Please note that Ryoichi Maenosono may not be available for the Q&A Discussion.
Donor and recipient sex affect transplant outcomes in an age-specific fashion
Ryoichi Maenosono1,2, Yeqi Nian1,3, Jasper Iske1,4, Yang Liu1, Haruhito Azuma2, Edgar Milford5, Stefan G. Tullius1.
1Division of Transplant Surgery, Department of Surgery, Brigham and Women's Hospital, Boston, MA, United States; 2Department of Urology, Osaka Medical College, Takatsuki, Japan; 3Department of Kidney Transplantation, Tianjin First Central Hospital, Nankai University, Tianjin, People's Republic of China; 4Institute of Transplant Immunology, Hannover Medical School, Hannover, Germany; 5Renal Division, Brigham and Women's Hospital, Boston, MA, United States
In diseases outside of transplantation, sex has been shown to impact immune responses. Effects of donor/recipient sex and hormonal changes over a life-time on alloimmune responses and transplant outcomes have not been delineated.
We analyzed SRTR data from 408,000 kidney transplant and determined the influence of recipient and donor sex in an age-specifically.
Death-censored 5-year graft survival in in age-matched young female recipients (15-34 years) had been inferior to that of male recipients. This outcome was independent of donor-sex (P < 0.0001 and P = 0.0002 for male and female donors, respectively). In contrast, graft survival was superior in older female recipients (55-74 years) (P = 0.0294 and P = 0.0032 vs. male recipients of comparable age receiving either female or male kidneys).
To delineate potential mechanisms, we made use of an experimental model that dissected the effects of recipient age and hormonal deprivation (ovariectomies).
Skin transplants in ovariectomized young female recipients (2-3 months) was prolonged vs. naive female and sham controls of comparable age (P = 0.0094). In contrast, graft survival was comparable in old (18 months) naïve, ovariectomized or sham control female recipients (P = 0.6798).
Assessing alloimmune responses, we observed a compromised proliferation and reduced CD4+ and CD8+ T cell counts in young ovariectomized mice (CD4+ 25.2 vs 23.3 %, P = 0.0008; CD8+, 17.2 vs 12.4 %, P < 0.0001). Moreover, ovariectomies in young females reduced the production of IFN-g+ and IL-17+ by CD4+ T cells while increasing amounts of CD4+CD25+FOXP3+ regulatory T cells (P = 0.0015).
When adding increased estradiol concentrations (17-b estradiol; 10-12 M and 10-10 M) in-vitro under Th1 polarizing conditions, naïve CD4+ T cells responded in a dose dependent manner (33.1 vs 35.2 %, P = 0.025). In contrast, high estradiol concentrations (10-8M reflective of levels during pregnancy) reduced amounts of CD4+ T-cells (P = 0.028, under Th1 polarizing conditions). In line, with those in-vitro findings, we observed a prolongation of graft survival when treating female recipients with pregnancy equivalent estrogen levels (sham vs treated, 9 vs 14 days, P = 0.0031).
Those data demonstrate significant effects of sex, aging, and hormonal levels on alloimmune responses and transplant outcomes.
