Polymorphism of Adhesion Molecule CD31 and Its Role in Acute Graft-Versus-Host Disease

Behar, Esther; Nj, Chao; Dd, Hiraki; Krishnaswamy, Shalini; Bw, Brown; Jl, Zehnder; Fc, Grumet

doi:10.1056/nejm199602013340502

Cited by 131 publications

(97 citation statements)

References 30 publications

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“…A few studies have described a link between the development of human atherosclerosis and the presence of CD31 SNPs. Interestingly, a number of the CD31 SNPs that have been associated with atherosclerosis (41)(42)(43)(44) are the same as those implicated in increased GVHD severity (45)(46)(47)(48)(49). The functional significance of these SNPs has yet to be explored, and their association with disease remains controversial (50).…”

Section: Discussionmentioning

confidence: 99%

CD31 signals confer immune privilege to the vascular endothelium

Cheung

Wang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Constitutive resistance to cell death induced by inflammatory stimuli activating the extrinsic pathway of apoptosis is a key feature of vascular endothelial cells (ECs). Although this property is central to the maintenance of the endothelial barrier during inflammation, the molecular mechanisms of EC protection from cell-extrinsic, proapoptotic stimuli have not been investigated. We show that the Ig-family member CD31, which is expressed by endothelial but not epithelial cells, is necessary to prevent EC death induced by TNF-α and cytotoxic T lymphocytes in vitro. Combined quantitative RT-PCR array and biochemical analysis show that, upon the engagement of the TNF receptor with TNF-α on ECs, CD31 becomes activated and, in turn, counteracts the proapoptotic transcriptional program induced by TNF-α via activation of the Erk/Akt pathway. Specifically, Akt activation by CD31 signals prevents the localization of the forkhead transcription factor FoxO3 to the nucleus, thus inhibiting transcription of the proapoptotic genes CD95/Fas and caspase 7 and de-repressing the expression of the antiapoptotic gene cFlar. Both CD31 intracellular immunoreceptor tyrosinebased inhibition motifs are required for its prosurvival function. In vivo, CD31 gene transfer is sufficient to recapitulate the cytoprotective mechanisms in CD31 − pancreatic β cells, which become resistant to immune-mediated rejection when grafted in fully allogeneic recipients.endothelium | immunology | inflammation | lymphocytes | transplantation

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Section: Discussionmentioning

confidence: 99%

CD31 signals confer immune privilege to the vascular endothelium

Cheung

Wang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Association studies using a candidate gene approach have been conducted for mHa genes (Behar et al 1996;Nichols et al 1996;Maruya et al 1998), while statistical methods that have been used differ among studies and a suitable method has not been established yet. In some studies, a proportion of mismatch at a candidate mHa locus is compared between the donor-recipient pairs with GVHD and those without GVHD.…”

Section: Introductionmentioning

confidence: 99%

Power of association test for detecting minor histocompatibility gene causing graft-versus-host disease following bone barrow transplantation

Ohashi

Maruya²,

Tokunaga

et al. 2003

J Hum Genet

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Incompatibility of minor histocompatibility antigen (mHa) is a major cause of acute graft-versus-host disease (GVHD) following bone marrow transplantation in human leukocyte antigen (HLA)-matched donorrecipient pairs. To avoid acute GVHD, as many mHa genes as possible need to be identified . In this study, we introduce a comparison of two proportions as an association test for detecting mHa genes in HLA-matched pairs with and without GVHD. Assuming multiple mHa loci, each with two alleles, we evaluated the effects of (1) minor allele frequency of the mHa locus of interest (denoted by p), and (2) probability of GVHD developing in a donorrecipient pair being incompatible at an mHa locus (denoted by r) on the powers of association tests for unrelated pairs and for sib pairs. Our results showed that based on a candidate gene approach, an mHa gene with high p and r values can be detected by the association test with a small sample size. Application of the present method to the Japanese population revealed that the association test for unrelated pairs is more suitable for detecting an mHa gene with a high r value than that for sib pairs. The present method will be helpful to researchers who evaluate the power of association study in advance.

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“…Previous studies have produced contradictory reports concerning the role of CD31-125 and/or CD31-563/670 polymorphism and acute GvHD following HST. [2][3][4][5][6][7] Behar et al suggested that donor and recipient CD31-125 nonidentity was a risk factor for acute GvHD grades II-IV, whereas Nichols et al found no influence of CD31 compatibility on acute GvHD. Furthermore, Maruya et al, Grumet et al and Balduini et al each reported that nonidentity or incompatibility for CD31-563/670 was a risk factor for acute GvHD and survival.…”

Section: Discussionmentioning

confidence: 99%

“…DNA typing for CD31-125 gene polymorphism was performed by PCR using sequence specific primers as described by Behar et al 2 DNA typing for CD31-563 gene polymorphisms were identified as above using a common forward 5 0 primer Cgg Tgg ATg Agg TCC AgA TT and reverse 3 0 primers CTC TCC CTC CTg TTC CTT gT (amplifying CD31 codon-563 asparagine (CD31-563N)) or TCT CCC TCC TgT TCC TTg C (amplifying CD31 codon-563 serine (CD31-563S)). DNA typing for CD31-670 gene polymorphisms were identified using a forward 5 0 primer Agg TCA CAA TgA CgA TgT CA (amplifying CD31 codon-670 arginine (CD31-670R)) or forward 5 0 primer ggT CAC AAT gAC gAT gTC g (amplifying CD31 codon-670 glycine (CD31-670G)) and a common reverse 3 0 primer TAC CTT CAT TgA CAC ATC gg.…”

Section: Methodsmentioning

confidence: 99%

Donor CD31 genotype and its association with acute graft-versus-host disease in HLA identical sibling stem cell transplantation

Goodman

Ewing

Evans

et al. 2005

Bone Marrow Transplant

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Summary:CD31 gene polymorphisms are implicated in the pathogenesis of graft-versus-host disease (GvHD) following haematopoietic stem cell transplantation (HST). We investigated the influence of CD31 genotype on the incidence of GvHD following HST from an human leukocyte antigen (HLA)-identical sibling donor. Donor and recipient CD31 codons 125, 563 and 670 DNA polymorphisms were determined in 85 cases of HLA identical sibling HST from two transplant centres. A correlation between CD31 genotype and acute GvHD was considered significant if observed in patients from both transplant centres independently. A strong correlation was identified between donor CD31 codon 125 genotype and the incidence of acute GvHD. Acute GvHD grades II-IV occurred in 27 of 46 (59%) recipients with a CD31 codon 125 leucine/valine heterozygous donor compared to nine of 39 (23%) recipients with a CD31 codon 125 homozygous donor (P ¼ 0.0019, relative-risk 2.45, 95% confidence interval 1.3-4.5). This correlation was significant in patients from both transplant centres (P ¼ 0.015 and P ¼ 0.019). We suggest that CD31 genotype may influence the function of donor-derived leukocytes and may be informative when there is a choice of comparable donors. Bone Marrow Transplantation (2005) 36, 151-156.

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Polymorphism of Adhesion Molecule CD31 and Its Role in Acute Graft-Versus-Host Disease

Abstract: The adhesion molecule CD31 is polymorphic. When donor and recipient genotypes are not identical, the risk of GVHD increases. Prospective CD31 typing may reduce the risk of acute GVHD.

Cited by 131 publications

References 30 publications

CD31 signals confer immune privilege to the vascular endothelium

CD31 signals confer immune privilege to the vascular endothelium

Power of association test for detecting minor histocompatibility gene causing graft-versus-host disease following bone barrow transplantation

Donor CD31 genotype and its association with acute graft-versus-host disease in HLA identical sibling stem cell transplantation

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