HLA-DPA1 Polymorphism Is a Risk Factor for Graft-Versus-Host Disease Following Unrelated Hematopoietic Stem Cell Transplantation (HSCT)

The HLA-DP molecule has been shown to be a target of allograft rejection and graft-versus-host-disease (GVHD) in HSCT. Nevertheless the way in which HLA-DP matching in HSCT should be approached remains unclear. Studies point out that some mismatched allele combinations result in a weaker alloreactive response than others, suggesting that epitope matching should be considered rather than allele matching. Most studies focus on the highly polymorphic beta chain of the DP molecule that is considered to play a dominant role in T cell interaction. Several groups have tried to identify immunogenic epitopes in the peptide binding groove of the beta chain to unravel DP immunogenicity, but there is no consensus on epitopes and amino acid residues. The alpha chain of the DP molecule is characterized by low polymorphism and therefore is considered less relevant in T cell recognition. Nonetheless, modeling studies identified amino acid position 31 in the peptide binding groove of the alpha chain as a potential immunogenic residue that influences peptide binding by the polymorphic residue Methionine (M) vs. Glutamine (Q). We hypothesized that HLA-DPA1 polymorphism at position 31 may impact patient outcomes after unrelated HSCT.

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Engraftment, GVHD, graft failure, relapse, and mortality had been analyzed in 81 patients who received HSCT in a single institute from 8/2003-12/2010 with a 10/10 matched unrelated donor. The median age was 47 years, and 58% were males. 30% had reduced-intensity conditioning and 70% were myeloablative. HLA-DPA1 polymorphism was determined using Luminex PCR-SSO method. Prognostic factors for outcomes were identified using Cox proportional hazards analysis. Variables analyzed included age, gender, co-morbidity, diagnosis, conditioning, cell source, donor characteristics, CMV serostatus, DPB1 mismatching, DPA1 polymorphism, and hematopoietic stem cell dose. Multivariable prognostic factors for each outcome were assessed using stepwise Cox proportional hazards.

Neither allele DPB1 mismatching nor recipient DPA1 allele polymorphism was associated with any of the outcome variables. Interestingly, in uni- and multivariable analysis homozygous M at position 31 (31M) of DPA1 in the donor was associated with a lower risk of acute GVHD compared to homozygous Q & heterozygous M/Q at position 31 (HR 0.54, P=0.031). Also, 31M donors, had a trend towards a lower risk of chronic GHVD (HR 0.52, P=0.08) and all-cause mortality (HR 0.63, P=0.11).

With the limitation of the small population size, this is the first clinical study describing a potential role of amino acid polymorphism in the alpha chain of the HLA-DP molecule in unrelated HSCT. These results show an increased risk of donor DPA polymorphism for aGVHD and warrant further investigation in a larger cohort.

No relevant conflicts of interest to declare.