Multicenter Analyses Demonstrate Significant Clinical Effects of Minor Histocompatibility Antigens on GvHD and GvL after HLA-Matched Related and Unrelated Hematopoietic Stem Cell Transplantation

Abstract

The effect of minor H antigen mismatching on the occurrence of graft-versus-host disease (GvHD) and graft-versus-leukemia (GvL) after HLA-matched hematopoietic stem cell transplantation (HSCT) has mainly been demonstrated in single-center studies. Yet, the International Histocompatibility and Immunogenetics Workshops (IHIW) provide a collaborative platform to execute crucial large studies. In collaboration with 20 laboratories of the IHIW, the roles of 10 autosomal and 10 Y chromosome-encoded minor H antigens were investigated on GvHD and relapse incidence in 639 HLA-identical related donor (IRD) and 210 HLA-matched unrelated donor (MUD) HSCT recipients. 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 these multicenter analyses show that none of the HLA class I-restricted HY antigens were found to be associated with any of the primary outcomes. Interestingly, of the HLA class II-restricted HY antigens analyzed, HLA-DQ5 positive recipients showed a significantly increased GvHD-free survival in female-to-male HSCT compared with male-to-female HSCT (P = .013). Yet, analysis of the overall gender effect, thus independent of the known HY antigens, between the gender groups demonstrated an increased GvHD incidence in the female-to-male transplantations (P < .005) and a decreased GvHD-free survival in the female-to-male transplantations (P < .001). 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 ratio [HR] = 5.28, P < .005), but not in MUD HSCT. Most striking was the influence of hematopoietic restricted minor H antigens on GvL as mismatching for hematopoietic minor H antigens correlated with lower relapse rates (P = .078), higher relapse-free survival (P = .029), and higher overall survival (P = .032) in recipients with GvHD, but not in those without GvHD. In conclusion, the significant GvHD effect of the broadly expressed minor H antigen HA-8 favors matching for HA-8 in IRD, but not in MUD, patient/donor pairs. The GvHD-GvL association demonstrating a significant lower relapse in hematopoietic minor H antigen mismatched patient/donor pairs underlines their clinical applicability for adoptive immunotherapy, enhancing the GvL effect in a GvHD controllable manner.

Adenosine Selectively Depletes Alloreactive T Cells to Prevent GVHD While Conserving Immunity to Viruses and Leukemia

“…In both HLA-matched and HLA-mismatched settings, T-cell recognition of minor histocompatibility antigens contributes to both GVHD and GVL. 29 Thus, employing an APC sharing lineage with a patient's-specific tumor may unfavorably deplete donor T cells recognizing minor antigens identifying the tumor, reducing the GVL response. Selective depletion has been achieved with a variety of stimulator types such as unmanipulated PBMCs, 30 ex vivo expanded CD8 + T lymphocytes, 31 and EBV-transformed B lymphoblastoid cell lines (EBV-LCL).…”

UGT2B17 minor histocompatibility mismatch and clinical outcome after HLA-identical sibling donor stem cell transplantation

“…Analysis of smaller cohorts of patient-donor pairs by other groups have detected a similar association. 14,15 More recently, Spierings et al 16 carried out a multicenter analysis exploring the clinical impact of several mHags on GVHD in a cohort of 639 patients receiving an allogeneic HSCT from an HLA-identical related donor and 210 from an unrelated donor. Although they tried to explore the role of mismatches for the mHags UGT2B17/A29 and UGT2B17/B44, the analysis could not be addressed because of the low numbers of relevant mismatched pairs, and they did not assess the impact on clinical outcome of the UGT2B17 mismatch regardless of the MHC restriction.…”

Minor histocompatibility Ags: identification strategies, clinical results and translational perspectives

“…41 However, for HY mismatches a reduced risk of relapse was clearly suggested, 42,43 whereas for hematopoietic-specific mHags such as HA-1 an association between GvT and mHag mismatch was also demonstrated in a relatively large cohort of 285 HLA-A2-positive CML patients, but exclusively when GvHD was also present. 44,45 Several follow-up studies were unable to demonstrate the association of specific mHag mismatches with either GvHD or GvT, possibly due to the small cohort size, 46-48 but a recent study investigating a large number of patients did demonstrate improved disease-free survival when at least one mHag mismatch was present, particularly in multiple myeloma patients. 49 Moreover, in a large retrospective study, allo-SCT from female donors to male recipients was found to have significantly lower relapse rates in comparison with all other gender combinations, indicating an important GvT effect mediated by HY responses.…”