Donor-recipient mismatches in MHC class I chain-related gene A in unrelated donor transplantation lead to increased incidence of acute graft-versus-host disease

Abstract

The polymorphic products of major histocompatibility complex class I-related chain A (MICA) genes are important in solid organ transplantation rejection. MICA expression is limited to gut epithelium and may play a role in triggering acute graft-versus-host disease (aGVHD). A total of 236 recipients of unrelated donor transplantation were studied. Donor-recipient human leukocyte antigen (HLA) match was 10/10 human leukocyte antigen (HLA-A, -B, -C, -DRB1, -DQB1) in 73% and MICA mismatch in 8.4%. Because of physical vicinity of the loci, MICA mismatch was significantly associated with mismatch at HLA-B and HLA-C. A higher rate of grade II-IV aGVHD was seen in MICA-mismatched patients (80% vs 40%, P ‫؍‬ .003) irrespective of degree of HLA matching (HLA 10/10 match: 75% vs 39%, P ‫؍‬ .02) and HLA any mismatch (83% vs 46%, P ‫؍‬ .003). The rate of grade II-IV gastrointestinal aGVHD was also higher in MICA-mismatched patients (35% vs 17%, P ‫؍‬ .05). We conclude that MICA may represent novel a transplantation antigen recognized by human allogeneic T cells. This study was registered at ClinicalTrials.gov (Identifier NCT00506922).

Matching for the nonconventional MHC-I MICA gene significantly reduces the incidence of acute and chronic GVHD

“…21,25 No significant mismatch in this SNP was found to be associated with any clinical outcome in our cohort (supplemental Table 6). Parmar et al 22 reported a higher rate of grade II-IV acute GVHD in MICA-mismatched vs matched patients. These findings were, however, immediately challenged.…”

“…[21][22][23][24][25] In 2 independent small cohorts of sibling and unrelated donor HCT, respectively, the recipients (but not the donors) were genotyped for the SNP encoding p.M129V, 38 which was found to be significantly associated with clinical outcome, albeit in opposite trends. 21,25 No significant mismatch in this SNP was found to be associated with any clinical outcome in our cohort (supplemental Table 6).…”

“…20 Previous studies have hinted at a role for MICA in GVHD, but these analyzed MICA diversity only in patients (not donors) and/or in small, single-center cohorts, which engendered controversial, if not opposite, conclusions. [21][22][23][24][25] Here we evaluate the MICA sequence in a retrospective multicenter European cohort of 922 patients having undergone HCT with HLA 10/10-allelematched unrelated donors. All known covariables relevant to HCT were included in the final analysis.…”

The impact of frequent HLA haplotypes in high linkage disequilibrium on donor search and clinical outcome after unrelated haematopoietic SCT

“…[11][12][13][14][15][16][17] Genes in the TNF block, MICA/MICB and microsatellite markers are of specific interest because they are in linkage disequilibrium (LD) with the classical HLA genes and could be inherited together as one genetic unit. [13][14][15][18][19][20][21] The presence of FH in patients also affects the probability and speed of identifying a matched UD. [22][23][24][25][26][27][28] It is essential to know the HLA distribution of each population at an allelic level in order to define whether a patient has a high or low probability of finding a matched donor.…”

“…5 The role of some of these non-HLA genes have been studied (reviewed [6][7][8][9][10] ): single nucleotide polymorphisms and/or microsatellites within cytokine (-receptor) genes and other non-HLA encoded genes, including those of the innate immune system, may indeed influence HSCT outcome. [11][12][13][14][15][16][17] Genes in the TNF block, MICA/MICB and microsatellite markers are of specific interest because they are in linkage disequilibrium (LD) with the classical HLA genes and could be inherited together as one genetic unit. [13][14][15][18][19][20][21] The presence of FH in patients also affects the probability and speed of identifying a matched UD.…”