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TIM-1, TIM-3 and TIM-4: A gene family that regulates tolerance and immunity

TIM-1、TIM-3 和 TIM-4：调节耐受性和免疫性的基因家族

基本信息

批准号：
7995554
负责人：
Rosemarie H DeKruyff
金额：
$ 20.59万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-09-30 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7995554
关键词：
Affect Allergens Antigens Apoptotic Asthma Atopic Dermatitis Breeding Cell Communication Cells Congenic Mice Dendritic Cells Development Disease Disease susceptibility Exposure to Food Food Hypersensitivity Gene Family General Population Generations Genes Genetic Polymorphism Genetic Variation Goals Grant Gut associated lymphoid tissue Homeostasis Hypersensitivity Immune Immune response Immunity Inbred BALB C Mice Inflammatory Instruction Laboratories Lamina Propria Lead Link Mediating Mesentery Molecular Mus Pathway interactions Phosphatidylserines Play Proteins Public Health Reagent Regulation Regulatory T-Lymphocyte Relative (related person)Rheumatoid Arthritis Role Signal Transduction Susceptibility Gene T cell response T-Cell Activation T-Lymphocyte T-Lymphocyte Subsets Th1 Cells Th1/Th2 Differentiation Pathway Th2 Cells Tissues Transgenic Mice Variant airway hyperresponsiveness allergic response atopy cell type congenic experience improved in vivo lymph nodes mouse model novel oral tolerance peripheral tolerance phosphatidylserine receptor prevent receptor response uptake

项目摘要

PROJECT SUMMARY (See instructions): The TIM gene family was identified using a congenic mouse model in which polymorphisms in TIM-1 and TIM-3 wre associated with Th1-Th2 differentiation and allergen-induced ainway hyperreactivity (AHR) between BALB/c and congenic HBA mice. The long-term goals of Project 3 are to understand how the Tim genes regulate peripheral tolerance, adaptive immune responses, and allergy. In the previous grant period we showed that TIM-1 is an important costimulatory molecule for T cells, that TIM-1 and TIM-4 modulate T cell responses and the development of tolerance, and that TIM-1 and TIM-4 are receptors for phosphatidylserine (PtdSer), a key molecule for recognition and uptake of apoptotic cells. We have found that TIM-3, expressed on Th1 cells and APC, is also a receptor for PtdSer and that the allelic variants of TIM-3 associated with asthma differ in their recognition of PtdSer. These results together suggest a new paradigm for TIM proteins as PtdSer receptors that by regulating the recognition and clearance of apoptotic cells, can regulate tissue homeostasis, T cell responses and the induction of peripheral tolerance. In Specific Aim 1 we will determine the mechanisms by which TIM-4 expressed on APC, and TIM-1, expressed on activated T cells and Th2 cells, regulate oral tolerance and prevent food allergy. We will examine mechanisms by which TIM-4 blockade inhibits oral tolerance induction. In Specific Aim 2, we will characterize the cell types and APC subset(s) in the lamina propria and mesenteric lymph node that express TIM-4, the conditions that modulate expression of TIM-3 and TIM-4 following exposure to danger signals such as bacterial products that initiate food allergy. We will examine the consequences of T cell interaction with TIM-expressing APC on T cell subset differentiation. In Specific Aim 3 we will investigate the role of TIM-3 polymorphic variants, which we have recently shown differ in recognition of apoptotic cells, in modulation of immune responses in BALB/c and HBA mice, and determine the roles of TIM-1 and TIM-3 in modulating the development of airway hyperreactivity in these strains. We have developed unique reagents that will enable us to accomplish these goals. We have generated panels of anti-TIM-1 and TIM-4 mAbs, we have generated TIM-4 and TIM-1 transgenic mice, and TlM-1 deficient mice are now breeding in our colony. Our laboratory has extensive experience in the study of tolerance as a mechanism that protects against Th2-driven immune responses and in the study of dendritic cells (DCs) and antigen-specific CD4+ Tpeg cells. These studies will greatly improve our understanding of immune regulation and lead to new therapies for inflammatory diseases.

项目概述（见说明）：