Identifying druglike inhibitors of myelin-reactive T cells by phenotypic high-throughput screening of a small-molecule library.
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.
Rossi
Christina
C
Center for Neurologic Diseases, Brigham and Women's Hospital, and Harvard Medical School, Cambridge, Massachusetts 02139, USA.
Padmanaban
Deepa
D
Ni
Jake
J
Yeh
Li-An
LA
Glicksman
Marcie A
MA
Waldner
Hanspeter
H
D000818:Animals; D005260:Female; D016130:Immunophenotyping; D007166:Immunosuppressive Agents / Q000302:isolation & purification / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009186:Myelin Sheath / Q000276:immunology / Q000378:metabolism*; D019151:Peptide Library; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*
D007166:Immunosuppressive Agents; D019151:Peptide Library