Effect of donor CTLA-4 alleles and haplotypes on graft-versus-host disease occurrence in Tunisian patients receiving a human leukocyte antigen–identical sibling hematopoietic stem cell transplant

Sellami, M.; Bani, M.; Torjemane, Lamia; Kâabi, H.; Ladeb, Saloua; Othmane, Tarek Ben; Hmida, Slama

doi:10.1016/j.humimm.2010.11.008

Cited by 20 publications

(21 citation statements)

References 24 publications

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“…However, for CD28’s inhibitory counter player CTLA-4 it has been shown that the 49G polymorphism, leading to comparatively weak B7-binding (55), is associated with enhanced T cell responses in vitro (55, 56) and a higher risk to develop chronic GvHD in vivo (57). These data are best interpreted as a lack of CTLA-4-mediated inhibition of alloreactive effector T cells causing more severe GvHD.…”

Section: Discussionmentioning

confidence: 99%

Protection of Mice from Acute Graft-versus-Host Disease Requires CD28 Co-stimulation on Donor CD4+ Foxp3+ Regulatory T Cells

Uri

Werner

Lühder³

et al. 2017

Front. Immunol.

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Acute graft-versus-host disease (aGvHD) is a major cause of morbidity and mortality after allogeneic hematopoietic stem cell plus T cell transplantation (allo-HSCT). In this study, we investigated the requirement for CD28 co-stimulation of donor CD4+ conventional (CD4+CD25−Foxp3−, Tconv) and regulatory (CD4+CD25+Foxp3+, Treg) T cells in aGvHD using tamoxifen-inducible CD28 knockout (iCD28KO) or wild-type (wt) littermates as donors of CD4+ Tconv and Treg. In the highly inflammatory C57BL/6 into BALB/c allo-HSCT transplantation model, CD28 depletion on donor CD4+ Tconv reduced clinical signs of aGvHD, but did not significantly prolong survival of the recipient mice. Selective depletion of CD28 on donor Treg did not abrogate protection of recipient mice from aGvHD until about day 20 after allo-HSCT. Later, however, the pool of CD28-depleted Treg drastically declined as compared to wt Treg. Consequently, only wt, but not CD28-deficient, Treg were able to continuously suppress aGvHD and induce long-term survival of the recipient mice. To our knowledge, this is the first study that specifically evaluates the impact of CD28 expression on donor Treg in aGvHD. Moreover, the delayed kinetics of aGvHD lethality after transplantation of iCD28KO Treg provides a novel animal model for similar disease courses found in patients after allo-HSCT.

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Section: Discussionmentioning

confidence: 99%

Protection of Mice from Acute Graft-versus-Host Disease Requires CD28 Co-stimulation on Donor CD4+ Foxp3+ Regulatory T Cells

Uri

Werner

Lühder³

et al. 2017

Front. Immunol.

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“…CTLA-4, an important immunologic checkpoint, and its genetic variations have been of interest in the HSCT realm because of its possible important role in immune modulation, especially as it relates to GVHD and the potency of the GVT effect. CTLA-4 SNPs have previously been shown to be associated with RFS, OS, and incidence of GVHD 5–9 as well as a possible surrogate marker for response to donor lymphocyte infusion after HSCT. 13 This raised the possibility that a personalized approach to HSCT donor selection and conditioning regimens based on genetic variation could be realized.…”

Section: Discussionmentioning

confidence: 99%

“…4 In HSCT studies, CTLA-4 SNPs have been associated with differences in RFS, OS, and GVHD but with discordant results from various investigators. 5–9 Previously we have shown that donor SNP rs4553808 is an independent pre-transplant predictor of outcomes in unrelated donor HSCT, with patients receiving transplants from donors with AG or GG genotypes having inferior relapse free survival (RFS) and OS compared to the AA genotype. 10 We hypothesized that these results could be validated in a larger, more homogenous cohort of patients and if validated could be basis for pre-transplantation donor CTLA-4 genotyping as a risk-stratification tool that would aid in prediction of relapse risk.…”

Section: Introductionmentioning

confidence: 99%

Cytotoxic T-Lymphocyte Antigen-4 Single Nucleotide Polymorphisms Are Not Associated with Outcomes after Unrelated Donor Transplantation: A Center for International Blood and Marrow Transplant Research Analysis

Sengsayadeth

Wang

Lee

et al. 2014

Biology of Blood and Marrow Transplantation

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Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4) plays an essential role in T cell homeostasis by restraining immune responses. AG and GG genotypes of donor CTLA-4 SNP rs4553808 in patients after unrelated donor (URD) hematopoietic stem cell transplants (HSCT) have been shown to be an independent predictor of inferior relapse free survival (RFS) and overall survival (OS) compared to the AA genotype in single center studies. We tested the hypothesis that SNP rs4553808 is associated with RFS, OS, non-relapse mortality (NRM) and the cumulative incidence of acute graft-versus-host disease (aGVHD) and chronic graft-versus-host disease (cGVHD) in adults with acute myeloid leukemia (AML) and advanced myelodysplastic syndrome (MDS) undergoing a first 8/8 or 7/8 HLA matched URD HSCT. Multivariable analysis adjusting for relevant donor and recipient characteristics showed no significant association between SNP rs4553808 and OS, RFS, NRM, and incidence of aGVHD and cGVHD. An exploratory analysis of other CTLA-4 SNPs as well as studying the interaction with ATG also demonstrated no significant associations. Our results indicate that CTLA-4 SNPs are not associated with HSCT outcomes.

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“…The study does not exclude the possibility that CRP may also be involved in other inflammatory processes leading to TRALI, including enhancing antibody-mediated respiratory burst by neutrophils, 9 synergizing with MHC class I antibodies in binding to the endothelium, 5,10 and causing pulmonary vascular leakage and/or complement cascade activation. The source of the MIP-2 secretion was not shown; however, their previous work demonstrated the source of MIP-2 secretion to be blood monocytes.…”

mentioning

confidence: 95%

GVHD meets GWAS

Waterhouse

2015

Blood

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Effect of donor CTLA-4 alleles and haplotypes on graft-versus-host disease occurrence in Tunisian patients receiving a human leukocyte antigen–identical sibling hematopoietic stem cell transplant

Cited by 20 publications

References 24 publications

Protection of Mice from Acute Graft-versus-Host Disease Requires CD28 Co-stimulation on Donor CD4+ Foxp3+ Regulatory T Cells

Protection of Mice from Acute Graft-versus-Host Disease Requires CD28 Co-stimulation on Donor CD4+ Foxp3+ Regulatory T Cells

Cytotoxic T-Lymphocyte Antigen-4 Single Nucleotide Polymorphisms Are Not Associated with Outcomes after Unrelated Donor Transplantation: A Center for International Blood and Marrow Transplant Research Analysis

GVHD meets GWAS

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