Sex Differences in Alloimmunity and Other Immunological Considerations in Organ Transplantation

Sex-based differences in human immunity are well-described in the general population, cumulatively favoring a more hyperinflammatory immune response among females in different scenarios. It is imperative to understand how this applies in the setting of transplantation, where dynamic immune function determines key clinical outcomes, including graft rejection and responses to infection. Sex differences unique to transplant immunity begin at the chromosomal level and are influenced by steroid hormones and sex-specific factors ranging from pre-existing pregnancy-induced alloimmunization to differential metabolism of routine immunosuppressive medications. Given active efforts for greater sex and gender equity in transplantation, and with increasing transplantation of older candidates, the unique immunological considerations at the cross-roads of biological sex and age are also critical to consider. Age is an important modifier of the relationship between sex and immune-related outcomes as young females appear to have a greater risk for poor outcomes related to alloimmunity compared to similarly-aged male counterparts, particularly when receiving an organ from a male donor. However, this risk does not endure in post-menopausal age categories and there are some limited data to suggest, in fact, that post-menopausal women may have a greater risk for transplant-related infection. Greater efforts to incorporate sex as a biological variable into transplant research will lead to a more tailored strategy for immunosuppressive management, rejection surveillance, infection prophylaxis and other considerations for optimization of transplant outcomes.