Permanent CNI Treatment for Prevention of Renal Allograft Rejection in Sensitized Hosts Can Be Replaced by Regulatory T Cells

Recent data suggest that donor‐specific memory T cells (Tmem) are an independent risk factor for rejection and poor graft function in patients and a major challenge for immunosuppression minimizing strategies. Many tolerance induction protocols successfully proven in small animal models e.g. costimulatory blockade, T cell depletion failed in patients. Consequently, there is a need for more predictive transplant models to evaluate novel promising strategies, such as adoptive transfer of regulatory T cells (Treg). We established a clinically more relevant, life‐supporting rat kidney transplant model using a high responder (DA to LEW) recipients that received donor‐specific CD4+/ 8+ GFP+ Tmem before transplantation to achieve similar pre‐transplant frequencies of donor‐specific Tmem as seen in many patients. T cell depletion alone induced long‐term graft survival in naïve recipients but could not prevent acute rejection in Tmem+ rats, like in patients. Only if T cell depletion was combined with permanent CNI‐treatment, the intragraft inflammation, and acute/chronic allograft rejection could be controlled long‐term. Remarkably, combining 10 days CNI treatment and adoptive transfer of Tregs (day 3) but not Treg alone also induced long‐term graft survival and an intragraft tolerance profile (e.g. high TOAG‐1) in Tmem+ rats. Our model allows evaluation of novel therapies under clinically relevant conditions. Adoptive transfer of green fluorescent protein expressing alloreactive memory CD4+ and CD8+ T cells 7 or even 100 days prior to kidney transplantation elicits an acute rejection refractory to T cell depletion, which can only be prevented by permanent cyclosporine A therapy or a combined treatment of cyclosporine A and regulatory T cells.