title: A systemically-administered small molecule antagonist of CCR9 acts as a tissue-selective inhibitor of lymphocyte trafficking.
abstract: A goal for developers of immunomodulatory drugs has long been a systemically administered small molecule that can selectively inhibit inflammation in specific tissues. The chemokine receptor CCR9 is an attractive target for this approach, as entry of T cells into the small intestine from blood requires interaction between CCR9 and its ligand CCL25. We have tested the ability of a small molecule CCR9 antagonist, CCX8037, to inhibit antigen-mediated T cell accumulation in the intestine. This compound prevented accumulation of gut-imprinted antigen-specific CD8 T cells within epithelium of the small intestine. Interestingly, the antagonist did not affect the robust generation of gut-imprinted CD8 T cells within mesenteric lymph nodes. To distinguish "gut-selective" from "general" T cell inhibition, we tested the drug's ability to influence accumulation of T cells within skin, a tissue in which CCR9 plays no known role, and we found no appreciable effect. This study demonstrates the feasibility of creating systemically-administered pharmaceuticals capable of tissue-selective immune modulation. This proof of concept is of utmost importance for designing effective treatments against various autoimmune disorders localized to a specific tissue.
authors.affiliation: Brigham and Women's Hospital, Department of Dermatology, Boston, Massachusetts, United States of America.
authors.forename: Noah J
authors.initials: NJ
authors.lastname: Tubo
authors.forename: Marc A
authors.initials: MA
authors.lastname: Wurbel
authors.forename: Trevor T
authors.initials: TT
authors.lastname: Charvat
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Schall
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Walters
authors.forename: James J
authors.initials: JJ
authors.lastname: Campbell
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D019742:Chemokines, CC / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology*; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D054388:Receptors, CCR / Q000037:antagonists & inhibitors*
chemical_list: C119309:CC chemokine receptor 9; C491541:Ccl25 protein, mouse; D019742:Chemokines, CC; D007155:Immunologic Factors; D054388:Receptors, CCR