Molecular disparity of HY antigen affects chronic graft-versus-host disease and relapse in female-to-male stem cell transplants

Background: Minor histocompatibility antigens play an important role in eliciting an alloimmune response in allogeneic hematopoietic stem cell transplantation (allo-HSCT). HY antigens, minor histocompatibility antigens originating from distinct regions of the Y chromosome, serve as immunogenic targets in female-to-male (FtoM) allo-HSCT, potentially increasing the risk of graft-versus-host disease (GVHD) and the development of allogeneic HY antibodies. Moreover, extensive HLA polymorphism and diverse peptide-binding specificities of HLA molecules can lead to varying alloimmunity and subsequent clinical risks/benefits among patients upon exposure to the HY antigen. Objective: In the current study, we investigated the clinical implications of HY molecular disparity using the predicted indirectly recognizable HY epitopes (PIRCHyE) score (PS) in 712 patients undergoing allo-HSCT from an HLA-matched related donor, including 336 gender-mismatched HSCT. Results: In FtoM (N = 194) allo-HSCT, higher PS-I, which theoretically reflects CD8+ T-cell alloreactivity triggered by HY antigens, was associated with a significantly higher rate of grade III-IV acute GVHD (P = .005) and an increased relapse rate (P = .01). In contrast, high PS-II correlated with reduced progression (P = .04) and a higher risk of chronic GVHD (P = .01). To further explore the interplay between CD4 T-helper cell responses (PS-II) and CD8 cytotoxic effects (PS-I), we simultaneously assessed the impact of PS-I and PS-II and found high PS-I/low PS-II was associated with a significantly higher relapse rate (P = .002) and lower progression-free survival (PFS) (P = .02). Conversely, a low PS-I/high PS-II was significantly associated with a higher chronic GVHD rate (P = .02) and a favorable trend in PFS (P = .2) in multivariate analysis. No such effects were observed in the male-to-female allo-HSCT group. Conclusion: These findings indicate that molecular assessment of HY antigens enables quantitative prediction of HY alloreactivity, which may enhance donor selection and help mitigate complications in allo-HSCT.