Session Type: Abstract Submissions (ACR)
Background/Purpose: Idiopathic inflammatory myopathies are a heterogeneous group of different diseases, classified into four main categories: dermatomyositis, polymyositis, immune-mediated necrotizing myopathy, and sporadic inclusion body myositis. The treatment of polymyositis consists of corticosteroids frequently associated to other immunosuppressive drugs. The obligatory and often severe side effects of these drugs, which have to be taken for several months or years, prompted us to propose alternative treatments, which have to be tested first in experimental animal models. Rapamycin is a known potent immunomodulator with less side effects compared to other immunosuppressants (e.g. ciclosporin). Rapamycin has been used for a decade in transplant patients to prevent graft rejection. In vivo, rapamycin has been described to increase the percentage of regulatory T cells. Our objective was to Study the role of rapamycin in an experimental autoimmune myositis (EAM) model of polymyositis in mouse (Allenbach Y et al. Am J Pathol, 2009, 174, 989-998).
Methods: EAM is induced by 3 injections of myosin coupled with complete Freund’s adjuvant. Mice received rapamycin (1 mg or 3 mg/kg/day) during 25 days starting before myosin immunization (preventive treatment), or during 10 days following the last myosin immunization (curative treatment). Muscle strength and histology, composition of lymphocyte subpopulations, and KLF2 pathway, a transcription factor controlling lymphocyte homing, were studied.
Results: Under preventive or curative treatment, an increase of muscle strength was observed with in parallel a decrease of muscle inflammation, both being well correlated (R2=-0.645, p<0.0001). Rapamycin induced a general decrease in frequency of effector T cells (lymphopenia in draining or non draining lymph nodes and spleen, harmoniously distributed between CD4+ and CD8+ T cells, but sparing B cells), and an increase in frequency of regulatory T cells (CD4+CD25+) in draining lymph nodes (rapamycin 3 mg/kg/day preventively treated mice compared to controls: 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). Furthermore, during preventive treatment, rapamycin increased the levels of KLF2 transcript in CD44low CD62Lhigh naive T cell (2,1 ±0,14 vs. 1,05 ±0,09, treated vs. untreated,p<0.05) and in CD62Llow CD44high activated T cell (1,02 ± 0,18 vs. 0,44 ± 0,08, treated vs. untreated, p<0.05).
Conclusion: Rapamycin is an effective treatment for EAM, resulting in a decrease in effector T cells, an increase in regulatory T cells, and upregulation of KFL2 in naive and activated T cells. Those observations suggest that rapamycin may represent an effective new therapeutic approach in patients with polymyositis. This approach may also be beneficial, since a deficiency in regulatory T cells has been reported during polymyositis.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/beneficial-role-of-rapamycin-in-experimental-autoimmune-myositis/