Identifying Druglike Inhibitors of Myelin-Reactive T Cells by Phenotypic High-Throughput Screening of a Small-Molecule Library
Christina Rossi,
Deepa Padmanaban,
Jake Ni,
Li-An Yeh,
Marcie A. Glicksman,
Hanspeter Waldner*
Brigham and Women's Hospital and Harvard Medical School
* To whom correspondence should be addressed. E-mail: hwaldner{at}rics.bwh.harvard.edu.
 |
Abstract |
|---|
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)- 
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 Lipinskis 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. (<I>Journal of Biomolecular Screening</I> XXXX:xx-xx)
