The Role of AID in Contact Sensitivity

AID 在接触敏感性中的作用

基本信息

批准号：
7847588
负责人：
PHILIP William ASKENASE
金额：
$ 38.77万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-22 至 2012-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7847588
关键词：
Address Adoptive Transfer Affinity Allergens Allergic Allergic Disease Allergic Reaction Allergic inflammation Antibodies Antibody Affinity Antibody Formation Antigens B-Lymphocyte Subsets B-Lymphocytes Bacterial Infections Biological Biological Assay Biology CD8B1 gene Cell surface Cells Complex Contact Dermatitis Delayed Hypersensitivity Dependence Development Disease Effector Cell Enzyme Activation Enzymes Event Exposure to Eye Funding Future Generations Goals Health system Histamine Immune Immune System Diseases Immunization Immunosuppression Individual Inflammation Inflammation Mediators Inflammatory Inflammatory Response Investigation Laboratories Lead Leukocytes Leukotrienes Mediating Mediator of activation protein Molecular Genetics Mouse Strains Pathway interactions Phase Pilot Projects Play Population Production Public Health Receptor Gene Receptors, Antigen, B-Cell Regulatory Pathway Research Research Personnel Resolution Role Staging T-Lymphocyte Techniques United States activation-induced cytidine deaminase allergic response base disorder control genetic analysis in vivo innovation new technology new therapeutic target novel prevent programs research study response technology/technique

项目摘要

DESCRIPTION (provided by applicant): The long term objective of this application is to understand the immunological mechanisms responsible for initiating allergic inflammation, with an eye to identifying novel therapeutic targets upstream of the response itself. This proposal aims to develop novel techniques and a new avenue of investigation which will allow the investigator to identify and characterize a rare population of leukocytes that plays a central role in the events that occur immediately following re-exposure to allergen and are necessary for the later development of the full allergic inflammatory response. In recent years, research has clearly demonstrated that contact sensitivity and delayed type hypersensitivity allergic responses are dependent on a novel immune circuit that involves a number of rare leukocyte subsets. Of these, a subpopulation of non-classical B cells plays a particularly central role. These B cells produce antibodies that, upon re-exposure to allergen, initiate a cascade of pro-inflammatory events required for the development of the later and more severe T cell-mediated hypersensitivity response. Importantly, interference with this pathway or these B cells prevents the development of the development of severe inflammation. While the B cells responsible for initiation of contact sensitivity have been shown to be similar to B-1 cells, they have not yet been fully characterized. Further understanding of these types of allergic responses is dependent on the identification and characterization of these cells. The activity of these cells is dependent on the enzyme activation-induced deaminase (AID), which is involved in a number of steps in the assembly of the B cell receptor gene. The dependence on AID distinguishes the initiating B cell from the general B-1 cell population. Therefore, the specific aims of this proposal are to: 1) Identify AID expressing subpopulations of B-1 cells and 2) determine the mechanism by which AID contributes to the initiation response. Multicolor flow assisted cytometery analysis using multiple cell surface markers and a new strain of mice that expresses a fluorescent marker in cells that have expressed AID will be used to identify these cells. In vivo adoptive transfer experiments will be used to characterize their biological activity. Finally, molecular genetic analysis of B cell receptor genes from individual cells will be developed and performed to identify the role of AID in the generation of the relevant initiating antibodies.Allergic diseases such as contact sensitivity and delayed type hypersensitivity can be very debilitating and are a rapidly increasing and costly burden on public health systems in the United States. This proposal will develop new technology to facilitate the characterization of the immune events upstream of the severe, delayed inflammation associated with these disorders. This will potentially lead to the identification of novel therapeutic targets to effectively prevent responses before they develop fully.

描述（由申请人提供）：本申请的长期目标是了解引发过敏性炎症的免疫机制，着眼于识别反应本身上游的新治疗靶点。该提案旨在开发新技术和新的研究途径，使研究人员能够识别和表征稀有的白细胞群体，这些白细胞群体在重新暴露于过敏原后立即发生的事件中发挥核心作用，并且对于以后的过敏反应是必要的。全面过敏性炎症反应的发展。近年来，研究清楚地表明，接触敏感性和迟发型超敏反应依赖于涉及许多稀有白细胞亚群的新型免疫回路。其中，非经典 B 细胞亚群发挥着特别重要的作用。这些 B 细胞产生抗体，当再次暴露于过敏原时，会引发一系列促炎事件，这是后来更严重的 T 细胞介导的超敏反应发展所必需的。重要的是，干扰该途径或这些 B 细胞可以防止严重炎症的发展。虽然负责启动接触敏感性的 B 细胞已被证明与 B-1 细胞相似，但它们尚未得到充分表征。对这些类型过敏反应的进一步了解取决于这些细胞的识别和表征。这些细胞的活性取决于酶激活诱导的脱氨酶 (AID)，它参与 B 细胞受体基因组装的许多步骤。对 AID 的依赖性将起始 B 细胞与一般 B-1 细胞群区分开来。因此，该提案的具体目标是：1) 鉴定表达 AID 的 B-1 细胞亚群；2) 确定 AID 促进起始反应的机制。使用多种细胞表面标记的多色流辅助细胞计数分析和在表达 AID 的细胞中表达荧光标记的新小鼠品系将用于识别这些细胞。体内过继转移实验将用于表征其生物活性。最后，将对单个细胞的 B 细胞受体基因进行分子遗传学分析，以确定 AID 在相关起始抗体生成中的作用。接触过敏和迟发型超敏反应等过敏性疾病可能会让人非常衰弱，并且是一种常见的疾病。美国公共卫生系统的负担迅速增加且代价高昂。该提案将开发新技术，以促进与这些疾病相关的严重、迟发性炎症上游免疫事件的表征。这将有可能导致新的治疗靶点的确定，以在反应完全发展之前有效地预防反应。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Intravenously delivered mesenchymal stem cell-derived exosomes target M2-type macrophages in the injured spinal cord.

DOI：
10.1371/journal.pone.0190358
发表时间：
2018
期刊：
PloS one
影响因子：
3.7
作者：
Lankford KL;Arroyo EJ;Nazimek K;Bryniarski K;Askenase PW;Kocsis JD
通讯作者：
Kocsis JD

Antibodies Enhance the Suppressive Activity of Extracellular Vesicles in Mouse Delayed-Type Hypersensitivity.

DOI：
10.3390/ph14080734
发表时间：
2021-07-27
期刊：
Pharmaceuticals (Basel, Switzerland)
影响因子：
0
作者：
Nazimek K;Bustos-Morán E;Blas-Rus N;Nowak B;Totoń-Żurańska J;Seweryn MT;Wołkow P;Woźnicka O;Szatanek R;Siedlar M;Askenase PW;Sánchez-Madrid F;Bryniarski K
通讯作者：
Bryniarski K

Free Extracellular miRNA Functionally Targets Cells by Transfecting Exosomes from Their Companion Cells.