Beneficial Role of Rapamycin in Experimental Autoimmune Myositis

Nicolas Prevel,David Klatzmann,Benoit Salomon,Olivier Benveniste,Yves Allenbach,Orhan Aktas

doi:10.1371/journal.pone.0074450

Abstract

IntroductionWe developed an experimental autoimmune myositis (EAM) mouse model of polymyositis where we outlined the role of regulatory T (Treg) cells. Rapamycin, this immunosuppressant drug used to prevent rejection in organ transplantation, is known to spare Treg. Our aim was to test the efficacy of rapamycin in vivo in this EAM model and to investigate the effects of the drug on different immune cell sub-populations.MethodsEAM is induced by 3 injections of myosin emulsified in CFA. Mice received rapamycin during 25 days starting one day before myosin immunization (preventive treatment), or during 10 days following the last myosin immunization (curative treatment).ResultsUnder preventive or curative treatment, an increase of muscle strength was observed with a parallel decrease of muscle inflammation, both being well correlated (R2 = −0.645, p<0.0001). Rapamycin induced a general decrease in muscle of CD4 and CD8 T cells in lymphoid tissues, but spared B cells. Among T cells, the frequency of Treg was increased in rapamycin treated mice in draining lymph nodes (16.9±2.2% vs. 9.3±1.4%, p<0.001), which were mostly activated regulatory T cells (CD62LlowCD44high: 58.1±5.78% vs. 33.1±7%, treated vs. untreated, p<0.001). In rapamycin treated mice, inhibition of proliferation (Ki-67+) is more important in effector T cells compared to Tregs cells (p<0.05). Furthermore, during preventive treatment, rapamycin increased the levels of KLF2 transcript in CD44low CD62Lhigh naive T cell and in CD62Llow CD44high activated T cell.ConclusionsRapamycin showed efficacy both as curative and preventive treatment in our murine model of experimental myositis, in which it induced an increase of muscle strength with a parallel decrease in muscle inflammation. Rapamycin administration was also associated with a decrease in the frequency of effector T cells, an increase in Tregs, and, when administered as preventive treatment, an upregulation of KFL2 in naive and activated T cells.

Highlights

We developed an experimental autoimmune myositis (EAM) mouse model of polymyositis where we outlined the role of regulatory T (Treg) cells
We previously described the induction of experimental autoimmune myositis (EAM) in mice by immunization with partiallypurified myosin [6]
In this EAM model, we demonstrated that regulatory T cells (Treg) can ameliorate the disease phenotype [6]

Summary

Introduction

We developed an experimental autoimmune myositis (EAM) mouse model of polymyositis where we outlined the role of regulatory T (Treg) cells Rapamycin, this immunosuppressant drug used to prevent rejection in organ transplantation, is known to spare Treg. We previously described the induction of experimental autoimmune myositis (EAM) in mice by immunization with partiallypurified myosin [6] This EAM model mimics closely polymyositis, showing muscle weakness and inflammation, and extensive CD8+ T cells and macrophages infiltrates. We further demonstrated that it was possible to induce the disease by adoptive transfer of unsorted lymph node cells or in vitro restimulated sorted CD4+ T cells in wild type mice In this EAM model, we demonstrated that regulatory T cells (Treg) can ameliorate the disease phenotype [6]

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