MARNI

Uterus transplantation (UTx) is a therapy for women with uterine infertility to achieve pregnancy and childbirth. In view of the recent increase number of procedures performed, that emerging technology could translate into clinical practice in the coming years. However, critical concerns remain with this procedure including the mechanisms involved in rejection (60% of recipient), the lack of biomarkers to identify early signs of rejection (they are asymptomatic and detected only with cervical biopsies), and the consequences at the maternofetal interface. In a preliminary study, we analyzed the immune profile of ectocervical biopsies from five patients following UTx, before and during their first episode of rejection. Using RNA sequencing, we identified 530 up-regulated genes and 207 down-regulated genes after rejection. Imaging mass cytometry confirmed that rejection was associated with major alterations of immune markers, including the involvement of B-cell structures linked to tertiary lymphoid structures, and an increase of HLA-DR- macrophages expressing granzyme B. We propose to refine our preliminary data on a larger retrospective cohort and confirm them on a prospective multicenter open study (MARNI), based on the analysis of a longitudinal collection of biological samples (including cervical biopsies, smears and blood, placenta and umbilical cord during delivery) from UTx recipients in France (Foch and Rennes Center), Sweden, United states (Houston) and Germany (NCT04615221). Methods of analysis will include RNA sequencing and qPCR, flow cytometry, ELISA multiplex, and imaging mass cytometry. The goal of this research will be to better characterized the role of TLS and granzyme-B expressing macrophages and their impact on the maternofetal interface. These new findings should lead to better understand the mechanisms of rejection in the TU and potentially develop new strategies aimed at improving the prevention and/or treatment of uterus transplant rejection.