Sex as a Biological Variable in Alloimmunity

• Applicant: Dr. Friederike Martin
• Subject Area: General and Visceral Surgery
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 508048528

Sex affects immune responses broadly. Recently we were able to demonstrate in a large-scale clinical analysis of the SRTR data base that young female kidney transplant recipients had inferior 5-year death censored graft survival compared to any other sex and age group. In contrast, graft survival was superior in older female compared to male recipients. We delineated those findings in experimental (mouse) skin and cardiac transplants, demonstrating that estrogen levels affected the fate of CD4+ T cells. High estrogen levels induced a pro-inflammatory alloimmune response with a switch of naïve CD4+ T cells towards T helper type 1 cell differentiation; low estrogen concentrations, in contrast, dampened the production of interferon γ and interleukin 17. Those data support the concept that estrogens affect transplant outcomes in a sex- and age-dependent fashion. Supported by our published data, we plan on delineating cellular and molecular pathways that are responsible for estrogen driven alloimmune responses. Our work package 1 will identify estrogen-mediated effects on specific immune cell populations during alloimmune response through single-cell RNA-sequencing (scRNA-seq) on immune cells collected from either estrogen-deprived mice or those with physiological estrogen levels following allograft transplantation. Estrogens act mainly via estrogen receptor alpha (ERα) and beta (ERβ), with ERα being highly expressed on T cells and antigen presenting cells (APCs) and accounting for the majority of estrogen mediated effects on immune cells. We therefore hypothesize that ERα-mediated signaling in CD4+ T cells and CD11c+ APCs is critical for the effects of estrogens on alloimmunity. To test our hypothesis, we will determine (in work package 2) the effects of different estrogen levels in female CD4+ T cell and CD11c+ cell specific ERα knockout mice on transplant survival and T cell and dendritic cell differentiation after fully mismatched heart transplantation. Transcriptomic analysis, using RNA-sequencing followed by pathway enrichment analysis, will be utilized to further determine the underlying molecular pathways.This project is designed to identify cellular and molecular mechanisms responsible for sex-specific differences in alloimmune response leading to a better understanding of sex as a biological variable in alloimmunity. We expect that data of our work will lead to a greater awareness of sex specific differences in alloimmunity while revealing novel therapeutic targets to improve transplantation outcomes.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Stefan Tullius, Ph.D.