MUCOSAL IMMUNITY IN INFLAMMATORY BOWEL DISEASE

炎症性肠病中的粘膜免疫

• 批准号: 6105491
• 负责人: Jerry R McGhee
• 金额: $ 13.93万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-01 至 1999-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6105491
• 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、细胞和免疫系统组成的庞大网络。 介体对细菌的防护负有主要责任 和通常通过粘膜获得的病毒感染。 这种外分泌物的免疫系统可以分为以下几个部位： 遇到抗原（诱导位点）并进入更大的表面积 其中 IgA B 细胞和浆细胞、T 辅助 (Th) 细胞和细胞毒性 T 淋巴细胞 (CTL) 发生，并产生分泌性 lgA (S-lgA) 抗体导致局部免疫保护（效应位点）。一个专业 我们研究的目标是表征 Th 细胞的性质 衍生的细胞因子，用于诱导 B 细胞成为产生 IgA 的血浆 正常和炎症状态下这些粘膜效应部位的细胞 状况。由于80%以上的粘膜组织存在于 胃肠道（GI），我们关于粘膜免疫的大部分知识 源于对肠道免疫反应的研究。溃疡性 结肠炎和克罗恩病的特点是 胃肠道固有层 B 细胞表达的同种型。这 我们对两种结肠炎小鼠模型的实验结果也 表明粘膜免疫系统受到炎症的极大干扰 在大肠中。我们假设这些机制 发炎的结肠粘膜中 B 细胞反应的改变是由于 CD4+ Th 细胞亚群和细胞因子谱的变化 这些子集。最近对小鼠系统的研究表明 CD4+ Th 细胞通常可以根据产生的细胞因子的概况进行细分， 现在已经有了关于人类 Th 细胞亚群的令人信服的证据 自身免疫性疾病、过敏性疾病和感染性疾病。两个子集，Th1 和 Th2 （l 型和 2 型）在小鼠和 l 型 Th 细胞中得到最好的表征 产生白介素-2 (IL-2)、干扰素 γ (IFN-gamma) 和肿瘤 细胞介导免疫 (CMI) 的坏死因子-β (TNF-β) 以防止细胞内寄生虫。 2 型 Th 细胞产生 IL-4， IL-5、IL-6 和 IL-10 并上调 IgG1 亚类、IgE 和 IgA 抗体 回应。在这笔赠款中，我们将检验以下假设：初始 Th2 细胞增加，随后从 Th2 型反应转变为 Thl 型反应 发生并引发炎症反应。这种转变远离 调节粘膜 IgA 反应的正常 Th2 细胞预计 导致粘膜免疫异常，可能是整个胃肠道。到 为了检验这个假设，我们将使用细胞因子敲除小鼠以及抗- 细胞因子治疗小鼠并确定 Th1 或 Th2 通路如何改变 影响结肠炎症。特别是，我们最近的研究表明 小鼠口服破伤风类毒素（TT）和粘膜免疫 佐剂霍乱毒素 (CT) 选择性诱导 Th2 细胞调节 血清 IgG1 和粘膜 IgA 反应。另一方面，口服免疫 重组鼠伤寒沙门氏菌表达 C 片段 (Tox C) TT 诱导良好的 CMI 反应和血清 IgG2a 以及较差的粘膜 IgA 回应。我们将评估 Th2（TT 加 CT）或 Thl（rS. 鼠伤寒-Tox C）实验性结肠炎小鼠的反应模式。 在相关研究中，我们将评估结肠炎症是否会导致 对口服药物的全身无反应（口服耐受性）崩溃 施用蛋白质抗原。我们将使用口服耐受模型 白喉类毒素并测试结肠炎症是否影响 对这种可溶性蛋白疫苗的口服耐受性的发展。我们将 比较小肠中的派尔氏集结 (PP) 与淋巴 大肠中的滤泡作为潜在的诱导位点。我们将 确定这两个位点的差异是否导致了该特征 小与大固有层中的 T 和 B 细胞反应 肠。我们还将确定表面 IgG 阳性 B 细胞是否 运输到结肠炎小鼠的发炎粘膜。在最后一个系列中 研究中，我们将使用小鼠肠上皮的体外系统 细胞（IEC）和上皮内淋巴细胞（IEL），以确定是否 不适当的细胞和细胞因子相互作用也可能导致肠道 炎。在这些拟议的研究中，我们将使用两种模型 小鼠实验性结肠炎，因为我们对 粘膜免疫系统源自对小鼠的研究。研究 在此更新申请中提出的建议应该会产生新的见解 小鼠 IBD 期间胃肠道粘膜免疫系统的作用。