Effect of donor and recipient gender disparities on fatal graft-vs.-host disease in a mouse model for major histocompatibility complex-matched unrelated-donor bone marrow transplantation.

Sex chromosome-linked minor histocompatibility determinants have been shown to affect the incidence and severity of graft-vs.-host disease (GVHD) in both humans and animals. On the basis of earlier studies done in mice and humans, it has often been assumed that this effect is due to a simple response of female donor cells recognizing recipient male HY antigens as foreign and reacting against them. However, the data of various clinical groups have not always supported this assumption. Moreover, since most of the earlier mouse studies focused only on the single transplant direction of female into male and/or were done under totally syngeneic conditions, the possibility of a GVHD response based on donor recognition of the recipient female HX antigen as foreign was never fully addressed. We have therefore reexamined the question in a more clinically relevant allogeneic transplantation setting, using a major histocompatibility complex (MHC)-matched, unrelated-donor mouse model. Five different donor/recipient sets were paired in all four possible gender combinations. The results indicated that, in addition to GVHD reaction against male HY, reaction against female HX was also possible. The results also showed that when the total level of GVHD due to autosomal chromosome minor histocompatibility disparities is extensive, it may masks the influence of gender-related factors on GVHD. Finally, the data also suggest the possibility that the sex chromosome-linked minor histocompatibility determinants may be polymorphic and thus capable of multiple allele expression.