Role of intraepithelial T cells in Toxoplasma gondii-induced inflammatory ileitis

上皮内 T 细胞在弓形虫诱发的炎症性回肠炎中的作用

• 批准号: 7706691
• 负责人: ERIC Y DENKERS
• 金额: $ 23.1万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-16 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7706691
• 关键词: Acute; Address; Anti-Inflammatory Agents; Anti-inflammatory; Bacteria; Biological Models; CD4 Positive T Lymphocytes; CD8 Antigens; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell physiology; Cells; Chronic; Clinical; Crohn' s disease; Dendritic Cells; Developed Countries; Developing Countries; Development; Disease; Epithelial; Epithelial Cells; Experimental Models; Extensive Necrosis; Goals; Human; Ileitis; Immune; Immune response; Incidence; Infection; Infiltration; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Interleukin-12; Intestinal Mucosa; Intestines; Lamina Propria; Lymphocyte; Mediating; Mediator of activation protein; Modeling; Molecular; Mouse Strains; Mucosal Immunity; Mus; Parasites; Pathogenesis; Pathology; Pattern; Play; Population; Production; Recruitment Activity; Research; Role; Site; Structure of aggregated lymphoid follicle of small intestine; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Tissues; Toxoplasma; Toxoplasma gondii; Toxoplasmosis; Wild Type Mouse; autoreactivity; chemokine; chemokine receptor; cytokine; cytotoxic; human disease; improved; insight; intestinal epithelium; intraepithelial; macrophage; oral infection; pathogen; reconstitution; response; treatment strategy

DESCRIPTION (provided by applicant): The broad, long-term objective of this application is to understand causes of intestinal inflammatory pathology induced during infection with the opportunistic protozoan pathogen Toxoplasma gondii. Ultimately, this will enable development of rational treatment strategies for inflammatory bowel diseases caused by dysregulated mucosal immunity in humans. Oral infection of C57BL/6 strain mice with Toxoplasma rapidly triggers a Crohn's disease-like pathology, characterized by overproduction of Type 1 cytokines leading to extensive necrosis in the small intestinal epithelium. Pathogenic populations of CD4+ T cells are believed to be mediators of disease. Studies in other model systems also suggest involvement of CD8+ T lymphocytes. Intraepithelial lymphocytes (IEL) are a major subset of T cells in the intestinal mucosa, the majority of which express the CD8 molecule. The hypothesis underlying this proposal is that dysregulated IEL responses play an important role in disease pathogenesis triggered by Toxoplasma and in human disease. To test this hypothesis, the specific aims are to isolate IEL and their subpopulations from T. gondii-infected mice and evaluate their ability to produce pro- and anti-inflammatory cytokines, as well as determining their cytotoxic activity on infected and noninfected target cells. Another aim is to determine if IEL from infected mice transfer pathology to infected and noninfected recipients, and if so whether this is dependent upon IEL cytokine production or cytotoxic activity. We will also determine if IEL are sufficient to cause pathology themselves, or if they act by triggering pathogenic lamina propria CD4+ T cells. Achieving these aims can be expected to contribute to a deeper understanding of IBD pathogenesis triggered by experimental infection, as well as during clinical disease. RELEVANCE: Chronic inflammatory bowel disease is a widespread and serious condition with increasing incidence in developed countries. Factors involved in disease pathogenesis are not well understood. We expect to gain insight into immunological causes of disease in humans by using Toxoplasma gondii infection as a trigger. The ultimate goal is to develop improved treatments for disease.

描述（由申请方提供）：本申请的广泛、长期目标是了解机会性原生动物病原体弓形虫感染期间诱导的肠道炎症病理学的原因。最终，这将使人类粘膜免疫失调引起的炎症性肠病的合理治疗策略的发展成为可能。弓形虫经口感染C57 BL/6品系小鼠迅速引发克罗恩病样病理，其特征在于1型细胞因子的过度产生，导致小肠上皮广泛坏死。CD 4 + T细胞的致病群体被认为是疾病的介质。在其他模型系统中的研究也表明涉及CD 8 + T淋巴细胞。上皮内淋巴细胞（IEL）是肠粘膜中T细胞的主要亚群，其中大多数表达CD 8分子。这一建议的假设是，失调的IEL反应在弓形虫引发的疾病发病机制和人类疾病中发挥重要作用。为了验证这一假设，具体的目标是从T.感染的小鼠，并评估它们产生促炎和抗炎细胞因子的能力，以及确定它们对感染和未感染的靶细胞的细胞毒性活性。另一个目的是确定感染小鼠的IEL是否将病理转移到感染和未感染的受体，如果是这样，这是否取决于IEL细胞因子的产生或细胞毒活性。我们还将确定IEL是否足以引起病理本身，或者它们是否通过触发致病性固有层CD 4 + T细胞起作用。实现这些目标有望有助于更深入地了解实验性感染引发的IBD发病机制以及临床疾病。 相关性：慢性炎症性肠病是一种广泛而严重的疾病，在发达国家的发病率不断增加。参与疾病发病机制的因素还不清楚。我们期望通过弓形虫感染作为触发因素来深入了解人类疾病的免疫学原因。最终目标是开发出更好的疾病治疗方法。