Recipient sex and estrogen levels affect alloimmune responses and transplant outcomes

Sex-specific influences have been shown for a variety of diseases. Although effects of sex and sex hormones on immunity have been recognized, their impact on alloimmune responses in solid organ transplantation remains unclear.

In analyses of more than 400000 kidney transplant patients from SRTR database, we found that younger female recipients had an inferior death-censored graft survival independent of donor sex. In contrast, graft survival was superior in older female recipients, indicating the impact of recipient sex hormones over chromosomal sex mismatches.

Our experimental skin and heart transplant models showed that the graft survival was prolonged in ovariectomized young female recipients but was comparable in ovariectomized and naïve old female recipients. Besides, young ovariectomized mice showed reduced CD4+ T cell population and compromised proliferation.

Deprivation of female hormones dampened the production of IFN-γ and IL-17+ by CD4+ T cells while augmenting the amount of Tregs. In vitro estradiol treatment promoted the switch of naïve CD4+ T cells into Th1 cells and altered Tregs in a dosage-dependent way. Both very low and very high estradiol concentrations dampened Th1 responses, promoted Tregs, and prolonged graft survival.

In summary, our clinical analysis demonstrated an impact of recipient sex on transplant outcomes in an age-specific fashion. Experimentally, we reproduced our clinical observations with inferior skin and heart graft survival rates in young and prolonged survival rates in old recipients. Notably, age- and sex-specific rejection kinetics were also observed under immunosuppression. On a cellular level, we observed reduced Th1 responses under hormonal deprivation and increased CD4+CD25+FOXP3+ counts with higher estrogen levels.