selecting for deafness is ethically different from the case of saviour siblings. As I state in my reply, I use the case of deafness not as a comparator for saviour siblings but rather to illustrate the different categories of risk that apply in selection cases Given this confusion, I restate my objection to relying on the non-identity problem in evaluating risk of harm associated with the embryo biopsy process for preimplantation genetic diagnosis. Finally, I reiterate that the individual interests of saviour siblings remain important in the decision-making matrix and emphasise that Saviour Siblings offers a more contextualised approach to the welfare of the child in selective reproduction, which includes both individual and collective interests. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Pyrosequencing™ : A one-step method for high resolution HLA typing

Directory of Open Access Journals (Sweden)

Marincola Francesco M

2003-11-01

Full Text Available Abstract While the use of high-resolution molecular typing in routine matching of human leukocyte antigens (HLA is expected to improve unrelated donor selection and transplant outcome, the genetic complexity of HLA still makes the current methodology limited and laborious. Pyrosequencing™ is a gel-free, sequencing-by-synthesis method. In a Pyrosequencing reaction, nucleotide incorporation proceeds sequentially along each DNA template at a given nucleotide dispensation order (NDO that is programmed into a pyrosequencer. Here we describe the design of a NDO that generates a pyrogram unique for any given allele or combination of alleles. We present examples of unique pyrograms generated from each of two heterozygous HLA templates, which would otherwise remain cis/trans ambiguous using standard sequencing based typing (SBT method. In addition, we display representative data that demonstrate long read and linear signal generation. These features are prerequisite of high-resolution typing and automated data analysis. In conclusion Pyrosequencing is a one-step method for high resolution DNA typing.

Probable C4d-negative accelerated acute antibody-mediated rejection due to non-HLA antibodies.

Science.gov (United States)

Niikura, Takahito; Yamamoto, Izumi; Nakada, Yasuyuki; Kamejima, Sahoko; Katsumata, Haruki; Yamakawa, Takafumi; Furuya, Maiko; Mafune, Aki; Kobayashi, Akimitsu; Tanno, Yudo; Miki, Jun; Yamada, Hiroki; Ohkido, Ichiro; Tsuboi, Nobuo; Yamamoto, Hiroyasu; Yokoo, Takashi

2015-07-01

We report a case of probable C4d-negative accelerated acute antibody-mediated rejection due to non-HLA antibodies. A 44 year-old male was admitted to our hospital for a kidney transplant. The donor, his wife, was an ABO minor mismatch (blood type O to A) and had Gitelman syndrome. Graft function was delayed; his serum creatinine level was 10.1 mg/dL at 3 days after transplantation. Open biopsy was performed immediately; no venous thrombosis was observed during surgery. Histology revealed moderate peritubular capillaritis and mild glomerulitis without C4d immunoreactivity. Flow cytometric crossmatching was positive, but no panel-reactive antibodies against HLA or donor-specific antibodies (DSAbs) to major histocompatibility complex class I-related chain A (MICA) were detected. Taken together, we diagnosed him with probable C4d-negative accelerated antibody-mediated rejection due to non-HLA, non-MICA antibodies, the patient was treated with steroid pulse therapy (methylprednisolone 500 mg/day for 3 days), plasma exchange, intravenous immunoglobulin (40 g/body), and rituximab (200 mg/body) were performed. Biopsy at 58 days after transplantation, at which time S-Cr levels were 1.56 mg/dL, found no evidence of rejection. This case, presented with a review of relevant literature, demonstrates that probable C4d-negative accelerated acute AMR can result from non-HLA antibodies. © 2015 Asian Pacific Society of Nephrology.

Subtotal body irradiation with linear accelerator as preparation for marrow engraftment in aplastic anemia

International Nuclear Information System (INIS)

Walbom-Joergensen, S.; Ernst, P.

1979-01-01

Two cases of multitransfused severe aplastic anemia were retransplanted with bone marrow from the same HLA compatible sibling donors after subtotal body irradiation (800 r). Only minor non hematologic toxicity was observed. No permanent take was seen in relation to this procedure. During the survival time of the patients (78-120 days) no signs of interstitial pneumonia were observed

Reduced-intensity conditioning and HLA-matched haemopoietic stem-cell transplantation in patients with chronic granulomatous disease: a prospective multicentre study.

Science.gov (United States)

Güngör, Tayfun; Teira, Pierre; Slatter, Mary; Stussi, Georg; Stepensky, Polina; Moshous, Despina; Vermont, Clementien; Ahmad, Imran; Shaw, Peter J; Telles da Cunha, José Marcos; Schlegel, Paul G; Hough, Rachel; Fasth, Anders; Kentouche, Karim; Gruhn, Bernd; Fernandes, Juliana F; Lachance, Silvy; Bredius, Robbert; Resnick, Igor B; Belohradsky, Bernd H; Gennery, Andrew; Fischer, Alain; Gaspar, H Bobby; Schanz, Urs; Seger, Reinhard; Rentsch, Katharina; Veys, Paul; Haddad, Elie; Albert, Michael H; Hassan, Moustapha

2014-02-01

In chronic granulomatous disease allogeneic haemopoietic stem-cell transplantation (HSCT) in adolescents and young adults and patients with high-risk disease is complicated by graft-failure, graft-versus-host disease (GVHD), and transplant-related mortality. We examined the effect of a reduced-intensity conditioning regimen designed to enhance myeloid engraftment and reduce organ toxicity in these patients. This prospective study was done at 16 centres in ten countries worldwide. Patients aged 0-40 years with chronic granulomatous disease were assessed and enrolled at the discretion of individual centres. Reduced-intensity conditioning consisted of high-dose fludarabine (30 mg/m(2) [infants HLA-matched related-donors or HLA-9/10 or HLA-10/10 matched unrelated-donors were infused. The primary endpoints were overall survival and event-free survival (EFS), probabilities of overall survival and EFS at 2 years, incidence of acute and chronic GVHD, achievement of at least 90% myeloid donor chimerism, and incidence of graft failure after at least 6 months of follow-up. 56 patients (median age 12·7 years; IQR 6·8-17·3) with chronic granulomatous disease were enrolled from June 15, 2003, to Dec 15, 2012. 42 patients (75%) had high-risk features (ie, intractable infections and autoinflammation), 25 (45%) were adolescents and young adults (age 14-39 years). 21 HLA-matched related-donor and 35 HLA-matched unrelated-donor transplants were done. Median time to engraftment was 19 days (IQR 16-22) for neutrophils and 21 days (IQR 16-25) for platelets. At median follow-up of 21 months (IQR 13-35) overall survival was 93% (52 of 56) and EFS was 89% (50 of 56). The 2-year probability of overall survival was 96% (95% CI 86·46-99·09) and of EFS was 91% (79·78-96·17). Graft-failure occurred in 5% (three of 56) of patients. The cumulative incidence of acute GVHD of grade III-IV was 4% (two of 56) and of chronic graft-versus-host disease was 7% (four of 56). Stable (≥90%) myeloid

Reduced-intensity conditioning allogeneic SCT as salvage treatment for relapsed multiple myeloma.

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de Lavallade, H; El-Cheikh, J; Faucher, C; Fürst, S; Stoppa, A-M; Coso, D; Bouabdallah, R; Chabannon, C; Gastaut, J-A; Blaise, D; Mohty, M

2008-06-01

The aim of this retrospective analysis was to assess the benefit of reduced-intensity conditioning allo SCT (RIC allo-SCT) in a cohort of 32 relapsed multiple myeloma (MM) patients. A total of 19 patients had an HLA-identical sibling donor ('donor' group), while 13 patients had no donor ('no-donor' group). There were no significant differences between these two groups as for prognosis risk factors. Eighteen patients from the 'donor' group could actually proceed to RIC allo-SCT. With a median follow-up of 36 (range, 21-60) months, six patients died from transplant-related toxicity (cumulative incidence, 33% (95% CI, 11-55%)). Only 4 patients from the 18 transplanted patients (22%; 95% CI, 7-48%) progressed after RIC allo-SCT, as compared to 12 (86%; 95% CI, 56-98%; P=0.0003) among the nontransplanted patients. In an 'intention-to-treat' analysis, the Kaplan-Meier estimate of PFS was significantly higher in the 'donor' group as compared to the 'no-donor' group (P=0.01; 46 versus 8% at 3 years). There was no difference in terms of overall survival. However, in multivariate analysis, actual performance of RIC allo-SCT was associated with better PFS (relative risk, 0.35; 95% CI, 0.15-0.82; P=0.01). These data suggest a potential benefit for RIC allo-SCT in the management of relapsed MM warranting further prospective investigations.

Post-transplant outcome in chronic myeloid leukemia

International Nuclear Information System (INIS)

Raza, S.; Ullah, K.; Ahmed, P.; Kamal, M.K.

2008-01-01

To determine post-transplant survival in chronic myeloid leukaemia patients undergoing allogeneic stem cell transplant. All patients of chronic myeloid leukaemia in chronic phase having HLA identical donor and age under 55 years, normal hepatic, renal and cardiac functions with good performance status were selected. Patients in accelerated phase or blast crisis, poor performance status, impaired hepatic, renal, cardiac functions or pregnancy were excluded. Survival was calculated from the date of transplant to death or last follow-up according to Kaplan-Meier and Cox (proportional hazard) regression analysis methods. Thirty seven patients with chronic myeloid leukaemia underwent allogeneic stem cell transplant from HLA identical sibling donors. Thirty two patients were male and five were females. Median age of patients was 28 years. All patients and donors were CMV positive. Post-transplant complications encountered were acute GvHD (Grade II-IV) (n=13, 35.1%), chronic GvHD in 18.9% (n=7), Veno Occlusive Disease (VOD) in 5.4% (n=2), acute renal failure in 2.7% (n=1), haemorrhagic cystitis in 2.7% (n=1), bacterial infections in 40.5% (n=15), fungal infections in 16.2% (n=6), CMV infection in 5.4% (n=2), tuberculosis in 5.4% (n=2), Herpes Zoster infection 2.7% (n=1) and relapse in 2.7% (n=1). Mortality was observed in 27% (n=10). Major causes of mortality were GvHD, VOD, septicemia, CMV infection and disseminated Aspergillosis. Overall Disease Free Survival (DFS) was 73% with a median duration of follow-up of 47.4 + 12 months. DFS was 81% in standard risk and 54.5% in high-risk group. Results of allogeneic stem cell transplant in standard risk group CML patients were good and comparable with other international centres, however, results in high-risk CML patients need further improvement, although, number of patients in this group is small. (author)

HLA AND CROSS·REACTIVE ANTIGEN GROUP MATCHING FOR CADAVER KIDNEY ALLOCATION1

Science.gov (United States)

Starzl, Thomas E.; Eliasziw, Michael; Gjertson, David; Terasaki, Paul I.; Fung, John J.; Trucco, Massimo; Martell, Joan; McMichael, John; Scantlebury, Velma; Shapiro, Ron; Donner, Allan

2010-01-01

Background Allocation of cadaver kidneys by graded human leukocyte antigen (HLA) compatibility scoring arguably has had little effect on overall survival while prejudicing the transplant candidacy of African-American and other hard to match populations. Consequently, matching has been proposed of deduced amino acid residues of the individual HLA molecules shared by cross-reactive antigen groups (CREGs). We have examined the circumstances under which compatibility with either method impacted graft survival. Methods Using Cox proportional hazards regression modeling, we studied the relationship between levels of conventional HLA mismatch and other donor and recipient factors on primary cadaver kidney survival between 1981 and 1995 at the University of Pittsburgh (n=1,780) and in the United Network for Organ Sharing (UNOS) Scientific Registry during 1991–1995 (n=31,291). The results were compared with those obtained by the matching of amino acid residues that identified CREG-compatible cases with as many as four (but not five and six) HLA mismatches. Results With more than one HLA mismatch (>85% of patients in both series), most of the survival advantage of a zero mismatch was lost. None of the HLA loci were “weak.” In the UNOS (but not Pittsburgh) category of one-HLA mismatch (n=1334), a subgroup of CREG-matched recipients (35.3%) had better graft survival than the remaining 64.7%, who were CREG-mismatched. There was no advantage of a CREG match in the two- to four-HLA incompatibility tiers. Better graft survival with tacrolimus was observed in both the Pittsburgh and UNOS series. Conclusions Obligatory national sharing of cadaver kidneys is justifiable only for zero-HLA-mismatched kidneys. The potential value of CREG matching observed in the one-HLA-mismatched recipients of the UNOS (but not the Pittsburgh) experience deserves further study. PMID:9381546

HIV control through a single nucleotide on the HLA-B locus

DEFF Research Database (Denmark)

Kløverpris, Henrik N; Harndahl, Mikkel; Leslie, Alasdair J

2012-01-01

Genetic variation within the HLA-B locus has the strongest impact on HIV disease progression of any polymorphisms within the human genome. However, identifying the exact mechanism involved is complicated by several factors. HLA-Bw4 alleles provide ligands for NK cells and for CD8 T cells, and str......Genetic variation within the HLA-B locus has the strongest impact on HIV disease progression of any polymorphisms within the human genome. However, identifying the exact mechanism involved is complicated by several factors. HLA-Bw4 alleles provide ligands for NK cells and for CD8 T cells......:02, which differ by only a single amino acid. Crucially, they occur primarily on identical HLA class I haplotypes and, as Bw6 alleles, do not act as NK cell ligands and are therefore largely unconfounded by other genetic factors. We show that in an outbred cohort (n = 2,093) of HIV C......-clade-infected individuals, a single amino acid change at position 9 of the HLA-B molecule critically affects peptide binding and significantly alters the cytotoxic T lymphocyte (CTL) epitopes targeted, measured directly ex vivo by gamma interferon (IFN-γ) enzyme-linked immunospot (ELISPOT) assay (P = 2 × 10...

Analysis of platelet eluate for the elucidation of sensitization to HLA in kidney transplant candidate

Directory of Open Access Journals (Sweden)

Hugo Mendonça Mundim

2015-07-01

Full Text Available While a 42-year-old male patient was being prepared for deceased-donor renal transplantation, anti-HLA-A2 antibodies were detected in the serum by enzyme-linked immunosorbent assay (ELISA method. The patient denied any transfusion history and previous transplant. Crossmatch by complement dependent cytotoxicity (CDC and CDC with anti-human globulin (CDC-AHG proved negative with a four-cell panel with positive typing for HLA-A2. Adsorption of antibodies with platelets and analysis of eluate were suggested to elucidate discrepancies in results by ELISA and by CDC-AHG. ELISA showed that adsorbed serum with platelets did not reveal antibodies for HLA-A2 specificity and suggested that they were removed by their specific binding with HLA-A2 antigens on the platelet surface. Eluate analysis by ELISA showed antibodies for HLA-A2 specificity. No antibodies for HLA-A2 specificity in the non-adsorbed serum were detected by CDC-AHG method. Revision of patient’s data showed that a previous transfusion had occurred, which may have been the source of HLA sensitization. The suggested method may be a contribution towards the evaluation of sensitivity between CDC-AHG and ELISA methods for characterizing antibodies in the patient’s serum.

Successful ABO-Incompatible Renal Transplantation:  Blood Group A1B Donor Into A2B Recipient With Anti-A1 Isoagglutinins.

Science.gov (United States)

Fadeyi, Emmanuel A; Stratta, Robert J; Farney, Alan C; Pomper, Gregory J

2016-08-01

Transplantation of the blood group A2B in a recipient was successfully performed in the setting of receiving a deceased donor kidney from an "incompatible" A1B donor. The donor and recipient were both typed for ABO blood group, including ABO genotyping. The donor and recipient were tested for ABO, non-ABO, and human leukocyte antigen (HLA) antibodies. The donor and recipient were typed for HLA antigens, including T- and B-flow cytometry crossmatch tests. The recipient's RBCs were negative with A1 lectin, and immunoglobulin G anti-A1 was demonstrated in the recipient's plasma. The donor-recipient pair was a four-antigen HLA mismatch, but final T- and B-flow cytometry crossmatch tests were compatible. The transplant procedure was uneventful; the patient experienced immediate graft function with no episodes of rejection or readmissions more than 2 years later. It may be safe to transplant across the A1/A2 blood group AB mismatch barrier in the setting of low titer anti-A1 isoagglutinins without the need for pretransplant desensitization even if the antibody produced reacts with anti-human globulin. © American Society for Clinical Pathology, 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

16(th) IHIW: analysis of HLA population data, with updated results for 1996 to 2012 workshop data (AHPD project report).

Science.gov (United States)

Riccio, M E; Buhler, S; Nunes, J M; Vangenot, C; Cuénod, M; Currat, M; Di, D; Andreani, M; Boldyreva, M; Chambers, G; Chernova, M; Chiaroni, J; Darke, C; Di Cristofaro, J; Dubois, V; Dunn, P; Edinur, H A; Elamin, N; Eliaou, J-F; Grubic, Z; Jaatinen, T; Kanga, U; Kervaire, B; Kolesar, L; Kunachiwa, W; Lokki, M L; Mehra, N; Nicoloso, G; Paakkanen, R; Voniatis, D Papaioannou; Papasteriades, C; Poli, F; Richard, L; Romón Alonso, I; Slavčev, A; Sulcebe, G; Suslova, T; Testi, M; Tiercy, J-M; Varnavidou, A; Vidan-Jeras, B; Wennerström, A; Sanchez-Mazas, A

2013-02-01

We present here the results of the Analysis of HLA Population Data (AHPD) project of the 16th International HLA and Immunogenetics Workshop (16IHIW) held in Liverpool in May-June 2012. Thanks to the collaboration of 25 laboratories from 18 different countries, HLA genotypic data for 59 new population samples (either well-defined populations or donor registry samples) were gathered and 55 were analysed statistically following HLA-NET recommendations. The new data included, among others, large sets of well-defined populations from north-east Europe and West Asia, as well as many donor registry data from European countries. The Gene[rate] computer tools were combined to create a Gene[rate] computer pipeline to automatically (i) estimate allele frequencies by an expectation-maximization algorithm accommodating ambiguities, (ii) estimate heterozygosity, (iii) test for Hardy-Weinberg equilibrium (HWE), (iv) test for selective neutrality, (v) generate frequency graphs and summary statistics for each sample at each locus and (vi) plot multidimensional scaling (MDS) analyses comparing the new samples with previous IHIW data. Intrapopulation analyses show that HWE is rarely rejected, while neutrality tests often indicate a significant excess of heterozygotes compared with neutral expectations. The comparison of the 16IHIW AHPD data with data collected during previous workshops (12th-15th) shows that geography is an excellent predictor of HLA genetic differentiations for HLA-A, -B and -DRB1 loci but not for HLA-DQ, whose patterns are probably more influenced by natural selection. In Europe, HLA genetic variation clearly follows a north to south-east axis despite a low level of differentiation between European, North African and West Asian populations. Pacific populations are genetically close to Austronesian-speaking South-East Asian and Taiwanese populations, in agreement with current theories on the peopling of Oceania. Thanks to this project, HLA genetic variation is more

HLA-typing analysis following allogeneic bone grafting for sinus lifting.

Science.gov (United States)

Piaia, Marcelo; Bub, Carolina Bonet; Succi, Guilherme de Menezes; Torres, Margareth; Costa, Thiago Henrique; Pinheiro, Fabricio Costa; Napimoga, Marcelo Henrique

2017-03-01

According to the Brazilian Association of Organ Transplants, in 2015, 19,408 bone transplants were performed in Brazil, over 90% by Dental Surgeons. The surgical technique itself has a respectable number of reports regarding its clinical efficacy, as measured by long-term survival of dental implants in grafted areas. Uncertainty remains, however, as to whether fresh frozen grafts from human bone donors remain immunologically innocuous in the body of the host. Six male with no previous medical history of note, including systemic diseases, surgery or blood transfusion were selected. These patients underwent reconstructive procedures (sinus lifting) using fresh frozen human bone from a tissue bank. All patients had venous blood samples collected prior to surgery and 6 months after the procedure. Anti-HLA analysis for the detection of HLA (human leukocyte antigen) antibodies was performed using methods such as the LABScreen PRA Class I and Class II, LABScreen Single Antigen Class I and Class II, Luminex Platform. Reactive individuals to the screening tests (LABScreen PRA) were further investigated to determine the specificity of the antibodies detected (LABScreen Single Antigen) with a cutoff value of median fluorescence intensity ≥500. As a result, it was observed that two patients (33%) were positive in screening tests, one presenting with anti-HLA Class I and II sensitization and the other with anti-HLA class II. The specificity analysis showed that the patients sensitized to HLA class II presented 4 specificities, 3 of which immunologically relevant. In the second individual, 23 specificities were identified, 6 of which immunologically important for HLA class I and 4 specificities for HLA class II, 3 of these were immunologically important. All specificities detected had average fluorescence. These findings are suggestive that sinus-lifting procedures with allogeneic bone can induce immunological sensitization.

Influence of kinship on donors' mental burden in living donor liver transplantation.

Science.gov (United States)

Erim, Yesim; Beckmann, Mingo; Kroencke, Sylvia; Sotiropoulos, Georgios C; Paul, Andreas; Senf, Wolfgang; Schulz, Karl-Heinz

2012-08-01

In the context of living donor liver transplantation (LDLT), German transplantation law stipulates that donor candidates should primarily be relatives of the recipients or persons with distinct and close relationships. In this study, we investigated the influence of the relationship between the donor and the recipient on the donor's emotional strain before transplantation. Donors were categorized according to the following subgroups: (1) parents donating for their children, (2) children donating for their parents, (3) siblings, (4) spouses, (5) other relatives, and (6) nonrelatives. The sample consisted of 168 donor candidates. Anxiety (F = 2.8, P = 0.02), depression (F = 2.6, P = 0.03), and emotional quality of life (F = 3.1, P = 0.01) differed significantly according to the relationship between the donor and the recipient. In comparison with healthy controls, parents donating for their children were significantly less stressed before LDLT and demonstrated fewer anxiety (P depression symptoms (P < 0.05). Adult children donating for their parents demonstrated the highest mental burden and the lowest emotional quality of life. However, this was not due to the responsibility of these children for their own families because differences between donors with children and donors without children could not be ascertained. This group should be given special attention before LDLT and during follow-up visits, and psychological help should be provided when it is necessary. Copyright © 2012 American Association for the Study of Liver Diseases.

The Human Figure Drawing with Donor and Nondonor Siblings of Pediatric Bone Marrow Transplant Patients.

Science.gov (United States)

Packman, Wendy L.; Beck, Vanessa L.; VanZutphen, Kelly H.; Long, Janet K.; Spengler, Gisele

2003-01-01

There is little research on the psychological impact of bone marrow transplantation (BMT) on family members. This study uses the Human Figure Drawing (HFD) to measure siblings' emotional distress toward BMT. Among the siblings, feelings of isolation, anger, depression, anxiety, and low self-esteem emerged as major themes. Findings indicate the…

Relevance of MICA and other non-HLA antibodies in clinical transplantation.

Science.gov (United States)

Sumitran-Holgersson, Suchitra

2008-10-01

The clinical importance of HLA-specific antibodies for organ allograft outcome is well established. In the past few years, there has been an increasing interest in non-HLA antigens as targets of injury in organ transplant recipients. This increased interest has been spurred by the fact that HLA-identical kidney transplants also undergo immunological rejections. Polymorphisms within non-HLA genes associated with evoking an immune response to alloantigens are currently being studied for their association with transplant outcome. Non-HLA antigens, such as the polymorphic MHC class I-related chain A (MICA), expressed on endothelial cells have been implicated in the pathogenesis of hyperacute, acute and chronic organ allograft rejections. Use of endothelial cells as targets may clarify the specificities of other clinically relevant non-HLA antibodies in graft rejections. This review summarizes past and current knowledge of the clinical importance and specificities of non-HLA antibodies, and mechanisms by which these antibodies may contribute to graft destruction in clinical transplantation. The aims of current research into the role of non-HLA antigens and their genetics in predicting outcome are to develop an improved insight into the basic science of transplantation and to develop a risk or prognostic index for use in the clinical setting. Non-HLA antibody responses are receiving increasing interest in acute and chronic rejection and specificity, affinity, and pathogenicity need to be investigated to estimate their contribution. Undoubtedly, this will continue to be an area of interest in terms of fully understanding the role of non-HLA antigens as targets of immune-mediated injury and the potential for clinical intervention.

Unravelling the role of allo-antibodies and Transplant Injury

Directory of Open Access Journals (Sweden)

Yoshiko Matsuda

2016-10-01

Full Text Available Alloimmunity driving rejection in the context of solid organ transplantation can be grossly divided into mechanisms predominantly driven by either T cell-mediated rejection (TCMR or antibody-mediated rejection (ABMR, though the co-existence of both types of rejections can be seen in a variable number of sampled grafts. Acute TCMR can generally be well controlled by the establishment of effective immunosuppression 1, 2. Acute ABMR is a low frequency finding in the current era of blood group and HLA donor/recipient matching and the avoidance of engraftment in the context of high-titer, pre-formed donor specific antibodies. However, chronic ABMR remains a major complication resulting in the untimely loss of transplanted organs 3-10. The close relationship between donor-specific antibodies (DSAs and ABMR has been revealed by the highly sensitive detection of human leukocyte antigen (HLA antibodies 11-16. Injury to transplanted organs by activation of humoral immune reaction in the context of HLA identical transplants and the absence of donor specific antibodies (DSAs, strongly suggest the participation of non HLA (nHLA antibodies in ABMR (17-25. In this review, we discuss the genesis of ABMR in the context of HLA and nHLA antibodies and summarize strategies for ABMR management.

Association between HLA-DR2 and production of tumour necrosis factor alpha and interleukin 1 by mononuclear cells activated by lipopolysaccharide

DEFF Research Database (Denmark)

Bendtzen, K; Morling, N; Fomsgaard, A

1988-01-01

The production of tumour necrosis factor (TNF) and interleukin 1 (IL-1) by lipopolysaccharide-activated mononuclear cells from 39 healthy donors was studied in vitro by bioassay and ELISA. The donors were typed for HLA-A, -B, -C, -DR, and -DP antigens. There was no detectable production of TNF be...

Transplantation tolerance after total lymphoid irradiation

Energy Technology Data Exchange (ETDEWEB)

Strober, S.; Slavin, S.; Fuks, Z.; Kaplan, H.S.; Gottlieb, M.; Bieber, C.; Hoppe, R.T.; Grumet, F.C.

1979-03-01

We have presented an animal model of tissue transplantation tolerance using the unusual effects of TLI on the immune system. The application of TLI to bone marrow and whole-organ transplantation in humans merits further study, since TLI offers several advantages over presently used therapeutic modalities. Current regimens used to prepare patients for marrow transplantation are lethal in the absence of allogeneic marrow engraftment, and marrow donors are restricted to HLA-matched siblings due to the danger of GHVD. On the other hand, TLI is a nonlethal procedure that has been used successfully in animals to transplant allogeneic marrow from unmatched donors without the development of GHVD. Thus, TLI might allow for marrow transplantation in all patients with a single sibling, whereas conventional procedures are feasible in only one of four such cases (probability of finding a single HLA-matched sibling). In addition, the induction of transplantation tolerance with TLI would obviate the requirement for the use of maintenance immunosuppressive drugs after whole-organ transplantation. Systemic infections associated with the use of these drugs currently account for the majority of deaths in heart transplant patients. Serious infectious complications associated with TLI are rare; thus this therapeutic regimen may offer considerable improvement in the long-term survival of organ graft recipients as compared to that presently obtained with immunosuppressive drugs.

HLA-A, -B, and -DR zero-mismatched kidneys shipped to the University of Wisconsin, Madison, 1993-2006: superior graft survival despite longer preservation time.

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Burlingham, William J; Muñoz del Rio, Alejandro; Lorentzen, David; Sollinger, Hans W; Pirsch, John D; Jankowska-Gan, Ewa; D'Alessandro, Anthony

2010-08-15

To determine the impact at a single center of the United Network for Organ Sharing-mandated sharing program for human leukocyte antigen (HLA)-A/-B/-DR 0-mismatched (0MM) kidneys, we analyzed the results of 264 kidney transplants from 0MM distant donors between 1993 and 2006, with a follow-up through January 31, 2007. We compared these results with that of concurrent kidneys transplanted from HLA more than 0MM local donors and with shipped more than 0MM kidneys from "payback" donors. Despite a significantly longer preservation time, we found an 11% increase in 8-year graft survival (63% vs. 52%; P0MM donor kidneys. Graft survival of 0MM shipped kidneys at 8 years was significantly better in nonsensitized (or=20% panel reactive antibodies) recipients, who showed an early (2 years) but short-lived benefit. The benefit of receiving a HLA-A, -B, and -DR 0MM shipped kidney remained strong and statistically significant (0.71 relative risk of graft loss vs. local; POrgan Sharing policy restricting mandated sharing of 0MM kidneys to sensitized and pediatric recipients will give greater flexibility to the local organ procurement organization in allocating organs. However, the survival benefit to nonsensitized patients is real and long lasting and will be lost.

A perspective on the selection of unrelated donors and cord blood units for transplantation

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Spellman, Stephen R.; Eapen, Mary; Logan, Brent R.; Mueller, Carlheinz; Rubinstein, Pablo; Setterholm, Michelle I.; Woolfrey, Ann E.; Confer, Dennis L.; Hurley, Carolyn K.

2012-01-01

Selection of a suitable graft for allogeneic hematopoietic stem cell transplantation involves consideration of both donor and recipient characteristics. Of primary importance is sufficient donor-recipient HLA matching to ensure engraftment and acceptable rates of GVHD. In this Perspective, the National Marrow Donor Program and the Center for International Blood and Marrow Transplant Research provide guidelines, based on large studies correlating graft characteristics with clinical transplantation outcomes, on appropriate typing strategies and matching criteria for unrelated adult donor and cord blood graft selection. PMID:22596257

The Kinetic Family Drawing with Donor and Nondonor Siblings of Pediatric Bone Marrow Transplant Patients.

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Packman, Wendy L.; Crittenden, Mary R.; Fischer, Jodie B. Rieger; Cowan, Morton J.; Long, Janet K.; Gruenert, Carol; Schaeffer, Evonne; Bongar, Bruce

1998-01-01

Utilizes the Kinetic Family Drawings-Revised (KFD-R) to measure siblings' (N=44) feelings and attitudes toward bone marrow transplants. Data from drawings and discussions with siblings underscore that not all children are affected by stress in the same way. How a particular child responds depends on factors such as life history, personality,…

Assessment of Impact of HLA Type on Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation for Chronic Lymphocytic Leukemia.

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Hill, Brian T; Ahn, Kwang Woo; Hu, Zhen-Huan; Aljurf, Mahmoud; Beitinjaneh, Amer; Cahn, Jean-Yves; Cerny, Jan; Kharfan-Dabaja, Mohamed A; Ganguly, Siddhartha; Ghosh, Nilanjan; Grunwald, Michael R; Inamoto, Yoshihiro; Kindwall-Keller, Tamila; Nishihori, Taiga; Olsson, Richard F; Saad, Ayman; Seftel, Matthew; Seo, Sachiko; Szer, Jeffrey; Tallman, Martin; Ustun, Celalettin; Wiernik, Peter H; Maziarz, Richard T; Kalaycio, Matt; Alyea, Edwin; Popat, Uday; Sobecks, Ronald; Saber, Wael

2018-03-01

Chronic lymphocytic leukemia (CLL) is a common hematologic malignancy with many highly effective therapies. Chemorefractory disease, often characterized by deletion of chromosome 17p, has historically been associated with very poor outcomes, leading to the application of allogeneic hematopoietic stem cell transplantation (allo-HCT) for medically fit patients. Although the use of allo-HCT has declined since the introduction of novel targeted therapy for the treatment of CLL, there remains significant interest in understanding factors that may influence the efficacy of allo-HCT, the only known curative treatment for CLL. The potential benefit of transplantation is most likely due to the presence of alloreactive donor T cells that mediate the graft-versus-leukemia (GVL) effect. The recognition of potentially tumor-specific antigens in the context of class I and II major histocompatibility complex on malignant B lymphocytes by donor T cells may be influenced by subtle differences in the highly polymorphic HLA locus. Given previous reports of specific HLA alleles impacting the incidence of CLL and the clinical outcomes of allo-HCT for CLL, we sought to study the overall survival and progression-free survival of a large cohort of patients with CLL who underwent allo-HCT from fully HLA-matched related and unrelated donors at Center for International Blood and Marrow Transplant Research transplantation centers. We found no statistically significant association of allo-HCT outcomes in CLL based on previously reported HLA combinations. Additional study is needed to further define the immunologic features that portend a more favorable GVL effect after allo-HCT for CLL. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Living donor risk model for predicting kidney allograft and patient survival in an emerging economy.

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Zafar, Mirza Naqi; Wong, Germaine; Aziz, Tahir; Abbas, Khawar; Adibul Hasan Rizvi, S

2018-03-01

Living donor kidney is the main source of donor organs in low to middle income countries. We aimed to develop a living donor risk model that predicts graft and patient survival in an emerging economy. We used data from the Sindh Institute of Urology and Transplantation (SIUT) database (n = 2283 recipients and n = 2283 living kidney donors, transplanted between 1993 and 2009) and conducted Cox proportional hazard analyses to develop a composite score that predicts graft and patient survivals. Donor factors age, creatinine clearance, nephron dose (estimated by donor/recipient body weight ratio) and human leukocyte antigen (HLA) match were included in the living donor risk model. The adjusted hazard ratios (HRs) for graft failures among those who received a kidney with living donor scores (reference to donor score of zero) of 1, 2, 3 and 4 were 1.14 (95%CI: 0.94-1.39), 1.24 (95%CI:1.03-1.49), 1.25 (95%CI:1.03-1.51) and 1.36 (95%CI:1.08-1.72) (P-value for trend =0.05). Similar findings were observed for patient survival. Similar to findings in high income countries, our study suggests that donor characteristics such as age, nephron dose, creatinine clearance and HLA match are important factors that determine the long-term patient and graft survival in low income countries. However, other crucial but undefined factors may play a role in determining the overall risk of graft failure and mortality in living kidney donor transplant recipients. © 2016 Asian Pacific Society of Nephrology.

HLA polymorphism in a Guarani-Indian population from Paraguay and its usefulness for the Hispano-Indian admixture study in Paraguay.

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Benitez, O; Busson, M; Charron, D; Loiseau, P

2011-02-01

In this study we investigated the human leucocyte antigen-A (HLA-A), -B and DRB1 polymorphism of Native American population of Paraguay, the Guarani Indians. We found that the HLA variability consisted of 5 HLA-A, 7 HLA-B and 6 HLA-DRB1 groups of alleles and of several specific alleles (B*1504, B*3505, B*3912, B*4004, B*5104, DRB1*0411, DRB1*1413) common in other Native American populations. The comparison of the HLA polymorphism of the Guaranis from Paraguay with the «Mestizos» of Paraguay and the Spaniards showed that the «Mestizos» of Paraguay are genetically very distant from the Guarani Indians of Paraguay but much more close to the Spaniards. This can be explained, at least in part, by the history of the country. Our results are of importance in transplantation, in particular in the search for an unrelated donor for a Paraguayan patient requiring hematopoietic stem cell transplantation. © 2010 Blackwell Publishing Ltd.

A glow of HLA typing in organ transplantation

Science.gov (United States)

2013-01-01

The transplant of organs and tissues is one of the greatest curative achievements of this century. In organ transplantation, the adaptive immunity is considered the main response exerted to the transplanted tissue, since the main goal of the immune response is the MHC (major histocompatibility complex) molecules expressed on the surface of donor cells. Cell surface molecules that induce an antigenic stimulus cause the rejection immune response to grafted tissue or organ. A wide variety of transplantation antigens have been described, including the major histocompatibility molecules, minor histocompatibility antigens, ABO blood group antigens and endothelial cell antigens. The sensitization to MHC antigens may be caused by transfusions, pregnancy, or failed previous grafts leading to development of anti-human leukocyte antigen (HLA) antibodies that are important factor responsible for graft rejection in solid organ transplantation and play a role in post-transfusion complication Anti-HLA Abs may be present in healthy individuals. Methods for HLA typing are described, including serological methods, molecular techniques of sequence-specific priming (SSP), sequence-specific oligonucleotide probing (SSOP), Sequence based typing (SBT) and reference strand-based conformation analysis (RSCA) method. Problems with organ transplantation are reservoir of organs and immune suppressive treatments that used to decrease rate of rejection with less side effect and complications. PMID:23432791

HLA-A, HLA-B, and HLA-DRB1 Allele and Haplotype Frequencies in Renal Transplant Candidates in a Population in Southern Brazil.

Science.gov (United States)

Saito, Patrícia Keiko; Yamakawa, Roger Haruki; Noguti, Erika Noda; Bedendo, Gustavo Borelli; Júnior, Waldir Veríssimo da Silva; Yamada, Sérgio Seiji; Borelli, Sueli Donizete

2016-05-01

Very few studies have examined the diversity of human leukocyte antigens (HLA) in the Brazilian renal transplant candidates. The frequencies of the HLA-A, HLA-B, and HLA-DRB1 alleles, haplotypes and phenotypes were studied in 522 patients with chronic renal failure, renal transplant candidates, registered at the Transplant Centers in north/northwestern Paraná State, southern Brazil. Patients were classified according to the ethnic group (319 whites [Caucasians], 134 mestizos [mixed race descendants of Europeans, Africans, and Amerindians; browns or "pardos"] and 69 blacks). The HLA typing was performed by the polymerase chain reaction sequence-specific oligonucleotide method (PCR-SSO), combined with Luminex technology. In the analysis of the total samples, 20 HLA-A, 32 HLA-B, and 13 HLA-DRB1 allele groups were identified. The most frequent allele groups for each HLA locus were HLA-A*02 (25.4%), HLA-B*44 (10.9%), and HLA-DRB1*13 (13.9%). The most frequent haplotypes were HLA-A*01-B*08-DRB1*03 (2.3%), A*02-B*44-DRB1*07 (1.2%), and A*03-B*07-DRB1*11 (1.0%). Significant differences (P < 0.05) were observed in the HLA-A*68, B*08, and B*58 allele frequencies among ethnic groups. This study provides the first data on the HLA-A, HLA-B, and HLA-DRB1 allele, phenotype and haplotype frequencies of renal transplant candidates in a population in southern Brazil. © 2015 Wiley Periodicals, Inc.

Computer Algorithms in the Search for Unrelated Stem Cell Donors

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David Steiner

2012-01-01

Full Text Available Hematopoietic stem cell transplantation (HSCT is a medical procedure in the field of hematology and oncology, most often performed for patients with certain cancers of the blood or bone marrow. A lot of patients have no suitable HLA-matched donor within their family, so physicians must activate a “donor search process” by interacting with national and international donor registries who will search their databases for adult unrelated donors or cord blood units (CBU. Information and communication technologies play a key role in the donor search process in donor registries both nationally and internationaly. One of the major challenges for donor registry computer systems is the development of a reliable search algorithm. This work discusses the top-down design of such algorithms and current practice. Based on our experience with systems used by several stem cell donor registries, we highlight typical pitfalls in the implementation of an algorithm and underlying data structure.

KIR and HLA interactions are associated with control of primary CMV infection in solid organ transplant recipients.

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van Duin, D; Avery, R K; Hemachandra, S; Yen-Lieberman, B; Zhang, A; Jain, A; Butler, R S; Barnard, J; Schold, J D; Fung, J; Askar, M

2014-01-01

Cytomegalovirus (CMV) infection remains a major source of morbidity and mortality in solid organ transplant recipients. Killer immunoglobulin-like receptors(KIR) are genetically polymorphic natural killer(NK) cell receptors important in antiviral responses. A retrospective, single-center cohort study was performed to study the interaction of KIR genotype and primary control of CMV infection after transplantation.Time to first CMV viremia was determined for a cohort of 531 CMV serology donor positive/recipient negative solid organ transplant recipients. Of the KIR genes,KIR2DL3 and KIR2DS2 were most strongly associated with time to CMV viremia in random survival forest analysis. As KIR2DL3 and KIR2DS2 both interact with HLA-C1, these interactions were evaluated. Seventy six recipients were found to be positive for both KIR2DL3 and KIR2DS2 and expressed only HLA-C1 antigens in both recipient and donor. These patients had a substantially reduced hazard of CMV viremia in the first year after solid organ transplantation (hazard ratio 0.44, 95% CI 0.27–0.72, p=0.0012). In KIR2DL3+/KIR2DS2+/HLA-C1/1 recipients who received an organ from a non-C1/1 donor, this protective effect was not observed. These results improve our understanding of human NK cell function in primary CMV infection after transplant.

Outcome after Desensitization in HLA or ABO-Incompatible Kidney Transplant Recipients: A Single Center Experience.

Science.gov (United States)

Kauke, Teresa; Klimaschewski, Sandra; Schoenermarck, Ulf; Fischereder, Michael; Dick, Andrea; Guba, Markus; Stangl, Manfred; Werner, Jens; Meiser, Bruno; Habicht, Antje

2016-01-01

The shortage of deceased donors led to an increase of living donor kidney (LDK) transplantations performed in the presence of donor-specific antibodies (DSA) or ABO incompatibility (ABOi) using various desensitization protocols. We herein analyzed 26 ABOi and 8 Luminex positive DSA patients who were successfully desensitized by anti-CD20, antigen-specific immunoadsorption and/or plasmapheresis to receive an LDK transplant. Twenty LDK recipients with non-donor-specific HLA-antibodies (low risk) and 32 without anti-HLA antibodies (no risk) served as control groups. 1-year graft survival rate and renal function was similar in all 4 groups (creatinine: 1.63 ± 0.5 vs 1.78 ± 0.6 vs 1.64 ± 0.5 vs 1.6 ± 0.3 mg/dl in ABOi, DSA, low risk and no risk group). The incidence of acute T-cell mediated rejections did not differ between the 4 groups (15% vs 12, 5% vs 15% vs 22% in ABOi, DSA, low risk and no risk), while antibody-mediated rejections were only found in the DSA (25%) and ABOi (7.5%) groups. Incidence of BK nephropathy (BKVN) was significantly more frequent after desensitization as compared to controls (5/34 vs 0/52, p = 0.03). We demonstrate favorable short-term allograft outcome in LDK transplant recipients after desensitization. However, the desensitization was associated with an increased risk of BKVN.

Characterization of CD4 T Cell Epitopes of Infliximab and Rituximab Identified from Healthy Donors

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Moustafa Hamze

2017-05-01

Full Text Available The chimeric antibodies anti-CD20 rituximab (Rtx and anti-TNFα infliximab (Ifx induce antidrug antibodies (ADAs in many patients with inflammatory diseases. Because of the key role of CD4 T lymphocytes in the initiation of antibody responses, we localized the CD4 T cell epitopes of Rtx and Ifx. With the perspective to anticipate immunogenicity of therapeutic antibodies, identification of the CD4 T cell epitopes was performed using cells collected in healthy donors. Nine T cell epitopes were identified in the variable chains of both antibodies by deriving CD4 T cell lines raised against either Rtx or Ifx. The T cell epitopes often exhibited a good affinity for human leukocyte antigen (HLA-DR molecules and were part of the peptides identified by MHC-associated peptide proteomics assay from HLA-DR molecules of dendritic cells (DCs loaded with the antibodies. Two-third of the T cell epitopes identified from the healthy donors stimulated peripheral blood mononuclear cells from patients having developed ADAs against Rtx or Ifx and promoted the secretion of a diversity of cytokines. These data emphasize the predictive value of evaluating the T cell repertoire of healthy donors and the composition of peptides bound to HLA-DR of DCs to anticipate and prevent immunogenicity of therapeutic antibodies.

Older Siblings Influence Younger Siblings' Motor Development

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Berger, Sarah E.; Nuzzo, Katie

2008-01-01

Evidence exists for two competing theories about the effects of having an older sibling on development. Previous research has found that having an older sibling has both advantages and disadvantages for younger siblings' development. This study examined whether and how older siblings influenced the onset of their own younger siblings' motor…

Intra-osseous injection of donor mesenchymal stem cell (MSC) into the bone marrow in living donor kidney transplantation; a pilot study.

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Lee, Hyunah; Park, Jae Berm; Lee, Sanghoon; Baek, Soyoung; Kim, HyunSoo; Kim, Sung Joo

2013-04-11

Mesenchymal stem cells (MSCs) are multi-potent non-hematopoietic progenitor cells possessing an immune-regulatory function, with suppression of proliferation of activated lymphocytes. In this study, adult living donor kidney transplantation (LDKT) recipients were given MSCs derived from the donor bone marrow to evaluate the safety and the feasibility of immunological changes related to the intra-osseous injection of MSC into the bone marrow. MSCs were derived from negative HLA cross-match donors. Donor bone marrow was harvested 5 weeks prior to KT. At the time of transplantation, 1 x 106 cell/kg of donor MSC was directly injected into the bone marrow of the recipient's right iliac bone. Patients' clinical outcomes, presence of mixed chimerism by short tandem repeat polymerase chain reaction, analysis of plasma FoxP3 mRNA and cytokine level, and mixed lymphocyte reaction (MLR) were performed. Seven patients enrolled in this study and received donor MSC injections simultaneously with LDKT. The median age of recipients was 36 years (32 ~ 48). The number of HLA mismatches was 3 or less in 5 and more than 3 in 2. No local complications or adverse events such as hypersensitivity occurred during or after the injection of donor MSC. There was no graft failure, but the biopsy-proven acute rejections were observed in 3 recipients during the follow-up period controlled well with steroid pulse therapy (SPT). The last serum creatinine was a median of 1.23 mg/dL (0.83 ~ 2.07). Mixed chimerism was not detected in the peripheral blood of the recipients at 1 and 8 week of post-transplantation. Donor-specific lymphocyte or T cell proliferation and Treg priming responses were observed in some patients. Plasma level of IL-10, a known mediator of MSC-induced immune suppression, increased in the patients with Treg induction. Donor MSC injection into the iliac bone at the time of KT was feasible and safe. A possible correlation was observed between the induction of inhibitory

Peptide Binding to HLA Class I Molecules: Homogenous, High-Throughput Screening, and Affinity Assays

DEFF Research Database (Denmark)

Harndahl, Mikkel; Justesen, Sune Frederik Lamdahl; Lamberth, Kasper

2009-01-01

, better signal-to-background ratios, and a higher capacity. They also describe an efficient approach to screen peptides for binding to HLA molecules. For the occasional user, this will serve as a robust, simple peptide-HLA binding assay. For the more dedicated user, it can easily be performed in a high-throughput...... the luminescent oxygen channeling immunoassay technology (abbreviated LOCI and commercialized as AlphaScreen (TM)). Compared with an enzyme-linked immunosorbent assay-based peptide-HLA class I binding assay, the LOCI assay yields virtually identical affinity measurements, although having a broader dynamic range...... screening mode using standard liquid handling robotics and 384-well plates. We have successfully applied this assay to more than 60 different HLA molecules, leading to more than 2 million measurements. (Journal of Biomolecular Screening 2009: 173-180)...

Renal en Paraguay anti-HLA antibodies monitoring in patients with chronic renal failure on waiting list for renal transplant in Paraguay

OpenAIRE

Fernanda Prieto; Claudia Cabañas; Verónica Villagra

2016-01-01

Introduction: Anti-HLA antibodies determination in the serum of patients on a waiting list for renal transplant is essential to optimize donor selection as well as for the induction and maintenance immunosuppression scheme, according to immunological risk. These antibodies could be present before transplantation as a result of being exposed to blood transfusions, pregnancies and previous transplants. The objective of the study was to determine immunization against HLA antigens, associated fac...

The impact of disclosure on donor gamete participants: donors, intended parents and offspring.

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Greenfeld, Dorothy A

2008-06-01

The present review examines recent publications that provide insight into how the trend toward nonanonymity and disclosure in gamete donation impacts donors, intended parents, and their donor-conceived children. Recent findings show an increase in donor programs that offer open-identity between donors and offspring. The psychological needs of gamete donors and their attitudes toward disclosure are increasingly given consideration. Qualitative research on how parents of donor gamete offspring make decisions about disclosure reveals that even when couples initially disagree about disclosing to offspring, most ultimately come to a united disclosure decision. The literature on the impact of disclosure on donor gamete offspring has extended to include children conceived through embryo donation and children born as a result of surrogacy. The absence of genetic or gestational link between parents and their child does not have a negative impact on parent-child relationships. Parents through surrogacy tend to disclose the method of family creation to their child, whereas parents through embryo donation tend to be secretive about their child's origins. The trend toward greater openness in gamete donation has been accompanied by an increase in programs offering open-identity donation. In addition, the psychological needs of gamete donors and their attitudes toward disclosure are increasingly being given consideration. Parents of donor gamete offspring give careful thought to their disclosure decisions, and the psychological well being of donor-conceived children does not seem to be impacted by those decisions.

Clinical relevance of pre and post-transplant immune markers in kidney allograft recipients: anti-HLA and MICA antibodies and serum levels of sCD30 and sMICA.

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Solgi, Ghasem; Furst, Daniel; Mytilineos, Joannis; Pourmand, Gholamreza; Amirzargar, Ali Akbar

2012-03-01

This retrospective study aims to determine the prognostic values of HLA and MICA antibodies, serum levels of sCD30 and soluble form of MHC class I related chain A (sMICA) in kidney allograft recipients. Sera samples of 40 living unrelated donor kidney recipients were tested by ELISA and Flow beads techniques for the presence of anti HLA and MICA antibodies and the contents of sCD30 and sMICA. HLA and MICA antibody specification was performed by LABScreen single antigen beads to determine whether the antibodies were directed against donor mismatches. Within first year post operatively 9 of 40 patients (22.5%) showed acute rejection episodes (ARE) that four of them lost their grafts compared to 31 functioning transplants (P=0.001). The presence of HLA antibodies before and after transplantation was significantly associated with ARE (P=0.01 and P=0.02 respectively). Sensitization to HLA class II antigens pre-transplant was strongly associated with higher incidence of ARE (P=0.004). A significant correlation was found between ARE and appearance of non-donor specific antibodies (P=0.02). HLA antibody positive patients either before or after transplantation showed lower graft survival rates than those without antibodies during three years follow-up (P=0.04 and P=0.02). Anti-MICA antibodies were observed in 8/40(20%) and 5/40(12.5%) of patients pre and post-transplant respectively. Coexistence of HLA and MICA antibodies was shown in 2 of 4 cases with graft loss. A significant increased level of sCD30 at day 14 (P=0.001) and insignificant decreased levels of sMICA pre and post operatively were detected in rejecting transplants compared to functioning graft group. Our findings support the view that monitoring of HLA and MICA antibodies as well as sCD30 levels early after transplant has predictive value for early and late allograft dysfunctions and the presence of these factors are detrimental to graft function and survival. Copyright © 2012 Elsevier B.V. All rights

The Royan Public Umbilical Cord Blood Bank: Does It Cover All Ethnic Groups in Iran Based on HLA Diversity?

Science.gov (United States)

Ebrahimkhani, Saeideh; Farjadian, Shirin; Ebrahimi, Marzieh

2014-04-01

Umbilical cord blood (UCB) stem cells allow the transplantation of partially human leukocyte antigen (HLA)-matched grafts and are a valuable resource for the treatment of hematologic malignancies and heritable hematologic, immunologic and metabolic diseases, especially when a compatible bone marrow donor is unavailable. The aim of this study was to determine how many ethnic groups in Iran are covered by the available UCB units based on HLA diversity. From 2009 until mid-2013, 4,981 (30.3%) of the 16,437 UCB samples collected met the storage criteria and were cryopreserved at a public cord blood bank (CBB) in Tehran, Iran. HLA-A, -B and -DRB1 were typed in 1,793 samples. The mean volume of the cryopreserved samples was 81.25 ± 20.3 ml. The range of total nucleated cells per unit was 51 × 10(7)-107 × 10(7). The most common HLA alleles were HLA-A*2 (17%) and HLA-A*24 (15.6%), HLA-B*35 (16.8%) and HLA-B*51 (13.9%), and HLA-DRB1*11 (20%) and HLA-DRB1*15 (14%). The predominant haplotypes were HLA-A*24-B*35-DRB1*11 (2%), HLA-A*02-B*50-DR*07 (1.8%), and HLA-A*02-B*51-DRB1*11 (1.5%). Based on the HLA-DRB1 profiles, the UCB units available at the Royan public UCB bank are a potentially adequate resource for hematopoietic stem cell transplantation for Iranian recipients belonging to particular ethnic groups. Regular educational programs to improve the public knowledge of UCB for transplantation can enhance the public CBB stocks for all Iranian ethnic groups in the future.

Usefulness of the nonself-self algorithm of HLA epitope immunogenicity in the specificity analysis of monospecific antibodies induced during pregnancy

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Rene J Duquesnoy

2015-05-01

Full Text Available Background HLAMatchmaker is a program to analyze the epitope specificities of HLA antibodies. It considers each HLA allele as a string of eplets. Intralocus and interlocus comparisons between donor and recipient alleles offer a structural assessment of compatibility and an analysis of allele panel reactivity patterns can generate information about epitope specificities of HLA antibodies. However, HLAMatchmaker cannot always generate conclusive interpretations of reactivity patterns of all monospecific antibodies which by definition recognize single epitopes. Hypothesis We have therefore developed a new antibody analysis approach that utilizes the nonself-self algorithm of HLA epitope immunogenicity. It is based in the concept that HLA antibodies originate from B-cells with immunoglobulin receptors to self HLA epitopes on one given allele and which can be activated by epitopes defined by a few nonself residue differences whereas the remainder of the structural epitope of the immunizing allele consists of self residues. Methods Three human monoclonal class I antibodies from HLA typed women sensitized during pregnancy were tested in Ig-binding assays with single alleles on a Luminex platformFindings Three new HLA epitopes were identified; they are defined by combinations of nonself and self residues for one allele of the antibody producer. Conclusion The nonself-self paradigm of HLA epitope immunogenicity offers a second approach to analyze HLA antibody specificities.

My sister's keeper?: genomic research and the identifiability of siblings

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Kohane Isaac S

2008-07-01

Full Text Available Abstract Background Genomic sequencing of SNPs is increasingly prevalent, though the amount of familial information these data contain has not been quantified. Methods We provide a framework for measuring the risk to siblings of a patient's SNP genotype disclosure, and demonstrate that sibling SNP genotypes can be inferred with substantial accuracy. Results Extending this inference technique, we determine that a very low number of matches at commonly varying SNPs is sufficient to confirm sib-ship, demonstrating that published sequence data can reliably be used to derive sibling identities. Using HapMap trio data, at SNPs where one child is homozygotic major, with a minor allele frequency ≤ 0.20, (N = 452684, 65.1% we achieve 91.9% inference accuracy for sibling genotypes. Conclusion These findings demonstrate that substantial discrimination and privacy risks arise from use of inferred familial genomic data.

Scripts for TRUMP data analyses. Part II (HLA-related data): statistical analyses specific for hematopoietic stem cell transplantation.

Science.gov (United States)

Kanda, Junya

2016-01-01

The Transplant Registry Unified Management Program (TRUMP) made it possible for members of the Japan Society for Hematopoietic Cell Transplantation (JSHCT) to analyze large sets of national registry data on autologous and allogeneic hematopoietic stem cell transplantation. However, as the processes used to collect transplantation information are complex and differed over time, the background of these processes should be understood when using TRUMP data. Previously, information on the HLA locus of patients and donors had been collected using a questionnaire-based free-description method, resulting in some input errors. To correct minor but significant errors and provide accurate HLA matching data, the use of a Stata or EZR/R script offered by the JSHCT is strongly recommended when analyzing HLA data in the TRUMP dataset. The HLA mismatch direction, mismatch counting method, and different impacts of HLA mismatches by stem cell source are other important factors in the analysis of HLA data. Additionally, researchers should understand the statistical analyses specific for hematopoietic stem cell transplantation, such as competing risk, landmark analysis, and time-dependent analysis, to correctly analyze transplant data. The data center of the JSHCT can be contacted if statistical assistance is required.

HLA-G and IL-10 in serum in relation to HLA-G genotype and polymorphisms

DEFF Research Database (Denmark)

Hviid, Thomas Vauvert F; Rizzo, Roberta; Christiansen, Ole B

2004-01-01

-mediated cell lysis and influence cytokine expression. Recently, a possible boarder immunoregulatory function of HLA-G also in adult life has been recognized. HLA-G gene polymorphism has been linked to differences in gene expression profile of alternatively spliced HLA-G transcripts and levels of specific HLA......% of the serum samples sHLA-G1/HLA-G5 could be detected. There was no correlation between sHLA-G1/HLA-G5 and IL-10 concentrations in serum. Soluble HLA-G1/HLA-G5 was not detected in any samples homozygous for a 14-bp insertion polymorphism in exon 8 of the 3'-untranslated region (3'UTR) of the HLA-G gene ( P=0...

HLA-G allelic variants are associated with differences in the HLA-G mRNA isoform profile and HLA-G mRNA levels

DEFF Research Database (Denmark)

Hviid, Thomas Vauvert F; Hylenius, Sine; Rørbye, Christina

2003-01-01

between mother and fetus in several ways. Finally, the expression of membrane-bound HLA-G and soluble HLA-G has been proposed to influence the outcome of pregnancy, and an aberrant HLA-G expression in pre-eclamptic placentas and spontaneous abortions has been reported. Here, an association between certain...... HLA-G polymorphisms and the mRNA levels of the different alternatively spliced HLA-G isoforms in first trimester trophoblast cell populations is reported. Several alternatively spliced HLA-G mRNA isoforms, including a 14-bp polymorphism in the 3'UTR end (exon 8) of the HLA-G gene, are expressed...

Co-infusion of haplo-identical CD19-chimeric antigen receptor T cells and stem cells achieved full donor engraftment in refractory acute lymphoblastic leukemia

Directory of Open Access Journals (Sweden)

Bo Cai

2016-11-01

Full Text Available Abstract Background Elderly patients with relapsed and refractory acute lymphoblastic leukemia (ALL have poor prognosis. Autologous CD19 chimeric antigen receptor-modified T (CAR-T cells have potentials to cure patients with B cell ALL; however, safety and efficacy of allogeneic CD19 CAR-T cells are still undetermined. Case presentation We treated a 71-year-old female with relapsed and refractory ALL who received co-infusion of haplo-identical donor-derived CD19-directed CAR-T cells and mobilized peripheral blood stem cells (PBSC following induction chemotherapy. Undetectable minimal residual disease by flow cytometry was achieved, and full donor cell engraftment was established. The transient release of cytokines and mild fever were detected. Significantly elevated serum lactate dehydrogenase, alanine transaminase, bilirubin and glutamic-oxalacetic transaminase were observed from days 14 to 18, all of which were reversible after immunosuppressive therapy. Conclusions Our preliminary results suggest that co-infusion of haplo-identical donor-derived CAR-T cells and mobilized PBSCs may induce full donor engraftment in relapsed and refractory ALL including elderly patients, but complications related to donor cell infusions should still be cautioned. Trial registration Allogeneic CART-19 for Elderly Relapsed/Refractory CD19+ ALL. NCT02799550

Distribution of HLA-A,B alleles in 13 panels of blood donors in France.

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Prevost, P; Busson, M; Marcelli-Barge, A

1984-05-01

In this study, we analysed 13 samples of the French population--4147 non-related individuals living in Bordeaux, Brest, Caen, Dijon, Limoges, Lyon, Marseille, Nancy, Paris, Poitiers, Rennes, Strasbourg and Toulouse--all of whom were typed for 10 alleles of the HLA-A locus and 16 alleles of the HLA-B locus. The results showed a strong heterogeneity (chi 2 = 675.13 for 324 df, p less than 10(5)). A diagram has been drawn up, showing the matrix of genetic distances obtained thanks to the B2 of Balkrishnan & Sanghvi (1968). This diagram enables us to envisage the hypothesis of 6 homogeneous clusters. A partition of chi 2 was used to test this 6 luster hypothesis: Paris and Caen (p = 0.98); Nancy, Strasbourg (p less than 5%); Rennes, Brest (p less than 1%); Dijon, Lyon, Marseille (p = 0.89); Limoges, Poitiers (p = 0.18); Toulouse, Bordeaux (p less than 10(-5)). The heterogeneity within these clusters represents only 1/43 of the total heterogeneity.

Clinicopathologic significance of HLA-G and HLA-E molecules in Tunisian patients with ovarian carcinoma.

Science.gov (United States)

Babay, Wafa; Ben Yahia, Hamza; Boujelbene, Nadia; Zidi, Nour; Laaribi, Ahmed Baligh; Kacem, Dhikra; Ben Ghorbel, Radhia; Boudabous, Abdellatif; Ouzari, Hadda-Imene; Rizzo, Roberta; Rebmann, Vera; Mrad, Karima; Zidi, Inès

2018-06-01

The human leukocyte antigen (HLA)-G and HLA-E, non classical HLA class I molecules, have been highly implicated in immune tolerance. HLA-G and HLA-E molecules were proposed as putative markers of several advanced cancers. As a step towards a better understanding of ovarian carcinoma, we evaluated the expression of both HLA-G and HLA-E molecules and explored their prognostic implication. HLA-G and HLA-E expression were studied by immunohistochemistry on ovarian carcinoma tissues. This expression was semi-quantitatively scored into four expression groups and correlated to clinicopathological parameters and patients' survival. HLA-G and HLA-E have been found to be highly expressed in ovarian carcinoma tissues (Respectively, 72.4% and 96.8%). They are frequently co-expressed. Univariate and multivariate analysis revealed that a positive HLA-G expression status in tumor tissue is a promising candidate parameter to predict disease recurrence in addition to the disease status in Tunisian patients with ovarian carcinoma. Moreover, the elevated HLA-E expression was associated with serous ovarian carcinoma subtype as well as with advanced stages of ovarian carcinoma. HLA-G and HLA-E are highly represented in ovarian carcinoma suggesting a potential association with progressive disease mechanism. HLA-G and HLA-E molecules might be new candidates' markers for ovarian carcinoma progression. Copyright © 2018 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

Presence of HLA-B27 is associated with changes of serum levels of mediators of the Wnt and hedgehog pathway.

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Aschermann, Sarah; Englbrecht, Matthias; Bergua, Antonio; Spriewald, Bernd M; Said-Nahal, Rhula; Breban, Maxime; Schett, Georg; Rech, Jürgen

2016-01-01

HLA-B27 is present in 5% of the Caucasian population and is strongly associated with the development of spondyloarthritis (SpA), a disease characterized by inflammation and substantial bone changes. We hypothesized that the presence of HLA-B27 in itself is associated with alterations of key regulatory of bone homeostasis. Sera of 241 individuals were assessed for the serum levels of Wnt pathway regulators, sclerostin and dickkopf (Dkk)-1 as well as Indian hedgehog (IHH) and collagen type I cleavage products (CTX1). Of the 151 HLA-B27+ subjects, 31 had SpA, 30 had anterior uveitis, 30 were healthy individuals and 60 healthy siblings of patients with SpA. Sclerostin levels were significantly (P<0.001) lower in HLA-B27+ subjects (314±21pg/mL) compared to HLA-B27 negative controls (mean±SEM: 492±30pg/mL), no matter if subjects were either healthy, or affected by SpA or uveitis. Similar results were found for Dkk-1. No differences between the groups with respect to the bone resorption marker CTX1 were found. In contrast, IHH levels were significantly (P<0.001) higher in the carriers of HLA-B27 than in the negative controls. Changes in key regulators of the Wnt pathway as well as IHH, a molecule regulating endochondral ossification, are found in HLA-B27 carriers, independent if they were healthy or affected by uveitis or SpA. Copyright © 2015 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.

Failure of lymphocyte-membrane HLA-A and -B expression in two siblings with combined immunodeficiency

NARCIS (Netherlands)

Schuurman, R.K.B.; Rood, J.J. van; Vossen, J.M.; Schellekens, P.Th.A.; Feltkamp-Vroom, Th.M.; Doyer, E.; Gmelig Meyling, F.H.J.; Visser, H.K.A.

1979-01-01

A diagnosis of partial combined immunodeficiency was made in two Turkish siblings with a history of multiple pyogenic infections and persistent candidiasis. They demonstrated severe hypo-γ-globulinemia, with B-lymphocytes, but deficient plasma cell differentiation. T-Lymphocytes were decreased in

THE TRUE IDENTITY OF COPELAND'S AQUATIC SCUTTLE FLY (DIPTERA: PHORIDAE) FROM INDIANA AND RECOGNITION OF A SIBLING SPECIES FROM TEXAS.

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Disney, R Henry L; Copeland, Robert S; Murrell, Ebony

2009-07-01

Among the insects reported by Copeland (1989) breeding in the waters retained by treeholes in Indiana was a scuttle fly identified by W. H. Robinson as Megaselia scalaris (Loew). It is here reported that in fact this fly, along with fresh material from Illinois and Missouri, is M. imitatrix Borgmeier, whose type series was from Puerto Rico. An aquatic species reported from Texas is recognized as a sibling species of M. imitatrix and is named M. hansonix Disney, sp. nov. A single female from Brazil represents a third species of this complex, thus raising doubts about the identity of specimens from Brazil attributed to M. imitatrix by Benton and Claugher (2000).

HLA-B*14

DEFF Research Database (Denmark)

Leitman, Ellen M.; Willberg, Christian B.; Tsai, Ming Han

2017-01-01

Immune control of human immunodeficiency virus type 1 (HIV) infection is typically associated with effective Gag-specific CD8+ T-cell responses. We here focus on HLA-B*14, which protects against HIV disease progression, but the immunodominant HLA-B*14-restricted anti-HIV response is Env specific...... higher functional avidity (P associated protection against HIV disease progression...... is significantly greater for HLA-B*14:02 than for HLA-B*14:01, consistent with the superior antiviral efficacy of the HLA-B*14-EL9 response. Thus, although Gag-specific CD8+ T-cell responses may usually have greater anti-HIV efficacy, factors independent of protein specificity, including functional avidity...

Computer-assisted prediction of HLA-DR binding and experimental analysis for human promiscuous Th1-cell peptides in the 24 kDa secreted lipoprotein (LppX) of Mycobacterium tuberculosis.

Science.gov (United States)

Al-Attiyah, R; Mustafa, A S

2004-01-01

The secreted 24 kDa lipoprotein (LppX) is an antigen that is specific for Mycobacterium tuberculosis complex and M. leprae. The present study was carried out to identify the promiscuous T helper 1 (Th1)-cell epitopes of the M. tuberculosis LppX (MT24, Rv2945c) antigen by using 15 overlapping synthetic peptides (25 mers overlapping by 10 residues) covering the sequence of the complete protein. The analysis of Rv2945c sequence for binding to 51 alleles of nine serologically defined HLA-DR molecules, by using a virtual matrix-based prediction program (propred), showed that eight of the 15 peptides of Rv2945c were predicted to bind promiscuously to >/=10 alleles from more than or equal to three serologically defined HLA-DR molecules. The Th1-cell reactivity of all the peptides was assessed in antigen-induced proliferation and interferon-gamma (IFN-gamma)-secretion assays with peripheral blood mononuclear cells (PBMCs) from 37 bacille Calmette-Guérin (BCG)-vaccinated healthy subjects. The results showed that 17 of the 37 donors, which represented an HLA-DR-heterogeneous group, responded to one or more peptides of Rv2945c in the Th1-cell assays. Although each peptide stimulated PBMCs from one or more donors in the above assays, the best positive responses (12/17 (71%) responders) were observed with the peptide p14 (aa 196-220). This suggested a highly promiscuous presentation of p14 to Th1 cells. In addition, the sequence of p14 is completely identical among the LppX of M. tuberculosis, M. bovis and M. leprae, which further supports the usefulness of Rv2945c and p14 in the subunit vaccine design against both tuberculosis and leprosy.

T Cell-Replete Peripheral Blood Haploidentical Hematopoietic Cell Transplantation with Post-Transplantation Cyclophosphamide Results in Outcomes Similar to Transplantation from Traditionally Matched Donors in Active Disease Acute Myeloid Leukemia.

Science.gov (United States)

How, Joan; Slade, Michael; Vu, Khoan; DiPersio, John F; Westervelt, Peter; Uy, Geoffrey L; Abboud, Camille N; Vij, Ravi; Schroeder, Mark A; Fehniger, Todd A; Romee, Rizwan

2017-04-01

Outcomes for patients with acute myeloid leukemia (AML) who fail to achieve complete remission remain poor. Hematopoietic cell transplantation (HCT) has been shown to induce long-term survival in AML patients with active disease. HCT is largely performed with HLA-matched unrelated or HLA-matched related donors. Recently, HCT with HLA-haploidentical related donors has been identified as a feasible option when HLA-matched donors are not immediately available. However, there are little data comparing outcomes for AML patients with active disease who receive haploidentical versus traditionally matched HCT. We retrospectively analyzed data from 99 AML patients with active disease undergoing allogeneic HCT at a single institution. Forty-three patients received unrelated donor HCT, 32 patients received matched related donor HCT, and 24 patients received peripheral blood haploidentical HCT with post-transplantation cyclophosphamide. We found no significant differences between treatment groups in terms of overall survival (OS), event-free survival, transplantation-related mortality, cumulative incidence of relapse, and cumulative incidence of acute and chronic graft-versus-host disease (GVHD). We performed univariate regression analysis of variables that modified OS in all patients and found only younger age at transplantation and development of chronic GVHD significantly improved outcome. Although limited by our relatively small sample size, these results indicate that haploidentical HCT in active AML patients have comparable outcomes to HCT with traditionally matched donors. Haploidentical HCT can be considered in this population of high-risk patients when matched donors are unavailable or when wait times for transplantation are unacceptably long. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

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.

Science.gov (United States)

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.

Association between HLA-DQA1, HLA-DQB1 and oral cancer

Directory of Open Access Journals (Sweden)

Sheng-Chien Tsai

2011-10-01

Full Text Available Cancer is one of the most common causes of morbidity and mortality. Genes whose products play a critical role in regulation of the immune response include the HLA antigen and cytokine families of genes. Oral cancer is common in men in developing countries, and its frequency is increased by using betel-quid, tobacco, and alcohol. The association between certain HLA Class I and Class II haplotypes and cancer has been documented in a variety of tumors. There was no previous data concerning the association of specific HLA Class II DQA1, DQB1 alleles, or haplotypes with oral cancer patients. In this study, we enrolled 134 Taiwanese patients with histologically confirmed oral cancer and 268 age- and gender-matched healthy Taiwanese adults as control group to investigate the association between HLA-DQA1, HLA-DQB1 allele frequencies and oral cancer patients by using polymerase chain reaction with sequence-specific primers. We found that both HLA-DQA1* and HLA-DQB1* allele frequencies in oral cancer patients revealed no significant difference from those of control groups. Haplotype frequencies of HLA*DQA1-0103-DQB1*0601 in oral cancer patients were significantly lower than those of the control group (odds ratio: 0.18, 95% confidence interval: 0.054–0.583, pc=0.02. Our data suggest that HLA DQA1*0103-DQB1*0601 haplotype may be protective with regard to the development of oral cancer.

HLA-A*0201 T-cell epitopes in severe acute respiratory syndrome (SARS) coronavirus nucleocapsid and spike proteins

International Nuclear Information System (INIS)

Tsao, Y.-P.; Lin, J.-Y.; Jan, J.-T.; Leng, C.-H.; Chu, C.-C.; Yang, Y.-C.; Chen, S.-L.

2006-01-01

The immunogenicity of HLA-A*0201-restricted cytotoxic T lymphocyte (CTL) peptide in severe acute respiratory syndrome coronavirus (SARS-CoV) nuclear capsid (N) and spike (S) proteins was determined by testing the proteins' ability to elicit a specific cellular immune response after immunization of HLA-A2.1 transgenic mice and in vitro vaccination of HLA-A2.1 positive human peripheral blood mononuclearcytes (PBMCs). First, we screened SARS N and S amino acid sequences for allele-specific motif matching those in human HLA-A2.1 MHC-I molecules. From HLA peptide binding predictions (http://thr.cit.nih.gov/molbio/hla_bind/), ten each potential N- and S-specific HLA-A2.1-binding peptides were synthesized. The high affinity HLA-A2.1 peptides were validated by T2-cell stabilization assays, with immunogenicity assays revealing peptides N223-231, N227-235, and N317-325 to be First identified HLA-A*0201-restricted CTL epitopes of SARS-CoV N protein. In addition, previous reports identified three HLA-A*0201-restricted CTL epitopes of S protein (S978-986, S1203-1211, and S1167-1175), here we found two novel peptides S787-795 and S1042-1050 as S-specific CTL epitopes. Moreover, our identified N317-325 and S1042-1050 CTL epitopes could induce recall responses when IFN-γ stimulation of blood CD8 + T-cells revealed significant difference between normal healthy donors and SARS-recovered patients after those PBMCs were in vitro vaccinated with their cognate antigen. Our results would provide a new insight into the development of therapeutic vaccine in SARS

Stem cell collection in unmanipulated HLA-haploidentical/mismatched related transplantation with combined granulocyte-colony stimulating factor-mobilised blood and bone marrow for patients with haematologic malignancies: the impact of donor characteristics and procedural settings.

Science.gov (United States)

Zhang, C; Chen, X-H; Zhang, X; Gao, L; Gao, L; Kong, P-Y; Peng, X-G; Sun, A-H; Gong, Y; Zeng, D-F; Wang, Q-Y

2010-06-01

Unmanipulated haploidentical/mismatched related transplantation with combined granulocyte-colony stimulating factor-mobilised peripheral blood stem cells (G-PBSCs) and granulocyte-colony stimulating factor-mobilised bone marrow (G-BM) has been developed as an alternative transplantation strategy for patients with haematologic malignancies. However, little information is available about the factors predicting the outcome of peripheral blood stem cell (PBSC) collection and bone marrow (BM) harvest in this transplantation. The effects of donor characteristics and procedure factors on CD34(+) cell yield were investigated. A total of 104 related healthy donors received granulocyte-colony stimulating factor (G-CSF) followed by PBSC collection and BM harvest. Male donors had significantly higher yields compared with female donors. In multiple regression analysis for peripheral blood collection, age and flow rate were negatively correlated with cell yield, whereas body mass index, pre-aphaeresis white blood cell (WBC) and circulating immature cell (CIC) counts were positively correlated with cell yields. For BM harvest, age was negatively correlated with cell yields, whereas pre-BM collection CIC counts were positively correlated with cell yield. All donors achieved the final product of >or=6 x10(6) kg(-1) recipient body weight. This transplantation strategy has been shown to be a feasible approach with acceptable outcomes in stem cell collection for patients who received HLA-haploidentical/mismatched transplantation with combined G-PBSCs and G-BM. In donors with multiple high-risk characteristics for poor aphaeresis CD34(+) cell yield, BM was an alternative source.

Characteristics and correlates of sibling relationships in two-parent African American families.

Science.gov (United States)

McHale, Susan M; Whiteman, Shawn D; Kim, Ji-Yeon; Crouter, Ann C

2007-06-01

The authors studied sibling relationships of African American youths and family and youth characteristics linked to sibling dynamics. Participants were fathers, mothers, and 2 siblings (M = 14.04 and M = 10.34 years of age) from 172 working-middle class 2-parent families. Cluster analyses of data collected in home interviews revealed 3 sibling relationship types: positive, negative, and distant. Parent education was lower, parent religiosity higher, and parent-child relationships more positive in the positive group; maternal discrimination experiences were higher in the negative group; youth ethnic identity was stronger in the positive group; and youth depression and risky behavior were higher in the negative group. The findings target sociocultural factors to consider in interventions for African American families.

Congenital amegakaryocytic thrombocytopenia in three siblings: molecular analysis of atypical clinical presentation.

Science.gov (United States)

Gandhi, Manish J; Pendergrass, Thomas W; Cummings, Carrie C; Ihara, Kenji; Blau, C Anthony; Drachman, Jonathan G

2005-10-01

An 11-year-old girl, presenting with fatigue and bruising, was found to be profoundly pancytopenic. Bone marrow exam and clinical evaluation were consistent with aplastic anemia. Family members were studied as potential stem cell donors, revealing that both younger siblings displayed significant thrombocytopenia, whereas both parents had normal blood counts. We evaluated this pedigree to understand the unusually late presentation of congenital amegakaryocytic thrombocytopenia (CAMT). The coding region and the intron/exon junctions of MPL were sequenced from each family member. Vectors representing each of the mutations were constructed and tested for the ability to support growth of Baf3/Mpl(mutant) cells. All three siblings had elevated thrombopoietin levels. Analysis of genomic DNA demonstrated that each parent had mutations/polymorphisms in a single MPL allele and that each child was a compound heterozygote, having inherited both abnormal alleles. The maternal allele encoded a mutation of the donor splice-junction at the exon-3/intron-3 boundary. A mini-gene construct encoding normal vs mutant versions of the intron-3 donor-site demonstrated that physiologic splicing was significantly reduced in the mutant construct. Mutations that incompletely eliminate Mpl expression/function may result in delayed diagnosis of CAMT and confusion with aplastic anemia.

Sibling differentiation: sibling and parent relationship trajectories in adolescence.

Science.gov (United States)

Feinberg, Mark E; McHale, Susan M; Crouter, Ann C; Cumsille, Patricio

2003-01-01

Studied here were the links between sibling differences in trajectories of change in the qualities of parent-child relationships and the qualities of sibling relationships across a 2-year period in adolescence. Participants were first- and second-born siblings (M age = 14.94 years for firstborns and M age = 12.46 years for secondborns) from 185 predominantly White, working and middle-class families. In home interviews, siblings reported on their dyadic family relationships. For reports of parent-child warmth but not parent-child conflict, results were consistent with sibling differentiation theory: Increasing differences between siblings over time in parent-child warmth were linked to trajectories of increasing warmth and decreasing conflict in the sibling relationship as reported by firstborns, and increasing warmth in the sibling relationship as reported by secondborns. The findings support the view that sibling differentiation may be a strategy for managing sibling conflict and rivalry.

Specific central nervous system recruitment of HLA-G(+) regulatory T cells in multiple sclerosis.

Science.gov (United States)

Huang, Yu-Hwa; Zozulya, Alla L; Weidenfeller, Christian; Metz, Imke; Buck, Dorothea; Toyka, Klaus V; Brück, Wolfgang; Wiendl, Heinz

2009-08-01

We have recently described a novel population of natural regulatory T cells (T(reg)) that are characterized by the expression of HLA-G and may be found at sites of tissue inflammation (HLA-G(pos) T(reg)). Here we studied the role of these cells in multiple sclerosis (MS), a prototypic autoimmune inflammatory disorder of the central nervous system (CNS). Sixty-four patients with different types of MS, 9 patients with other neurological diseases, and 20 healthy donors were included in this study. Inflamed brain lesions from 5 additional untreated MS patients were examined. HLA-G(pos) T(reg) were analyzed in the cerebrospinal fluid (CSF) by flow cytometry and in inflammatory demyelinating lesions of MS brain specimens by immunohistochemistry. Functional capacity was accessed and transmigration was determined using an in vitro model of the human blood-brain barrier (BBB). HLA-G(pos) T(reg) were found enriched in the inflamed CSF of MS patients and in inflammatory demyelinating lesions of MS brain specimens. HLA-G(pos) T(reg) showed a strong propensity to transmigrate across BBB, which was vigorously driven by inflammatory chemokines, and associated with a gain of suppressive capacity upon transmigration. CSF-derived HLA-G(pos) T(reg) of MS patients represented a population of activated central memory activated T cells with an upregulated expression of inflammatory chemokine receptors and exhibiting full suppressive capacity. Unlike natural FoxP3-expressing T(reg), HLA-G(pos) T(reg) derived from peripheral blood were functionally unimpaired in MS. In MS, HLA-G(pos) T(reg) may serve to control potentially destructive immune responses directly at the sites of CNS inflammation and to counterbalance inflammation once specifically recruited to the CNS.

HLA-DRB and HLA-DQ genetic variability in patients with aspirin-exacerbated respiratory disease.

Science.gov (United States)

Esmaeilzadeh, Hossein; Nabavi, Mohammad; Amirzargar, Ali Akbar; Aryan, Zahra; Arshi, Saba; Bemanian, Mohammad Hassan; Fallahpour, Morteza; Mortazavi, Negar; Rezaei, Nima

2015-01-01

Major histocompatibility complex (MHC) class II is involved in T-cell activation, cytokine secretion, and induction of immune responses. Cytokines, staphylococcus super antigens, and eosinophil activation are proposed to play important roles in aspirin-exacerbated respiratory disease (AERD). This study is aimed at investigating the association of HLA-DRB and DQ genetic variabilities in patients with AERD. A genetic association analysis in three different groups, including 33 patients with AERD, 17 patients with aspirin-tolerant asthma (ATA), and 100 healthy controls was performed. Oral aspirin challenge (OAC) test was performed to identify aspirin hypersensitivity. Pulmonary function test (PFT) was performed for all patients. Eosinophil percentage in nasal smear and peripheral blood and serum immunoglobin (Ig)E were investigated. HLA-DRB, HLA-DQA1, and HLA-DQB1 were genotyped using polymerase chain reaction. HLA-DQB1*0302 (OR, 5.49, 95% confidence interval [CI],(2.40-12.59)), HLA-DQA1*0301 (OR, 2.90, 95% CI, (1.49-5.67)), HLA-DRB4 (OR, 2.94, 95% CI, (1.61-5.36)), and HLA-DRB1*04 (OR, 3.19, 95% CI, (1.57-6.47)) were higher in patients with AERD compared with controls. In patients with AERD, HLA-DQB1*0301 (OR,0.22, 95% CI, (0.09-0.54)), HLA-DQA1*0501 (OR, 0.42, 95% CI, (0.21-0.81)), HLA-DRB1*11 (OR, 0.30, 95% CI, (0.12-0.73)), and HLA-DRB3 (OR, 0.38, 95% CI, (0.21-0.70)) were significantly lower compared with healthy controls. Patients with AERD had lower frequencies of HLA-DQB1*0301 (OR, 0.27, 95% CI, (0.08-0.86)), and HLA-DRB1*011 (OR, 0.27, 95% CI, (0.08-0.86)) compared with ATA. Haplotypes of HLA-DRB1*04/ DQA1*0301/ DQB1*0302 (OR, 4.25, 95% CI, (1.94-9.29)) and HLA-DRB1*07 /DQA1*0201/ DQB1*0201 (OR, 3.52, 95% CI, (1.54-8.06)) were higher in patients with AERD compared with controls (all p < 0.05). Results of this study suggest that HLA-DQB1*0302 and HLA-DRB1*04 and their related haplotypes are genes involved in predisposing patients to AERD, whereas HLA-DQB1

Comparing outcomes of matched related donor and matched unrelated donor hematopoietic cell transplants in adults with B-Cell acute lymphoblastic leukemia.

Science.gov (United States)

Segal, Eric; Martens, Michael; Wang, Hai-Lin; Brazauskas, Ruta; Weisdorf, Daniel; Sandmaier, Brenda M; Khoury, H Jean; de Lima, Marcos; Saber, Wael

2017-09-01

Allogeneic hematopoietic cell transplantation (HCT) using human leukocyte antigen (HLA)-matched related donors (RDs) and allogeneic HCT using HLA-matched unrelated donors (URDs) produce similar outcomes for patients with acute myelogenous leukemia, whereas the donor source has been reported to be a predictor of outcomes in myelodysplastic syndrome. Post-HCT outcomes for 1458 acute lymphoblastic leukemia patients from 2000 to 2011 were analyzed, and RD and URD transplants were compared. The median age was 37 years (range, 18-69 years). In the multivariate analysis, HLA 8/8 allele-matched URD recipients had similar transplant-related mortality (TRM) and all-cause mortality in comparison with RD recipients (hazard ratios [HRs], 1.16 [95% confidence interval (CI), 0.91-1.48] and 1.01 [95% CI, 0.85-1.19], respectively); 7/8 URD recipients had a greater risk of TRM and all-cause mortality in comparison with RD recipients (HRs, 1.92 [95% CI, 1.47-2.52] and 1.29 [95% CI, 1.05-1.58], respectively). The risk of TRM and all-cause mortality was also greater for 7/8 URD recipients versus 8/8 URD recipients. Compared with RD recipients, both 8/8 and 7/8 URD recipients had a lower risk of relapse (HRs, 0.77 [95% CI, 0.62-0.97] and 0.75 [95% CI, 0.56-1.00], respectively). Both 8/8 and 7/8 URD recipients had a greater risk of acute graft-versus-host disease (GVHD; HRs, 2.18 [95% CI, 1.76-2.70] and 2.65 [95% CI, 2.06-3.42], respectively) and chronic GVHD (HRs, 1.28 [95% CI, 1.06-1.55] and 1.46 [95% CI, 1.14-1.88], respectively) in comparison with RD recipients. In the absence of RD transplantation, 8/8 URD transplantation is a viable alternative with similar survival outcomes, whereas 7/8 URD transplantation is associated with poorer overall survival. Cancer 2017;123:3346-55. © 2017 American Cancer Society. © 2017 American Cancer Society.

Outside-in HLA class I signaling regulates ICAM-1 clustering and endothelial cell-monocyte interactions via mTOR in transplant antibody-mediated rejection.

Science.gov (United States)

Salehi, Sahar; Sosa, Rebecca A; Jin, Yi-Ping; Kageyama, Shoichi; Fishbein, Michael C; Rozengurt, Enrique; Kupiec-Weglinski, Jerzy W; Reed, Elaine F

2018-05-01

Antibody-mediated rejection (AMR) resulting in transplant allograft vasculopathy (TAV) is the major obstacle for long-term survival of solid organ transplants. AMR is caused by donor-specific antibodies to HLA, which contribute to TAV by initiating outside-in signaling transduction pathways that elicit monocyte recruitment to activated endothelium. Mechanistic target of rapamycin (mTOR) inhibitors can attenuate TAV; therefore, we sought to understand the mechanistic underpinnings of mTOR signaling in HLA class I Ab-mediated endothelial cell activation and monocyte recruitment. We used an in vitro model to assess monocyte binding to HLA I Ab-activated endothelial cells and found mTOR inhibition reduced ezrin/radixin/moesin (ERM) phosphorylation, intercellular adhesion molecule 1 (ICAM-1) clustering, and monocyte firm adhesion to HLA I Ab-activated endothelium. Further, in a mouse model of AMR, in which C57BL/6. RAG1 -/- recipients of BALB/c cardiac allografts were passively transferred with donor-specific MHC I antibodies, mTOR inhibition significantly reduced vascular injury, ERM phosphorylation, and macrophage infiltration of the allograft. Taken together, these studies indicate mTOR inhibition suppresses ERM phosphorylation in endothelial cells, which impedes ICAM-1 clustering in response to HLA class I Ab and prevents macrophage infiltration into cardiac allografts. These findings indicate a novel therapeutic application for mTOR inhibitors to disrupt endothelial cell-monocyte interactions during AMR. © 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.

Return behavior of occasional and multigallon blood donors: the role of theory of planned behavior, self-identity, and organizational variables.

Science.gov (United States)

Wevers, Anne; Wigboldus, Daniël H J; van Baaren, Rick; Veldhuizen, Ingrid J T

2014-03-01

For blood establishments it is important that blood donors return for a donation. Past research has stressed the importance of theory of planned behavior (TPB) on return behavior, but self-identity (SI) and organizational variables (OVs) might play a role as well. This study added SI and OVs to the TPB to identify the determinants for return behavior. Whole blood donors (n = 2005) completed a questionnaire assessing TPB, SI, and OVs. OVs contained "perceived satisfaction with the blood bank" and "feeling pressure from the blood bank to donate blood." Return behavior over the past 2 years was dichotomized as low return (0%-50%) versus high return (51%-100%). Logistic regression analyses assessed the effects of TPB, SI, and OVs on high return, separately for occasional donors (two to 10 lifetime donations) and multigallon donors (>10 lifetime donations). Results showed that, for all donors, affective attitude was positively associated with return behavior, whereas pressure to donate blood was negatively associated with return behavior. The point estimates of self-efficacy, SI, and perceived satisfaction are high for multigallon donors, but do not reach significance. For all donors, positive feelings about donating blood stimulate return behavior, while experiencing a pressure to donate blood emanating from the blood bank was not beneficial. Results suggest that multigallon donors are more stimulated to return when they score higher on self-efficacy, SI, and perceived satisfaction. Interventions aiming at donor retention need to be carefully formulated to avoid negative effects of feeling pressure to donate blood. © 2013 American Association of Blood Banks.

Post-traumatic stress disorder and health-related quality of life in the siblings of the pediatric bone marrow transplantation survivors and post-traumatic stress disorder in their mothers.

Science.gov (United States)

Gizli Çoban, Özge; Sürer Adanır, Aslı; Özatalay, Esin

2017-09-01

Although BMT is lifesaving in many childhood diseases, it was found to be related to anxiety, depression, and PTSD in parents, and PTSD, anxiety and overall low self-esteem in siblings. Research on siblings' HRQoL is limited. The aim of this study was to investigate PTSD and HRQoL in siblings (donor and non-donor) of pediatric BMT survivors and PTSD in their mothers, compared to the healthy controls. Thirty-five siblings and their mothers and 35 healthy peers and their mothers were recruited as the study group and as the comparison group, respectively. In children, Child PTSD-Reaction Index for PTSD and PedsQL for HRQoL were used. PTSD Checklist-Civilian Version was used for PTSD in mothers. The study group, both children and mothers, obtained significantly higher PTSD rates than the control group. Children in the study group also reported significantly poorer HRQoL than the control group in all scales. As a novel finding, there was a significant negative correlation between siblings' and mothers' PTSD scores and siblings' PedsQL scores, indicating that PTSD symptoms in siblings and mothers significantly led to impairment in siblings' HRQoL or vice versa. Thus, the identification and treatment of siblings and mothers with PTSD seems imperative. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

The Japan Marrow Donor Program, 25 years of experience in achieving 20,000 bone marrow transplantations: organization structure, activity, and financial basis.

Science.gov (United States)

Saito, Hidehiko; Ito, Masaharu; Kato, Shunichi; Kodera, Yoshihisa; Okamoto, Shinichiro; Taniguchi, Shuichi; Takanashi, Minoko; Kanamori, Heiwa; Masaoka, Toru; Takaku, Fumimaro

2018-01-24

The Japan Marrow Donor Program (JMDP), established in 1991, has continued to grow in its capacity to facilitate unrelated bone marrow (BMT) and peripheral blood stem cell transplantation (PBSCT) for the past 25 years in Japan. The current donor pool is 463,465 (as of 31 December 2016) and 20,237 transplants were performed with the help of the Japanese Red Cross, government, and supporters. As JMDP introduced PBSCT in 2010, the vast majority of transplants are BMT. All donors are fully typed for HLA-A, B, C, and DR. The peak age of registered donors is around 40 years. The 8/8 HLA-matched donors are found in our registry for 96% of the patients and 54% of the patients receive a transplant. The median time between the initiation of donor search and the transplantation is approximately 122 days. The median interval between the initiation of donor search and identification of the first potential donor is 40 days. The most common diseases for which unrelated BMT/PBSCT is indicated are acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), myelodysplastic syndrome (MDS), and malignant lymphoma. In recent years we have seen a marked increase in elderly patients who received BMT.

Siblings' personality traits and types of sibling relationship in childhood

Directory of Open Access Journals (Sweden)

Tina Kavčič

2011-01-01

Full Text Available The contribution presents a follow-up study of sibling relationship and personality in 87 sibling dyads in early/middle childhood from parental perspective. At Time 1 all siblings attended pre-school and one year later approximately half of the older siblings entered compulsory school. At both times of measurement siblings' mothers and fathers independently reported on their children's personality characteristics using the Inventory of Child Individual Differences (Halverson et al., 2003; Slovene adaptation, Zupančič & Kavčič, 2009 and on the observed sibling warmth, agonism, and rivalry using the Parental Expectations and Perceptions of Children's Sibling Relationships Questionnaire (Kramer, 2001. The predictive relationship obtained by two sets of cross-rater analyses (between maternal ratings of child personality and paternal reports on sibling relationship, and vice versa suggested that (a personality traits of both siblings and (b the match between siblings' personalities are associated with sibling type (affectionate, involved or average membership. Among personality traits, disagreeableness seems to be an especially significant contributor to sibling relationship quality.

HLA-A*01:03, HLA-A*24:02, HLA-B*08:01, HLA-B*27:05, HLA-B*35:01, HLA-B*44:02, and HLA-C*07:01 Monochain Transgenic/H-2 Class I Null Mice

DEFF Research Database (Denmark)

Boucherma, Rachid; Kridane-Miledi, Hédia; Bouziat, Romain

2013-01-01

We have generated a panel of transgenic mice expressing HLA-A*01:03, -A*24:02, -B*08:01, -B*27:05, -B*35:01, -B*44:02, or -C*07:01 as chimeric monochain molecules (i.e., appropriate HLA α1α2 H chain domains fused with a mouse α3 domain and covalently linked to human β2-microglobulin). Whereas...... a quantitative and qualitative restoration of the peripheral CD8(+) T cell repertoire, which exhibited a TCR diversity comparable with C57BL/6 WT mice. Potent epitope-specific, HLA-restricted, IFN-γ-producing CD8(+) T cell responses were generated against known reference T cell epitopes after either peptide...

When Your "Problem" Becomes Mine: Adult Female Siblings' Perspectives of Having a Brother with a Disability

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Pompeo, Michelle N.

2009-01-01

This study is a retrospective look at adult female siblings' perspectives of their childhoods and present identities based on having a brother with a disability. This paper focuses on siblings' experiences within educational and public domains, and how such experiences have shaped their personalities and career choices. Qualitative findings were…

Chimerism and tolerance without GVHD or engraftment syndrome in HLA-mismatched combined kidney and hematopoietic stem cell transplantation.

Science.gov (United States)

Leventhal, Joseph; Abecassis, Michael; Miller, Joshua; Gallon, Lorenzo; Ravindra, Kadiyala; Tollerud, David J; King, Bradley; Elliott, Mary Jane; Herzig, Geoffrey; Herzig, Roger; Ildstad, Suzanne T

2012-03-07

The toxicity of chronic immunosuppressive agents required for organ transplant maintenance has prompted investigators to pursue approaches to induce immune tolerance. We developed an approach using a bioengineered mobilized cellular product enriched for hematopoietic stem cells (HSCs) and tolerogenic graft facilitating cells (FCs) combined with nonmyeloablative conditioning; this approach resulted in engraftment, durable chimerism, and tolerance induction in recipients with highly mismatched related and unrelated donors. Eight recipients of human leukocyte antigen (HLA)-mismatched kidney and FC/HSC transplants underwent conditioning with fludarabine, 200-centigray total body irradiation, and cyclophosphamide followed by posttransplant immunosuppression with tacrolimus and mycophenolate mofetil. Subjects ranged in age from 29 to 56 years. HLA match ranged from five of six loci with related donors to one of six loci with unrelated donors. The absolute neutrophil counts reached a nadir about 1 week after transplant, with recovery by 2 weeks. Multilineage chimerism at 1 month ranged from 6 to 100%. The conditioning was well tolerated, with outpatient management after postoperative day 2. Two subjects exhibited transient chimerism and were maintained on low-dose tacrolimus monotherapy. One subject developed viral sepsis 2 months after transplant and experienced renal artery thrombosis. Five subjects experienced durable chimerism, demonstrated immunocompetence and donor-specific tolerance by in vitro proliferative assays, and were successfully weaned off all immunosuppression 1 year after transplant. None of the recipients produced anti-donor antibody or exhibited engraftment syndrome or graft-versus-host disease. These results suggest that manipulation of a mobilized stem cell graft and nonmyeloablative conditioning represents a safe, practical, and reproducible means of inducing durable chimerism and donor-specific tolerance in solid organ transplant recipients.

HLA restriction of non-HLA-A, -B, -C and -D cell mediated lympholysis (CML)

International Nuclear Information System (INIS)

Goulmy, E.; Termijtelen, A.; Bradley, B.A.; Rood, J.J. van

1976-01-01

The aim of our study was to define target determinations other than those coded for by the classical HLA-A, -B, -C or -D loci which were responsible for killing in CML. In one of the families studied, strong evidence was found for the existence of a determinant coded for within the HLA region. CML was restricted to targets carrying the classical HLA-Bw35 and Cw4 determinants but the targets were neither HLA-Bw35 nor Cw4 themselves. We therefore concluded that this new HLA determinant was either the product of a new locus closely associated with HLA-B or that it was a product of the classical HLA-B locus which has not been recognized by serology. (author)

HLA-DPB1 and HLA class I confer risk of and protection from narcolepsy

DEFF Research Database (Denmark)

Ollila, Hanna M; Ravel, Jean-Marie; Han, Fang

2015-01-01

Type 1 narcolepsy, a disorder caused by a lack of hypocretin (orexin), is so strongly associated with human leukocyte antigen (HLA) class II HLA-DQA1(∗)01:02-DQB1(∗)06:02 (DQ0602) that very few non-DQ0602 cases have been reported. A known triggering factor for narcolepsy is pandemic 2009 influenza......-class-II-independent associations with HLA-A(∗)11:01 (OR = 1.32 [1.13-1.54], p = 4.92 × 10(-4)), HLA-B(∗)35:03 (OR = 1.96 [1.41-2.70], p = 5.14 × 10(-5)), and HLA-B(∗)51:01 (OR = 1.49 [1.25-1.78], p = 1.09 × 10(-5)) were also seen across ethnic groups in the HLA class I region. These effects might reflect modulation...... of autoimmunity or indirect effects of HLA class I and HLA-DP alleles on response to viral infections such as that of influenza....

Bone marrow transplantation for patients with chronic myeloid leukemia

International Nuclear Information System (INIS)

Goldman, J.M.; Apperley, J.F.; Jones, L.

1986-01-01

Between February 1981 and December 1984 we treated 52 patients with chronic myeloid leukemia in the chronic phase and 18 patients with more advanced disease by high-dose chemoradiotherapy followed by allogeneic bone marrow transplantation using marrow cells from HLA-identical sibling donors. In addition, the 40 patients who had not previously undergone splenectomy received radiotherapy to the spleen. To prevent graft versus host disease, cyclosporine was given either alone or in conjunction with donor marrow depleted of T cells. Of the 52 patients treated in the chronic phase, 38 are alive after a median follow-up of 25 months (range, 7 to 50); the actuarial survival at two years was 72%, and the actuarial risk of relapse was 7%. Of the 18 patients with more advanced disease, 4 have survived; the actuarial two-year survival was 18%, and the actuarial risk of relapse was 42%. We conclude that the probability of cure is highest if transplantation is performed while the patient remains in the chronic phase of chronic myeloid leukemia. T-cell depletion may have reduced the incidence and severity of graft versus host disease. The value of irradiation to the spleen before transplantation has not been established

Is there a differential strength of specific HLA mismatches in kidney transplants?

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Sasaki, N; Idica, A; Terasaki, P

2008-05-01

In this article we attempted to identify whether there is a specific mismatched antigen that might be detrimental to kidney transplant outcome. The frequency of function versus failure of transplant cases was tallied within subpopulations among a subset of the 2006 United Network for Organ Sharing transplant dataset. We examined 7998 cadaveric and 11,420 living donor kidney transplants that were mismatched for a single class I antigen. When tested by five different criteria, the results were relatively similar for the HLA class I, A- and B-locus mismatches. HLA A1 was identified as the single most dominant immunogenic mismatch. However, when the P values were multiplied by 68, the number of comparisons, A1 was only marginally significant. We concluded that at least for class I specificities, the 68 specificities were about equal immunogenicity in kidney transplantation.

Kidney graft recipients with pretransplantation HLA CLASS I antibodies and high soluble CD30 are at high risk for graft loss.

Science.gov (United States)

Rodríguez, Libia M; París, Sara C; Arbeláez, Mario; Cotes, José M; Süsal, Caner; Torres, Yolanda; García, Luís F

2007-08-01

In the present study, we investigated whether pretransplantation HLA class I and class II antibodies and pretransplantation levels of soluble CD30 (sCD30) and IgA anti-Fab autoantibodies are predictive of kidney allograft survival. Pretransplantation sera of 504 deceased-donor kidney recipients were tested for IgG HLA class I and class II antibodies, sCD30, and IgA anti-Fab levels using the CTS 4 ELISA kit. Kidney graft survival was estimated by Kaplan-Meier method and multivariate Cox regression. Regardless of the presence of HLA class II antibodies, recipients with high HLA class I reactivity had lower 1-year graft survival than recipients with low reactivity (p sCD30 had lower 5-year graft survival rate than those with low sCD30 (p sCD30 effect was observed in presensitized and nonsensitized recipients, demonstrated a synergistic effect with HLA class I antibodies (p kidney graft survival. Our results indicate that high pretransplantation sCD30 levels and HLA class I positivity increase the risk of kidney graft loss regardless of other factors. Consequently, such determinations should be routinely performed to estimate recipients' risks of graft rejection before transplantation.

Sibling popularity: A moderator of sibling influence for adolescent substance use.

Science.gov (United States)

Wallace, Lacey N

Sibling substance use is a known correlate of adolescent substance use. Yet, not all siblings are equally influential. Sibling influence has been found to vary by age gap, sex, and birth order. Little research, however, has investigated whether siblings' peer context is also a source of variation. The present study tested whether more popular siblings were more influential for adolescent use of cigarettes, alcohol, and marijuana. Data were obtained from sibling pairs in the National Longitudinal Study of Adolescent Health. Findings indicate that older siblings have more influence on younger sibling marijuana use when they have more friends. These findings contribute to prior work examining which siblings are more influential and highlight the need to consider siblings as part of a greater peer context.

Desensitization protocol in highly HLA-sensitized and ABO-incompatible high titer kidney transplantation.

Science.gov (United States)

Uchida, J; Machida, Y; Iwai, T; Naganuma, T; Kitamoto, K; Iguchi, T; Maeda, S; Kamada, Y; Kuwabara, N; Kim, T; Nakatani, T

2010-12-01

A positive crossmatch indicates the presence of donor-specific alloantibodies and is associated with a graft loss rate of >80%; anti-ABO blood group antibodies develop in response to exposure to foreign blood groups, resulting in immediate graft loss. However, a desensitization protocol for highly HLA-sensitized and ABO-incompatible high-titer kidney transplantation has not yet been established. We treated 6 patients with high (≥1:512) anti-A/B antibody titers and 2 highly HLA-sensitized patients. Our immunosuppression protocol was initiated 1 month before surgery and included mycophenolate mofetil (1 g/d) and/or low-dose steroid (methylprednisolone 8 mg/d). Two doses of the anti-CD20 antibody rituximab (150 mg/m(2)) were administered 2 weeks before and on the day of transplantation. We performed antibody removal with 6-12 sessions of plasmapheresis (plasma exchange or double-filtration plasmapheresis) before transplantation. Splenectomy was also performed on the day of transplantation. Postoperative immunosuppression followed the same regimen as ABO-compatible cases, in which calcineurin inhibitors were initiated 3 days before transplantation, combined with 2 doses of basiliximab. Of the 8 patients, 7 subsequently underwent successful living-donor kidney transplantation. Follow-up of our recipients showed that the patient and graft survival rates were 100%. Acute cellular rejection and antibody-mediated rejection episodes occurred in 1 of the 7 recipients. These findings suggest that our immunosuppression regimen consisting of rituximab infusions, splenectomy, plasmapheresis, and pharmacologic immunosuppression may prove to be effective as a desensitization protocol for highly HLA-sensitized and ABO-incompatible high-titer kidney transplantation. Copyright © 2010 Elsevier Inc. All rights reserved.

A game-theoretic approach to donor kidney sharing.

Science.gov (United States)

O'Brien, B J

1988-01-01

Graft survival in renal transplantation is a function, amongst other things, of the degree of histocompatibility lymphocyte-A (HLA) tissue matching achieved between donor and recipient. Yet a donor procured at centre A might match a transplant candidate at centre B and vice versa. This raises the question of whether, and under what circumstances, surgeons will offer and exchange donor kidneys and gain from such trade in terms of graft survival. We analyse the problem in a game-theoretic framework where the choice of strategy 'to offer or not?' is evaluated in the context of the uncertainty of reciprocation by the other player(s) in the game. The equilibrium solution to a number of variations of the game is predicted to be non-cooperation resulting in collectively sub-optimal graft survival rates. Some policy options for improving cooperation are considered including exchange incentives and coercive measures.

Why search for a sperm donor online? The experiences of women searching for and contacting sperm donors on the internet.

Science.gov (United States)

Jadva, Vasanti; Freeman, Tabitha; Tranfield, Erika; Golombok, Susan

2018-06-01

Whilst studies have examined the experiences of women who use clinic donors, to date there has been limited research investigating women's motivations and experiences of searching for a sperm donor online. A total of 429 women looking for a sperm donor on Pride Angel (a website that facilitates contact between donors and recipients) completed an online survey. Fifty-eight percent (249) saw advantages of obtaining donated sperm online with the most common advantage reported as being able to connect with and meet the donor (n = 50 (24%)). A third (n = 157 (37%)) of the participants gave disadvantages, the most common reported was encountering 'dishonest donors' (n = 63 (40%)). Most recipients (n = 181 (61%)) wanted the donor to be 'just a donor' (i.e. to provide sperm and have no further contact). Whilst it was important for recipients to know the identity of the donor, some did not see this as important for the child and thus the level of information that parents have about the donor, and that which the child has, can differ. Finding a donor online blurs the distinction between categories of 'anonymous', 'known' and 'identity release' donations. Whilst the survey had a large sample size, the representativeness of the sample is not known.

HLA-G in human reproduction

DEFF Research Database (Denmark)

Hviid, Thomas Vauvert F

2005-01-01

The non-classical human leukocyte antigen (HLA) class Ib genes, HLA-E, -G and -F, are located on chromosome 6 in the human major histocompatibility complex (MHC). HLA class Ib antigens resemble the HLA class Ia antigens in many ways, but several major differences have been described. This review ...... transplantation and in inflammatory or autoimmune disease, and of HLA-G in an evolutionary context, are also briefly examined....

Outcomes of Children with Hemophagocytic Lymphohistiocytosis Given Allogeneic Hematopoietic Stem Cell Transplantation in Italy.

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Messina, Chiara; Zecca, Marco; Fagioli, Franca; Rovelli, Attilio; Giardino, Stefano; Merli, Pietro; Porta, Fulvio; Aricò, Maurizio; Sieni, Elena; Basso, Giuseppe; Ripaldi, Mimmo; Favre, Claudio; Pillon, Marta; Marzollo, Antonio; Rabusin, Marco; Cesaro, Simone; Algeri, Mattia; Caniglia, Maurizio; Di Bartolomeo, Paolo; Ziino, Ottavio; Saglio, Francesco; Prete, Arcangelo; Locatelli, Franco

2018-06-01

We report on 109 patients with hemophagocytic lymphohistiocytosis (HLH) undergoing 126 procedures of allogeneic hematopoietic stem cell transplantation (HSCT) between 2000 and 2014 in centers associated with the Italian Pediatric Hematology Oncology Association. Genetic diagnosis was FHL2 (32%), FHL3 (33%), or other defined disorders known to cause HLH (15%); in the remaining patients no genetic abnormality was found. Donor for first transplant was an HLA-matched sibling for 25 patients (23%), an unrelated donor for 73 (67%), and an HLA-partially matched family donor for 11 children (10%). Conditioning regimen was busulfan-based for 61 patients (56%), treosulfan-based for 21 (20%), and fludarabine-based for 26 children (24%). The 5-year probabilities of overall survival (OS) and event-free survival (EFS) were 71% and 60%, respectively. Twenty-six patients (24%) died due to transplant-related causes, whereas 14 (13%) and 10 (9%) patients experienced graft rejection and/or relapse, respectively. Twelve of 14 children given a second HSCT after graft failure/relapse are alive and disease-free. Use of HLA-partially matched family donors was associated with higher risk of graft failure and thus with lower EFS (but not with lower OS) in multivariable analysis. Active disease at transplantation did not significantly affect prognosis. These data confirm that HSCT can cure most HLH patients, active disease not precluding successful transplantation. Because in HLH patients HLA-haploidentical HSCT performed through CD34 + cell positive selection was found to be associated with poor sustained engraftment of donor cells, innovative approaches able to guarantee a more robust engraftment are warranted in patients given this type of allograft. Copyright © 2018 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

HLA class I-mediated control of HIV-1 in the Japanese population, in which the protective HLA-B*57 and HLA-B*27 alleles are absent.

Science.gov (United States)

Naruto, Takuya; Gatanaga, Hiroyuki; Nelson, George; Sakai, Keiko; Carrington, Mary; Oka, Shinichi; Takiguchi, Masafumi

2012-10-01

We investigated the effect of HLA class I alleles on clinical parameters for HIV-1 disease progression in the Japanese population, where two strongly protective alleles, HLA-B*57 and HLA-B*27, are virtually nonexistent. HLA-B alleles showed a dominant role, primarily through HLA-B*67:01 and the HLA-B*52:01-C*12:02 haplotype. Neither a rare-allele nor a heterozygote advantage was found, suggesting that the effect of HLA alleles in the Japanese population is either different from those observed in Africans and Caucasians or undetectable due to limited power.

Identification of an HLA-B*27 variant, B*27:120, by sequence-based typing in a Taiwanese bone marrow stem cell donor.

Science.gov (United States)

Yang, K L; Lin, P Y

2018-05-20

One nucleotide substitution at residue 577 of HLA-B*27:04:01 results in a novel allele, HLA-B*27:120. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Treatment of chronic granulocytic leukemia by chemotherapy, total body irradiation and allogeneic bone marrow transplantation

Energy Technology Data Exchange (ETDEWEB)

Doney, K; Buckner, C D; Sale, G E; Ramberg, R; Boyd, C; Thomas, E D [Fred Hutchinson Cancer Research Institute; Washington Univ., Seattle (USA). School of Medicine)

1978-01-01

Fourteen patients with chronic granulocytic leukemia received bone marrow grafts from HLA identical siblings. Ten patients were in blast crisis prior to grafting, three were in an accelerated phase of their disease, and one was aplastic secondary to chemotherapy. Prior to transplant all patients were conditioned with chemotherapy including cyclophosphamide plus 1,000 rad of total body irradiation. Ten patients achieved engraftment while four died 1 to 26 days after marrow infusion without functioning grafts. Two patients reveived a second infusion of donor marrow because of delayed engraftment. Neither marrow cell dose nor presence of myelofibrosis correlated with succesful engraftment. Three out of ten engrafted patients developed graft-versus-host disease. Interstitial pneumonia occurred in seven patients. The immediate cause of death was bacterial septicemia in six patients. All evidence of leukemia disappeared in nine out of ten evaluable patients. The median survival was 43 days. One patient had a complete remission of 16 months duration.

Treatment of chronic granulocytic leukemia by chemotherapy, total body irradiation and allogeneic bone marrow transplantation

International Nuclear Information System (INIS)

Doney, K.; Buckner, C.D.; Sale, G.E.; Ramberg, R.; Boyd, C.; Thomas, E.D.; Washington Univ., Seattle

1978-01-01

Fourteen patients with chronic granulocytic leukemia received bone marrow grafts from HLA identical siblings. Ten patients were in blast crisis prior to grafting, three were in an accelerated phase of their disease, and one was aplastic secondary to chemotherapy. Prior to transplant all patients were conditioned with chemotherapy including cyclophosphamide plus 1,000 rad of total body irradiation. Ten patients achieved engraftment while four died 1 to 26 days after marrow infusion without functioning grafts. Two patients reveived a second infusion of donor marrow because of delayed engraftment. Neither marrow cell dose nor presence of myelofibrosis correlated with succesful engraftment. Three out of ten engrafted patients developed graft-versus-host disease. Interstitial pneumonia occurred in seven patients. The immediate cause of death was bacterial septicemia in six patients. All evidence of leukemia disappeared in nine out of ten evaluable patients. The median survival was 43 days. One patient had a complete remission of 16 months duration. (Author)

Expectations and experiences of gamete donors and donor-conceived adults searching for genetic relatives using DNA linking through a voluntary register.

Science.gov (United States)

van den Akker, O B A; Crawshaw, M A; Blyth, E D; Frith, L J

2015-01-01

What are the experiences of donor-conceived adults and donors who are searching for a genetic link through the use of a DNA-based voluntary register service? Donor-conceived adults and donors held positive beliefs about their search and although some concerns in relation to finding a genetically linked relative were reported, these were not a barrier to searching. Research with donor-conceived people has consistently identified their interest in learning about-and in some cases making contact with-their donor and other genetic relatives. However, donor-conceived individuals or donors rarely have the opportunity to act on these desires. A questionnaire was administered for online completion using Bristol Online Surveys. The survey was live for 3 months and responses were collected anonymously. The survey was completed by 65 donor-conceived adults, 21 sperm donors and 5 oocyte donors who had registered with a DNA-based voluntary contact register in the UK. The questionnaire included socio-demographic questions, questions specifically developed for the purposes of this study and the standardized Aspects of Identity Questionnaire (AIQ). Motivations for searching for genetic relatives were varied, with the most common reasons being curiosity and passing on information. Overall, participants who were already linked and those awaiting a link were positive about being linked and valued access to a DNA-based register. Collective identity (reflecting self-defining feelings of continuity and uniqueness), as assessed by the AIQ, was significantly lower for donor-conceived adults when compared with the donor groups (P 0.05) for donor-conceived adults. Participants were members of a UK DNA-based registry which is unique. It was therefore not possible to determine how representative participants were of those who did not register for the service, those in other countries or of those who do not seek information exchange or contact. This is the first survey exploring the

HLA class I antibodies trigger increased adherence of monocytes to endothelial cells by eliciting an increase in endothelial P-selectin and, depending on subclass, by engaging FcγRs.

Science.gov (United States)

Valenzuela, Nicole M; Mulder, Arend; Reed, Elaine F

2013-06-15

Ab-mediated rejection (AMR) of solid organ transplants is characterized by intragraft macrophages. It is incompletely understood how donor-specific Ab binding to graft endothelium promotes monocyte adhesion, and what, if any, contribution is made by the Fc region of the Ab. We investigated the mechanisms underlying monocyte recruitment by HLA class I (HLA I) Ab-activated endothelium. We used a panel of murine mAbs of different subclasses to crosslink HLA I on human aortic, venous, and microvascular endothelial cells and measured the binding of human monocytic cell lines and peripheral blood monocytes. Both anti-HLA I murine (m)IgG1 and mIgG2a induced endothelial P-selectin, which was required for monocyte adhesion to endothelium irrespective of subclass. mIgG2a but not mIgG1 could bind human FcγRs. Accordingly, HLA I mIgG2a but not mIgG1 treatment of endothelial cells significantly augmented recruitment, predominantly through FcγRI, and, to a lesser extent, FcγRIIa. Moreover, HLA I mIgG2a promoted firm adhesion of monocytes to ICAM-1 through Mac-1, which may explain the prominence of monocytes during AMR. We confirmed these observations using human HLA allele-specific mAbs and IgG purified from transplant patient sera. HLA I Abs universally elicit endothelial exocytosis leading to monocyte adherence, implying that P-selectin is a putative therapeutic target to prevent macrophage infiltration during AMR. Importantly, the subclass of donor-specific Ab may influence its pathogenesis. These results imply that human IgG1 and human IgG3 should have a greater capacity to trigger monocyte infiltration into the graft than IgG2 or IgG4 due to enhancement by FcγR interactions.

Cytotoxic T cell recognition of an endogenous class I HLA peptide presented by a class II HLA molecule.

Science.gov (United States)

Chen, B P; Madrigal, A; Parham, P

1990-09-01

Human leukocytes were stimulated in vitro with peptides corresponding in sequence to the highly variable helix of the alpha 1 domain of various HLA-B and -C molecules. A CD4+ CD8- cytotoxic T cell line, CTL-AV, that is specific for the HLA-B7 peptide presented by HLA-DR11.1 was obtained. The HLA-DR11.2 molecule, which only differs at three residues from HLA-DR11.1, did not present the HLA-B7 peptide to CTL-AV. Peptides from the alpha 1 domain helix of other HLA-A and HLA-B molecules, but not HLA-C molecules, competed with the HLA-B7 peptide for binding to HLA-DR11.1. A cell line (WT50) that coexpresses HLA-B7 and HLA-DR11.1 was killed by CTL-AV in the absence of any added HLA-B7 peptide. The processing and presentation of HLA-B7 in these cells appears to be through the endogenous, and not the exogenous, pathway of antigen presentation. Thus, Brefeldin A inhibits presentation and chloroquine does not. Furthermore, introduction of purified HLA-B7 molecules into HLA-DR11.1+, HLA-B7- cells by cytoplasmic loading via osmotic lysis of pinosomes, but not by simple incubation, rendered them susceptible to CTL-AV killing. These results provide an example of class II major histocompatibility complex (MHC) presentation of a constitutively synthesized self protein that uses the endogenous pathway of antigen presentation. They also emphasize the capacity for presentation of MHC peptides by MHC molecules.

Human leukocyte antigen in the allocation of kidneys from cadaveric donors in the United States.

Science.gov (United States)

Ting, Alan; Edwards, Leah Bennett

2004-02-27

Minorities wait longer for a cadaveric donor kidney transplant than whites. For example, the median waiting time to transplant for candidates listed from 1997 to 1998 was 874 days for whites, 1,493 days for blacks, 1,281 days for Hispanics, 1,491 days for Asians, and 1,466 days for others. The current allocation algorithm has been criticized as contributing to decreased access to transplants for racial minorities. There are two levels in the current algorithm: The first is mandatory national sharing between donors and patients with zero human leukocyte antigen (HLA)-A, B, and DR mismatches. The second occurs if there are no candidates and local placement is accomplished based on an algorithm with an HLA component that assigns seven, five, and two points to zero, one, and two HLA-B and DR mismatches, respectively. An analysis of the data shows that a higher percentage of white recipients (21%) received zero antigen mismatched kidneys compared with other races: blacks (7%), Hispanics (14%), and Asians (7%). Whites also received the highest percentage of kidneys with zero B and DR mismatches and one B and DR mismatch compared with the other races. These data indicate that the current algorithm favors whites over minorities, and it is most likely that giving points for HLA-B matching is a strong contributory factor. To address this inequity, the Organ Procurement and Transplantation Network and United Network for Organ Sharing Board of Directors approved a recommendation in November 2002 to change the HLA points to award two points for zero DR mismatches and one point for one DR mismatch. Obviously it will take some time to gather sufficient data to allow meaningful analysis of the effect of the policy change.

Determination of Eligibility in Related Pediatric Hematopoietic Cell Donors: Ethical and Clinical Considerations. Recommendations from a Working Group of the Worldwide Network for Blood and Marrow Transplantation Association.

Science.gov (United States)

Bitan, Menachem; van Walraven, Suzanna M; Worel, Nina; Ball, Lynne M; Styczynski, Jan; Torrabadella, Marta; Witt, Volker; Shaw, Bronwen E; Seber, Adriana; Yabe, Hiromasa; Greinix, Hildegard T; Peters, Christina; Gluckman, Eliane; Rocha, Vanderson; Halter, Joerg; Pulsipher, Michael A

2016-01-01

Related donors for hematopoietic cell (HC) transplantation are a growing population in recent years because of expanding indications for allogeneic transplantation. The safety and welfare of the donor are major concerns for the transplantation community, especially for related sibling donors of young recipients who are children and, thus, not able to fully consent. Because donation of HC does not improve the donor's own physical health and carries a risk of side effects, careful assessment of medical risks specific to the individual donor, as well as consideration of ethical and legal aspects associated with donation from a child, must be considered. In addition, donor centers must balance the needs of both the donor and the recipient, understanding the inherent conflict parents may have as they can be overly focused on the very sick child receiving a transplant, rather than on the relatively less significant health or emotional problems that a sibling donor may have, which could impact risk with donation. Likewise, consideration must be made regarding the nature of the relationship of the sibling donor to the recipient and also aspects of performing research on pediatric HC donors. In this article, as members of the Donor Issues Committee of the Worldwide Network for Blood and Marrow Transplantation, we review key ethical concerns associated with pediatric donation and then give recommendations for screening potential child donors with underlying health conditions. These recommendations are aimed at protecting the physical and emotional well-being of childhood donors and arise out of the Third International Conference on Health and Safety of Donors sponsored by the Worldwide Network for Blood and Marrow Transplantation. Copyright © 2016 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

El complejo mayor de histocompatibilidad humano: sistema HLA

Directory of Open Access Journals (Sweden)

Luis Fernando García

1989-02-01

to such diseases. In tissue transplantation the HLA compatibility between donor and recipient correlates with graft survival. The HLA system also seems to playa very important role In the immunological phenomena that occur during pregnancy. Due to the theoretical and practical importance of the HLA system In genetics, Immunology and medicine, Its study will continue to be a very active field for basic and clinical research.

Bullying among siblings.

Science.gov (United States)

Wolke, Dieter; Skew, Alexandra J

2012-01-01

Parents are often concerned about repeated conflicts between their daughters and sons. However, there is little empirical research of sibling bullying. To conduct a review of existing studies of sibling bullying. Are there any associations between sibling bullying and peer bullying at school? What are the consequences of sibling bullying? Is there good justification why sibling bullying has been so neglected in research? Studies of sibling relationships were reviewed. Four quantitative studies were identified that report on both sibling and peer bullying. Sibling bullying is frequent with up to 50% involved in sibling bullying every month and between 16% and 20% involved in bullying several times a week. Experience of sibling bullying increases the risk of involvement in bullying in school. Both, bullying between siblings and school bullying make unique contributions to explaining behavioral and emotional problems. There is a clear dose-effect relationship of involvement of bullying at home and at school and behavioral or emotional problems. Those involved in both have up to 14 times increased odds of behavioral or emotional problems compared to those involved in only one context or not at all. The empirical evidence is limited and studies are mostly cross-sectional studies. Nevertheless, the review suggests that for those victimized at home and at school behavioral and emotional problems are highly increased. Sibling relationships appear to be a training ground with implications for individual well-being. Strengthening families and parenting skills and increasing sibling support is likely to reduce bullying and increase well-being.

HLA-DQA1 and HLA-DQB1 allele diversity and its extended haplotypes in Madeira Island (Portugal).

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Spínola, H; Lemos, A; Couto, A R; Parreira, B; Soares, M; Dutra, I; Bruges-Armas, J; Brehm, A

2017-02-01

This study shows, for the first time, high-resolution allele frequencies of HLA-DQA1 loci in Madeira Island (Portugal) and allows us to better understand and refine present knowledge on DQB1 variation, with the identification of several alleles not previously reported in this population. Estimates on haplotype profile, involving HLA-A, HLA-B, HLA-DRB1, HLA-DQA1 and HLA-DQB1, are also reported. © 2016 John Wiley & Sons Ltd.

HLA-A AND HLA-B ALLELES ASSOCIATED IN PSORIASIS PATIENTS FROM MUMBAI, WESTERN INDIA

Science.gov (United States)

Umapathy, Shankarkumar; Pawar, Aruna; Mitra, R; Khuperkar, D; Devaraj, J P; Ghosh, K; Khopkar, U

2011-01-01

Background: Psoriasis, a common autoimmune disorder characterized by T cell-mediated keratinocyte hyperproliferation, is known to be associated with the presence of certain specific Human Leukocyte Antigen (HLA) alleles. Aim: To evaluate distribution of HLA-A and HLA-B alleles and hence identify the susceptible allele of psoriasis from patients in Western India. Materials and Methods: The study design included 84 psoriasis patients and 291 normal individuals as controls from same geographical region. HLA-A and HLA-B typing was done using Serology typing. Standard statistical analysis was followed to identify the odds ratio (OR), allele frequencies, and significant P value using Graphpad software. Results: The study revealed significant increase in frequencies of HLA-A2 (OR-3.976, P<0.0001), B8 (OR-5.647, P<0.0001), B17 (OR-5.452, P<0.0001), and B44 (OR-50.460, P<0.0001), when compared with controls. Furthermore, the frequencies of HLA-A28 (OR-0.074, P=0.0024), B5 (OR-0.059, P<0.0001), B12 (OR-0.051, P=0.0002), and B15 (OR-0.237, P=0.0230) were significantly decreased in psoriasis patients. Conclusion: This study shows the strong association of HLA-A2, B8, and B17 antigens with psoriasis conferring susceptibility to psoriasis patients from Western India, while the antigens HLA-A28, B5, and B12 show strong negative association with the disease. PMID:22121262

Renal en Paraguay anti-HLA antibodies monitoring in patients with chronic renal failure on waiting list for renal transplant in Paraguay

Directory of Open Access Journals (Sweden)

Fernanda Prieto

2016-06-01

Full Text Available Introduction: Anti-HLA antibodies determination in the serum of patients on a waiting list for renal transplant is essential to optimize donor selection as well as for the induction and maintenance immunosuppression scheme, according to immunological risk. These antibodies could be present before transplantation as a result of being exposed to blood transfusions, pregnancies and previous transplants. The objective of the study was to determine immunization against HLA antigens, associated factors and their impact on the waiting list for a renal transplant. Methods: In this observational retrospective cross sectional study, 254 patients on the waiting list for renal transplant were included. These patients attended the Public Health central laboratory between July 2013 and July 2015. Results: 30% of the 254 studied patients presented anti-HLA antibodies. The most significant sensitizing event was the exposure to a previous transplant (p=<0.05. Multiparous women were in second place, 69% of them presenting positive PRA (panel reactive antibodies (p=<0.05. Finally 24% of poly transfused patients presented anti-HLA antibodies (p=<0.05. Conclusions: During the 2 year of the study, 51 patients were transplanted, presenting only one of them anti-HLA antibodies before transplantation. This results clearly indicate that the immunization against HLA represents a barrier for transplantation access.

HLA-DRB1*16-restricted recognition of myeloid cells, including CD34+ CML progenitor cells

NARCIS (Netherlands)

Ebeling, Saskia B.; Ivanov, Roman; Hol, Samantha; Aarts, Tineke I.; Hagenbeek, Anton; Verdonck, Leo F.; Petersen, Eefke J.

2003-01-01

The therapeutic effect of a human leucocyte antigen (HLA)-identical allogeneic stem cell transplantation (allo-SCT) for the treatment of haematological malignancies is mediated partly by the allogeneic T cells that are administered together with the stem cell graft. Chronic myeloid leukaemia (CML)

Dynamical system modeling to simulate donor T cell response to whole exome sequencing-derived recipient peptides: Understanding randomness in alloreactivity incidence following stem cell transplantation.

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Vishal Koparde

Full Text Available Quantitative relationship between the magnitude of variation in minor histocompatibility antigens (mHA and graft versus host disease (GVHD pathophysiology in stem cell transplant (SCT donor-recipient pairs (DRP is not established. In order to elucidate this relationship, whole exome sequencing (WES was performed on 27 HLA matched related (MRD, & 50 unrelated donors (URD, to identify nonsynonymous single nucleotide polymorphisms (SNPs. An average 2,463 SNPs were identified in MRD, and 4,287 in URD DRP (p<0.01; resulting peptide antigens that may be presented on HLA class I molecules in each DRP were derived in silico (NetMHCpan ver2.0 and the tissue expression of proteins these were derived from determined (GTex. MRD DRP had an average 3,670 HLA-binding-alloreactive peptides, putative mHA (pmHA with an IC50 of <500 nM, and URD, had 5,386 (p<0.01. To simulate an alloreactive donor cytotoxic T cell response, the array of pmHA in each patient was considered as an operator matrix modifying a hypothetical cytotoxic T cell clonal vector matrix; each responding T cell clone's proliferation was determined by the logistic equation of growth, accounting for HLA binding affinity and tissue expression of each alloreactive peptide. The resulting simulated organ-specific alloreactive T cell clonal growth revealed marked variability, with the T cell count differences spanning orders of magnitude between different DRP. Despite an estimated, uniform set of constants used in the model for all DRP, and a heterogeneously treated group of patients, higher total and organ-specific T cell counts were associated with cumulative incidence of moderate to severe GVHD in recipients. In conclusion, exome wide sequence differences and the variable alloreactive peptide binding to HLA in each DRP yields a large range of possible alloreactive donor T cell responses. Our findings also help understand the apparent randomness observed in the development of alloimmune responses.

Sibling rivalry: related bacterial small RNAs and their redundant and non-redundant roles.

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Caswell, Clayton C; Oglesby-Sherrouse, Amanda G; Murphy, Erin R

2014-01-01

Small RNA molecules (sRNAs) are now recognized as key regulators controlling bacterial gene expression, as sRNAs provide a quick and efficient means of positively or negatively altering the expression of specific genes. To date, numerous sRNAs have been identified and characterized in a myriad of bacterial species, but more recently, a theme in bacterial sRNAs has emerged: the presence of more than one highly related sRNAs produced by a given bacterium, here termed sibling sRNAs. Sibling sRNAs are those that are highly similar at the nucleotide level, and while it might be expected that sibling sRNAs exert identical regulatory functions on the expression of target genes based on their high degree of relatedness, emerging evidence is demonstrating that this is not always the case. Indeed, there are several examples of bacterial sibling sRNAs with non-redundant regulatory functions, but there are also instances of apparent regulatory redundancy between sibling sRNAs. This review provides a comprehensive overview of the current knowledge of bacterial sibling sRNAs, and also discusses important questions about the significance and evolutionary implications of this emerging class of regulators.

Sibling rivalry: Related bacterial small RNAs and their redundant and non-redundant roles

Directory of Open Access Journals (Sweden)

Clayton eCaswell

2014-10-01

Full Text Available Small RNA molecules (sRNAs are now recognized as key regulators controlling bacterial gene expression, as sRNAs provide a quick and efficient means of positively or negatively altering the expression of specific genes. To date, numerous sRNAs have been identified and characterized in a myriad of bacterial species, but more recently, a theme in bacterial sRNAs has emerged: the presence of more than one highly related sRNAs produced by a given bacterium, here termed sibling sRNAs. Sibling sRNAs are those that are highly similar at the nucleotide level, and while it might be expected that sibling sRNAs exert identical regulatory functions on the expression of target genes based on their high degree of relatedness, emerging evidence is demonstrating that this is not always the case. Indeed, there are several examples of bacterial sibling sRNAs with non-redundant regulatory functions, but there are also instances of apparent regulatory redundancy between sibling sRNAs. This review provides a comprehensive overview of the current knowledge of bacterial sibling sRNAs, and also discusses important questions about the significance and evolutionary implications of this emerging class of regulators.

Outcome of allogeneic hematopoietic stem cell transplantation for childhood acute lymphoblastic leukemia in second complete remission: a single institution study

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Eun-Jung Lee

2012-03-01

Full Text Available Purpose : The survival rate for childhood acute lymphoblastic leukemia (ALL has improved significantly. However, overall prognosis for the 20 to 25% of patients who relapse is poor, and allogeneic hematopoietic stem cell transplantation (HSCT offers the best chance for cure. In this study, we identified significant prognostic variables by analyzing the outcomes of allogeneic HSCT in ALL patients in second complete remission (CR. Methods : Fifty-three ALL patients (42 men, 79% who received HSCT in second CR from August 1991 to February 2009 were included (26 sibling donor HSCTs, 49%; 42 bone marrow transplantations, 79%. Study endpoints included cumulative incidence of acute and chronic graft-versus-host disease (GVHD, relapse, 1-year transplant-related mortality (TRM, disease-free survival (DFS, and overall survival (OS. Results : Cumulative incidences of acute GVHD (grade 2 or above and chronic GVHD were 45.3% and 28.5%, respectively. The estimated 5-year DFS and OS for the cohort was 45.2¡?#?.8%; and 48.3¡?#?%,; respectively. Only donor type, i.e., sibling versus unrelated, showed significant correlation with DFS in multivariate analysis (P=0.010. The rates of relapse and 1 year TRM were 28.9¡?#?.4%; and 26.4¡?#?.1%;, respectively, and unrelated donor HSCT (P=0.002 and HLA mismatch (P =0.022 were significantly correlated with increased TRM in univariate analysis. Conclusion : In this single institution study spanning more than 17 years, sibling donor HSCT was the only factor predicting a favorable result in multivariate analysis, possibly due to increased TRM resulting from unrelated donor HSCT.

An initial look at sibling reports on children's behavior: comparisons with children's self-reports and relations with siblings' self-reports and sibling relationships.

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Epkins, C C; Dedmon, A M

1999-10-01

The authors examined siblings' reports of children's depression, anxiety, and aggression, and their reports of the sibling relationship, and compared them with children's self-reports. In two samples, including 169 sibling pairs (age M = 9.98 years, SD = 1.51), no significant differences emerged in the levels of depression and anxiety found in siblings' reports of children's behavior and children's self-reports, although siblings reported children to have significantly higher levels of aggression than the children self-reported. Age, the difference in ages between siblings, sex, and sibling sex were not related to siblings' reports of children's behavior. The relations between children's and siblings' reports of children's behavior were significant, yet moderate (average r = .22). Both siblings' self-reports of internalizing behavior and their perceptions of aspects of the sibling relationship (affection, rivalry, hostility, and satisfaction with the sibling relationship) explained significant, and unique, variance in siblings' reports of children's internalizing behavior. The findings for aggressive behavior were similar, although siblings' perceptions of affection in the sibling relationship were not significantly related to their reports of children's aggression. The potential uses and benefits of sibling reports of children's behavior, and sibling and family relationships, are discussed.

Polymorphism of HLA in the Romanian population.

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Reed, E; Ho, E; Lupu, F; McManus, P; Vasilescu, R; Foca-Rodi, A; Suciu-Foca, N

1992-01-01

We have investigated the HLA-class I and class II polymorphism in a population of 83 Romanians using conventional serology together with PCR amplification and oligonucleotide typing of HLA-class II genes. Romanians show a higher frequency of HLA-A11, B13, B18, B37, B39, B51 and DR2 than other European populations. HLA-DRB1*1501 and 1601 account for the high frequency of the serologic specificity DR2. In Romanians, HLA-DR2 is in linkage disequilibrium with HLA-B18 and HLA-Bw52 rather than with HLA-B7 as in the case in other Europeans. Unexpected HLA-DR2 haplotypes include HLA-DRB1*1502, DQA1*0102, DQB1*0601; HLA-DRB1*1602, DQA1*0102, DQB1*0502. Other unusual haplotypes include HLA-DRB1*0405, DQA1*03, DQB1*0302; HLA-DRB1*1305, DQA1*0103, DQB1*0603; and HLA-DRB1*1405, DQA1*0101, DQB1*05032. Analysis of the genetic distance between Romanians and other Europeans who have been studied serologically are consistent with the hypothesis that Romanians descend from Roman ancestors who colonized Dacia between the 1st century B.C. and 1st century A.D.

Generation of B-cell chronic lymphocytic leukemia (B-CLL)-reactive T-cell lines and clones from HLA class I-matched donors using modified B-CLL cells as stimulators: implications for adoptive immunotherapy.

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Hoogendoorn, M; Wolbers, J Olde; Smit, W M; Schaafsma, M R; Barge, R M Y; Willemze, R; Falkenburg, J H F

2004-07-01

Allogeneic stem cell transplantation following reduced-intensity conditioning is being evaluated in patients with advanced B-cell chronic lymphocytic leukemia (B-CLL). The curative potential of this procedure is mediated by donor-derived alloreactive T cells, resulting in a graft-versus-leukemia effect. However, B-CLL may escape T-cell-mediated immune reactivity since these cells lack expression of costimulatory molecules. We examined the most optimal method to transform B-CLL cells into efficient antigen-presenting cells (APC) using activating cytokines, by triggering toll-like receptors (TLRs) using microbial pathogens and by CD40 stimulation with CD40L-transfected fibroblasts. CD40 activation in the presence of IL-4 induced strongest upregulation of costimulatory and adhesion molecules on B-CLL cells and induced the production of high amounts of IL-12 by the leukemic cells. In contrast to primary B-CLL cells as stimulator cells, these malignant APCs were capable of inducing the generation of B-CLL-reactive CD8(+) CTL lines and clones from HLA class I-matched donors. These CTL lines and clones recognized and killed primary B-CLL as well as patient-derived lymphoblasts, but not donor cells. These results show the feasibility of ex vivo generation of B-CLL-reactive CD8(+) CTLs. This opens new perspectives for adoptive immunotherapy, following allogeneic stem cell transplantation in patients with advanced B-CLL.

Polymorphism in the interleukin-7 receptor-alpha and outcome after allogeneic hematopoietic cell transplantation with matched unrelated donor

DEFF Research Database (Denmark)

Shamim, Z; Spellman, S; Haagenson, M

2013-01-01

Interleukin-7 (IL-7) is essential for T cell development in the thymus and maintenance of peripheral T cells. The α-chain of the IL-7R is polymorphic with the existence of SNPs that give rise to non-synonymous amino acid substitutions. We previously found an association between donor genotypes...... significance of IL-7Rα SNP genotypes in 590-recipient/donor pairs that received HLA-matched unrelated donor HCT for haematological malignancies. Consistent with the primary studies, the rs1494555GG and rs1494558TT genotypes of the donor were associated with aGvHD and chronic GvHD in the univariate analysis...

Donor Specific Anti-HLA Antibodies with Antibody Mediated Rejection and Long-term Outcomes Following Heart Transplantation

Science.gov (United States)

Clerkin, Kevin J.; Farr, Maryjane A.; Restaino, Susan W.; Zorn, Emmanuel; Latif, Farhana; Vasilescu, Elena R.; Marboe, Charles C.; Colombo, Paolo C.; Mancini, Donna M.

2017-01-01

Introduction Donor specific anti-HLA antibodies (DSA) are common following heart transplantation and are associated with rejection, cardiac allograft vasculopathy (CAV), and mortality. Currently a non-invasive diagnostic test for pathologic AMR (pAMR) does not exist. Methods 221 consecutive adult patients underwent heart transplantation from January 1st, 2010 through August 31th, 2013 and followed through October 1st, 2015. The primary objective was to determine whether the presence of DSA could detect AMR at the time of pathologic diagnosis. Secondary analyses included the association of DSA (stratified by MHC Class and de-novo status) during AMR with new graft dysfunction, graft loss (mortality or retransplantation), and development of CAV. Results During the study period 69 individual patients (31.2%) had DSA (24% had de-novo DSA) and there were 74 episodes of pAMR in 38 unique patients. The sensitivity of DSA at any MFI to detect concurrent pAMR was only 54.3%. The presence of any DSA during pAMR increased the odds of graft dysfunction (OR 5.37, 95% CI 1.34–21.47, p=0.018), adjusting for age, gender, and timing of AMR. Circulating Class II DSA after transplantation increased the risk of future pAMR (HR 2.97, 95% CI 1.31–6.73, p=0.009). Patients who developed de-novo Class II DSA had a 151% increase in risk of graft loss (contingent on 30-day survival) compared with those who did not have DSA (95% CI 1.11–5.69, p=0.027). Conclusions DSA were inadequate to diagnose pAMR, but Class II DSA provided prognostic information regarding future pAMR, graft dysfunction with pAMR, and graft loss. PMID:27916323

Donor-specific anti-HLA antibodies with antibody-mediated rejection and long-term outcomes following heart transplantation.

Science.gov (United States)

Clerkin, Kevin J; Farr, Maryjane A; Restaino, Susan W; Zorn, Emmanuel; Latif, Farhana; Vasilescu, Elena R; Marboe, Charles C; Colombo, Paolo C; Mancini, Donna M

2017-05-01

Donor-specific anti-HLA antibodies (DSA) are common after heart transplantation and are associated with rejection, cardiac allograft vasculopathy, and mortality. A noninvasive diagnostic test for pathologic antibody-mediated rejection (pAMR) does not exist. From January 1, 2010, through August 31, 2013, 221 consecutive adult patients underwent heart transplantation and were followed through October 1, 2015. The primary objective was to determine whether the presence of DSA could detect AMR at the time of pathologic diagnosis. Secondary analyses included association of DSA (stratified by major histocompatibility complex class and de novo status) during AMR with new graft dysfunction, graft loss (mortality or retransplantation), and development of cardiac allograft vasculopathy. During the study period, 69 patients (31.2%) had DSA (24% had de novo DSA), and there were 74 episodes of pAMR in 38 patients. Sensitivity of DSA at any mean fluorescence intensity to detect concurrent pAMR was only 54.3%. The presence of any DSA during pAMR increased the odds of graft dysfunction (odds ratio = 5.37; 95% confidence interval [CI], 1.34-21.47; p = 0.018), adjusting for age, sex, and timing of AMR. Circulating class II DSA after transplantation increased risk of future pAMR (hazard ratio = 2.97; 95% CI, 1.31-6.73; p = 0.009). Patients who developed de novo class II DSA had 151% increased risk of graft loss (contingent on 30-day survival) compared with patients who did not have DSA (95% CI, 1.11-5.69; p = 0.027). DSA were inadequate to diagnose pAMR. Class II DSA provided prognostic information regarding future pAMR, graft dysfunction with pAMR, and graft loss. Copyright © 2017 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

HLA antibody-incompatible kidney transplantation between jehovah's witnesses--a case report.

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Greenberg, A; Macphee, I; Popoola, J; Sage, D; Iqbal, R; Fossati, N; Heap, S; Morsy, M; Kessaris, N

2013-06-01

Desensitization before HLA antibody-incompatible (HLAi) transplantation involves nonspecific apheresis of HLA antibodies. Clotting factors and albumin are also removed and have to be replaced. This makes transplantation difficult because it increases the risk of bleeding. Such risk is further compounded when certain blood products are refused on religious grounds. We present a case of successful HLAi transplantation in a Jehovah's Witness across a positive-flow cytometric HLA crossmatch from a live donor who was also a Jehovah's Witness. This was achieved by giving rituximab 1 month before transplantation and starting prednisolone, tacrolimus, and mycophenolate mofetil 10 days before surgery. In preparation, the patient also underwent 4 sessions of double-filtration plasma exchange each followed by low-dose intravenous immunoglobulin. The night before transplantation, the fibrinogen was low, requiring 2 pools of cryoprecipitate. The organ was retrieved through laparoscopic hand-assisted retroperitoneoscopic nephrectomy and transplanted into the recipient with no complications. In addition, the patient received basiliximab during surgery. Sixteen months after transplantation the serum creatinine was 70 μmol/L (0.79 mg/dL) and there were no rejection episodes. To our knowledge this is the world's first live-related kidney transplant across the HLAi barrier between 2 Jehovah's Witnesses. This case may allow further HLAi transplants to be carried out in Jehovah's Witnesses in the future around the world. Copyright © 2013 Elsevier Inc. All rights reserved.

Siblings of children with life-limiting conditions: psychological adjustment and sibling relationships.

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Fullerton, J M; Totsika, V; Hain, R; Hastings, R P

2017-05-01

This study explored psychological adjustment and sibling relationships of siblings of children with life-limiting conditions (LLCs), expanding on previous research by defining LLCs using a systematic classification of these conditions. Thirty-nine siblings participated, aged 3-16 years. Parents completed measures of siblings' emotional and behavioural difficulties, quality of life, sibling relationships and impact on families and siblings. Sibling and family adjustment and relationships were compared with population norms, where available, and to a matched comparison group of siblings of children with autistic spectrum disorder (ASD), as a comparable 'high risk' group. LLC siblings presented significantly higher levels of emotional and behavioural difficulties, and lower quality of life than population norms. Their difficulties were at levels comparable to siblings of children with ASD. A wider impact on the family was confirmed. Family socio-economic position, time since diagnosis, employment and accessing hospice care were factors associated with better psychological adjustment. Using a systematic classification of LLCs, the study supported earlier findings of increased levels of psychological difficulties in siblings of children with a LLC. The evidence is (i) highlighting the need to provide support to these siblings and their families, and (ii) that intervention approaches could be drawn from the ASD field. © 2016 John Wiley & Sons Ltd.

Siblings exposed to intimate partner violence: linking sibling relationship quality & child adjustment problems.

Science.gov (United States)

Piotrowski, Caroline C; Tailor, Ketan; Cormier, Damien C

2014-01-01

Although the majority of families that experience intimate partner violence (IPV) have more than one child, most research to date has focused upon a single child within these families. A significant body of research has indicated siblings play an important role in children's adjustment and well-being. To address this gap, the three main goals of the present study were to compare the adjustment of older and younger siblings exposed to IPV, to describe and compare the quality of these sibling relationships from multiple perspectives, and to investigate how sibling adjustment and relationship quality influence children's adjustment. Forty-seven sibling pairs and their mothers were recruited from the community. Mothers self-reported on their violent experiences using the Conflict Tactics Scale, and also estimated the length of time their children were exposed to IPV. Mothers and children completed assessments of child adjustment and the quality of sibling relationships. Observers also assessed the quality of sibling interaction. Results indicated that adjustment between siblings was highly inter-related. On average, mothers reported sibling relationships as less positive but also as less hostile than did siblings themselves. Higher levels of sibling hostility, lower levels of sibling warmth and higher levels of disengagement each significantly predicted child adjustment; however, these effects were predicated upon the adjustment of the other sibling. The sibling relationships of children exposed to IPV made a difference in their individual adjustment, and their adjustment issues influenced how they feel about and interacted with their sibling. Sibling hostility played a stronger role in adjustment issues than sibling warmth. The nature of sibling influences and the direction of future research were discussed. Copyright © 2013 Elsevier Ltd. All rights reserved.

Molecular variation at the HLA-A, B, C, DRB1, DQA1, and DQB1 loci in full heritage American Indians in Arizona: private haplotypes and their evolution.

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Williams, R; Chen, Y-F; Endres, R; Middleton, D; Trucco, M; Williams, J Dunn; Knowler, W

2009-12-01

A sample of 492 full heritage, unrelated residents of the Gila River Indian Community (GRIC) of Arizona were characterized for their high-resolution DNA alleles at the HLA-A, B, C, DRB1, DQA1, and DQB1 loci. Only five allelic categories are found at HLA-A, 10 at HLA-B, 8 at HLA-C and HLA-DR, and 4 at DQA1 and DQB1. There is little evidence for population structure at the 6 loci. Two 'private' alleles, B*5102 and B*4005, which are found nearly exclusively in American Indian populations in the desert southwest and northern Mexico, are likely new mutations after the first inhabitation of the area, the evolution of which are reflected in the contemporary distribution of their respective haplotypes. DRB1*1402 has the highest reported frequency of any specificity at the DRB1 locus, 0.7461, and serves as a sensitive probe for locating related east Asian populations. The haplotypes in this population also exhibit a highly restricted distribution and strong genetic disequilibria, which has important implications for matching solid organ and bone marrow allografts. It is shown that, when one considers HLA-A-B-DRB1 homozygotes as allograft donors for all full heritage members of the GRIC, 50% of the community would find a non-mismatched organ within the homozygotes for the six most common haplotypes. This raises questions about transplantation policy and whether, in the presence of high-frequency private alleles and a restricted number of haplotypes, the full heritage American Indian community of the desert southwest should act as its own pool of donors for its affected members.

A New UK 2006 National Kidney Allocation Scheme for deceased heart-beating donor kidneys.

Science.gov (United States)

Johnson, Rachel J; Fuggle, Susan V; Mumford, Lisa; Bradley, J Andrew; Forsythe, John L R; Rudge, Chris J

2010-02-27

In 2004, it was agreed that a new allocation scheme for kidneys from deceased heart-beating donors was required in the United Kingdom to address observed inequities in access to transplant. The 2006 National Kidney Allocation Scheme (2006 NKAS) was developed to meet agreed objectives and preparatory work included a review of the criteria for human leukocyte antigen (HLA) matching and simulation evidence about the effectiveness of alternative schemes. ALGORITHM FOR 2006 NKAS: The 2006 NKAS gives absolute priority to all 000 HLA-A, -B, -DR-mismatched patients and well-matched pediatric patients (inequity of access will take a number of years to address fully.

Sibling Incest.

Science.gov (United States)

Phillips-Green, Mary J.

2002-01-01

Recently, sibling incest, a type of intrafamilial incest, has received notice from mental health professionals; however, many professionals still do not recognize the seriousness of the problem. This article reviews current research on the individual and family dynamics that allow sibling incest to occur, the effects of sibling incest on victims,…

Strain-based HLA association analysis identified HLA-DRB1*09:01 associated with modern strain tuberculosis.

Science.gov (United States)

Toyo-Oka, L; Mahasirimongkol, S; Yanai, H; Mushiroda, T; Wattanapokayakit, S; Wichukchinda, N; Yamada, N; Smittipat, N; Juthayothin, T; Palittapongarnpim, P; Nedsuwan, S; Kantipong, P; Takahashi, A; Kubo, M; Sawanpanyalert, P; Tokunaga, K

2017-09-01

Tuberculosis (TB) occurs as a result of complex interactions between the host immune system and pathogen virulence factors. Human leukocyte antigen (HLA) class II molecules play an important role in the host immune system. However, no study has assessed the association between HLA class II genes and susceptibility to TB caused by specific strains. This study investigated the possible association of HLA class II genes with TB caused by modern and ancient Mycobacterium tuberculosis (MTB). The study included 682 patients with TB and 836 control subjects who were typed for HLA-DRB1 and HLA-DQB1 alleles. MTB strains were classified using a large sequence polymorphism typing method. Association analysis was performed using common HLA alleles and haplotypes in different MTB strains. HLA association analysis of patients infected with modern MTB strains showed significant association for HLA-DRB1*09:01 (odds ratio [OR] = 1.82; P-value = 9.88 × 10 -4 ) and HLA-DQB1*03:03 alleles (OR = 1.76; P-value = 1.31 × 10 -3 ) with susceptibility to TB. Haplotype analysis confirmed that these alleles were in strong linkage disequilibrium and did not exert an interactive effect. Thus, the results of this study showed an association between HLA class II genes and susceptibility to TB caused by modern MTB strains, suggesting the importance of strain-specific analysis to determine susceptibility genes associated with TB. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

HLA in bone marrow transplantation

International Nuclear Information System (INIS)

Tsuji, Kimiyoshi

1989-01-01

It has been well understood that human major histocompatibility antigen system, HLA is the most important role in the allo transplantation. Therefore, the structure of HLA genes was presented by the recent information (1987). Moreover, their functions in vitro and in vivo also were described. Finally, bone marrow transplantation and HLA network system in Japan against HLA mismatched case was proposed. It is eagerly expected that functional and clinical bone marrow transplantation in Japan could be succeeded. (author)

Birth of a healthy infant after preimplantation genetic diagnosis by sequential blastomere and trophectoderm biopsy for β-thalassemia and HLA genotyping.

Science.gov (United States)

Milachich, Tanya; Timeva, Tanya; Ekmekci, Cumhur; Beyazyurek, Cagri; Tac, Huseyin Avni; Shterev, Atanas; Kahraman, Semra

2013-07-01

Preimplantation genetic diagnosis (PGD) is a widely used technique for couples at genetic risk and involves the diagnosis and transfer of unaffected embryos generated through in vitro fertilization (IVF) techniques. For those couples who are at risk of transmitting a genetic disease to their offspring, preimplantation embryos can be selected according to their genetic status as well as human leukocyte antigen (HLA) compatibility with the affected child. Stem cells from the resulting baby's umbilical cord blood can be used for transplantation to the affected sibling without graft rejection. Here we report successful hematopoietic stem cell transplantation (HSCT) after the birth of a healthy infant, who was born after successful PGD testing with both cleavage stage and blastocyst stage biopsy for the purpose of diagnosis of β-thalassemia and HLA compatibility. The specific feature of this work is not only to have the first successful HSCT achieved in Bulgaria after using preimplantation HLA typing technique, it also demonstrates how to accomplish this success via cross-border collaboration of different units, which makes the application of these sophisticated methods possible in hospitals not having the necessary equipments and expertise. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

HLA-G molecule as inductor of immunotolerance

International Nuclear Information System (INIS)

Alfonso Valdes, Maria E

2009-01-01

HLA-G are molecules are (non-classic) class I antigens from main histocompatibility system. There are sis isoforms of HLA-G antigen codifying four proteins united to a membrane (HLA-G1, HLA-G2, HLA-G3, HLA-G4), and three soluble isoforms (HLA-G5, HLA-G6, HLA-G7). The first ones are expressed in cells of placental extravillous cytotrophoblast (Langhans' layer), amnios epithelial cells, fetal endothelial cells, mesenchymal macrophages of chorionic villi, and in epithelial cells of thymus medulla; the second ones in amniotic fluid, in maternal peripheral blood and that of the umbilical cord. There was a HLA-G expression in some types of tumors, stroma cells under inflammation conditions, virus-infected cells and in serum of transplant patients. There are strong evidences of HLA-G molecules role in tolerance induction to these physiological and pathological situations through suppression of lithic activity of NK cells and of cytotoxic T lymphocytes. This knowledge may be very useful in future therapeutical management of these entities as well as to favor the success of tissue and organ transplant

Soluble CD30 and Cd27 levels in patients undergoing HLA antibody-incompatible renal transplantation.

Science.gov (United States)

Hamer, Rizwan; Roche, Laura; Smillie, David; Harmer, Andrea; Mitchell, Daniel; Molostvov, Guerman; Lam, For T; Kashi, Habib; Tan, Lam Chin; Imray, Chris; Fletcher, Simon; Briggs, David; Lowe, David; Zehnder, Daniel; Higgins, Rob

2010-08-01

HLA antibody-incompatible transplantation has a higher risk of rejection when compared to standard renal transplantation. Soluble CD30 (sCD30) has been shown in many, but not all, studies to be a biomarker for risk of rejection in standard renal transplant recipients. We sought to define the value of sCD30 and soluble CD27 (sCD27) in patients receiving HLA antibody-incompatible transplants. Serum taken at different time points from 32 HLA antibody-incompatible transplant recipients was retrospectively assessed for sCD30 and sCD27 levels by enzyme-linked immunosorbent assay (ELISA). This was compared to episodes of acute rejection, post-transplant donor-specific antibody (DSA) levels and 12 month serum creatinine levels. No association was found between sCD27 and sCD30 levels and risk of acute rejection or DSA levels. Higher sCD30 levels at 4-6 weeks post-transplantation were associated with a higher serum creatinine at 12 months. Conclusion patients undergoing HLA antibody-incompatible transplantation are at a high risk of rejection but neither sCD30 (unlike in standard transplantation) nor sCD27 was found to be a risk factor. High sCD30 levels measured at 4-6 weeks post-transplantation was associated with poorer graft function at one year. Copyright © 2010 Elsevier B.V. All rights reserved.

Keeping mum about dad: "contracts" to protect gamete donor anonymity.

Science.gov (United States)

Rees, Anne

2012-06-01

This article considers the legal status of so-called contracts for anonymity between fertility clinics and donors of gametes that were made in the period before legislation authorising disclosure. It notes that while clinics frequently cite the existence of these "contracts" to argue against retrospective legislation authorising disclosure of the donor's identity, they may be nothing more than one-sided statements of informed consent. However, the article notes that even if an agreement between a donor and a clinic is not contractual, it does not follow that a person conceived through assisted reproductive technology has any right of access to the identity of the donor. The writer has not been able to locate examples of written promises by the clinics promising anonymity. There are written promises by the donors not to seek the identity of the recipients. These promises do not bind the resulting offspring nor do they appear to be supported by consideration. The article suggests that the basis for any individual donor to restrain a clinic from revealing their identity may be found in promissory estoppel. Nevertheless, there is no real issue in Australia concerning clinics revealing these details absent legislative authority. The issue is whether parliaments will legislate to authorise the disclosure. The article notes that it would be rare for parliaments to legislate to overturn existing legal contracts but suggests that the contract argument may not be as strong as has been thought.

HLA class I antibodies trigger increased adherence of monocytes to endothelial cells by eliciting an increase in endothelial P-selectin and, depending on subclass, by engaging FcγRs1

Science.gov (United States)

Valenzuela, Nicole M; Mulder, Arend; Reed, Elaine F

2013-01-01

Antibody-mediated rejection of solid organ transplants is characterized by intragraft macrophages. It is incompletely understood how donor specific antibody binding to graft endothelium promotes monocyte adhesion, and what, if any, contribution is made by the Fc region of the antibody. We investigated the mechanisms underlying monocyte recruitment by HLA class I antibody-activated endothelium. We used a panel of murine monoclonal antibodies of different subclasses to crosslink HLA I on human aortic, venous and microvascular endothelial cells, and measured the binding of human monocytic cell lines and peripheral blood monocytes. Both anti-HLA I murine IgG1 and mIgG2a induced endothelial P-selectin, which was required for monocyte adhesion to endothelium irrespective of subclass. Mouse IgG2a but not mIgG1 could bind human FcγRs. Accordingly, HLA I mIgG2a but not mIgG1 treatment of endothelial cells significantly augmented recruitment, predominantly through FcγRI, and, to a lesser extent, FcγRIIa. Moreover, HLA I mIgG2a promoted firm adhesion of monocytes to ICAM-1 through Mac-1, which may explain the prominence of monocytes during antibody mediated rejection. We confirmed these observations using human HLA allele specific monoclonal antibodies and IgG purified from transplant patient sera. HLA I antibodies universally elicit endothelial exocytosis leading to monocyte adherence, implying that P-selectin is a putative therapeutic target to prevent macrophage infiltration during antibody-mediated rejection. Importantly, the subclass of donor specific antibody may influence its pathogenesis. These results imply that hIgG1 and hIgG3 should have a greater capacity to trigger monocyte infiltration into the graft than IgG2 or IgG4 due to enhancement by FcγR interactions. PMID:23690477

Desensitization Protocol in Recipients of Deceased Kidney Donor With Donor-Specific Antibody-Low Titers.

Science.gov (United States)

Kanter Berga, J; Sancho Calabuig, A; Gavela Martinez, E; Puig Alcaraz, N; Avila Bernabeu, A; Crespo Albiach, J; Molina Vila, P; Beltrán Catalan, S; Pallardó Mateu, L

2016-11-01

Kidney transplantation is the better option for end-stage renal disease (ESRD), but for patients with human leukocyte antigen (HLA) sensitization, the wait times are significantly longer than for patients without antibodies. Many desensitization protocols have been described involving strong immunosuppression, the use of apheresis, and B-cell-modulating therapies. We have designed a desensitization protocol from day 0 for deceased donor kidney transplantation. Our aim was to present our initial experience with five kidney transplant patients. All patients had a negative complement-dependent cytotoxicity cross-match. The desensitization protocol included five to seven doses of thymoglobulin (1.25 mg/kg) and three sessions of plasmapheresis (PP) within the first week after transplantation, with intravenous immunoglobulin (500 mg/kg) after each PP session and one dose of rituximab on day 8. The presence of donor-specific antibodies (DSA) was analyzed by use of Luminex technology; levels between 1000 and 3000 mean fluorescence intensity were considered for desensitization. The median age was 44 years and median renal replacement therapy time was 9 years. All recipients presented 1 to 3 DSA specificities. There were no severe side effects related to PP, infusion of intravenous immunoglobulin, or rituximab. The median follow-up period was 19.3 months. Median serum creatinine level at last follow-up was 1.7 mg/dL. A kidney biopsy was performed in all patients. Graft and patient survival was 100%. Until now, few data are available concerning whether HLA-incompatible kidney transplantation after desensitization would benefit patients with ERSD. The desensitization strategy using the combination of PP, low doses of intravenous immunoglobulin, and rituximab at our center resulted in a satisfactory clinical outcome. Copyright © 2016 Elsevier Inc. All rights reserved.

Human mesenchymal stem cells suppress donor CD4(+) T cell proliferation and reduce pathology in a humanized mouse model of acute graft-versus-host disease.

Science.gov (United States)

Tobin, L M; Healy, M E; English, K; Mahon, B P

2013-05-01

Acute graft-versus-host disease (aGVHD) is a life-threatening complication following allogeneic haematopoietic stem cell transplantation (HSCT), occurring in up to 30-50% of patients who receive human leucocyte antigen (HLA)-matched sibling transplants. Current therapies for steroid refractory aGVHD are limited, with the prognosis of patients suboptimal. Mesenchymal stem or stromal cells (MSC), a heterogeneous cell population present in many tissues, display potent immunomodulatory abilities. Autologous and allogeneic ex-vivo expanded human MSC have been utilized to treat aGVHD with promising results, but the mechanisms of therapeutic action remain unclear. Here a robust humanized mouse model of aGVHD based on delivery of human peripheral blood mononuclear cells (PBMC) to non-obese diabetic (NOD)-severe combined immunodeficient (SCID) interleukin (IL)-2rγ(null) (NSG) mice was developed that allowed the exploration of the role of MSC in cell therapy. MSC therapy resulted in the reduction of liver and gut pathology and significantly increased survival. Protection was dependent upon the timing of MSC therapy, with conventional MSC proving effective only after delayed administration. In contrast, interferon (IFN)-γ-stimulated MSC were effective when delivered with PBMC. The beneficial effect of MSC therapy in this model was not due to the inhibition of donor PBMC chimerism, as CD45(+) and T cells engrafted successfully in this model. MSC therapy did not induce donor T cell anergy, FoxP3(+) T regulatory cells or cause PBMC apoptosis in this model; however, it was associated with the direct inhibition of donor CD4(+) T cell proliferation and reduction of human tumour necrosis factor-α in serum. © 2012 British Society for Immunology.

What makes siblings different? The development of sibling differences in academic achievement and interests.

Science.gov (United States)

Jensen, Alexander C; McHale, Susan M

2015-06-01

To illuminate processes that contribute to the development of sibling differences, this study examined cross-lagged links between parents' beliefs about sibling differences in academic ability and differences between siblings' grade point averages (GPAs), and cross-lagged links between differences in siblings' GPAs and sibling differences in academic interests. Data were collected from mothers, fathers, firstborn youth (M age at Time 1 = 15.71, SD = 1.07), and secondborn youth (M age at Time 1 = 13.18, SD = 1.29) from 388 European American families on 3 annual occasions. Findings revealed that, after controlling for siblings' average grades and prior differences in performance, parents' beliefs about sibling differences in academic ability predicted differences in performance such that youth rated by parents as relatively more competent than their sibling earned relatively higher grades the following year. Siblings' relative school performance, however, did not predict parents' beliefs about differences between siblings' competencies. Further, after controlling for average interests and grades, sibling differences in GPA predicted differences in siblings' interests such that youth who had better grades than their siblings reported relatively stronger academic interests the following year. Differences in interest, however, did not predict sibling differences in GPA. Findings are discussed in terms the role of sibling dynamics in family socialization. (c) 2015 APA, all rights reserved).

The Emerging Importance of Non-HLA Autoantibodies in Kidney Transplant Complications.

Science.gov (United States)

Cardinal, Héloise; Dieudé, Mélanie; Hébert, Marie-Josée

2017-02-01

Antibodies that are specific to organ donor HLA have been involved in the majority of cases of antibody-mediated rejection in solid organ transplant recipients. However, recent data show that production of non-HLA autoantibodies can occur before transplant in the form of natural autoantibodies. In contrast to HLAs, which are constitutively expressed on the cell surface of the allograft endothelium, autoantigens are usually cryptic. Tissue damage associated with ischemia-reperfusion, vascular injury, and/or rejection creates permissive conditions for the expression of cryptic autoantigens, allowing these autoantibodies to bind antigenic targets and further enhance vascular inflammation and renal dysfunction. Antiperlecan/LG3 antibodies and antiangiotensin II type 1 receptor antibodies have been found before transplant in patients with de novo transplants and portend negative long-term outcome in patients with renal transplants. Here, we review mounting evidence suggesting an important role for autoantibodies to cryptic antigens as novel accelerators of kidney dysfunction and acute or chronic allograft rejection. Copyright © 2017 by the American Society of Nephrology.

Evolving paradigms for desensitization in managing broadly HLA sensitized transplant candidates.

Science.gov (United States)

Reinsmoen, Nancy L; Lai, Chi-Hung; Vo, Ashley; Jordan, Stanley C

2012-04-01

The broadly human leukocyte antigen (HLA) sensitized patient awaiting organ transplantation remains a persistent and significant problem for transplant medicine. Sensitization occurs as a consequence of exposure to HLA antigens through pregnancy, blood and platelet transfusions, and previous transplants. Early experience with desensitization protocols coupled with improved diagnostics for donor-specific antibodies (DSAs) and renal pathology have greatly improved transplant rates and outcomes for patients once considered un-transplantable or at high risk for poor outcomes. More recent advances have occurred through implementation of a national allocation system requiring the entering of unacceptable antigens that reduces the rate of crossmatch positivity. Current desensitization therapies include high-dose intravenous immunoglobulin (IVIG), plasma exchange (PLEX) with low-dose IVIG, and IVIG combined with rituximab. Developing therapies include proteasome inhibitors aimed at plasma cells and modifiers of complement-mediated injury. Here we discuss the important advancements in desensitization including defining the risk for antibody-mediated rejection prior to transplantation and the evolution of therapies aimed at reducing the impact of antibody injury on allografts.

Describing the Peptide Binding Specificity of HLA-C

DEFF Research Database (Denmark)

Rasmussen, Michael; Harndahl, Mikkel Nors; Nielsen, Morten

for 5 HLA-C molecules and for all, but one, molecule we find a high frequency of binders, >70%, among these peptides. To extend the examined peptide space, we use bioinformatic prediction tools to search for additional binders. Finally, we update our prediction tool, NetMHCpan, with the HLA-C affinity......Human leukocyte antigen (HLA) presents peptides to T-cells for immune scrutiny. Whereas HLA-A and -B have been described in great detail, HLA-C has received much less attention. Here, to increase the coverage of HLA-C and the accuracy of the corresponding tools, we have generated HLA-C molecules...... data and show that the predictive performance for HLA-C molecules now is increased to a level comparable withthat of HLA-A and -B. These novel HLA-C molecules and predictors are successfully used to generate HLA-C tetramers and validate HLA-C-restricted T cell responses....

Structural Features of Sibling Dyads and Attitudes toward Sibling Relationships in Young Adulthood

Science.gov (United States)

Riggio, Heidi R.

2006-01-01

This study examined sibling-dyad structural variables (sex composition, age difference, current coresidence, position adjacency, family size, respondent and/or sibling ordinal position) and attitudes toward adult sibling relationships. A sample of 1,053 young adults (M age = 22.1 years) described one sibling using the Lifespan Sibling Relationship…

Relapsed Diffuse Large B-Cell Lymphoma Treated by Reduced-Intensity Allogeneic Stem Cell Transplantation with Donor Lymphocyte Infusion

International Nuclear Information System (INIS)

Chudhry, Q.N.; Ahmed, P.; Ullah, K.; Satti, T.M.; Raza, S.; Mehmood, S.K.; Akram, M.; Ahmed, S.

2010-01-01

A 42 years old male with relapsed diffuse large B-cell lymphoma was given second-line chemotherapy followed by reduced intensity allogeneic stem cell transplantation from HLA matched brother. Twelve weeks post transplant, his disease relapsed evidenced by the appearance of lymphoma cells in the peripheral blood and declining donor chimerism. Donor lymphocyte infusion was given that induced complete lymphoma remission. The patient is well 3 years post transplant with his disease in complete remission. (author)

HLA-DRB1*03:01 and HLA-DRB1*04:01 modify the presentation and outcome in autoimmune hepatitis type-1.

Science.gov (United States)

van Gerven, N M F; de Boer, Y S; Zwiers, A; Verwer, B J; Drenth, J P H; van Hoek, B; van Erpecum, K J; Beuers, U; van Buuren, H R; den Ouden, J W; Verdonk, R C; Koek, G H; Brouwer, J T; Guichelaar, M M J; Vrolijk, J M; Coenraad, M J; Kraal, G; Mulder, C J J; van Nieuwkerk, C M J; Bloemena, E; Verspaget, H W; Kumar, V; Zhernakova, A; Wijmenga, C; Franke, L; Bouma, G

2015-06-01

The classical human leukocyte antigen (HLA)-DRB1*03:01 and HLA-DRB1*04:01 alleles are established autoimmune hepatitis (AIH) risk alleles. To study the immune-modifying effect of these alleles, we imputed the genotypes from genome-wide association data in 649 Dutch AIH type-1 patients. We therefore compared the international AIH group (IAIHG) diagnostic scores as well as the underlying clinical characteristics between patients positive and negative for these HLA alleles. Seventy-five percent of the AIH patients were HLA-DRB1*03:01/HLA-DRB1*04:01 positive. HLA-DRB1*03:01/HLA-DRB1*04:01-positive patients had a higher median IAIHG score than HLA-DRB1*03:01/HLA-DRB1*04:01-negative patients (P<0.001). We did not observe associations between HLA alleles and alanine transaminase levels (HLA-DRB1*03:01: P=0.2; HLA-DRB1*04:01; P=0.5); however, HLA-DRB1*03:01 was independently associated with higher immunoglobulin G levels (P=0.04). The HLA-DRB1*04:01 allele was independently associated with presentation at older age (P=0.03) and a female predominance (P=0.04). HLA-DRB1*03:01-positive patients received immunosuppressive medication and liver transplantation. In conclusion, the HLA-DRB1*03:01 and HLA-DRB1*04:01 alleles are both independently associated with the aggregate diagnostic IAIHG score in type-1 AIH patients, but are not essential for AIH development. HLA-DRB1*03:01 is the strongest genetic modifier of disease severity in AIH.

Fludarabine Melphalan reduced-intensity conditioning allotransplanation provides similar disease control in lymphoid and myeloid malignancies: analysis of 344 patients.

Science.gov (United States)

Bryant, A; Nivison-Smith, I; Pillai, E S; Kennedy, G; Kalff, A; Ritchie, D; George, B; Hertzberg, M; Patil, S; Spencer, A; Fay, K; Cannell, P; Berkahn, L; Doocey, R; Spearing, R; Moore, J

2014-01-01

This was an Australasian Bone Marrow Transplant Recipient Registry (ABMTRR)-based retrospective study assessing the outcome of Fludarabine Melphalan (FluMel) reduced-intensity conditioning between 1998 and 2008. Median follow-up was 3.4 years. There were 344 patients with a median age of 54 years (18-68). In all, 234 patients had myeloid malignancies, with AML (n=166) being the commonest indication. There were 110 lymphoid patients with non-hodgkins lymphoma (NHL) (n=64) the main indication. TRM at day 100 was 14% with no significant difference between the groups. OS and disease-free survival (DFS) were similar between myeloid and lymphoid patients (57 and 50% at 3 years, respectively). There was no difference in cumulative incidence of relapse or GVHD between groups. Multivariate analysis revealed four significant adverse risk factors for DFS: donor other than HLA-identical sibling donor, not in remission at transplant, previous autologous transplant and recipient CMV positive. Chronic GVHD was associated with improved DFS in multivariate analysis predominantly due to a marked reduction in relapse (HR:0.44, P=0.003). This study confirms that FluMel provides durable and equivalent remissions in both myeloid and lymphoid malignancies. Disease stage and chronic GVHD remain important determinants of outcome for FluMel allografting.

Are elder siblings helpers or competitors? Antagonistic fitness effects of sibling interactions in humans

Science.gov (United States)

Nitsch, Aïda; Faurie, Charlotte; Lummaa, Virpi

2013-01-01

Determining the fitness consequences of sibling interactions is pivotal for understanding the evolution of family living, but studies investigating them across lifetime are lacking. We used a large demographic dataset on preindustrial humans from Finland to study the effect of elder siblings on key life-history traits. The presence of elder siblings improved the chances of younger siblings surviving to sexual maturity, suggesting that despite a competition for parental resources, they may help rearing their younger siblings. After reaching sexual maturity however, same-sex elder siblings' presence was associated with reduced reproductive success in the focal individual, indicating the existence of competition among same-sex siblings. Overall, lifetime fitness was reduced by same-sex elder siblings' presence and increased by opposite-sex elder siblings' presence. Our study shows opposite effects of sibling interactions depending on the life-history stage, and highlights the need for using long-term fitness measures to understand the selection pressures acting on sibling interactions. PMID:23173210

Imputing Variants in HLA-DR Beta Genes Reveals That HLA-DRB1 Is Solely Associated with Rheumatoid Arthritis and Systemic Lupus Erythematosus.

Directory of Open Access Journals (Sweden)

Kwangwoo Kim

Full Text Available The genetic association of HLA-DRB1 with rheumatoid arthritis (RA and systemic lupus erythematosus (SLE is well documented, but association with other HLA-DR beta genes (HLA-DRB3, HLA-DRB4 and HLA-DRB5 has not been thoroughly studied, despite their similar functions and chromosomal positions. We examined variants in all functional HLA-DR beta genes in RA and SLE patients and controls, down to the amino-acid level, to better understand disease association with the HLA-DR locus. To this end, we improved an existing HLA reference panel to impute variants in all protein-coding HLA-DR beta genes. Using the reference panel, HLA variants were inferred from high-density SNP data of 9,271 RA-control subjects and 5,342 SLE-control subjects. Disease association tests were performed by logistic regression and log-likelihood ratio tests. After imputation using the newly constructed HLA reference panel and statistical analysis, we observed that HLA-DRB1 variants better accounted for the association between MHC and susceptibility to RA and SLE than did the other three HLA-DRB variants. Moreover, there were no secondary effects in HLA-DRB3, HLA-DRB4, or HLA-DRB5 in RA or SLE. Of all the HLA-DR beta chain paralogs, those encoded by HLA-DRB1 solely or dominantly influence susceptibility to RA and SLE.

Role of Killer Immunoglobulin-Like Receptor and Ligand Matching in Donor Selection

Directory of Open Access Journals (Sweden)

Meral Beksaç

2012-01-01

Full Text Available Despite all efforts to improve HLA typing and immunosuppression, it is still impossible to prevent severe graft versus host disease (GVHD which can be fatal. GVHD is not always associated with graft versus malignancy and can prevent stem cell transplantation from reaching its goals. Overall T-cell alloreactivity is not the sole mechanism modulating the immune defense. Innate immune system has its own antigens, ligands, and mediators. The bridge between HLA and natural killer (NK cell-mediated reactions is becoming better understood in the context of stem cell transplantation. Killer immunoglobulin-like receptors (KIRs constitute a wide range of alleles/antigens segregated independently from the HLA alleles and classified into two major haplotypes which imprints the person's ability to suppress or to amplify T-cell alloreactivity. This paper will summarize the impact of both activating and inhibitory KIRs and their ligands on stem cell transplantation outcome. The ultimate goal is to develop algorithms based on KIR profiles to select donors with maximum antileukemic and minimum antihost effects.

An SSP-PCR method for the rapid detection of disease-associated alleles HLA-A*29 and HLA-B*51.

Science.gov (United States)

Amstutz, U; Schaerer, D; Andrey, G; Wirthmueller, U; Largiadèr, C R

2018-05-15

HLA-A*29 and HLA-B*51 are associated with birdshot uveitis and Behçet's disease, respectively, and are used as a diagnostic criterion in patients with suspected disease, requiring their detection in diagnostic laboratories. While commercial tests for individual HLA alleles are available for other disease-associated HLA variants, no similar allele-specific assays are available for HLA-A*29 and -B*51. Here, we report SSP-PCR methods for the detection of HLA-A*29 and -B*51 using a single PCR reaction per allele. The assays were tested in 30 and 32 previously HLA-typed samples, respectively, representing >97% of HLA-A alleles and >93% of HLA-B alleles in a European population. A concordance of 100% was observed with previous typing results, validating these methods for use in a diagnostic or research context. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Treatment options for patients with acute myeloid leukemia with a matched sibling donor: a decision analysis.

Science.gov (United States)

Sung, Lillian; Buckstein, Rena; Doyle, John J; Crump, Michael; Detsky, Allan S

2003-02-01

The role of allogeneic bone marrow transplantation (BMT) in the consolidation of young adults with acute myeloid leukemia (AML) with matched sibling donors (MSD) is controversial. Although BMT is associated with increased event free survival compared with intensive chemotherapy (CT) consolidation, BMT also is associated with increased treatment-related mortality and likely decreased quality of life and life expectancy in patients who do not develop recurrent disease. The authors used decision analysis to compare three strategies for maximizing quality-adjusted life years (QALYs) in patients with AML in first remission with an MSD: BMT All, BMT None (consolidation CT only), or BMT in high-risk patients, as defined by baseline cytogenetic testing (Test strategy). A second decision-analysis tree was then constructed that compared BMT with CT specifically for patients with intermediate cytogenetics. Using expected QALYs as the outcome measure, the Test, BMT All, and BMT None strategies were associated with 20.10 QALYs, 19.63 QALYs, and 18.38 QALYs, respectively. Thus, the Test strategy, with CT for low-risk patients and BMT for intermediate risk and high-risk patients, was expected to be the optimal strategy. In the intermediate cytogenetic decision analysis, although the expected QALY for BMT recipients was higher compared with CT recipients (19.78 QALYs vs. 18.75 QALYs), because of uncertainty in variable estimates, the optimal choice was less clear. CT consolidation is a reasonable option for patients with AML who have favorable cytogenetics, even if an MSD is available. This model provides a framework from which patients with AML and their physicians can make decisions about consolidation therapy. Copyright 2003 American Cancer Society.DOI 10.1002/cncr.11098

Identification of four novel HLA-B alleles, B*1590, B*1591, B*2726, and B*4705, from an East African population by high-resolution sequence-based typing.

Science.gov (United States)

Luo, M; Mao, X; Plummer, F A

2005-02-01

We report here four novel HLA-B alleles, B*1590, B*1591, B*2726, and B*4705, identified from an East African population during sequence-based HLA-B typing. The novel alleles were confirmed by sequencing two separate polymerase chain reaction products, and by molecular cloning and sequencing multiple clones. B*1590 is identical to B*1510 at exon 2 and exon 3, except for a difference (GCCGTC) at codon 158. Sequence differences at codon 152 (GAGGTG) and codon 167 (TGGTCG) differentiate B*1591 from B*1503 at exon 3. B*2726 is identical to B*2708 at exon 2 and exon 3, except for a difference (AAGCAG) at codon 70. B*4705 was identified in three Kenyan women. The allele is identical to B*47010101/02 at exon 2 and exon 3, except for differences at codon 97 (AGGAAT) and codon 99 (TTTTAT). These new alleles have been named by the WHO Nomenclature Committee. Identification of these novel HLA-B alleles reflects the genetic diversity of this East African population.