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Aug 11, 2011
 |  BC Innovations  |  Targets & Mechanisms

Gutsy call on Th17 cells

Researchers at the Yale School of Medicine have shown that the small intestine regulates proinflammatory T helper type 17 cells via two mechanisms, including one that leads to an immunosuppressive, regulatory phenotype.1 The findings could give companies and researchers new therapeutic options in T helper type 17 cell-associated autoimmune diseases like multiple sclerosis.

Originally identified in a pair of 2005 studies,2,3 the IL-17 (IL-17A)-producing subset of CD4+ T cells known as T helper type 17 (Th17) cells has been implicated as a driver of proinflammatory processes and tissue damage in many autoimmune diseases, including MS.4,5 Indeed, several preclinical-stage biotechs working in autoimmune diseases, such as Lycera Corp. and Tempero Pharmaceuticals Inc., have built their platforms around strategies to dampen the pathogenic Th17 cell response.6

In its ongoing effort to understand how the body restrains an aberrant, pathogenic Th17 cell response while also inducing tolerance, the Yale group evaluated T cell receptor (TCR) activators. Some of these compounds, such as CD3-specific antibodies, are known to promote immune tolerance.

In a mouse model of tolerance induction, TCR activation with CD3-specific antibodies or a Staphylococcus aureus-derived enterotoxin led to clearance of T cells from circulation in conjunction with an increase in Th17 cells in the small intestine, most of which localized to the duodenum. The researchers tested multiple CD3-specific antibodies, including MacroGenics Inc.'s teplizumab.

Next, the group elucidated the origins of these gut Th17 cells.In the mouse gut, the researchers found that Il-17 produced by Th17 cells induced upregulation ofchemokine CC motif ligand 20 (Ccl20; Mip3a) in intestinal epithelial cells. This chemoattractant drew a subset of Th17 cells that expressed CC chemokine receptor 6 (Ccr6; Cd196) into the gut (see "Model for gut-mediated regulation of...

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