Research ArticleAutoimmunity

First-in-class inhibitor of the T cell receptor for the treatment of autoimmune diseases

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Science Translational Medicine  21 Dec 2016:
Vol. 8, Issue 370, pp. 370ra184
DOI: 10.1126/scitranslmed.aaf2140

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Toning down T cell signaling to treat autoimmunity

T cells are important for fighting infectious agents, but T cells that recognize the body’s own cells are often central to the development of autoimmune disease, leading Borroto et al. to develop a compound that hampers T cell signaling without completely blocking it. Treatment with this compound prevented or treated autoimmune disease in multiple mouse models, and the compound was demonstrated to skew human T cell differentiation toward less inflammatory subsets. Treatment with the compound did not prevent T cell pathogen responses in mice, suggesting that it would not leave patients susceptible to infection.

Abstract

Modulating T cell activation is critical for treating autoimmune diseases but requires avoiding concomitant opportunistic infections. Antigen binding to the T cell receptor (TCR) triggers the recruitment of the cytosolic adaptor protein Nck to a proline-rich sequence in the cytoplasmic tail of the TCR’s CD3ε subunit. Through virtual screening and using combinatorial chemistry, we have generated an orally available, low–molecular weight inhibitor of the TCR-Nck interaction that selectively inhibits TCR-triggered T cell activation with an IC50 (median inhibitory concentration) ~1 nM. By modulating TCR signaling, the inhibitor prevented the development of psoriasis and asthma and, furthermore, exerted a long-lasting therapeutic effect in a model of autoimmune encephalomyelitis. However, it did not prevent the generation of a protective memory response against a mouse pathogen, suggesting that the compound might not exert its effects through immunosuppression. These results suggest that inhibiting an immediate TCR signal has promise for treating a broad spectrum of human T cell–mediated autoimmune and inflammatory diseases.

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