Abstract
Graft vs Host Disease (GVHD) is a major cause of morbidity and mortality following bone marrow/hematopoietic stem cell transplantation (BMT/HSCT). While HLA-matched biological siblings are the most desired donors, 70% of patients do not have a matching donor in their family and HLA matched unrelated donors (MUD) are the only hope. Regardless, GVHD still occurs in 30% BMT/HSCT, mostly in MUD HSCT. As of now, only the HLA-A, B, C, DR, DQ, and DP located in the, alpha, beta and delta blocks are considered for matching. We stipulated that the gamma block (GB) encoding immune responses could be an additional tool to select the best donor/recipient pair in MUD transplants.
Using SNP based molecular assay for GB-typing, we studied 52 recipient/donor pairs who received HSCT at our Institution.
Overall 10.1% of related (2/22), 100% haploidentical (4/4) and 65.4% of MUD/recipient pairs (17/22) were GB mismatched showing MUD/recipient pairs as 7 times more likely to harbor GB-mismatch compared to related pairs. A limited clinical outcome study showed that GB-mismatch had a higher incidence of grade 2–4 acute GVHD (p=0.044) and chronic GVHD (p=0.048). Multivariate regression showed GB-mismatch is associated with higher transplant related mortality (p=0.020) and a trend for severe acute GVHD (HR 2.450, 95% CI 0.96−6.22; p=0.060) after controlling for donor type. The 25 GB SNPs we examined span both exons and introns of C4 gene. While 46.7% GB-mismatched MUD/recipient and 50% of the haploidentical recipient/donor pairs had SNPs detected in the exons, 75% of the SNP-mismatches occurred in the introns in related pairs. Since the exons are more relevant to functional proteins and introns are more associated with regulation of expression of genes, this distinction of occurrence of GB SNPs in the exons of MUD and haploidentical cases might have practical significance. All related recipient/donor pairs had ⩽3 GB SNP mismatches; whereas all haploidentical and 11/17 MUD/recipient pairs had ⩾3 GB SNPs. Hence there could be more substance to the SNPs in GB as we proceed with larger studies.
Our limited data shows that GB disparity can be an additional marker for donor selection for better BMT/HSCT outcome. More retrospective and prospective studies with long-term follow up are needed.
