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Evaluation of the immune modulatory effects of statins and glucocorticoids in experimental colitis

Grant number: 13/11042-6
Support type:Scholarships in Brazil - Master
Effective date (Start): March 01, 2014
Effective date (End): April 12, 2015
Field of knowledge:Biological Sciences - Immunology - Applied Immunology
Principal Investigator:Cristina Ribeiro de Barros Cardoso
Grantee:Paulo José Basso
Home Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated research grant:10/20162-7 - The role of hypothalamus-pituitary-adrenal (HPA) axis and exogenous glucocorticoids in the modulation of immune response in inflammatory bowel disease, AP.JP

Abstract

Crohn's disease (CD) and Ulcerative Colitis (UC) are the main conditions that comprise the Inflammatory Bowel Diseases (IBD), whose etiology involves genetic, immunological and environmental factors. The uncontrolled inflammation in the intestinal mucosa is related to exacerbated T cell reactions, mainly Th1 and Th17 cells in CD, in addition to ineffective regulatory T cells (Tregs) response. Glucocorticoids (GCs) are steroidal anti-inflammatory drugs used in the IBD treatment. However, over 30% of patients are unresponsive to GCs therapy and require surgical interventions. Furthermore, cholesterol-lowering drugs referred to as statins may exert pleiotropic actions, primarily anti-inflammatory effects and their concomitant use with steroids may lead to favorable outcome in several autoimmune and inflammatory conditions such as IBD. Nevertheless, there are only few data regarding the exact regulatory role of statins and their association with other drugs such as GCs in the modulation of the immune system. Therefore, the aim of this study is to evaluate the immune modulatory effects of the concomitant use of statins and GCs in experimental colitis induced by dextran sulfate sodium (DSS). Healthy and colitis mice will receive simple or combined treatment and the clinical signs of disease as well as survival will be assessed. The local inflammatory response will be analyzed by histopathology (HE) staining and flow cytometry. The presence of neutrophils, eosinophils and macrophages will be evaluated by myeloperoxidase, eosinophil peroxidase and N-acetyl glucosaminidase assays, respectively, on colon segments. The subpopulation of CD4 T cells producing IL-4, IFN-³, IL-17 and regulatory T cells (Tregs) will be characterized in spleen and mesenteric lymph nodes. The immune modulatory capacity of GCs and statins in colitis will be evaluated by cytokine measurement of Th1, Th2, Th17 and Treg profile by ELISA assays and through suppression experiments of Tregs from mice under GCs/statins therapy. Finally, the elucidation of the mechanisms and the immune modulatory capacity of GCs and statins in the gut inflammation may provide more effective therapeutic strategies for UC and/ or CD. (AU)