COSTIMULATION BLOCKADE FOR PRIMATE RENAL TRANSPLANTATION

灵长类动物肾移植的联合刺激封锁

• 批准号: 2718801
• 负责人: DAVID M HARLAN
• 金额: $ 170万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2718801
• 关键词: Macaca mulatta; artificial immunosuppression; homologous transplantation; kidney transplantation; transplant rejection; transplantation immunology

Current treatments to prevent allograft rejection while quite effective are nevertheless costly, associated with significant systemic toxicity, and indiscriminately impair immune system function so that transplant recipients are at increased risk for a variety of infectious illnesses and cancers. Furthermore, traditional immunosuppressive therapies have proven unable to prevent the rejection of potentially curative islet transplants in individuals with insulin dependent diabetes mellitus (IDDM). Rodent and non-human primate model studies have suggested that anti-CD154 (CD40L) antibody-based treatments, alone or in combination with other immune system modulators may significantly improve the approach to patients requiring health sustaining allo-transplants. Preliminary data suggests that this therapy may more specifically impair the anti-graft immune response, can be administered intermittently, and may be associated with less toxicity. Our overall goal is to develop this novel therapy for clinical application. We will study highly relevant non-human primate islet and kidney allograft models, transitioning into clinical trials as warranted by preclinical studies. Among the several critical questions to be addressed: (1) what is the immunological mechanism underlying the prevention of allograft rejection?. (2) are anti-CD154-based therapies safe and effective when co-administered with "traditional" immunosuppressive agents including calcineurin phosphatase inhibitors, glucocorticoids, and/or mycophenolate mofetil?. (3) is the efficacy of anti-CD154-based therapies enhanced by increasing the donor antigen load in the form of co-administered donor-specific bone marrow? (4) is the efficacy of anti-CD154-based therapies enhanced by agents that interfere with the B7 receptors (CD80 and CD86) ability to interact with their counter-receptors and CTLA4 (CD152)? (5) how specific is the immune inhibition? (6) will anti-CD154-based therapy reverse and/or decrease the incidence of chronic rejection?. (7) can rejection episodes occurring following induction therapy with anti-CD154 can be safely rescued?. and (8) are anti-CD154 antibody mediated effects the result of blocking CD154's interaction with CD40?. direct effects on cells expressing CD154?. or both?

目前预防同种异体移植排斥反应的治疗方法相当有效 然而，成本高昂，并与显着的全身毒性相关， 并不加区别地损害免疫系统功能，从而使移植 接受者患各种传染病的风险增加 癌症。此外，传统的免疫抑制疗法已被证明 无法防止潜在治愈性胰岛移植的排斥反应 患有胰岛素依赖型糖尿病（IDDM）的个体。啮齿动物和 非人类灵长类动物模型研究表明，抗 CD154 (CD40L) 基于抗体的治疗，单独或与其他免疫联合治疗 系统调节器可以显着改善患者的治疗方法 需要维持健康的同种异体移植。初步数据表明 该疗法可能更具体地损害抗移植物免疫 反应，可以间歇性施用，并且可能与 毒性较小。我们的总体目标是开发这种新颖的疗法 临床应用。我们将研究高度相关的非人类灵长类动物 胰岛和肾同种异体移植模型，过渡到临床试验 经临床前研究证实。在几个关键问题中 需要解决的问题： (1) 其免疫学机制是什么？ 预防同种异体移植排斥反应？ (2) 是基于抗 CD154 的疗法 与“传统”联合用药安全有效 免疫抑制剂，包括钙调神经磷酸酶抑制剂， 糖皮质激素和/或吗替麦考酚酯？ (3) 功效为 通过增加供体抗原负荷增强基于抗 CD154 的治疗 以共同施用供体特异性骨髓的形式？ (4) 是 通过干扰药物增强抗 CD154 疗法的疗效 与 B7 受体（CD80 和 CD86）相互作用的能力 反受体和 CTLA4 (CD152)？ (5) 免疫的特异性如何 抑制？ (6) 基于抗 CD154 的治疗是否会逆转和/或减少 慢性排斥反应的发生率？ (7)是否会发生排斥反应 抗CD154诱导治疗后能否安全获救？和 (8)抗CD154抗体介导的效应是阻断的结果 CD154 与 CD40 的相互作用？对表达 CD154? 的细胞有直接影响。 或两者兼而有之？