sirolimus and Multiple-Sclerosis--Relapsing-Remitting

The routine therapies for relapsing-remitting multiple sclerosis (RRMS) are common disease-modifying medications, yet are not effective in all patients. The aim of the present clinical trial was to evaluate the therapeutic effects of rapamycin on the clinical and radiological aspects, regulatory T cells proliferation and FOXP3 and GARP gene expression in the patients with RRMS. In this study, eight patients with RRMS were chosen and included in the trial. Patients received rapamycin (Rapacan, Biocon, India) for six months. Magnetic resonance imaging (MRI) of the patients' brain was taken before and after the therapy. Patients' expanded disability status scale (EDSS), and FoxP3 and GARP gene expression, and Treg cell proliferation were also been evaluated. All the patients had some degrees of significant reduction in mean plaque area size (P = 0.012, Z = -2.520), and minimum and maximum size of the plaques (P = 0.012, Z = -2.521). EDSS of 50% of patients was decreased after the treatment, yet it was not significant (P = 0.059, Z = -1.89). The expression rate of FOXP3 (P = 0.003) and GARP genes in Tregs increased after the therapy. We found a promising response to rapamycin among our cases with minor side effects and it may be considered as a therapeutic option of this disease.

Topics: Adult; Female; Forkhead Transcription Factors; Gene Expression; Humans; Immunosuppressive Agents; Magnetic Resonance Imaging; Male; Membrane Proteins; Middle Aged; Multiple Sclerosis, Relapsing-Remitting; Outcome Assessment, Health Care; Sirolimus; T-Lymphocytes, Regulatory

Rapamycin is an oral immunosuppressant drug previously reported to efficiently induce naturally occurring CD4(+)CD25(+)FoxP3(+) regulatory T ((n)T(reg)) cells re-establishing long-term immune self-tolerance in autoimmune diseases. We investigated the effect of rapamycin administration to SJL/j mice affected by PLP(139-151)-induced relapsing-remitting experimental autoimmune encephalomyelitis (RR-EAE). We found that oral or intraperitoneal treatment at the peak of disease or at the end of the first clinical attack, dramatically ameliorated the clinical course of RR-EAE. Treatment suspension resulted in early reappearance of disease. Clinical response was associated with reduced central nervous system demyelination and axonal loss. Rapamycin induced suppression of IFN-gamma, and IL-17 release from antigen-specific T cells in peripheral lymphoid organs. While CD4(+)FoxP3(+) cells were unaffected, we observed disappearance of CD4(+)CD45RB(high) effector T (T(eff)) cells and selective expansion of T(reg) cells bearing the CD4(+)CD45RB(low)FoxP3(+)CD25(+)CD103(+) extended phenotype. Finally, the dual action of rapamycin on both T(eff) and T(reg) cells resulted in modulation of their ratio that closely paralleled disease course. Our data show that rapamycin inhibits RR-EAE, provide evidence for the immunological mechanisms, and indicate this compound as a potential candidate for the treatment of multiple sclerosis.

Topics: Animals; Antigens, Differentiation, T-Lymphocyte; Antigens, Surface; Disease Models, Animal; Drug Administration Routes; Encephalomyelitis, Autoimmune, Experimental; Female; Immune Tolerance; Immunosuppressive Agents; Interferon-gamma; Interleukin-17; Mice; Multiple Sclerosis, Relapsing-Remitting; Myelin Proteolipid Protein; Peptide Fragments; Phenotype; Secondary Prevention; Sirolimus; T-Lymphocytes, Regulatory; Treatment Outcome