Cytokine Dysregulation in Autoimmune Hemolytic Anemia

自身免疫性溶血性贫血中的细胞因子失调

基本信息

批准号：
7586913
负责人：
Katrina K Hoyer
金额：
$ 9万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
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：
2009-07-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7586913
关键词：
Acute Address Animals Antibodies Antibody Formation Antigen Targeting Antigens Atypical lymphocyte Autoantibodies Autoantigens Autoimmune Diseases Autoimmune Process Autoimmune hemolytic anemia Autoimmunity CD28 gene CD4 Positive T Lymphocytes California Cells Cessation of life Cytokine Signaling Data Dendritic Cells Dendritic cell activation Development Disease Employee Strikes Erythrocytes Evolution Genetic Models Hybridomas Immune Immune System Diseases Immunization Infection Inflammation Inflammatory Lead Lymphocyte Lymphocyte Function Lymphoproliferative Disorders Mediating Mentors Modeling Mus Organ Pathway interactions Phase Phenotype Play Principal Investigator Process Production Reaction Reagent Research Personnel Role San Francisco Secondary to Self Tolerance Serum Signal Transduction Stimulus Surface T-Cell Activation T-Lymphocyte Tissues Universities Work abstracting anergy anti-IgG autoreactive T cell base cytokine killings mouse model novel overexpression prevent response

项目摘要

DESCRIPTION (provided by applicant): Autoimmune hemolytic anemia (AIHA) is characterized by the production of antibodies directed against self red blood cells. Given the frequent association between AIHA and other autoimmune disorders, generalized immune dysfunction likely plays a role in the disease process. Under normal conditions, self-reactive lymphocytes are killed, inactivated or suppressed by regulatory T cells, resulting in unresponsiveness to selfantigens. Disruption of these control mechanisms results in the survival and pathogenic activation of selfreactive lymphocytes. It is unclear how self-reactive lymphocytes are spontaneously activated in the absence of overt infection or other stimuli, leading to autoimmune disease. If the initiators of activation and subsequent disease can be delineated, and the antigen targets of pathogenic antibodies identified, means of controlling these autoimmune reactions may be uncovered. In this study, we use a mouse model of spontaneous, acute systemic autoimmunity that principally manifests as AIHA to define the stimuli that are required for the development of autoimmune disease. The overall objective of this proposal is to define the immunological abnormalities in a model of spontaneous autoimmunity and to identify the target antigens in this disease. The central hypothesis underlying this proposal is that abnormal cytokine production and uncontrolled activation of dendritic cells due to the absence of regulatory T cell suppression results in autoimmunity. The successful completion of this project will elucidate the immune abnormalities (including the role of dendritic cells, cytokines and antigen-specific lymphocytes) in AIHA development, and strengthen our understanding of what triggers and maintains autoimmunity. I will proceed with the mentored phase of this project under the guidance of Dr. Abul Abbas at the University of California San Francisco, and then look forward to completing these aims as an independent investigator. (End of Abstract)

描述（由申请人提供）：自身免疫性溶血性贫血（AIHA）的特征是产生针对自我红细胞的抗体。鉴于AIHA与其他自身免疫性疾病之间的频繁关联，普遍的免疫功能障碍可能在疾病过程中起作用。在正常条件下，自反应性淋巴细胞被调节T细胞杀死，灭活或抑制，从而对自减酸剂产生反应。这些控制机制的破坏导致自我反应性淋巴细胞的存活和致病激活。目前尚不清楚在没有明显的感染或其他刺激的情况下自发激活的自我反应性淋巴细胞，导致自身免疫性疾病。如果可以划定激活和随后的疾病的发起者，并发现了鉴定的致病抗体抗原靶标，则可以发现控制这些自身免疫反应的方法。在这项研究中，我们使用了自发的急性全身自身免疫的小鼠模型，该模型主要表现为AIHA来定义自身免疫性疾病发展所需的刺激。该提案的总体目的是在自发自身免疫模型中定义免疫学异常，并确定该疾病中的靶抗原。该提议的基本假设是，由于缺乏调节性T细胞抑制导致自身免疫性，由于缺乏调节性T细胞的细胞因子产生和树突状细胞的不受控制激活。该项目的成功完成将阐明免疫异常（包括树突状细胞，细胞因子和抗原特异性淋巴细胞的作用）在AIHA发育中，并增强我们对触发和维持自身免疫性的理解。我将在加利福尼亚大学旧金山大学的Abul Abbas博士的指导下继续进行该项目的指导阶段，然后期待完成这些目标。（抽象的结尾）