Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand.

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Bibliographic Details
Title:	Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand.
Authors:	Solt, Laura A., Kumar, Naresh, Nuhant, Philippe, Yongjun Wang, Lauer, Janelle L., Jin Liu, Istrate, Monica A., Kamenecka, Theodore M., Roush, William R., Vidović, Dušica, Schürer, Stephan C., Jihong Xu, Wagoner, Gail, Drew, Paul D., Griffin, Patrick R., Burris, Thomas P.
Source:	Nature. 4/28/2011, Vol. 472 Issue 7344, p491-494. 4p. 4 Graphs.
Subjects:	Interleukins, Nuclear receptors (Biochemistry), Cytokines, Autoimmune disease treatment, Acetamide, Cell differentiation, T-cell receptor genes, Therapeutics
Abstract:	T-helper cells that produce interleukin-17 (TH17 cells) are a recently identified CD4+ T-cell subset with characterized pathological roles in autoimmune diseases. The nuclear receptors retinoic-acid-receptor-related orphan receptors α and γt (RORα and RORγt, respectively) have indispensible roles in the development of this cell type. Here we present SR1001, a high-affinity synthetic ligand-the first in a new class of compound-that is specific to both RORα and RORγt and which inhibits TH17 cell differentiation and function. SR1001 binds specifically to the ligand-binding domains of RORα and RORγt, inducing a conformational change within the ligand-binding domain that encompasses the repositioning of helix 12 and leads to diminished affinity for co-activators and increased affinity for co-repressors, resulting in suppression of the receptors' transcriptional activity. SR1001 inhibited the development of murine TH17 cells, as demonstrated by inhibition of interleukin-17A gene expression and protein production. Furthermore, SR1001 inhibited the expression of cytokines when added to differentiated murine or human TH17 cells. Finally, SR1001 effectively suppressed the clinical severity of autoimmune disease in mice. Our data demonstrate the feasibility of targeting the orphan receptors RORα and RORγt to inhibit specifically TH17 cell differentiation and function, and indicate that this novel class of compound has potential utility in the treatment of autoimmune diseases. [ABSTRACT FROM AUTHOR]
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Database:	Psychology and Behavioral Sciences Collection

Description
Abstract:	T-helper cells that produce interleukin-17 (TH17 cells) are a recently identified CD4+ T-cell subset with characterized pathological roles in autoimmune diseases. The nuclear receptors retinoic-acid-receptor-related orphan receptors α and γt (RORα and RORγt, respectively) have indispensible roles in the development of this cell type. Here we present SR1001, a high-affinity synthetic ligand-the first in a new class of compound-that is specific to both RORα and RORγt and which inhibits TH17 cell differentiation and function. SR1001 binds specifically to the ligand-binding domains of RORα and RORγt, inducing a conformational change within the ligand-binding domain that encompasses the repositioning of helix 12 and leads to diminished affinity for co-activators and increased affinity for co-repressors, resulting in suppression of the receptors' transcriptional activity. SR1001 inhibited the development of murine TH17 cells, as demonstrated by inhibition of interleukin-17A gene expression and protein production. Furthermore, SR1001 inhibited the expression of cytokines when added to differentiated murine or human TH17 cells. Finally, SR1001 effectively suppressed the clinical severity of autoimmune disease in mice. Our data demonstrate the feasibility of targeting the orphan receptors RORα and RORγt to inhibit specifically TH17 cell differentiation and function, and indicate that this novel class of compound has potential utility in the treatment of autoimmune diseases. [ABSTRACT FROM AUTHOR]
ISSN:	00280836
DOI:	10.1038/nature10075