MUCOSAL IMMUNITY IN INFLAMMATORY BOWEL DISEASE

炎症性肠病中的粘膜免疫

• 批准号: 5210705
• 负责人: Jerry R McGhee
• 金额: --
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/5210705
• 关键词: B lymphocyte; antibacterial antibody; antibody formation; cell migration; cholera toxin; colitis; cytokine; diphtheria toxoid; disease /disorder model; helper T lymphocyte; histology; inflammatory bowel diseases; laboratory mouse; microorganism immunology; mucosal immunity; oral tolerance; tetanus toxoid; tissue /cell culture

The mucosal immune system is a vast network of tissues, cells and mediators which bears a major responsibility for protection from bacterial and viral infections which are normally acquired through mucous membranes. This immune system of external secretions can be divided into sites where antigen is encountered (inductive sites) and into larger surface areas where IgA B cells and plasma cells, T helper (Th) cells and cytotoxic T lymphocytes (CTLs) occur, and where production of secretory lgA (S-lgA) antibodies result in local immune protection (effector sites). A major goal of our research has been to characterize the nature of Th cells and derived cytokines for induction of B cells to become lgA-producing plasma cells in these mucosal effector sites under both normal and inflamed conditions. Since over 80 % of mucosal tissues are found in the gastrointestinal (GI) tract, most of our knowledge about mucosal immunity has stemmed from studies of immune responses in the gut. Ulcerative colitis and Crohn's disease are characterized by alterations in the isotypes expressed by B cells in the lamina propria of the GI tract. The results of our experiments with two mouse models of colitis have also shown that the mucosal immune system is greatly perturbed by inflammation in the large intestine. We postulate that the mechanism of these alterations of B cell responses in inflamed colonic mucosa are due to changes in CD4+ Th cell subsets and in the cytokine profiles exhibited by these subsets. Recent studies in the murine system have shown that CD4+ Th cells can often be subdivided based upon profiles of cytokines produced, and convincing evidence is now at hand for Th cell subsets in humans with autoimmune, allergic and infectious diseases. Two subsets, Thl and Th2 (type l and type 2) are best characterized in mice and type l Th cells produce interleukin-2 (IL-2), interferon gamma (IFN-gamma) and tumor necrosis factor-beta (TNF-beta) for cell-mediated immunity (CMI) in order to protect against intracellular parasites. Type 2 Th cells produce IL-4, IL-5, IL-6 and IL-10 and upregulate IgG1 subclass, IgE and IgA antibody responses. In this grant, we will examine the hypothesis that an initial increase in Th2 cells followed by a shift from Th2 to Thl type responses takes place and initiates an inflammatory response. This shift away from normal Th2 cells which regulate mucosal IgA responses would be expected to result in aberrant mucosal immunity, perhaps in the entire GI tract. To test this hypothesis we will use cytokine knockout mice as well as anti- cytokine treated mice and determine how alterations in Thl or Th2 pathways affect colonic inflammation. In particular, our recent studies have shown that oral immunization of mice with tetanus toxoid (TT) and the mucosal adjuvant cholera toxin (CT) selectively induces Th2 cells which regulate serum IgG1 and mucosal IgA responses. On the other hand, oral immunization with recombinant Salmonella typhimurium expressing the C fragment (Tox C) of TT induced good CMI responses and serum IgG2a and poor mucosal IgA responses. We will assess changes in the Th2 (TT plus CT) or Thl (rS. typhimurium -Tox C) response patterns in mice with experimental colitis. In related studies, we will assess whether colonic inflammation causes a breakdown in systemic unresponsiveness (oral tolerance) to orally administered protein antigens. We will use the model of oral tolerance to diphtheria toxoid and test whether colonic inflammation affects the development of oral tolerance to this soluble protein vaccine. We will compare Peyer's patches (PP) in the small intestine with lymphoid follicles in the large bowel as potential inductive sites. We will determine if differences in these two sites account for the characteristic T and B cell responses in the lamina propria of the small versus large intestine. We will also determine whether surface IgG-positive B cells traffic to the inflamed mucosa of colitic mice. In a final series of studies, we will use in vitro systems of murine intestinal epithelial cells (IEC) and intraepithelial lymphocytes (IEL), to determine if inappropriate cell and cytokine interactions could also lead to intestinal inflammation. In these proposed studies, we will use two models of experimental colitis in the mouse, since much of our understanding of the mucosal immune system has been derived from studies in mice. The studies proposed in this renewal application should yield new insights into the role of the mucosal immune system in the GI tract during murine IBD.

粘膜免疫系统是一个由组织、细胞和