Beneficial role of rapamycin in experimental autoimmune myositis

PLoS One. 2013 Nov 12;8(11):e74450. doi: 10.1371/journal.pone.0074450. eCollection 2013.

Abstract

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. 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.

Methods: EAM 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).

Results: Under preventive or curative treatment, an increase of muscle strength was observed with a parallel decrease of muscle inflammation, both being well correlated (R(2) = -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 (CD62L(low)CD44(high): 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 CD44(low) CD62L(high) naive T cell and in CD62L(low) CD44(high) activated T cell.

Conclusions: Rapamycin 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.

Trial registration: ClinicalTrials.gov NCT00525889.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism
  • B-Lymphocytes / pathology
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism
  • Disease Models, Animal
  • Female
  • Immunosuppressive Agents / administration & dosage
  • Immunosuppressive Agents / adverse effects
  • Immunosuppressive Agents / pharmacology*
  • Inflammation / immunology
  • Inflammation / metabolism
  • Inflammation / pathology
  • Kruppel-Like Transcription Factors / metabolism
  • Lymphocyte Count
  • Lymphopenia / chemically induced
  • Lymphopenia / pathology
  • Mice
  • Muscle Strength / drug effects
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / pathology
  • Nervous System Autoimmune Disease, Experimental / immunology*
  • Nervous System Autoimmune Disease, Experimental / metabolism
  • Nervous System Autoimmune Disease, Experimental / prevention & control
  • Signal Transduction / drug effects
  • Sirolimus / administration & dosage
  • Sirolimus / adverse effects
  • Sirolimus / pharmacology*
  • T-Lymphocytes, Regulatory / drug effects*
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism

Substances

  • Immunosuppressive Agents
  • Klf2 protein, mouse
  • Kruppel-Like Transcription Factors
  • Sirolimus

Associated data

  • ClinicalTrials.gov/NCT00525889

Grants and funding

This project was sponsored by the grants from the Association Francaise contre les Myopathies to A.F.M. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.