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Inflammasome and Toll-like receptor 4 activation in histamine-mediated response by newborn dendritic cells and Th1 cells

Grant number: 12/16847-0
Support Opportunities:Scholarships in Brazil - Scientific Initiation
Effective date (Start): November 01, 2012
Effective date (End): October 31, 2015
Field of knowledge:Biological Sciences - Immunology - Cellular Immunology
Principal Investigator:Maria Notomi Sato
Grantee:Anna Cláudia Calvielli Castelo Branco
Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil


The neonatal immune system has a relative immaturity of the adaptive response, with no memory immune and sub-optimal activation of the IL-12/IFN-gamma axis, generated by inappropriate activation of dendritic cells (DCs) and consequently of Th1 cells. Neonatal immune responses show some peculiarities, as exacerbated inflammatory response to Toll-like receptors (TLR) agonists. So far, it is clear the role of other factors, such as histamine, in the inflammatory response modulation. These features underscore the pursuit of strategies to enhance the DCs and Th1 cells using immune adjuvants such as TLRs agonists, inflammasomes inducers, and blocking histamine receptors. Thus, the aim of this project is to analyze the influence of histamine and its receptors in the response mediated by activation via TLR4 and inflammasome in the newborn cells (human umbilical cord) compared with adult cells. Furthermore, it will be evaluated the histamine modulatory effect by blockade with antagonists in DCs and in the generation of Th1 response. To this end, it will be analyzed the effect of histamine and its receptors (H1R, H2R, H3R, and H4R) in the secretion of pro-inflammatory cytokines induced by an agonist of TLR4 and inflammasome inducers (LPS + ATP or Cl097) in mononuclear cells from the umbilical cord and adults. In order to evaluate the action of histamine and H4R receptor will also be evaluated in monocyte-derived DCs activated by inflammasome inducers (LPS + ATP or CL097), it will be measured the secretion of IL-1alpha and IL-18, expression of molecules, signaling via AP1 and caspase 1, and generation of heterologous T cells that secrete IL-4 or IFN-gamma. The study of strategies to enhance the immune response may contribute to improving our understanding of neonatal immunity and obtaining vaccine formulations.(AU)

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