Multi-center analyses demonstrate significant clinical effects of minor Histocompatibility antigens on GvHD and GvL after HLA matched related and unrelated stem-cell transplant.

The effect of minor H antigen mismatching on the occurrence of GvHD and GvL after HLA-matched hematopoietic stem-cell transplantation (HSCT) has mainly been demonstrated in single center studies. Notably, the International Histocompatibility and Immunogenetics Workshops (IHIWS) provide a collaborative platform to execute crucial large studies. In collaboration with 20 laboratories of the IHIWS, the role of 10 autosomal and 10 Y-chromosome encoded minor H antigens was investigated on GvHD and relapse incidence in 639 HLA-identical related donor (IRD) and 210 HLA-matched unrelated donor (MUD) HSCT. Donor and recipient DNA samples were genotyped for the minor H antigens HA-1, HA-2, HA-3, HA-8, HB-1, ACC-1, ACC-2, SP110, PANE1, UGT2B17, and HY. The correlations with the primary outcomes GvHD (acute or chronic GvHD), survival, and relapse were statistically analyzed. The results of this multi-center analyses show that of all autosomally encoded minor H antigens, only mismatching for the broadly expressed minor H antigen HA-8 increased the GvHD incidence in IRD HSCT (Hazard Ration (HR)=5.28; p<0.005), but not in MUD HSCT. Interestingly, none of the HLA class I- or II-restricted HY antigens were found to be associated with any primary outcomes, though an analysis on the overall gender effect between the groups demonstrated a lower GvHD incidence in the female to male transplants (p=0.015) and an increase of GvHD free survival in the male to female transplants (p=0.013). Of interest was the significantly increased GvHD-free survival in female-to-male HSCT compared to male-to-female HSCT (p=0.013) in HLA-DQ5-positive recipients. Most striking was the influence of hematopoietic minor H antigens on GvL. Mismatched for the latter minor H antigens were found to correlate with lower relapse rates (p=0.078), higher relapse free survival (p=0.029) and higher overall survival (p=0.032) in recipients with GvHD, but not in those without GvHD. In conclusion, the observed significant GvHD effect of the single broadly expressed minor H antigen HA-8 favors matching for HA-8 in IRD patient/donor pairs, but not in MUD pairs. The GvHD-GvL association resulting in significant lower relapse in hematopoietic minor H antigen mismatched patient/donor pairs underlines their clinical applicability for adoptive immunotherapy to enhance the GvL effect in a GvHD controllable situation.