Janus kinase inhibitors differentially inhibit specific cytokine signals in the mesenteric lymph node cells of IBD patients.

ABSTRACT

BACKGROUND: Janus kinase (JAK) inhibitors (JAKinibs) are effective small molecule therapies for treating Crohn's Disease (CD) and Ulcerative Colitis (UC), collectively known as inflammatory bowel disease (IBD). By preventing JAKs from phosphorylating signal transducer and activator of transcription proteins, JAKinibs disrupt cytokine signaling pathways that promote inflammation. Despite considerable overlap in the JAKs they target, first and second generation JAKinibs display different clinical efficacies in CD and UC. METHODS: We conducted a comparative phosflow study of four JAKinibs (filgotinib, upadacitinib, tofacitinib, and deucravacitinib) to observe subtle mechanistic differences that may dictate their clinical behavior. Resected mesenteric lymph node (MLN) cells from 19 patients (9 CD, 10 UC) were analyzed by flow cytometry in the presence or absence of different cytokine stimuli and titrated JAKinibs. RESULTS: We found a higher potency of the JAK 1/3-preferential inhibitor, tofacitinib, for JAK 3-dependent cytokine signaling pathways in comparison to filgotinib, but a higher potency of the JAK 1-preferential inhibitors, filgotinib and upadacitinib, for JAK 3-independent cytokine signaling pathways. Deucravacitinib, a TYK2-preferential inhibitor, demonstrated a much narrower selectivity by inhibiting only IL-10 and IFN-ßpathways, albeit more potently than the other JAKinibs . Additionally, we found some differences in the sensitivity of immune cells from CD versus UC and patients with versus without a CD-associated NOD2 polymorphism to phosphorylate signal transducer and activator of transcriptions in response to specific cytokine stimulation. CONCLUSIONS: Despite their similarities, differences exist in the relative potencies of different JAKinibs against distinct cytokine families to explain their clinical efficacy.