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In many infectious diseases, the immune response operates as a double-edged sword. While required for protective immunity, infection-induced inflammation can be detrimental if it is not properly controlled, causing collateral body damage and potentially leading to death. It is in this context that the potent anti-inflammatory cytokine interleukin-10 (IL-10) is required to dampen the pro-inflammatory immune response that hallmarks trypanosomosis. Effective control of this infection requires not just the action of antibodies specific for the parasite's variable surface glycoprotein (VSG) coat antigens, but also a pro-inflammatory immune response mediated mainly by IFNγ, TNF, and NO. However, strict control of inflammation is mandatory, as IL-10-deficient mice succumb from an unrestrained cytokine storm within 10 days of a Trypanosome brucei infection. The relevant cellular source of IL-10 and the associated molecular mechanisms implicated in its trypanosomosis associated production are poorly understood. Using an IL-10 reporter mouse strain (Vert-X), we demonstrate here that NK cells, CD8+ T cells and CD4+ T cells as well as B cells and plasma cells constitute potential cellular sources of IL-10 within the spleen and liver during acute infection. The IL-10 wave follows peak pro-inflammatory cytokine production, which accompanied the control of peak parasitemia. Similar results were observed following conventional experimental needle infection and physiological infections via T. brucei-infected tsetse flies. Our results show that conditional T cell-specific ablation of the IL-10 regulating Prdm1 gene (encoding for the Blimp-1 transcription factor), leads to an uncontrolled trypanosome-induced pro-inflammatory syndrome like the one observed in infected IL-10-deficient mice. This result indicates that the biological role of IL-10-derived from non-T cells, including NK cells, is of minor importance when considering host survival. The cytokine IL-27 that is also considered to be an IL-10 regulator, did not affect IL-10 production during infection. Together, these data suggest that T. brucei activates a Blimp-1-dependent IL-10 regulatory pathway in T cells that acts as a critical anti-inflammatory rheostat, mandatory for host survival during the acute phase of parasitemia. ispartof: FRONTIERS IN IMMUNOLOGY vol:11 ispartof: location:Switzerland status: published

Background:Commonly used islet transplantation protocols experiencesignificant islet injury and graft loss; therefore new methods to support thelong-term benefits of this treatment are needed. Recent studies have shownthat non-endothelial bone marrow-derived multipotent adult progenitor cells(MAPC) possess significant immune-modulating abilities and can secreteangiogenic molecules, which could make them ideal in islet transplantationprocedures to improve graft outcome.Methods:Islets (150) were co-transplanted with or without human MAPC(250 000), as separate or composite pellets, under the kidney capsule ofsyngeneic alloxan-induced diabetic C57BL/6 mice. Blood glucose levels werefrequently monitored and intraperitoneal glucose tolerance tests were carriedout. Grafts and serum were harvested at 2 and 5 weeks after transplantation.Results:Human MAPC were able to produce several angiogenic growthfactors, among which vascular endothelial growth factor (VEGF) is one of themost important, and to induce angiogenesis in thein vivochorioallantoicmembrane (CAM) assay. Islet-human MAPC co-transplantation particularly asa composite pellet significantly improved the outcome of islet transplantation asmeasured by the initial glycemic control, diabetes reversal rate, glucosetolerance, and serum C-peptide concentration compared with transplantationof islets alone. Likewise islet-human MAPC recipients had increased intra-graftCD31 gene expression levels compared to islet alone recipients, suggestingstable blood vessel formation. Indeed, significantly more blood vessel area anddensity in addition to higher vessel/islet ratio were detected with islets-humanMAPC composites, which suggests that direct contact with human MAPC ismore beneficial than indirect contact for mouse islets.Conclusions:The present data encourage the use of human MAPC in islettransplantation protocols. Our results demonstrate the improvement of isletgraft function. (Less)