Marked suppression of T cells by a benzothiophene derivative in patients with human T-lymphotropic virus type I-associated myelopathy tropical spastic paraparesis

In a search for new anti-autoimmune agents that selectively suppress activa tion of autoreactive T cells, one such agent, 5-methyl-3-(1-methylethoxy)be nzo [b] thiophene-2-carboxamide (CI-959-A), was found to be effective. This compound, which is known to suppress tumor necrosis factor alpha (TNF-alph a)-induced CD54 expression, inhibited the primary proliferative response of the T cell to antigen (Ag)-presenting cells (APCs) including allogenic den dritic cells (DCs), autologous Epstein-Barr virus-infected B cells, and hum an T lymphotropic virus type I (HTLV-I)-infected T cells. Autoreactive T ce lls from patients with HTLV-I-associated myelopathy/tropical spastic parapa resis (HAM/TSP) spontaneously proliferate in vitro, and their activation is reported to be associated with CD54 expression. The spontaneous proliferat ion of T cells from patients with HAM/TSP was entirely blocked by CI-959-A, However, in this study, the T cell proliferation in 15 patients with HAM/T SP was found to depend more extensively on major histocompatibility complex (MHC) class II and CD86 than on CD54 Ags, Since most important APCs for th e development of HAM/TSP are DCs and HTLV-I-infected T cells, the effect of CI-959-A on DC generation and on the expression of surface molecules on ac tivated T cells is examined. CI-959-A suppressed recombinant granulocyte-ma crophage colony stimulating factor (GM CSF)- and recombinant interleukin-4- dependent differentiation of DCs from monocytes and inhibited the expressio n of CD54 and, more extensively, MHC class II and CD86 Ags, CI-959-A showed little toxicity toward lymphoma or HTLV-I-infected T-cell lines or toward monocytes and cultured DCs, These results suggest that CI-959-A might be a potent anti-HAM/TSP agent.