Gut Homing Receptors on CD8 T Cells Are Retinoic Acid Dependent and Not Maintained by Liver Dendritic or Stellate Cells

BACKGROUND & AIMS: Lymphocytes primed by intestinal dendritic cells (DC) express the gut-homing receptors CCR9 and α4β7, which recognize CCL25 and mucosal addressin cell-adhesion molecule-1 in the intestine promoting the development of regional immunity. In mice, imprinting of CCR9 and α4β7 is dependent on retinoic acid during T-cell activation. Tissue specificity is lost in primary sclerosing cholangitis (PSC), an extraintestinal manifestation of inflammatory bowel disease, when ectopic expression of mucosal addressin cell-adhesion molecule-1 and CCL25 in the liver promotes recruitment of CCR9+α4β7+ T cells to the liver. We investigated the processes that control enterohepatic T-cell migration and whether the ability to imprint CCR9 and α4β7 is restricted to intestinal DCs or can under some circumstances be acquired by hepatic DCs in diseases such as PSC. METHODS: Human and murine DCs from gut, liver, or portal lymph nodes and hepatic stellate cells were used to activate CD8 T cells. Imprinting of CCR9 and α4β7 and functional migration responses were determined. Crossover activation protocols assessed plasticity of gut homing. RESULTS: Activation by gut DCs imprinted high levels of functional CCR9 and α4β7 on naïve CD8 T cells, whereas hepatic DCs and stellate cells proved inferior. Imprinting was RA dependent and demonstrated plasticity. CONCLUSIONS: Imprinting and plasticity of gut-homing human CD8 T cells requires primary activation or reactivation by gut DCs and is retinoic acid dependent. The inability of liver DCs to imprint gut tropism implies that α4β7+CCR9+ T cell that infiltrate the liver in PSC are primed in the gut

Brevianes Revisited

Breviones are a new family of secondary metabolites that were originally isolated from the New Zealand endemic fungus Penicillium brevicompactum var. Dierckx. These compounds are generally characterized by a new carbon skeleton, known as breviane, which that has three possible structural variations, such as breviane, abeo-breviane, and abeo-norbreviane. Brevianes present a basic diterpenic tricyclic core that is mevalonic in origin and is similar to that of perhydrophenanthrene. The core bears four methyl groups at positions C4, C8, C10, and C13 and has defined stereochemistry at positions C5, C8, C9, C10, and C14. The C1'-C7' side chain has been proposed to have a polyketide biosynthetic origin and is joined to the diterpenic moiety through carbons C2'-C15'. The cyclization and lactonization of this part of the molecule leads to the characteristic breviane spiranic ring fused to the α-pyrone

CCL25/CCR9 Interactions Regulate Large Intestinal Inflammation in a Murine Model of Acute Colitis

CCL25/CCR9 is a non-promiscuous chemokine/receptor pair and a key regulator of leukocyte migration to the small intestine. We investigated here whether CCL25/CCR9 interactions also play a role in the regulation of inflammatory responses in the large intestine.Acute inflammation and recovery in wild-type (WT) and CCR9(-/-) mice was studied in a model of dextran sulfate sodium (DSS)-induced colitis. Distribution studies and phenotypic characterization of dendritic cell subsets and macrophage were performed by flow cytometry. Inflammatory bowel disease (IBD) scores were assessed and expression of inflammatory cytokines was studied at the mRNA and the protein level.CCL25 and CCR9 are both expressed in the large intestine and are upregulated during DSS colitis. CCR9(-/-) mice are more susceptible to DSS colitis than WT littermate controls as shown by higher mortality, increased IBD score and delayed recovery. During recovery, the CCR9(-/-) colonic mucosa is characterized by the accumulation of activated macrophages and elevated levels of Th1/Th17 inflammatory cytokines. Activated plasmacytoid dendritic cells (DCs) accumulate in mesenteric lymph nodes (MLNs) of CCR9(-/-) animals, altering the local ratio of DC subsets. Upon re-stimulation, T cells isolated from these MLNs secrete significantly higher levels of TNFα, IFNγ, IL2, IL-6 and IL-17A while down modulating IL-10 production.Our results demonstrate that CCL25/CCR9 interactions regulate inflammatory immune responses in the large intestinal mucosa by balancing different subsets of dendritic cells. These findings have important implications for the use of CCR9-inhibitors in therapy of human IBD as they indicate a potential risk for patients with large intestinal inflammation

Gemcitabine and vinorelbine followed by docetaxel in patients with advanced non-small-cell lung cancer: a multi-institutional phase II trial of nonplatinum sequential triplet combination chemotherapy (JMTO LC00-02)

To evaluate the efficacy and toxicity of the sequential nonplatinum combination chemotherapy consisting of gemcitabine (GEM) and vinorelbine (VNR) followed by docetaxel (DOC) in patients with advanced non-small-cell lung cancer (NSCLC), we conducted the multiinstitutional phase II study. A total of 44 chemotherapy-naive patients with advanced NSCLC were treated with GEM 1000 mg m−2 and VNR 25 mg m−2 intravenously on days 1 and 8 every 3 weeks for three cycles. DOC 60 mg m−2 was then administrated intravenously at 3-week intervals for three cycles. Patients were evaluated for response and toxicity with each cycle of the treatment. The major objective response rate was 47.7% (95% confidence interval (CI), 33.8–62.1%). Median survival time (MST) was 15.7 months and 1-year survival rate was 59%. In the GEM/VNR cycle, grade 3/4 neutropenia occurred in 36.3%, grade 3/4 anaemia in two patients (4.5%) and grade 3 thrombocytopenia in one patient (2.3%). Grade 3 pneumonitis occurred in two patients (4.5%) in GEM/VNR cycles. In the DOC cycles, grade 3/4 neutropenia occurred in 39.4% but no patient experienced grade 3/4 anaemia or thrombocytopenia. Of the 44 eligible patients, 33 patients completed three cycles of GEM/VNR and 22 patients completed six cycles of planned chemotherapy (three cycles of GEM/VNR followed by three cycles of DOC). The sequential triplet nonplatinum chemotherapy consisted of GEM/VNR followed by DOC, and was very active and well tolerated. This study forms the basis for an ongoing phase III trial that compares this nonplatinum triplet and standard platinum doublet combination (carboplatin/paclitaxel)

Mechanisms of T cell organotropism

F.M.M.-B. is supported by the British Heart Foundation, the Medical Research Council of the UK and the Gates Foundation