Regulation of Antigen-Specific T Cells and Arthrites Inflammation by B Cells

B 细胞对抗原特异性 T 细胞和关节炎炎症的调节

基本信息

批准号：
8088223
负责人：
STEVEN K. LUNDY
金额：
$ 11.69万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-06-01 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8088223
关键词：
Activated B-Lymphocyte Adoptive Transfer Adverse effects Animal Model Antibodies Antigen-Presenting Cells Antigens Arthritis B-Cell Activation B-Lymphocyte Subsets B-Lymphocytes Biological Assay CD4 Positive T Lymphocytes Cartoons Cell Communication Cell Death Cell Line Cell Therapy Cells Cessation of life Coculture Techniques Differentiation and Growth Disease Down-Regulation Effector Cell Engineering Fibroblasts Helper-Inducer T-Lymphocyte Immune Immune system Immunosuppression In Vitro Infection Inflammation Inflammatory Injection of therapeutic agent Interleukin-1 Interleukin-10 Interleukin-17 Intervention Joints Lead Left Leukocytes MHC Class II Genes Mediating Methotrexate Modeling Mus Patients Pharmacologic Substance Phenotype Physiologic pulse Play Process Proliferating Recruitment Activity Refractory Regulation Regulatory T-Lymphocyte Relative (related person)Research Rheumatoid Arthritis Rheumatoid Factor Risk Role Signal Transduction T cell regulation T-Cell Activation T-Lymphocyte T-Lymphocyte Subsets TNF gene TNFSF10 gene TNFSF5 gene TNFSF6 gene TRANCE protein Testing Therapeutic Therapeutic Agents Time Transforming Growth Factor beta Tumor Necrosis Factor Ligand Superfamily Member 6 Tumor Necrosis Factor-alpha Work base bone cytokine genetically modified cells human disease improved in vivo interest macrophage neutralizing antibody prevent response

项目摘要

DESCRIPTION (provided by applicant): The long-term objective of this research is to improve treatment of rheumatoid arthritis (RA) by developing cell-based therapies that target auto reactive T cells. The hypothesis to be tested is that defined subsets of activated B cells can mediate down-regulation of inflammation by inhibiting the activity of T helper cells. This hypothesis is based on the preliminary finding that a subset of B cells from immunized mice is capable of mediating T cell death in an antigen-specific and Fas ligand (CD178)-dependent manner. These 'regulatory' B cells have been observed in other models of inflammation in mice, as well as in human diseases. Aim 1: Study the induction and/or down-regulation of immune regulatory molecules on B cell subsets following in vitro and in vivo stimulation. Aim 2: Analyze the cell-cell interactions required to induce cell death or regulation of Th cells following coculture of activated B cell subsets with arthritis antigen-specific Th cells. Aim 3: Study the ability of antigen-loaded, 'regulatory' B cells to maintain regulatory phenotype, skew the ThlL-17 response, and prevent or treat arthritis in mice. Aim 4: Determine the relative contribution of endogenous CD178+ B cells to the in vivo regulation of ThlL-17 response and joint inflammation. These aims will be achieved using established models of arthritis in mice. B cells from these mice will be analyzed for expression of regulatory molecules after various modes of stimulation. Assays for T cell activation and death will be carried out by coculture of T cells from immunized mice and antigen-pulsed purified B cells. Cell-cell interactions between B and T cells will be blocked by neutralizing antibodies to determine which interactions are critical to T cell regulation. Expansion of murine B cells for adoptive transfer will be achieved using CD40L-transduced fibroblasts, and culture parameters will be optimized to produce large numbers of regulatory B cells. B cells will be injected into mice prior to or during established arthritis to study in vivo regulatory effects. An arthritis model involving injection of arthritogenic antigens will be tested in B cell deficient mice in order to further substantiate the importance of regulatory B cells. Relevance: Regulatory B cells have potential in treating RA because of their ability to specifically identify, interact with, and eliminate the T cells involved in arthritis progression. Elimination of disease-causing T cells, while sparing bystander T cells would be a significant improvement over current non-specific therapeutic strategies.

描述（由申请人提供）：这项研究的长期目标是通过开发靶向自动反应性T细胞的基于细胞的疗法来改善类风湿关节炎（RA）。要测试的假设是，活化B细胞的定义亚集可以通过抑制T辅助细胞的活性来介导炎症下调。该假设是基于初步发现，即免疫小鼠的B细胞子集能够以抗原特异性和FAS配体（CD178）依赖性方式介导T细胞死亡。这些“调节性” B细胞已在小鼠以及人类疾病的其他炎症模型中观察到。 AIM 1：研究体外和体内刺激后B细胞子集对免疫调节分子的诱导和/或下调。目标2：分析用关节炎抗原特异性TH细胞共培养激活B细胞亚群后诱导细胞死亡或调节TH细胞所需的细胞细胞相互作用。 AIM 3：研究抗原负载的“调节” B细胞保持调节表型，偏向THLL-17反应以及预防或治疗小鼠关节炎的能力。目标4：确定内源性CD178+ B细胞对THLL-17反应和关节炎症体内调节的相对贡献。这些目标将使用小鼠的关节炎模型来实现。这些小鼠的B细胞将在各种刺激模式后分析调节分子的表达。 T细胞激活和死亡的测定将通过免疫小鼠的T细胞和抗原脉冲纯化的B细胞进行共培养。 B和T细胞之间的细胞细胞相互作用将通过中和抗体来阻止，以确定哪些相互作用对T细胞调节至关重要。使用CD40L转导的成纤维细胞来实现鼠B细胞的扩展，用于产卵，并且将优化培养参数以产生大量的调节B细胞。 B细胞将在既定关节炎之前或在研究体内调节作用前注入小鼠。在B细胞缺乏小鼠中将测试涉及注射关节抗原的关节炎模型，以进一步证实调节B细胞的重要性。相关性：调节性B细胞有潜力治疗RA，因为它们具有特异性识别，相互作用和消除参与关节炎进展的T细胞的能力。消除引起疾病的T细胞，而宽大的旁观者T细胞将对当前的非特异性治疗策略进行显着改善。