Role of B Cells in Transplant Tolerance

B 细胞在移植耐受中的作用

• 批准号: 8538966
• 负责人: Heidi Yeh
• 金额: $ 15.88万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8538966
• 关键词: ARHGEF5 gene; Adoptive Transfer; Adverse effects; Animals; Antibodies; Antibody Therapy; Antigen Presentation; Antigen-Presenting Cells; Antigens; Autoimmune Diseases; B-Lymphocyte Subsets; B-Lymphocytes; CCL1 gene; CCL2 gene; Cells; Chemotactic Factors; Data; Delayed Hypersensitivity; Dendritic Cells; Development; Failure; Flow Cytometry; Genes; Goals; Graft Survival; Human; Immunity; Immunohistochemistry; Immunosuppression; Immunosuppressive Agents; Intravenous; Leukocytes; Messenger RNA; Microarray Analysis; Modeling; Morbidity - disease rate; Mus; Organ Transplantation; Patients; Pharmaceutical Preparations; Play; Population; Production; Protocols documentation; Regimen; Regulatory T-Lymphocyte; Role; T-Lymphocyte; Transforming Growth Factor beta; Transplant Recipients; Transplantation; Up-Regulation; Western Blotting; allergic airway inflammation; improved; in vitro testing; interest; islet allograft; monocyte chemoattractant protein 1 receptor; novel; prevent; protein expression; receptor; reconstitution; success

DESCRIPTION (provided by applicant): The major impediments to the success of organ transplantation remain the failure of current immunosuppressive drugs to prevent rejection and the morbidities associated with the side effects of those drugs. Strategies for achieving tolerance would avoid both these problems. Most tolerance inducing protocols target the T cell compartment, especially regulatory T cells (Tregs) that can specifically suppress alloreactive immunity. However, recent studies suggest that there is an analogous subset of B cells in mice and humans. The combination of anti-CD45RB and anti-TIM1 results in almost 100% long term islet allograft survival, and this effect is dependent on the presence of recipient B cells. TIM1+ cells from tolerant mice are able to transfer tolerance to untreated animals in a donor specific manner. Tolerance transfer requires the presence of native Tregs in the second recipient. We hypothesize that combined antibody therapy induces a regulatory B cell population (Bregs) that interacts with Tregs to promote tolerance. This proposal seeks to elucidate the interaction of Bregs with Tregs and the molecules that are important in governing tolerance in this model.

描述（由申请人提供）：器官移植成功的主要障碍仍然是当前的免疫抑制药物未能防止排斥反应以及与这些药物的副作用相关的发病率。实现宽容的策略可以避免这两个问题。大多数耐受诱导方案以 T 细胞区室为目标，尤其是可以特异性抑制同种反应性免疫的调节性 T 细胞 (Treg)。然而，最近的研究表明，小鼠和人类体内也存在类似的 B 细胞亚群。抗 CD45RB 和抗 TIM1 的组合导致几乎 100% 的胰岛同种异体移植物长期存活，并且这种效果取决于受体 B 细胞的存在。来自耐受小鼠的 TIM1+ 细胞能够以供体特异性方式将耐受性转移至未经治疗的动物。耐受性转移需要第二个接受者体内存在天然 Tregs。我们假设联合抗体疗法会诱导调节性 B 细胞群 (Bregs) 与 Tregs 相互作用以促进耐受。该提案旨在阐明 Bregs 与 Tregs 以及在该模型中控制耐受性的重要分子之间的相互作用。