Cenicriviroc, a CCR2/CCR5 antagonist, promotes the generation of type 1 regulatory T cells.

Autor: Madan U; Centre for Immuno-biology and Immunotherapy, NCR-Biotech Science Cluster, Translational Health Science and Technology Institute, Faridabad, Haryana, India., Verma B; Centre for Immuno-biology and Immunotherapy, NCR-Biotech Science Cluster, Translational Health Science and Technology Institute, Faridabad, Haryana, India., Awasthi A; Centre for Immuno-biology and Immunotherapy, NCR-Biotech Science Cluster, Translational Health Science and Technology Institute, Faridabad, Haryana, India.; Immunology-Core Lab, NCR Biotech Science Cluster, Translational Health Science and Technology Institute, Faridabad, Haryana, India.
Jazyk: angličtina
Zdroj: European journal of immunology [Eur J Immunol] 2024 Jul; Vol. 54 (7), pp. e2350847. Date of Electronic Publication: 2024 Apr 21.
DOI: 10.1002/eji.202350847
Abstrakt: Cenicriviroc, a dual CCR2/CCR5 antagonist, initially developed as an anti-HIV drug, has shown promising results in nonalcoholic steatohepatitis phase 2 clinical trials. It inhibits the infiltration and activation of CCR2 + /CCR5 + monocytes and macrophages to the site of liver injury, preventing liver fibrosis. However, the role of Cenicriviroc in the modulation of helper T cell differentiation and functions remains to be explored. In inflamed colons of Crohn's disease patients, CCR2 + and CCR5 + CD4+ T cells are enriched. Considering the role of CCR2 + and CCR5 + T cells in IBD pathogenesis, we investigated the potential role of Cenicriviroc in colitis. Our in vitro studies revealed that Cenicriviroc inhibits Th1-, Th2-, and Th17-cell differentiation while promoting the generation of type 1 regulatory T cells (Tr1), known for preventing inflammation through induction of IL-10. This study is the first to report that Cenicriviroc promotes Tr1 cell generation by up-regulating the signature of Tr1 cell transcription factors such as c-Maf, Prdm1, Irf-1, Batf, and EGR-2. Cenicriviroc displayed a protective effect in experimental colitis models by preventing body weight loss and intestinal inflammation and preserving epithelial barrier integrity. We show that Cenicriviroc induced IL-10 and inhibited the generation of pro-inflammatory cytokines IFN-γ, IL-17, IL-6, and IL-1β during colitis. Based on our data, we propose Cenicriviroc as a potential therapeutic in controlling tissue inflammation by inhibiting the generation and functions of effector T cells and promoting the induction of anti-inflammatory Tr1 cells.
(© 2024 Wiley‐VCH GmbH.)
Databáze: MEDLINE
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