4 research outputs found
Delayed and limited administration of the JAKinib tofacitinib mitigates chronic DSS-induced colitis
In inflammatory bowel disease, dysregulated T cells express pro-inflammatory cytokines. Using a chronic azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced colitis model resembling ulcerative colitis, we evaluated whether and when treatment with the Janus kinase (JAK) inhibitor tofacitinib could be curative. Comparing the treatment with two and three cycles of tofacitinib medication in drinking water â intermittently with DSS induction â revealed that two cycles were not only sufficient but also superior over the 3-x regimen. The two cycles of the 2-x protocol paralleled the second and third cycles of the longer protocol. T cells were less able to express interferon gamma (IFN-Îł) and the serum levels of IFN-Îł, interleukin (IL)-2, IL-6, IL-17, and tumor necrosis factor (TNF) were significantly reduced in sera, while those of IL-10 and IL-22 increased under the 2-x protocol. Likewise, the frequency and effector phenotype of regulatory T cells (Tregs) increased. This was accompanied by normal weight gain, controlled clinical scores, and restored stool consistency. The general and histologic appearance of the colons revealed healing and tissue intactness. Importantly, two phases of tofacitinib medication completely prevented AOM-incited pseudopolyps and the hyper-proliferation of epithelia, which was in contrast to the 3-x regimen. This implies that the initial IBD-induced cytokine expression is not necessarily harmful as long as inflammatory signaling can later be suppressed and that time-restricted treatment allows for anti-inflammatory and tissue-healing cytokine activities
Deep phenotypical characterization of human CD3CD56 T cells by mass cytometry
CD56 T cells are a group of proâinflammatory CD3 lymphocytes with characteristics of natural killer cells, being involved in antimicrobial immune defense. Here, we performed deep phenotypic profiling of CD3CD56 cells in peripheral blood of normal human donors and individuals sensitized to birchâpollen or/and house dust mite by highâdimensional mass cytometry combined with manual and computational data analysis. A coâregulation between major conventional Tâcell subsets and their respective CD3CD56 cell counterparts appeared restricted to CD8, MAIT, and TCRγΎ Tâcell compartments. Interestingly, we find a coâregulation of several CD3CD56 cell subsets in allergic but not in healthy individuals. Moreover, using FlowSOM, we distinguished a variety of CD56 Tâcell phenotypes demonstrating a hitherto underestimated heterogeneity among these cells. The novel CD3CD56 subset description comprises phenotypes superimposed with naive, memory, type 1, 2, and 17 differentiation stages, in part represented by a phenotypical continuum. Frequencies of two out of 19 CD3CD56 FlowSOM clusters were significantly diminished in allergic individuals, demonstrating less frequent presence of cells with cytolytic, presumably protective, capacity in these donors consistent with defective expansion or their recruitment to the affected tissue. Our results contribute to defining specific cell populations to be targeted during therapy for allergic conditions