MICA-129 Genotype, Soluble MICA and Anti-MICA Antibodies as Biomarkers of Chronic Graft Versus Host Disease.

Abstract

1138 Poster Board I-160 Background The MHC class I-related chain A (MICA) molecules is of particular in non T-cell receptor (TCR)-mediated immune function. MICA engages NKG2D, a C-type lectin expressed on effector cells including NK, and T cells. Such engagement triggers NK cells and co-simulates T lymphocytes to mount adequate immune response. Further, a soluble isoform of MICA (sMICA) has been implicated in the pathogenesis of a variety of cancers, auto-immune and other organ transplant-related disorders through NKG2D receptor down regulation. Functionally relevant polymorphism of the MICA gene may also contribute to inter-patients variability in allo-immune responses as observed in various clinical settings including organ-transplantation. A methionine (met) to valine (val) change at position 129 of the alpha 2-heavy chain domain categorized the MICA alleles into strong (MICA-129 met) and weak (MICA-129 val) binders of NKG2D receptor. Given the demonstrated importance of MICA in immune pathways, in this study, we explored the MICA-related parameters namely MICA-129 gene polymorphism, pre- and post-transplant serum levels of soluble MICA (sMICA) and anti-MICA antibodies (MICA Abs) in a HLA-matched sibling HSCT setting. Results We evaluated whether MICA-129 gene polymorphism, pre- and post-HSCT sMICA and MICA Abs could influence the incidence of chronic graft-versus-host disease (c.GvHD) and relapse of their disease in 211 HLA-identical sibling pairs. In multivariate analysis on chronic GvHD risk, 3 factors reached significance: recipient MICA-129 val/val genotype (HR = 1.52; 95% confidence interval [95%CI] = 1.02-2.24; P =.04), older recipient age (3 15 years) (HR = 3.36; 95%CI = 1.65-6.84; P =.001) and source of stem cells (PBSC vs BM) (HR = 1.67; 95%CI = 1.10-2.53; P =.017). Since acute GvHD (aGvHD) is a major risk factor of subsequent c.GvHD, we then introduced aGvHD as a time-dependant co-variate in the multivariate analysis model. This analysis confirmed that the risk conferred by the MICA-129 val/val genotype is independent from aGvHD. Elevated post-HSCT sMICA serum levels were also independently associated with c.GvHD (p =.0001) regardless of history of acute GvHD. On the contrary, the presence of pre-transplant MICA Abs confers protection against c.GvHD (p =.04). There was an inverse relationship between MICA Abs and sMICA suggesting an antibody-based neutralization of deleterious effects of sMICA. Similarly, these genetic and phenotype characteristics of MICA influence the incidence of relapse. Conclusion Altogether, these data suggest that the studied MICA genotype and phenotype specificities could be used as relevant biomarkers for c.GvHD monitoring. Disclosures No relevant conflicts of interest to declare.

Methodological and clinical aspects of alloimmunization after granulocyte transfusion in patients undergoing allogeneic stem cell transplantation

“…In HSCT, MICA allo-antigens may represent a novel transplantation antigen, Parmar et al noticed higher rates of aGVHD in MICA mismatched patients irrespective of HLA matching (32). Other investigators showed similar effects of MICA mismatching in worsening of aGVHD (31,41). Kitcharoen et al noticed improved survival in MICA-matched donor-recipient pairs (42).…”

“…In renal (24,25), lung (26,27), heart (28,29) and liver (30) transplantation, recent reports identified posttransplantation MICA antibody development as a risk factor for allograft rejection. In HSCT these alloantibodies are described as an independent risk factor for development of acute and chronic GVHD (graft vs host disease) (31,32). Therefore, in this exploratory retrospective study, we have investigated alloimmunization against HLA and MICA antigens by microparticle-based flow cytometry technology following GT to address their role for outcome in HSCT patients requiring GT during clinical course.…”

Sequence‐based typing of major histocompatibility complex class I chain‐related gene A alleles by use of exons 2–5 information

“…The MICA allele group 129val (alleles 004/005/006/008/ 009/013/016/019/022/024/027/028/033/044/048/049/053/054/ 056/057/058) is characterized by an amino acid substitution at pos 129 (M → V, methionine → valine) which has been shown to significantly reduce binding affinity to the NKG2D receptor in vitro (20). Till date, the functional relevance of this polymorphism has been marginally investigated (21).…”

Microarrays for high‐throughput genotyping ofMICAalleles using allele‐specific primer extension

“…The incidence of graft versus host disease (GvHD) has been shown to increase in cases of HSCT matching HLA genotypes and mismatched MICA genotypes (6). MICA-129val was shown to be correlated with susceptible chronic GvHD in a French study (7). In addition, MICA-129met has been associated with susceptible early onset ankylosing spondylitis in Algerians (8).…”