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Comparison of rapamycin and methylprednisolone for treating inflammatory muscle disease in a murine model of experimental autoimmune myositis.

ABSTRACT: Idiopathic inflammatory myopathies (IIMs) are a group of autoimmune inflammatory muscle diseases. Rapamycin has been shown to ameliorate inflammation and improve muscle function in a mouse model of experimental autoimmune myositis (EAM). In the present study, the therapeutic effect of rapamycin was compared with methylprednisolone (MP) on EAM. Mice were injected with myosin for 10 days to induce EAM and were subsequently treated with rapamycin (1.5 mg/kg), MP (40 mg/kg) or placebo (DMSO) for 14 days. The rapamycin-treated group exhibited significantly decreased severe inflammation and improved muscle strength compared with the MP-treated group. The plasma transforming growth factor-? (TGF-?) concentration in the rapamycin-treated group was significantly higher compared with the placebo group. However, both treatment groups exhibited significantly lower plasma interleukin-10 levels compared with the placebo group. Moreover, splenic regulatory T cell frequency in both the rapamycin- and MP-treated animals was significantly lower than that in the animals of the placebo group. Rapamycin showed better immune suppressive effects than MP in this model of EAM, and these effects were likely to be mediated by the TGF-? signaling pathway.

SUBMITTER: Kang J

PROVIDER: S-EPMC7291653 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Comparison of rapamycin and methylprednisolone for treating inflammatory muscle disease in a murine model of experimental autoimmune myositis.

Kang Juan J Feng Dongyun D Yang Feng F Tian Xiaojia X Han Wenjuan W Jia Hongge H

Experimental and therapeutic medicine 20200505 1

Idiopathic inflammatory myopathies (IIMs) are a group of autoimmune inflammatory muscle diseases. Rapamycin has been shown to ameliorate inflammation and improve muscle function in a mouse model of experimental autoimmune myositis (EAM). In the present study, the therapeutic effect of rapamycin was compared with methylprednisolone (MP) on EAM. Mice were injected with myosin for 10 days to induce EAM and were subsequently treated with rapamycin (1.5 mg/kg), MP (40 mg/kg) or placebo (DMSO) for 14 ...[more]

PMID: 32536994

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Project description: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.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).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.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.

Project description:BackgroundAs a first-line therapeutic option for multisystem inflammatory syndrome in children (MIS-C) with surging demand, intravenous immunoglobulin (IVIG) is associated with escalating costs and supply shortages, particularly in low-income and middle-income countries. This study compares the effectiveness of methylprednisolone alone versus IVIG combined with methylprednisolone for managing MIS-C.MethodsWe conducted a retrospective cohort study from January 2022 to June 2023 at Vietnam National Children's Hospital. We used propensity score matching to compare the short-term outcomes based on immunomodulatory therapy with methylprednisolone alone or IVIG plus methylprednisolone.ResultsWe included 391 patients, comprising 255 boys and 136 girls, who fulfilled the MIS-C case definition of the US Centers for Disease Control and Prevention. Most patients (80.8%) received intravenous methylprednisolone monotherapy, and 19.2% were administered IVIG in addition to methylprednisolone. In general, the laboratory values indicative of hyperinflammatory and hyperthrombotic states displayed significant early response within 2-3 days after initial treatment, including white cell count (SE=1.77, p<0.001), NEU (SE=0.76, p=0.03), C reactive protein (SE=-46.51, p<0.001), PLT (SE=38.05, p=0.002), fibrinogen (SE=-0.37, p=0.002), d-dimer (SE=-849.8, p=0.02)); while subsequent improvement in cardiac markers was also observed, with pro-B-type natriuretic peptide (SE=-165.2, p<0.001) on day 5 and troponin I (SE=-0.05, p=0.004) on day 7. After propensity score weighting, there were 41 patients in each treatment group. Notably, there were no significant differences in the incidence of cardiac events between treatment groups regarding left ventricular dysfunction and coronary artery dilation or aneurysms (10.3% vs 20.7%, p=0.074 and 63.4% vs 56.1%, p=0.653, respectively). While the median paediatric intensive care unit length of stay (LOS) and hospital LOS were slightly lengthier in the IVIG and methylprednisolone group compared with those of the methylprednisolone group, these differences were not statistically significant ((5 vs 4, p=0.782) and (9 vs 7, p=0.725), respectively).ConclusionsInitial treatment with methylprednisolone monotherapy appears not inferior in effectiveness to adjunctive IVIG plus methylprednisolone in MIS-C. Further investigations in randomised controlled trials deserve to be undergone to clarify if IVIG-sparing glucocorticoids are a viable option for achieving favourable outcomes in MIS-C, particularly in resource-limited settings with barriers approaching IVIG therapy.

Dataset Information

Comparison of rapamycin and methylprednisolone for treating inflammatory muscle disease in a murine model of experimental autoimmune myositis.

Publications

Comparison of rapamycin and methylprednisolone for treating inflammatory muscle disease in a murine model of experimental autoimmune myositis.

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