Adjuvant Therapies Improving the Anti-Rejection Effects of Costimulation Blockade

描述（由申请人提供）：器官移植需要使用免疫抑制药物来防止移植器官的排斥反应，这大大限制了其益处并增加了其风险。不幸的是，所有的方案，无论使用的药物，是不完全和短暂的有效性，并诱导一定程度的免疫功能不全的生活。自发现以来，共刺激阻断（CoB）已被建议作为一种手段，实现无限期，耐受性良好，抗原特异性预防同种异体移植排斥反应。示例性方法是阻断CD 28/B7途径。虽然在一些啮齿动物模型中非常有效，但CD 28/B7阻断不足以单独防止灵长类动物（包括人类）的排斥反应。已经提出了几种CoB抗性排斥的机制，许多与活化的同种异体反应性记忆表型T细胞的相对存在有关。我们现在已经发现，在灵长类动物中，用CD 2特异性融合蛋白LFA-3-IG（alefacept）与靶向CD 28/B7的融合蛋白阿巴西普协同治疗，成功地预防了肾同种异体移植排斥。我们假设alefacept特异性靶向许多促进CoB抗性的因素，包括异源同种异体反应性T细胞记忆，同时避免干扰有助于促进CoB介导的同种异体移植物接受的外周机制，包括T细胞调节和供体抗原特异性T细胞消除。因此，我们建议研究alefacept改善CoB的机制，并利用这些信息优化其使用，开发一种临床适用的治疗方法，以防止同种异体移植排斥反应，而不使用钙调磷酸酶抑制剂，类固醇或总T细胞耗竭。在开发该方案时，我们将专门测试alefacept消除预先存在的和诱导记忆T细胞的能力，评估alefacept对同种特异性和记忆T细胞以及病毒特异性记忆T细胞的绝对和相对作用。在整个研究中，我们将确定该方案对同种免疫的影响在多大程度上改变了保护性病毒免疫。基于初步证据表明供体特异性抗原输注的有益作用，我们还将确定移植时抗原暴露在多大程度上改善了该方案效果的持久性，增强了同种异体特异性效应而不改变其对保护性免疫的作用。由于该方案使用了批准用于临床使用的药物，这将提供数据支持可立即翻译的策略，以防止人类排斥反应，并建立关于T细胞记忆在阻碍基于CoB的免疫调节中的作用的可推广知识。 公共卫生相关性：需要免疫抑制药物来防止器官移植排斥反应;不幸的是，尚未开发出最佳有效的无毒药物方案。共刺激阻断（CoB）已被证明可以预防啮齿动物的排斥反应，但在灵长类动物中的效果要差得多;然而，我们已经开发了一种将CoB与融合蛋白alefacept配对的方案，并表明它可以预防灵长类动物的肾移植排斥反应，假设是由于alefacept对抗CoB抗性排斥机制的作用。我们建议确定alefacept的作用机制，重点关注其对同种异体和病毒特异性免疫的影响，并在此过程中将此方案发展为耐受性良好，临床适用和机械合理的治疗方法，以防止同种异体移植排斥反应。

DESCRIPTION (provided by applicant): Organ transplantation requires the use of immunosuppressive drugs to prevent rejection of the transplanted organ, substantially limiting its benefit and augmenting its risk. Unfortunately, all regimens, regardless of the agents used, are incompletely and transiently effective, and induce some degree of immune incompetence for life. Since its discovery, costimulation blockade (CoB) has been suggested as a means of attaining indefinite, well-tolerated, antigen-specific prophylaxis from allograft rejection. An exemplary approach is blockade of the CD28/B7 pathway. Although exceedingly effective in some rodent models, CD28/B7 blockade is not alone sufficient to prevent rejection in primates, including humans. Several mechanisms of CoB- resistant rejection have been suggested, many related to the relative presence of activated alloreactive memory-phenotype T cells. We now have found that treatment with the CD2 specific fusion protein LFA-3-Ig (alefacept) synergizes with the CD28/B7-targeted fusion protein abatacept successfully preventing renal allograft rejection in primates. We hypothesize that alefacept specifically targets many of the factors fostering CoB resistance, including heterologous alloreactive T cell memory, while avoiding interference with peripheral mechanisms that serve to foster CoB-mediated allograft acceptance, including T cell regulation and donor antigen-specific T cell elimination. We therefore propose to investigate the mechanisms by which alefacept improved CoB and use this information to optimize its use, developing a clinically applicable therapy to prevent allograft rejection without the use of calcineurin inhibitors, steroids, or gross T cell depletion. In developing the regimen, we will specifically test alefacept's ability to eliminate pre-existing and induce memory T cells, evaluating the absolute and relative effects of alefacept on allospecific and memory T cells, and viral specific memory T cells. Throughout the study, we will determine the degree to which this regimen's influence on alloimmunity alters protective viral immunity. Based on preliminary evidence suggesting a salutary role for donor specific antigen infusion, we also will determine the degree to which antigen exposure at transplant improves the durability of the effect of this regimen, augmenting the allospecific effect without altering its effect on protective immunity. As this regimen uses agents that are approved for clinical use, this will provide data in support of an immediately translatable strategy to prevent rejection in humans, and establish generalizable knowledge regarding the role of T cell memory in thwarting CoB-based immune modulation. PUBLIC HEALTH RELEVANCE: Immunosuppressive drugs are required to prevent organ transplant rejection; unfortunately, an optimally effective, non-toxic drug regimen is yet to be developed. Costimulation blockade (CoB) has been shown to prevent rejection in rodents, but is far less effective in primates; however, we have developed a regimen pairing CoB with a fusion protein, alefacept, and have shown that it prevents renal allograft rejection in primates, hypothetically due to alefacept's effects countering CoB-resistant mechanisms of rejection. We propose to determine the mechanisms involved in alefacept's action focusing on its effects on allo- and viral-specific immunity, and in doing so develop this regimen into a well-tolerated, clinically applicable, and mechanistically sound therapy to prevent allograft rejection.