Sex-specific influences have been shown for a variety of diseases. Whether donor or recipient sex and sex-hormone levels impact alloimmune responses remains unclear. In uni- and multifactorial analyses of more than 400.000 SRTR listed kidney transplant patients, we found that younger female recipients had an inferior death-censored graft survival that was independent of donor sex. In contrast, graft survival was superior in older female recipients, suggesting the impact of recipient sex-hormones over chromosomal sex mismatches. Those clinical changes were delineated in experimental skin and heart transplant models showing a prolongation of graft survival in ovariectomized young female recipients. In contrast, graft survival was comparable in ovariectomized and naïve old female recipients. Young ovariectomized mice showed reduced amounts and a compromised T cell proliferation. Deprivation of female hormones dampened the production of IFN-ɣ and IL-17 by CD4 T cells while augmenting systemic counts of T regs. Increasing estradiol concentrations in-vitro promoted the switch of naïve CD4 T-cells into Th1 cells; high physiological estradiol concentrations dampening Th1 responses, promoted T regs, and prolonged graft survival. Thus, clinical observations demonstrate age-specific graft survival patterns in female recipients. Estrogen levels, in turn, impact the fate of T-cell subsets, providing relevant and novel information on age and sex-specific alloimmunity.
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