Rapamycin inhibits relapsing experimental autoimmune encephalomyelitis by both effector and regulatory T cells modulation.
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.
Clinical Neuroimmunology Unit, Department of Neuroscience, Institute of Experimental Neurology, San Raffaele Scientific Institute DIBIT, Milan, Italy.
Marianna
M
Esposito
Francesca
F
Ruffini
Matteo
M
Bellone
Nicola
N
Gagliani
Manuela
M
Battaglia
Gianvito
G
Martino
Roberto
R
Furlan
D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000187:drug effects / Q000378:metabolism; D000954:Antigens, Surface / Q000276:immunology; D004195:Disease Models, Animal; D004333:Drug Administration Routes; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology* / Q000503:physiopathology; D005260:Female; D007108:Immune Tolerance / Q000187:drug effects*; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007371:Interferon-gamma / Q000187:drug effects / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D051379:Mice; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology; D018991:Myelin Proteolipid Protein / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D010641:Phenotype; D055502:Secondary Prevention; D020123:Sirolimus / Q000494:pharmacology* / Q000627:therapeutic use; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology; D016896:Treatment Outcome
D000945:Antigens, Differentiation, T-Lymphocyte; D000954:Antigens, Surface; D007166:Immunosuppressive Agents; D020381:Interleukin-17; D018991:Myelin Proteolipid Protein; D010446:Peptide Fragments; C435023:myelin proteolipid protein (139-151); D007371:Interferon-gamma; D020123:Sirolimus