Inflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), are complex chronic inflammatory conditions of the gastrointestinal tract that are driven by perturbed cytokine pathways. Anti-tumor necrosis factor-α (TNF) antibodies are a mainstay therapeutic approach for IBD. However, up to 40% of patients are non-responsive to anti-TNF agents, and identifying alternative therapeutic targets is a priority. Here we show that expression of the cytokine Oncostatin M (OSM) and its receptor (OSMR) is increased in the inflamed intestine of IBD patients compared to healthy controls, and correlates closely with histopathological disease severity. OSMR is expressed in non-hematopoietic, non-epithelial intestinal stromal cells, which respond to OSM by producing various pro-inflammatory molecules including interleukin-6 (IL-6), the leukocyte adhesion factor ICAM-1, and chemokines that attract neutrophils, monocytes, and T cells. In an animal model of anti-TNF resistant intestinal inflammation, genetic deletion or pharmacological blockade of OSM significantly attenuates colitis. Furthermore, high pre-treatment OSM expression is strongly associated with failure of anti-TNF therapy based on analysis of over 200 IBD patients, including two cohorts from phase 3 clinical trials of infliximab and golimumab. OSM is thus a potential biomarker and therapeutic target for IBD, with particular relevance for anti-TNF resistant patients.
IL-1β promotes chronic intestinal inflammation through recruitment of granulocytes, activation of ILCs, accumulation of pathogenic T cells, and promotion of Th17 responses.
There are no mucosal adjuvant formulations licensed for human use, despite protection against many mucosally-transmitted infections probably requiring immunity at the site of pathogen entry1. Polyethyleneimines (PEI) are organic polycations used as nucleic acid transfection reagents in vitro, and gene and DNA vaccine delivery vehicles in vivo2, 3. Here we show that PEI has unexpected and unusually potent mucosal adjuvant activity in conjunction with viral subunit glycoprotein antigens. Single intranasal administration of influenza HA or HSV-2 gD with PEI elicited robust protection from otherwise lethal infection, and was superior to existing experimental mucosal adjuvants. PEI formed nanoscale complexes with antigen that were taken up by antigen presenting cells in vitro and in vivo, promoted DC trafficking to draining lymph nodes and induced non-proinflammatory cytokine responses. PEI adjuvanticity required release of host dsDNA that triggered Irf-3-dependent signaling. PEI therefore merits further investigation as a mucosal adjuvant for human use.
NOD2 is an intracellular sensor that contributes to immune defense and inflammation. Here we investigated whether NOD2 mediates its effects through control of microRNAs (miRNAs). miR-29 expression was upregulated in human dendritic cells (DCs) in response to NOD2 signals, and miR-29 regulated the expression of multiple immune mediators. In particular, miR-29 downregulated interleukin-23 (IL-23) by targeting IL-12p40 directly and IL-23p19 indirectly, likely via reduction of ATF2. DSS-induced colitis was worse in miR-29-deficient mice and was associated with elevated IL-23 and T helper 17 signature cytokines in the intestinal mucosa. Crohn's disease (CD) patient DCs expressing NOD2 polymorphisms failed to induce miR-29 upon pattern recognition receptor stimulation and showed enhanced release of IL-12p40 on exposure to adherent invasive E. coli. Therefore, we suggest that loss of miR-29-mediated immunoregulation in CD DCs might contribute to elevated IL-23 in this disease.
Saponins represent a promising class of vaccine adjuvant. Together with the TLR4-ligand MPL, QS-21 is part of the Adjuvant System AS01, a key component of the malaria and zoster candidate vaccines that display demonstrated clinical efficacy. However, the mechanism of action of QS-21 in this liposomal formulation is poorly understood. Upon intra-muscular immunisation, we observed that QS-21 rapidly accumulated in CD169+ resident macrophages of the draining lymph node where it elicited a local innate immune response. Depletion of these cells abrogated QS-21-mediated innate cell recruitment to the lymph node, dendritic cell (DC) phenotypic maturation as well as the adjuvant effect on T-cell and antibody responses to co-administered antigens. DCs rather than lymph node-resident macrophages were directly involved in T-cell priming by QS-21, as revealed by the decrease in antigen-specific T-cell response in Batf3−/− mice. Further analysis showed that the adjuvant effect of QS-21 depended on the integration of Caspase-1 and MyD88 pathways, at least in part through the local release of HMGB1. Taken together, this work unravels the key role of lymph node sentinel macrophage in controlling the adjuvant effect of a molecule proven to improve vaccine response in humans.
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