Analyzing the antibody against H-Y antigen in hematopoietic cell transplant patients

Male recipients of female Hematopoietic Cell Transplants (F→M HCT), compared to all other donor/recipient combinations observe the highest risk of both acute and chronic Graft Versus Host Disease (GVHD), but also demonstrate significantly decreased risk of relapse due to Graft Versus Leukemia (GVL) effect. This is due to donor T- and B-cell targeting of male-specific minor Histocompatibility Antigens (mHAgs). Clinical studies and murine models suggest that the protein product of the SMCY (KDM5D) gene is a major T-cell target for H-Y (Y-chromosome histocompatibility antigen) specific responses. Previous research has demonstrated the relevance and clinical significance of antibody to H-Y antigen; however, antibody to SMCY has not been previously characterized. This study demonstrates the presence antibody reactive to SMCY, SMCX, peptide fragments from the protein product of DBY, and antibody reactive to a panel of recombinant H-Y antigens and X-chromosome homologs, in the blood of HCT patients and healthy donors. Significant differences in the frequency of reactivity with individual peptides were observed among sample groups, with a high frequency of responses to peptides corresponding to a region within the interval KDM5D₂₈₁₋₃₇₅. This region contains the FIDSYICQV sequence, an epitope recognized by CD8⁺ HLA-A*0201-restricted T cells frequently isolated in the blood of F→M HCT patients. Frequent responses against recombinant proteins UTY, and SMCY-f, the only fraction of SMCY currently purified, were also observed in healthy donors and F→M HCT patients. Our results indicate that antibody to SMCY is frequently observed in the blood of HCT patients and healthy donors compared to other H-Y antigens, which suggests that SMCY is a clinically relevant target for antibody in HCT.