Novel Costimulatory Antagonists for SLE

SLE 的新型共刺激拮抗剂

基本信息

批准号：
7479107
负责人：
Anne Davidson
金额：
$ 40.1万
依托单位：
FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-06-16 至 2010-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7479107
关键词：
Address Adrenal Cortex Hormones Adverse effects Affinity Alkylating Agents Anti-DNA Antibodies Antibodies Antigens Antiphospholipid Syndrome Autoantibodies Autoantigens Autoimmune Diseases Autoimmune Process B cell differentiation B-Cell Development B-Lymphocyte Subsets B-Lymphocytes Cell Survival Cells Chimeric Proteins Clinical Trials Clinical Trials Design Collaborations Congenic Strain Cyclophosphamide Defect Dendritic Cells Deposition Disease Disease remission Enrollment Human Human Development Human Genome Hybridomas Immune response Immunoglobulin Genes Immunologics Immunosuppression Immunosuppressive Agents Individual Inflammation Inflammatory Kidney Knowledge Life Link Lupus Mature B-Lymphocyte Mediating Modeling Mus Nephritis Organ Pathogenesis Patients Phase II Clinical Trials Plasma Cells Proliferative Glomerulonephritis Recurrent disease Regulation Rheumatism Role Science Serum Signal Transduction Somatic Mutation Staging Syndrome Systemic Lupus Erythematosus T-Lymphocyte TNFSF5 gene Testing Therapeutic immunosuppression Toxic effect Transgenic Mice Treatment Efficacy anti-dsDNA antibodies autoreactive B cell base congenic design human study improved interest macrophage novel novel strategies prevent receptor response

项目摘要

DESCRIPTION (provided by applicant): The TNF-like trimers BAFF and APRIL are recently identified molecules essential for B cell development and survival. Levels of BAFF and APRIL are elevated in autoimmune rheumatic diseases including SLE. Blockade of BAFF and APRIL delays the onset of SLE in murine models. We have preliminary observations that short term administration of the soluble BAFF and APRIL antagonist TACI-Ig together with the T cell costimulatory blocker CTLA41g can induce remission of late stage SLE in NZB/W F1 mice. This proposal will explore the mechanism of action of BAFF/APRIL blockade, both alone and in combination with CTLA41g, using soluble BAFF receptor fusion proteins that block BAFF or both BAFF and APRIL. The studies in Aim 1 will focus on how BAFF/APRIL blockade influences the effector B cells that mediate the inflammatory and non-inflammatory manifestations of SLE. The studies described in Aim 2A will focus on the effect of BAFF/APRIL blockade on the selection of autoreactive B cell subsets and on the autoreactive immunoglobulin gene repertoire. This will allow us to determine whether the decreased B cell survival that results from BAFF/APRIL blockade is linked to alterations in B cell selection. The studies described in Aim 2B will help us determine the immunosuppressive potential of the various forms of BAFF/APRIL blockade by analyzing primary and recall B cell responses to T independent and T dependent antigens. Finally, we have a unique opportunity, through collaboration with Human Genome Sciences, to study the mechanism of action of BAFF blockade in the first clinical trial of a BAFF blocker in human SLE.

描述（由申请人提供）：最近发现了类似TNF的三聚体Baff和April，这对于B细胞发育和生存至关重要。包括SLE在内的自身免疫性疾病中的BAFF和4月份的水平升高。 Baff和April的封锁延迟了鼠模型中SLE的发作。我们有初步的观察结果，即可溶性BAFF和APRIN拮抗剂TACI-IG以及T细胞共刺激阻滞剂CTLA41G的短期施用可以诱导NZB/W F1小鼠中的后期SLE的缓解。该提案将使用可溶性BAFF受体融合蛋白，探索BAFF/4月封锁的作用机理，并与CTLA41G结合使用，该蛋白可以阻止BAFF或BAFF和BAFF和APRIL。 AIM 1中的研究将重点介绍BAFF/4月阻断如何影响介导SLE炎症和非炎性表现的效应B细胞。 AIM 2A中描述的研究将重点介绍BAFF/4月封锁对选择自动反应性B细胞亚群和自动反应性免疫球蛋白基因库的影响。这将使我们能够确定BAFF/4月阻滞导致的B细胞存活是否与B细胞选择的改变有关。 AIM 2B中描述的研究将帮助我们通过分析对T独立和T依赖性抗原的主要和回忆B细胞反应来确定各种形式的BAFF/4月阻断的免疫抑制潜力。最后，通过与人类基因组科学的合作，我们有一个独特的机会，可以研究Baff阻滞的作用机理，这是人类SLE中BAFF阻滞剂的首次临床试验。