Increased Disease Relapse in HLA-DPB1 Matched Recipients of Unrelated Donor Transplants Is Not Confined to Pairs Matched for the Other Five HLA loci.
Authors: Shaw Bronwen E. , Marsh Steven G.E. , Mayor Neema P. , Madrigal J. Alejandro 
Published: October 2019

Abstract
A number of studies, considering diverse populations of recipients of Unrelated Donor (UD) Haematopoietic Stem Cell Transplants (HSCT), have shown an impact of the matching status of HLA-DPB1 on transplantation complications and/or outcome. Most of these studies have been performed in pairs who are completely matched for the other five important HLA loci, 10/10 (HLA-A, -B, -C, -DRB1, -DQB1). This excludes any additive or confounding effects due to other HLA mismatches. However, it is also known that while strong linkage disequilibrium exists between the other five HLA loci, this does not extend to DP. It may therefore be possible to analyse DPB1 matching as an individual risk factor (irrespective of the matching status for the other HLA molecules). We have analysed the outcome in 423 mixed transplant pairs who have received an HSCT from an unrelated donor. The majority of transplant protocols included T cell depletion (TCD) with CAMPATH (>75%). All pairs had high resolution tissue typing performed for six HLA loci. Of the pairs, 282 were matched at 10/10 alleles and 141 had mismatches for one or more of 10/10 alleles. There was no association between matching for DPB1 and matching for the other HLA types. In the 282 HLA matched pairs, 29% were DPB1 matched, and in the 141 HLA mismatched pairs, 28% were matched for DPB1. We first analysed the impact of DPB1 matching in only those pairs who were matched for five HLA loci (N=282). The three year probability of relapse was 61% (median: 461 days). There was a highly significantly increase in disease relapse in DPB1 matched pairs (74%) as compared to those pairs with either one or two DPB1 mismatches (56%) (log rank, p=0.001). There was no difference in this effect as the number of DPB1 incompatibilities increased (i.e. one or two incompatibilities were equally protective, 56% versus 55% respectively, log rank p=0.959). This finding persisted in a multivariate analysis including factors known to be associated with disease relapse. We next analysed the impact of DPB1 matching on disease relapse in the group overall (N=423). There was a significantly increased risk of relapse in this cohort if DPB1 was matched (log rank; p=0.0001). This finding persisted when only the pairs with one or more mismatches for 10/10 alleles were considered (N=141) (log rank; p=0.031). When the cohort was divided according to disease subgroup, we found similar results in both CML and ALL - the risk of disease relapse when DPB1 is matched was significantly higher than when it was mismatched (log rank; p=0.0009 and p=0.013 respectively). Although there was no significant difference in the overall survival dependant on DPB1 matching in the group overall, in ALL DPB1 matched pairs had a significantly worse overall survival (log rank; p=0.025). Thus, in recipients of TCD UD HSCT, a match for DPB1 is associated with a significantly increased risk of disease relapse, irrespective of the matching status for the other HLA molecules. No other HLA locus had any impact on disease relapse. We speculate that this may indicate that DPB1 plays a different role within the immune system to the other HLA molecules. It is possible that DPB1 interacts with molecules besides T cells (such as NK cells) for which it may serve as a ligand. These effects may be more marked following transplants using CAMPATH, as many cell types are depleted, and thus the ratio of recovering cells is skewed in comparison to the situation which exists after a T cell replete transplant.