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IL-7 receptor influences anti-TNF responsiveness and T cell gut homing in inflammatory bowel disease.
- Source :
-
The Journal of clinical investigation [J Clin Invest] 2019 Apr 02; Vol. 129 (5), pp. 1910-1925. Date of Electronic Publication: 2019 Apr 02 (Print Publication: 2019). - Publication Year :
- 2019
-
Abstract
- It remains unknown what causes inflammatory bowel disease (IBD), including signaling networks perpetuating chronic gastrointestinal inflammation in Crohn's disease (CD) and ulcerative colitis (UC), in humans. According to an analysis of up to 500 patients with IBD and 100 controls, we report that key transcripts of the IL-7 receptor (IL-7R) pathway are accumulated in inflamed colon tissues of severe CD and UC patients not responding to either immunosuppressive/corticosteroid, anti-TNF, or anti-α4β7 therapies. High expression of both IL7R and IL-7R signaling signature in the colon before treatment is strongly associated with nonresponsiveness to anti-TNF therapy. While in mice IL-7 is known to play a role in systemic inflammation, we found that in humans IL-7 also controlled α4β7 integrin expression and imprinted gut-homing specificity on T cells. IL-7R blockade reduced human T cell homing to the gut and colonic inflammation in vivo in humanized mouse models, and altered effector T cells in colon explants from UC patients grown ex vivo. Our findings show that failure of current treatments for CD and UC is strongly associated with an overexpressed IL-7R signaling pathway and point to IL-7R as a relevant therapeutic target and potential biomarker to fill an unmet need in clinical IBD detection and treatment.
- Subjects :
- Adolescent
Adult
Aged
Animals
Colon pathology
Cytokines metabolism
Endoscopy
Female
Gene Expression Profiling
Gene Expression Regulation
Graft vs Host Disease metabolism
Humans
Inflammation
Integrins metabolism
Intestinal Mucosa metabolism
Leukocytes, Mononuclear cytology
Male
Mice
Mice, Inbred NOD
Mice, SCID
Middle Aged
Signal Transduction
Young Adult
Colitis, Ulcerative metabolism
Colon metabolism
Crohn Disease metabolism
Receptors, Interleukin-7 metabolism
T-Lymphocytes cytology
Tumor Necrosis Factor-alpha antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1558-8238
- Volume :
- 129
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- The Journal of clinical investigation
- Publication Type :
- Academic Journal
- Accession number :
- 30939120
- Full Text :
- https://doi.org/10.1172/JCI121668