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

Abstract

Recent data suggest that donor-specific memory T cells (T mem ) 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, lifesupporting rat kidney transplant model using a high responder (DA to LEW) recipients that received donorspecific CD4 + / 8 + GFP + T mem before transplantation to achieve similar pre-transplant frequencies of donorspecific T mem as seen in many patients. T cell depletion alone induced long-term graft survival in naïve recipients but could not prevent acute rejection in T mem + 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 longterm graft survival and an intragraft tolerance profile (e.g. high TOAG-1) in T mem + rats. Our model allows evaluation of novel therapies under clinically relevant conditions.

Human CD45RA− FoxP3hi Memory-Type Regulatory T Cells Show Distinct TCR Repertoires With Conventional T Cells and Play an Important Role in Controlling Early Immune Activation

“…Although TregCM show similar suppression activity regarding the proliferation of responder cells with TregN in the long timepoint, they could faster switch-on the effector function and control the activation of Tconv, particular memory Tconv at the early timepoint, by inhibiting their activation marker expression and early cytokine production. This is especially important in the transplant setting (24).…”

“…Thus, we hypothesized that a switch of phenotype of Treg to memory Treg (either TregCM or TregEM) might also affect some aspects of functionality, particularly control during early immune activation. Fast activation could be especially important in SOT, as many patients have high levels of donor-specific TconvM that would require fast control to prevent acute rejection (24).…”

Strategy to achieve biomarker-driven immunosuppression after solid organ transplantation by an academic-industry partnership within the European BIO-DrIM consortium

“…Recent data in an experimental rat kidney transplant model revealed that induced T-cell sensitization by pre-transplant adoptive transfer of donor-reactive memory/effector T cells up to levels comparable to patients at high risk (high-responder) required high-dose CNI-based immunosuppression for preserving long-term graft function [36] . The biomarker studies suggest that selective targeting of activated donor-specific memory/effector T cells might be a new strategy to switch high-into low-responders (from a biomarker to a target) -but how might this be feasible?…”

Mechanisms and Rescue Strategies of Calcineurin Inhibitor Mediated Tolerance Abrogation Induced by Anti-CD4 mAb Treatment

“…CNI seem to be most effective in preventing reactivation of preformed memory T cells (3,11). Indeed, although clinical studies are focusing on CNI-sparing protocols, mainly because of their nephrotoxicity, some patients have to be (re)-converted to CNI because of rejection (12). Consequently, CNI remain the standard immunosuppression at least for high-responders (13)(14)(15).…”