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PublisherThe University of Arizona.
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AbstractCrohn's Disease (CD) is a chronic inflammatory bowel disease that destroys a patient's gastrointestinal (GI) tract. CD is thought to be mediated mostly by cluster of differentiation 4 (CD4)+ T helper 1 (TH1) T-cells initially in response to the commensal gut microbiota, leading to chronic inflammation and destruction of the intestines.1 Environmental factors, genetic predisposition, dysbiosis, and antibiotic use are some of the proposed mechanisms for CD development.2-4 The current treatments include anti-Interleukin(IL)-12/23 monoclonal5 antibody (mAb), anti-Tumor Necrosis Factor-α (TNF-α) mAb,6 antibiotics,7 corticosteroids,8, and anti-α4β7 mAb9 therapies. In some patients, these treatments do not allow long-term remission, and others become resistant to the medications. These therapies target downstream cytokines such as TNFα,6 α4β7,9, and IL-12/235 produced by effector T-cells (Teff). A new pharmaceutical target that looks promising is the cytokine IL-7. Commensal gut microbiota promotes Teff cells to make Interferon-γ (IFN-γ) that then stimulates intestinal epithelial cells (IECs) to produce IL-7, causing the upregulation of the α4β7 Teff cell gut-homing integrin. As more Teff cells migrate to the intestines and produce IFN-γ, increased IL-7 production by IECs occurs, creating a positive feedback loop.10, 11 Thus, decreasing IL-7 with a monoclonal antibody could decrease Teff cell migration to the intestines, and subsequently decrease the pro-inflammatory cytokines that promote chronic inflammation and tissue destruction seen in CD. Dysbiosis, the change in the microbiota profile that results in disease, has been strongly correlated to CD.12 However, the use of Fecal Microbiota Transplants (FMTs) to attempt to normalize the microbiota has not been entirely successful for all CD patients.13 Administering an anti-IL-7Rα mAb before FMT could decrease inflammatory cells, increasing the likelihood that the FMT is successful, and allow for remission in CD patients.
Degree ProgramGraduate College
Cellular & Molecular Medicine