Role of myeloid regulatory cells (MRCs) in maintaining tissue homeostasis and promoting tolerance in autoimmunity, inflammatory disease and transplantation

Giada Amodio,Johannes Roth,Michaela Pekarova,Patricia Conde,Aurélie Moreau,Barbaros H Oral,Elizabeth J Ryan,Gianluca Matteoli,Silvia Gregori,Yahya Sohrabi,Joanna Cichy,Jordi Ochando,Maria-Cristina Cuturi

doi:10.1007/s00262-018-2264-3

Abstract

Myeloid cells play a pivotal role in regulating innate and adaptive immune responses. In inflammation, autoimmunity, and after transplantation, myeloid cells have contrasting roles: on the one hand they initiate the immune response, promoting activation and expansion of effector T-cells, and on the other, they counter-regulate inflammation, maintain tissue homeostasis, and promote tolerance. The latter activities are mediated by several myeloid cells including polymorphonuclear neutrophils, macrophages, myeloid-derived suppressor cells, and dendritic cells. Since these cells have been associated with immune suppression and tolerance, they will be further referred to as myeloid regulatory cells (MRCs). In recent years, MRCs have emerged as a therapeutic target or have been regarded as a potential cellular therapeutic product for tolerance induction. However, several open questions must be addressed to enable the therapeutic application of MRCs including: how do they function at the site of inflammation, how to best target these cells to modulate their activities, and how to isolate or to generate pure populations for adoptive cell therapies. In this review, we will give an overview of the current knowledge on MRCs in inflammation, autoimmunity, and transplantation. We will discuss current strategies to target MRCs and to exploit their tolerogenic potential as a cell-based therapy.

Highlights

Dysregulation of the immune system and uncontrolled inflammation contribute to disease pathology
myeloid regulatory cells (MRCs) promote a tolerogenic microenvironment that sustains the generation of T-regulatory cells (Tregs), thereby, the induction of tolerance
We review therapeutic approaches targeting MRCs or exploiting MRC-based cell therapy to restore tolerance

Summary

Introduction

Dysregulation of the immune system and uncontrolled inflammation contribute to disease pathology. The identification of specific biomarkers and consensus on the assays to determine tolDC suppressive activity are critical to better define their role in different autoimmune diseases This knowledge is required to enable the development of targeted interventions to promote tolDC differentiation, recruitment to sites of inflammation, and maintenance of their regulatory function. Tolerogenic treatment with costimulatory blockade allowed inflammatory Ly6Chigh monocytes infiltrating the allograft, early after transplantation, to differentiate into suppressive Ly6Clow macrophages through a CSF1-dependent mechanism [49] These pre-clinical experiments show that targeting either donor- or recipient-derived monocytes represents a promising therapeutic approach to promote long-term graft acceptance in organ transplantation. The selection of the optimum immunosuppressive regimen that can sustain tolerance is an important consideration for the clinical application of tolDC-based therapy to prevent graft rejection

Conclusions and perspectives

Compliance with ethical standards