Antibody response to H-Y minor histocompatibility antigens correlates with chronic graft versus host disease and disease remission

Abstract

H-Y antigens are important targets of graft versus host disease (GVHD) and graft versus leukemia in male patients who receive hematopoietic stem cell transplants from female donors (F → M HSCT). In previous studies, we demonstrated that male patients who receive stem cells from female donors (F → M HSCT) frequently develop antibody responses to H-Y antigen DBY. To determine whether other Y-chromosome encoded proteins elicit B-cell immune responses in F → M HSCT, we developed ELISA for 5 H- Y antigens: DBY, UTY, ZFY, RPS4Y and EIF1AY and their respective X-homologues. Serum samples from 125 HSCT patients and 136 normal donors were tested (Table below). Overall, 51% of male patients with female donors developed antibody to at least 1 H-Y antigen compared to 18% with antibody to any H-X homolog (p < 0.001). All H-X responders were also H-Y responders, and the magnitude of each H-Y response was greater than the corresponding H-X response. Normal males and M → M HSCT patients rarely had antibody detected for any H-Y antigen, however 41% of females had antibody detected for at least one H-Y antigen. F → M HSCT serial samples revealed: 1) antibody to H-Y antigens were absent pre-HSCT, 2) DBY antibody developed 4–8 months post-HSCT either concurrently or before UTY, ZFY, and RPS4Y antibodies, and 3) each H-Y antibody response persisted for at least two years post-HSCT. In order to explore the clinical significance of B-cell response to H-Y antigens, we measured 66 well-characterized F → M HSCT patients six months to two years post-HSCT with our novel five H-Y antigens ELISA panel and correlated these results with clinical outcome. The overall incidence of limited or extensive cGVHD in this cohort was 53%. The presence of an antibody response to 1 or more H-Y antigens was highly significantly correlated with the development of cGVHD (p < 0.001), and persistent disease remission (p < 0.001). Logistic regression models examining donor age, patient age, unrelated donor, HLA-mismatched donor, stem cell source, disease, T cell depletion, or nonmyeloablative conditioning failed to establish association of these risk factors with either cGVHD or H-Y serologic response. However, H-Y serologic response is strongly associated with cGVHD in a multivariable logistic model (p = 0.007). These results support the hypothesis that B cell responses to H-Y mHA play an important role in the pathogenesis of cGVHD and suggests that anti-B cell therapy may be useful in the treatment of this disease.TableAntibody Response to H-Y AntigensH-Y antigen:DBYUTYZFYRPS4YEIF1AY≥1 H-Y≥1 H-XF→M HSCT34/79 (43%)18/79 (23%)17/79 (22%)5/79 (6%)5/79 (6%)40/79 (51%)14/79 (18%)M→M HSCT004/46 (9%)004/46 (9%)6/46 (13%)Normal Females11/70 (16%)4/70 (6%)3/70 (4%)15/70 (21%)9/70 (13%)29/70 (41%)12/70 (17%)Normal Males1/64 (2%)001/64 (2%)3/64 (5%)%5/64 (8%)5/64 (8%) Open table in a new tab