The Role of AID in Contact Sensitivity

AID 在接触敏感性中的作用

• 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
• 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

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学机制，着眼于识别反应本身上游的新型治疗靶点。该提案旨在开发新技术和新的研究途径，使研究者能够识别和表征在再次暴露于过敏原后立即发生的事件中起核心作用的罕见白细胞群体，并且是后期全面过敏性炎症反应发展所必需的。近年来，研究已经清楚地表明，接触敏感性和迟发型超敏反应依赖于一种新的免疫回路，涉及一些罕见的白细胞亚群。其中，非经典B细胞亚群起着特别重要的作用。这些B细胞产生抗体，在再次暴露于过敏原时，引发一系列促炎事件，这些促炎事件是发展更晚和更严重的T细胞介导的超敏反应所必需的。重要的是，干扰这一途径或这些B细胞可以防止严重炎症的发展。虽然已经证明负责引发接触敏感性的B细胞与B-1细胞相似，但它们尚未被完全表征。对这些类型的过敏反应的进一步理解取决于这些细胞的鉴定和表征。这些细胞的活性依赖于酶活化诱导的脱氨酶（AID），其参与B细胞受体基因组装的多个步骤。对AID的依赖性将起始B细胞与一般B-1细胞群体区分开来。因此，该建议的具体目的是：1）鉴定表达AID的B-1细胞亚群和2）确定AID促进起始应答的机制。使用多种细胞表面标志物的多色流式细胞术分析和在表达AID的细胞中表达荧光标志物的新小鼠品系将用于鉴定这些细胞。体内过继转移实验将用于表征其生物活性。最后，将开发和进行来自单个细胞的B细胞受体基因的分子遗传学分析，以确定AID在相关起始抗体产生中的作用。变应性疾病如接触敏感性和迟发型超敏反应可以是非常衰弱的，并且是美国公共卫生系统的快速增加和昂贵的负担。该提案将开发新技术，以促进与这些疾病相关的严重延迟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识别，以有效地防止反应之前，他们充分发展。

项目成果

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)
• 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.

• DOI: 10.1371/journal.pone.0122991
• 发表时间: 2015
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Bryniarski K;Ptak W;Martin E;Nazimek K;Szczepanik M;Sanak M;Askenase PW
• 通讯作者: Askenase PW