A systemically-administered small molecule antagonist of CCR9 acts as a tissue-selective inhibitor of lymphocyte trafficking.
A systemically-administered small molecule antagonist of CCR9 acts as a tissue-selective inhibitor of lymphocyte trafficking.
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DOI：
10.1371/journal.pone.0050498
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Campbell JJ
中科院分区：
文献类型：
--
作者：
Tubo NJ;Wurbel MA;Charvat TT;Schall TJ;Walters MJ;Campbell JJ
长期以来，免疫调节药物开发者的一个目标是开发一种全身给药的小分子，可以选择性地抑制特定组织中的炎症。趋化因子受体CCR9是这种方法的一个有吸引力的靶点，因为T细胞从血液进入小肠需要CCR9与其配体CCL25之间的相互作用。我们已经测试了小分子CCR9拮抗剂CCX8037抑制肠中抗原介导的T细胞积累的能力。该化合物防止肠道印迹抗原特异性CD8 T细胞在小肠上皮内的积累。有趣的是，拮抗剂不影响肠系膜淋巴结内肠道印迹CD8 T细胞的稳健产生。为了区分“肠道选择性”和“一般”T细胞抑制，我们测试了药物影响皮肤内T细胞积累的能力，皮肤是一种CCR9没有发挥已知作用的组织，我们没有发现明显的效果。本研究证明了创造能够进行组织选择性免疫调节的全身给药药物的可行性。这种概念验证对于设计针对定位于特定组织的各种自身免疫性疾病的有效治疗至关重要。
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.
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影响因子：
30.5
作者：
通讯作者：
--
阻止淋巴细胞定位到胃肠道粘膜作为炎症性肠病的治疗策略。
影响因子：
29.4
作者：
Villablanca EJ;Cassani B;von Andrian UH;Mora JR
通讯作者：
Mora JR
影响因子：
4.4
作者：
Wurbel, Marc-Andre;Malissen, Marie;Campbell, James J.
通讯作者：
Campbell, James J.
DOI：
10.1084/jem.194.10.1541
发表时间：
2001-11-19
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Reiss Y;Proudfoot AE;Power CA;Campbell JJ;Butcher EC
通讯作者：
Butcher EC
DOI：
10.1124/jpet.110.169714
发表时间：
2010-10-10
影响因子：
3.5
作者：
Walters, Matthew J.;Wang, Yu;Schall, Thomas J.
通讯作者：
Schall, Thomas J.