Rapamycin inhibits relapsing experimental autoimmune encephalomyelitis by both effector and regulatory T cells modulation. 2010

Marianna Esposito, and Francesca Ruffini, and Matteo Bellone, and Nicola Gagliani, and Manuela Battaglia, and Gianvito Martino, and Roberto Furlan
Clinical Neuroimmunology Unit, Department of Neuroscience, Institute of Experimental Neurology, San Raffaele Scientific Institute DIBIT, Milan, Italy.

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.

UI MeSH Term Description Entries
D007108 Immune Tolerance The specific failure of a normally responsive individual to make an immune response to a known antigen. It results from previous contact with the antigen by an immunologically immature individual (fetus or neonate) or by an adult exposed to extreme high-dose or low-dose antigen, or by exposure to radiation, antimetabolites, antilymphocytic serum, etc. Immunosuppression (Physiology),Immunosuppressions (Physiology),Tolerance, Immune
D007166 Immunosuppressive Agents Agents that suppress immune function by one of several mechanisms of action. Classical cytotoxic immunosuppressants act by inhibiting DNA synthesis. Others may act through activation of T-CELLS or by inhibiting the activation of HELPER CELLS. While immunosuppression has been brought about in the past primarily to prevent rejection of transplanted organs, new applications involving mediation of the effects of INTERLEUKINS and other CYTOKINES are emerging. Immunosuppressant,Immunosuppressive Agent,Immunosuppressants,Agent, Immunosuppressive,Agents, Immunosuppressive
D007371 Interferon-gamma The major interferon produced by mitogenically or antigenically stimulated LYMPHOCYTES. It is structurally different from TYPE I INTERFERON and its major activity is immunoregulation. It has been implicated in the expression of CLASS II HISTOCOMPATIBILITY ANTIGENS in cells that do not normally produce them, leading to AUTOIMMUNE DISEASES. Interferon Type II,Interferon, Immune,gamma-Interferon,Interferon, gamma,Type II Interferon,Immune Interferon,Interferon, Type II
D010446 Peptide Fragments Partial proteins formed by partial hydrolysis of complete proteins or generated through PROTEIN ENGINEERING techniques. Peptide Fragment,Fragment, Peptide,Fragments, Peptide
D010641 Phenotype The outward appearance of the individual. It is the product of interactions between genes, and between the GENOTYPE and the environment. Phenotypes
D004195 Disease Models, Animal Naturally-occurring or experimentally-induced animal diseases with pathological processes analogous to human diseases. Animal Disease Model,Animal Disease Models,Disease Model, Animal
D004333 Drug Administration Routes The various ways of administering a drug or other chemical to a site in a patient or animal from where the chemical is absorbed into the blood and delivered to the target tissue. Administration Routes, Drug,Administration Route, Drug,Drug Administration Route,Route, Drug Administration,Routes, Drug Administration
D004681 Encephalomyelitis, Autoimmune, Experimental An experimental animal model for central nervous system demyelinating disease. Inoculation with a white matter emulsion combined with FREUND'S ADJUVANT, myelin basic protein, or purified central myelin triggers a T cell-mediated immune response directed towards central myelin. The pathologic features are similar to MULTIPLE SCLEROSIS, including perivascular and periventricular foci of inflammation and demyelination. Subpial demyelination underlying meningeal infiltrations also occurs, which is also a feature of ENCEPHALOMYELITIS, ACUTE DISSEMINATED. Passive immunization with T-cells from an afflicted animal to a normal animal also induces this condition. (From Immunol Res 1998;17(1-2):217-27; Raine CS, Textbook of Neuropathology, 2nd ed, p604-5) Autoimmune Encephalomyelitis, Experimental,Encephalomyelitis, Allergic,Encephalomyelitis, Experimental Autoimmune,Allergic Encephalomyelitis,Allergic Encephalomyelitis, Experimental,Autoimmune Experimental Encephalomyelitis,Experimental Allergic Encephalomyelitis,Experimental Autoimmune Encephalomyelitis,Encephalomyelitis, Autoimmune Experimental,Encephalomyelitis, Experimental Allergic,Experimental Allergic Encephalomyelitides,Experimental Encephalomyelitis, Autoimmune
D005260 Female Females
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia

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