LAUSR

Introduction: The main goal in transplantation is to induce specific ra than general immunosuppression. The CD45 protein is an essential regu of T and B cell antigen receptor signaling. We have previously shown T cells expressing low levels of CD45RChave strong immunoregulatory p erties while T cells expressing high levels of CD45RC are essentially effe cells. Thus, we investigated the effect of depleting CD45RC cells on survival. Methods: Tregs were analyzed for the expression of CD45 isoforms by cytometry. LEW-1A ratswere grafted in a heterotopic positionwith a LEW heart. NSG mice were 2Gy-irradiated or grafted with human skin and inje with 5x10 or 1,5x10 human PBMCs respectively. Animals were treated 0.8 mg/kg/2.5d for 20d of anti-CD45RC mAb (OX22 or MT2 clones isotype. Humoral responses were assessed after KLH + CFA or exogen red blood cells immunization. FACS Aria-sorted Tregs were i.v. transferre 4,5Gy-irradiated recipients. CD45RC Tregswere analyzed byRNA sequen Results: First, we have shown that CD45RC is the only CD45-isoform expressed by Foxp3 Tregs both in human and rat. Interestingly, trans treatment with anti-CD45RCMabs induced transplant tolerance in a fully match cardiac allograft model in rat. Importantly, this treatment prevented cifically anti-donor humoral responses while preserved primary and mem responses against cognate antigens. As expected, anti-CD45RC Mab duced rapid cell death of CD45RC T cells through intrinsic cell signa while preserved CD45RC Tregs. Furthermore, the short-term treatm induced a transient homeostatic proliferation and sustained transcripti changes in long-term CD8 and CD4 CD45RC Tregs that mainta an indefinite, dominant and donor-specific tolerance, as adoptive transf Tregs succeeded in this allograft combination only. Finally, we transl these findings to human, in humanized mice models of xenogeneic GV and human skin allograft rejection. We demonstrated that ex vivo deple of CD45RC PBMCs prevented development of GVHD, and that trans treatment with anti-human CD45RC Mabs delayed GVHD development allograft rejection. Conclusion: This is the first proof of concept that targeting CD45RC short-term Mabs treatment is an efficient innovative strategy to indu donor-specific tolerance in transplantation without any other treatment.