Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0014070 (encephalomyelitis)
 13,017 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Leflunomide inhibits de novo pyrimidine synthesis and is a novel, immunosuppressive agent that has been successfully used to treat rheumatoid arthritis. Here, we investigated the efficacy of leflunomide and its mode of action in experimental autoimmune encephalomyelitis (EAE), which is a T helper cell type 1 cell-borne disease model to simulate inflammatory aspects of multiple sclerosis and was induced in Lewis rats by adoptive transfer of myelin basic protein (MBP)-specific T line cells. Given in vivo for 7 days after cell transfer, leflunomide suppressed clinical signs of disease even in uridine-substituted animals. MBP-specific T line cells that had been antigen-activated in vitro in the presence of A77 1726 (active metabolite of leflunomide) produced less interferon-gamma, whereas interleukin (IL)-10 secretion had a tendency to be increased without changes in signal transducer and activator of transcription 6 trafficking. Furthermore, these T cells exhibited reduced chemotaxis and induced a significantly mitigated disease course upon transfer into naive rats. The effects of leflunomide on MBP-specific memory type T line cells in vitro may not be mediated by pyrimidine depletion, as they were not reversible by exogenous uridine. Moreover, A77 1726 led to increased expression of CD86 (B7-2) and secretion of IL-10 in cultured microglial cells in vitro, strengthening their down-modulatory impact on activated, autoantigen-specific T cells. In conclusion, our observations underline that the immunomodulatory potential of leflunomide in effector cells of EAE is clinically relevant and is not exclusively dependent on the depletion of cellular pyrimidine pools.
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PMID:Modulation of effector cell functions in experimental autoimmune encephalomyelitis by leflunomide--mechanisms independent of pyrimidine depletion. 1532 36

Oral atorvastatin has prevented or reversed paralysis in the multiple sclerosis (MS) model experimental autoimmune encephalomyelitis (EAE), and reduced development of new MS lesions in clinical trials. Besides inhibiting development of encephalitogenic T cells, atorvastatin treatment of EAE has been associated with an induction of anti-inflammatory myelin-reactive T-helper type (Th)-2 cells. To investigate the clinical significance of atorvastatin-mediated Th2 differentiation, we first evaluated atorvastatin treatment in interleukin (IL)-4 green fluorescent protein-enhanced transcript (4-GET) reporter mice. Atorvastatin treatment failed to induce IL-4-producing Th2 cells in vivo; however, when T cells from atorvastatin-treated 4-GET mice were reactivated in vitro, T cells preferentially differentiated into Th2 cells, while antigen-specific T-cell proliferation and secretion of proinflammatory cytokines (interferon gamma, IL-17, tumor necrosis factor and IL-12) were reduced. Oral atorvastatin also prevented or reversed EAE in signal transducer and activator of transcription 6-deficient (STAT6-/-) mice, which cannot generate IL-4-producing Th2 cells. Further, atorvastatin treatment did not induce or expand Foxp3+ regulatory T cells in either wild-type or STAT6-/- mice. In vivo proliferation of T cells, as measured by incorporation of bromodeoxyuridine, was inhibited in atorvastatin-treated wild-type and STAT6-/- mice. These data imply that atorvastatin ameliorates central nervous system autoimmune disease primarily by inhibiting proliferation of proinflammatory encephalitogenic T cells, and not simply through induction of anti-inflammatory Th2 cells. This cytostatic effect may be a relevant mechanism of action when considering use of statins in MS and other inflammatory conditions.
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PMID:Neither T-helper type 2 nor Foxp3+ regulatory T cells are necessary for therapeutic benefit of atorvastatin in treatment of central nervous system autoimmunity. 2449 70