EFFICACY OF COSTIMULATION BLOCKADE IN PREVENTING, TREATING ALLOGRAFT REJECTION

联合刺激阻断在预防和治疗同种异体移植排斥方面的功效

• 批准号: 6352624
• 负责人: ALLAN D KIRK
• 金额: $ 34万
• 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: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6352624
• 关键词: CD antigens; FK506; Macaca mulatta; biological models; biopsy; blocking antibody; bone marrow; cell adhesion molecules; cellular immunity; cyclosporines; cytokine; genetic transcription; homologous transplantation; humoral immunity; immunocytochemistry; immunosuppression; immunotherapy; interleukin 12; interleukin 2; kidney transplantation; mixed lymphocyte reaction test; monoclonal antibody; nonhuman therapy evaluation; polymerase chain reaction; prednisone; skin transplantation; transplant rejection; transplantation immunology

Successful allotransplantation currently requires continuous administration of immunosuppressive medication to prevent immunological graft rejection. These drugs are expensive and their non-specific effects greatly increase the risk of infection and malignancy. Therapies with long lasting, antigen specific effects have thus been sought. Recently, it has been shown that T cells can be made specifically non-reactive by allowing for T cell receptor engagement while preventing signaling through co- stimulatory receptors including CD28 and possibly CD154. We have initiated extensive studies in non-human primates showing that monoclonal antibodies (Mabs) that block CD154 prevent and treat allograft rejection and that their effects appear, preliminary, to be long lasting and graft specific. Additional study has been initiated with agents that block CD28 activation by interrupting its association with its ligands CD80 and CD86. The role of this project will be to investigate Mabs that block the function of CD28 and CD154 in an applicable pre-clinical model and to provide information for the design of a clinical trial with these promising agents. We will utilize a well established rhesus monkey renal allograft model to study the efficacy and safety of induction with costimulation blocking agents alone and in combination with conventional agents. Extensive collaboration with project 2 will ensure that transplants will be performed between animals with defined donor and recipient MHC disparity. We will monitor the potential side effects of each agent, and optimize the duration and dosing of each induction regimen. We will test for allograft tolerance using secondary skin grafts from donor and third party animals complemented by assays for immune competence to environmental antigens. We will investigate the mechanism of costimulation blockade induced graft acceptance. We will assay the intragraft cytokine milieu by RT-PCR and with project 2 by immunohistochemistry. Particular attention will be directed to the intragraft transcription of cytokines, costimulation molecules, and adhesion molecules associated with ischemia re-perfusion injury. Peripheral donor-specific immune responses will be studied by mixed lymphocyte reaction, allo-antibody determination, limiting dilution analysis and cytotoxicity assays. We will also test whether graft acceptance established by costimulation blockade is dependent on the suppressed expression of Th1 cytokines IL-2 and IL-12. Using neutralizing antibodies against IL-12 and the administration of recombinant IL-2 and IL-12, the ability of these cytokines to reverse the effects of costimulation blockade will be assessed during induction and after prolonged graft survival. We will also apply mechanistic concepts derived from project 4 in vivo. In collaboration with project, we will test whether co-administered donor-specific hematopoietic stem cells at the time of transplantation promote graft acceptance, and adapt the methods for expansion of primitive marrow derived stem cells to the rhesus model. We will transition the most successful method for preventing graft rejection into clinical trials planned with project 2 and project 3 investigators.

当前成功的同倍植入术需要连续 给予免疫抑制药物以防止免疫学 移植拒绝。这些药物很昂贵，其非特异性影响 大大增加了感染和恶性肿瘤的风险。疗法长 因此，人们寻求了持久的抗原特异性作用。最近，它有 已显示，可以通过允许的 用于T细胞受体的参与，同时防止通过共同信号传导 刺激受体，包括CD28，可能是CD154。我们已经发起了 非人类灵长类动物的广泛研究表明单克隆抗体 （mAb）阻止CD154预防和治疗同种异体移植排斥的（ 它们的效果显得持久和特定于移植。 额外的研究已经开始使用阻断CD28激活的药物 通过中断其与配体CD80和CD86的关联。角色 这个项目的将是调查阻断功能的mabs 适用的临床前模型中的CD28和CD154，并提供 临床试验设计的信息 代理商。我们将利用良好的恒河猴肾脏同种异体移植 研究诱导与共刺激的功效和安全性的模型 单独阻断药物并与常规代理结合使用。 与项目2的广泛合作将确保移植将 在具有定义供体和受体MHC的动物之间进行 差距。我们将监视每个代理的潜在副作用，以及 优化每种感应方案的持续时间和剂量。我们将测试 使用供体的次级皮肤移植物和第三 派对动物补充了对免疫能力的测定 环境抗原。我们将研究共刺激的机制 封锁引起的移植物接受。我们将分析细胞因子 RT-PCR的MILIEU，并与免疫组织化学进行项目2。特别的 注意将针对细胞因子的内部转录， 共刺激分子和与缺血相关的粘附分子 再灌注损伤。外围供体特异性免疫反应将是 通过混合淋巴细胞反应，同种抗体测定，研究 限制稀释分析和细胞毒性测定。我们还将测试 CORTIMUTURATION BLASKADE确定的移植物接受是否为 取决于Th1细胞因子IL-2和IL-12的抑制表达。 使用针对IL-12的中和抗体和给药 重组IL-2和IL-12，这些细胞因子逆转的能力 在归纳期间将评估CORTIMUTUTION BLASKADE的影响，并 长时间的移植物存活后。我们还将应用机械概念 源自Vivo项目4。与项目合作，我们将 测试是否共同管理供体特异性造血干细胞 移植时间可促进接枝的接受，并适应 将原始骨髓衍生的干细胞扩展到恒河猴的方法 模型。我们将过渡最成功的预防移植方法 拒绝对项目2和项目3计划的临床试验 调查人员。