Identifying druglike inhibitors of myelin-reactive T cells by phenotypic high-throughput screening of a small-molecule library

• Published in: Journal of biomolecular screening Vol. 12; no. 4; pp. 481 - 489
• Main Authors: Rossi, Christina, Padmanaban, Deepa, Ni, Jake, Yeh, Li-An, Glicksman, Marcie A, Waldner, Hanspeter
• Format: Journal Article
• Language: English
• Published: United States 01.06.2007
• Subjects: Animals; Female; Immunophenotyping; Immunosuppressive Agents - isolation & purification; Immunosuppressive Agents - metabolism; Immunosuppressive Agents - pharmacology; Mice; Mice, Transgenic; Myelin Sheath - immunology; Myelin Sheath - metabolism; Peptide Library; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; T-Lymphocytes - metabolism
• ISSN: 1087-0571; 2472-5552
• DOI: 10.1177/1087057107301272

Inflammatory T cells that are reactive to myelin protein components of the CNS play a critical role in the pathogenesis of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). The authors have previously generated mice that predominantly harbor T cells transgenic for a T-cell receptor (TCR) that is specific to the myelin proteolipid protein (PLP) 139-151 and that spontaneously develop MS-like paralysis. T cells from healthy transgenic mice respond to stimulation with PLP139-151 in a highly specific manner by proliferation and secretion of proinflammatory cytokines such as interleukin (IL)-2 and interferon (INF)-gamma in vitro. To identify druglike compounds that may inhibit inflammatory T-cell responses, the authors have developed a high-throughput screening assay with primary T cells from PLP TCR transgenic mice. They have screened 41,184 small-molecule compounds that follow Lipinski's rules for their inhibitory activity on the proliferation and secretion of proinflammatory cytokines in PLP-reactive T cells. To this end, the screen identified 6 nontoxic compounds with a molecular weight <500 that inhibited inflammatory responses in PLP-reactive T cells in a concentration-dependent fashion. The identified compounds represent valid leads that may be developed into novel therapeutics for MS that could be administered orally.