Regulatory Cell Therapy in Organ Transplantation: Achievements and Open Questions.

Marta Fortunato,Laura Passeri,Silvia Gregori,Konstantina Morali

doi:10.3389/fimmu.2021.641596

Abstract

The effective development of innovative surgical applications and immunosuppressive agents have improved remarkable advancements in solid organ transplantation. Despite these improvements led to prevent acute rejection and to promote short-term graft survival, the toxicity of long-term immunosuppression regiments has been associated to organ failure or chronic graft rejection. The graft acceptance is determined by the balance between the regulatory and the alloreactive arm of the immune system. Hence, enhance regulatory cells leading to immune tolerance would be the solution to improve long-term allograft survival which, by reducing the overall immunosuppression, will provide transplanted patients with a better quality of life. Regulatory T cells (Tregs), and regulatory myeloid cells (MRCs), including regulatory macrophages and tolerogenic dendritic cells, are promising cell populations for restoring tolerance. Thus, in the last decade efforts have been dedicated to apply regulatory cell-based therapy to improve the successful rate of organ transplantation and to promote allogeneic tolerance. More recently, this approach has been translated into clinical application. The aim of this review is to summarize and discuss results on regulatory cell-based strategies, focusing on Tregs and MRCs, in terms of safety, feasibility, and efficacy in clinical studies of organ transplantation.

Highlights

Solid organ transplantation (SOT) is a life-saving treatment for patients with end-organ dysfunction
The discovery of DC-10, a subset of monocytederived human DC that secrete IL-10 and express the tolerogenic molecules ILT4 and HLA-G [31], allowed the improvement of the protocol to generate allo-specific Tr1 cells leading to a population, which contains up to 15% of differentiated Tr1 cells [29] (Figure 1)
Some of the burden include the difficulties in implementing GMP-compliant protocols to manufacture cell products, the cumbersome legislation for running trials, and the regulatory and ethical approvals, which vary among the countries

Summary

Introduction

Solid organ transplantation (SOT) is a life-saving treatment for patients with end-organ dysfunction. Thanks to advances in the surgical techniques and in the use of effective immunosuppressive drugs, acute transplant rejection has been declined. Toxicity of immunosuppressive regimens and chronic rejection remain the main limiting factors for organ acceptance and patient survival [1]. In the context of SOT these cell-based approaches in pre-clinical animal models demonstrated their ability to modulate alloreactive immune responses, to prevent organ rejection, and to promote long-term tolerance [4,5,6]. These results prompted the development of protocols to expand or generate regulatory cell products for clinical

Objectives

Findings

Conclusion