This comprehensive analysis is the first to examine the role of mHAg disparities in the outcome of HLA-matched unrelated HSCT and failed to corroborate results in HLA-identical sibling transplants where single mHAg mismatches have been associated with significantly increased rates of acute GvHD (HA-1,HA-2,HA-8,CD31), decreased survival (HA-8,CD31), and lower rates of disease recurrence (HA-1,HA-2).20–24,34–36
The present study comprised the largest number of HLA-matched recipient/donor pairs evaluated to date. Nevertheless, small subgroup size and the greater disparity in HLA and non-HLA associated polymorphic genes between unrelated donor/recipient pairs may have limited the power of our analysis.37
Other limitations of the study include a predominance of bone marrow as a graft source and a low number of patients under the age of 20 which may restrict the relevance of these findings in peripheral blood and pediatric transplants.
We did observe that single CD31563 mHAg mismatches in the HvG vector in HLA-A2 positive individuals were found to potentially reduce the risk of developing grades III–IV acute GVHD, although the biological mechanism remains unclear. Significant associations with outcomes were also observed for multiple mismatches in HLA-A1 positive recipient donor pairs, mismatching at HA-3 plus CD31 in the HvG direction was associated with increased survival and decreased treatment related mortality, and in HLA-A2 pairs mismatched for HA-1, HA-2, HA-8, or CD31in the HvG direction there was a significantly lower rate of acute GvHD, but may reflect the influence of CD31 mismatching. In all cases it is unclear whether the differences reflect a true biologic impact of mismatching or a random effect.
In HLA-identical sibling transplants HA-3 disparity alone had no impact on GvHD, whereas multiple studies indicated that CD31 nonidentity is a significant risk factor for overall survival and acute GvHD.24
Any clinical risk of HA-3 mismatching is minimized by the fact that a majority of Caucasians (77%) express the HA-3 mHAg, making the likelihood of a mismatch low. It is noteworthy that in contrast to the majority of the other mHAg studied, HA-3 and CD31 are not restricted to hematopoietic cells but have a wide range of cell and tissue expression. CD31 (PECAM-1) functions as a homotypic adhesion molecule that is expressed on a variety of cells and tissues, including endothelial cells, platelets, and leukocytes. CD31 has never been directly demonstrated to be immunogenic nor function as a mHAg, as this latter property has been implied indirectly through the demonstration that recipient/donor pairs mismatched for CD31 allelic forms have higher risks of GvHD.24
Cavanagh et al. showed that donor heterozygosity for CD31563
alleles was associated with decreased survival in matched sibling HSCT, a finding that suggests that any effect of CD31 polymorphisms on HSCT outcomes may instead reflect inherent functional properties of CD31 isoforms and are not due to mHAg effects.24
However, we failed to confirm this effect in unrelated donor HSCT and further failed to observe any significant association between the presence of specific CD31 alleles in the recipient or donor and any outcome (data not shown).
Although the present study comprised the largest number of fully HLA-matched unrelated donor HSCT cases evaluated to date, statistical power to detect significant differences was low for many comparisons due in part to the relative infrequency of some mHAg alleles, low likelihood of mismatches (e.g., HA-2, HA-3), 25
and the study size limitations resulting from mHAg HLA presentation restrictions. In addition to the mHAg panel, analysis of the mHAg effects of HY disparity was also negative, potentially due to low power, with only 15% of the population at risk. Given these considerations, statistical power will remain a limitation to the characterization of mHAg disparities on unrelated HSCT outcomes. However, it should be noted that the original effects of HA-1 and HA-2 mismatching in HLA identical sibling HSCT outcomes were detected with as few as 117 HLA-A2 positive study subjects, in contrast to the present study which involved 430 HLA-A2 positive unrelated pairs.20,22
These findings suggest that additional HLA disparities (HLA-DP) and other factors may mask the impact of mHAg disparity in unrelated donor HSCT.
The majority of the current study population (86%) was mismatched at HLA-DP, which has been recently associated with an increased risk of acute GvHD and lower relapse rates in unrelated donor HSCT.37
The high rate of HLA-DP mismatching in our population may mask any contributions of mHAg mismatching to risk of acute GvHD in unrelated donor HSCT. By extension, the clinical impact of mHAg disparities in unrelated HSCT may be rendered moot given the likelihood that recipient/donor pairs who are selected based on allele-level matching at HLA-A, B, C, DRB1 and DQB1 are likely to be mismatched at HLA-DP. Another hypothesis to explain our findings is differences in patient immunosuppression and management, as risk for HA-1 associated GvHD may be lower in patients receiving both methotrexate and cyclosporine than in those who receive either alone.21
The failure of our studies to show a significant effect of mHAg disparities on outcomes in unrelated donor HSCT indicates the importance of other genetic determinants. While further studies may be warranted to verify the possible biological significance of CD31 mismatching in unrelated donor HSCT, the clinical utility of matching for mHAg is limited by the lack of significant clinical correlation with outcome and the low frequencies of many mHAg genotypes.25,38