COSTIMULATION BLOCKADE FOR PRIMATE RENAL TRANSPLANTATION

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，代价高昂，与重大的全身毒性有关， 不分青红皂白地损害免疫系统功能，因此移植 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经证明 无法阻止潜在治愈的胰岛移植的排斥反应 在患有胰岛素依赖型糖尿病(IDDM)的个体中。啮齿动物和 非人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 系统调节器可能会显著改善患者的治疗方法 需要健康的同种异体移植。初步数据显示 这种疗法可能会更具体地损害抗移植物免疫 反应，可以间歇给药，并可能与 毒性更小。我们的总体目标是开发这种新的治疗方法 临床应用。我们将研究高度相关的非人类灵长类 胰岛和肾移植模型，过渡到临床试验 经临床前研究证实。在以下几个关键问题中 应解决：(1)免疫机制是什么？ 预防同种异体移植排斥反应？(2)以抗CD154为基础的治疗 与“传统型”联合给药安全有效 包括钙调神经磷酸酶抑制剂在内的免疫抑制剂， 糖皮质激素和/或霉酚酸酯？(3)是否有效？ 通过增加供体抗原负载量加强抗CD154为基础的治疗 以联合移植供者特有的骨髓的形式？(4) 干扰剂增强基于CD154的抗病毒治疗的疗效 通过B7受体(CD80和CD86)与其相互作用 抗受体和CTLA4(CD152)？(5)免疫的特异性 抑制？(6)基于CD154的抗治疗会逆转和/或减少 慢性排斥反应的发生率？(7)拒绝事件会发生吗？ 经抗CD154诱导治疗后，能否安全抢救？和 (8)抗CD154抗体介导的效应是否为阻断结果 CD154‘S与CD40的相互作用？对表达CD154？的细胞的直接作用。 还是两者兼而有之？

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?