*Purpose: Donor and recipient sex impact transplant outcomes. The biology of sex-specific alloimmune responses has not been studied in detail.

*Methods: Using clinical data from more than 335,000 kidney transplant recipients collected in the Scientific Registry of Transplant Recipients, we examined the association of recipient sex on graft survival stratified by multivariable cox proportional hazards regression models. To delineate mechanistic aspects, we made use of skin transplant models under controlled hormonal changes assessing the impact of donor/recipient sex mismatches.

*Results: Younger female recipients (15-34 years) demonstrated significantly reduced 5-year graft survival rates (Log-rank, P < 0.0001). The impact of recipient sex on graft survival demonstrated an age-specific pattern with an improvement of graft survival in female recipients with increasing age (P < .0001). Multivariable hazard ratios for graft survival were 1.139 (95% CI, 1.034 to 1.254) in younger female recipients and 0.810 (95% CI, 0.729 to 0.898) in older female recipients (55-74 years). Experimentally, skin transplants demonstrated a prolonged survival in young male compared to female recipients (12 vs. 9 days, P = 0.0020). Graft survival in female recipients had been linked to hormonal levels with prolonged graft survival observed in female young ovariectomized recipients (9 vs. 11 days, P = 0.0094). Age prolonged graft survival in both old male and female skin transplant recipients. Notably, ovariectomies in old mice did not alter graft survival. Hormonal deprivation in young recipients led to changes in frequency and subset composition of both, CD4⁺ or CD8⁺ T-cells. Moreover, T-cells of ovariectomized female demonstrated a compromised proliferation and reduced IFN-γ production. In vitro, CD4⁺IFN-γ⁺ cells demonstrated an augmented Th1 polarization in presence of 17β-estradiol at levels reflective of a normal estrus cycle (10^-10M). Alloimmunity, at the same time had been linked to hormonal levels, with elevated estrogen levels (10^-8M reflective of levels during pregnancy) demonstrating compromised Th1 polarization.

*Conclusions: Those data link hormonal levels, aging and donor/recipient sex mismatches to clinical transplant outcomes supported by a detailed experimental immune analysis.

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