A new anti-rheumatic drug, T-614, effectively suppresses the development of autoimmune encephalomyelitis.
In the present study, we examined the therapeutic effects of T-614 (3-formylamino-7-methylsulfonylaminoxy-4H-1-benzopyran-4-one), a new anti-rheumatic drug, on a T cell-mediated autoimmune disease, experimental autoimmune encephalomyelitis (EAE). T-614 dose-dependently suppressed the development of active EAE induced in Lewis rats by immunization with myelin basic protein (MBP) when administered for 2 weeks starting on the day of immunization (day 0 to 14). Amelioration of clinical signs was also obtained by the treatment at the effector phase (day 7 to 14) of the disease. Furthermore, T-614 treatment of recipient rats that had received MBP-sensitized lymphoid cells resulted in suppression of the clinical severity of EAE. Immunohistological examination revealed that the number of TCR alpha beta-expressing T cells and the extent of MHC class II expression in the spinal cord of rats treated with T-614 was markedly reduced. In vitro study using MBP-specific T cells showed that the addition of T-614 inhibited the proliferative responses of T cells and the production of pro-inflammatory cytokines such as IFN-gamma, IL-6 and TNF produced by T and accessory cells. Taken together, these findings imply that T-614 suppresses the development of EAE by inhibiting the proliferation of autoreactive T cells and pro-inflammatory cytokine production not only by T cells but also by macrophages/microglia. This may be attributable to the result that T-614 is more effective at the effector phase rather than the induction phase. Thus, this drug has a potential value for the treatment of various T cell-mediated autoimmune diseases including multiple sclerosis (MS) as well as rheumatoid arthritis.
Aikawa
Y
Y
Department of Neuropathology, Tokyo Metropolitan Institute for Neuroscience, Japan.
Tanuma
N
N
Shin
T
T
Makino
S
S
Tanaka
K
K
Matsumoto
Y
Y
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000276:immunology / Q000494:pharmacology*; D018501:Antirheumatic Agents / Q000276:immunology* / Q000494:pharmacology*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy; D001578:Benzopyrans / Q000276:immunology / Q000494:pharmacology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D007371:Interferon-gamma / Q000032:analysis; D007375:Interleukin-1 / Q000096:biosynthesis / Q000276:immunology; D015850:Interleukin-6 / Q000096:biosynthesis / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D017628:Microglia / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D004676:Myelin Basic Protein / Q000276:immunology / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D013116:Spinal Cord / Q000276:immunology / Q000473:pathology; D013449:Sulfonamides / Q000276:immunology / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D000894:Anti-Inflammatory Agents, Non-Steroidal; D018501:Antirheumatic Agents; D001578:Benzopyrans; D007375:Interleukin-1; D015850:Interleukin-6; D004676:Myelin Basic Protein; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; C077313:T 614; D007371:Interferon-gamma