Adjuvant Therapies Improving the Anti-Rejection Effects of Costimulation Blockade

描述(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，无论使用哪种药物，所有方案都不完全有效，而且是暂时有效的，并导致某种程度的终身免疫无能。自发现以来，共刺激阻断(COB)一直被认为是一种无限期、耐受性好、抗原特异性的预防同种异体移植排斥反应的方法。一种典型的方法是阻断CD28/B7途径。虽然在某些啮齿动物模型中非常有效，但CD28/B7的阻断并不足以单独防止包括人类在内的灵长类动物的排斥反应。已经提出了几种抗CoB排斥的机制，其中许多机制与激活的同种异体反应表型T细胞的相对存在有关。我们现在发现，用CD2特异性融合蛋白LFA-3-Ig(Alefacept)治疗与CD28/B7靶向融合蛋白abatacept协同作用成功地防止了灵长类动物的肾移植排斥反应。我们假设，alefacept专门针对许多促进Cob抵抗的因素，包括异种同种异体反应性T细胞记忆，同时避免干扰用于促进Cob介导的同种异体移植接受的外围机制，包括T细胞调节和供者抗原特异性T细胞消除。因此，我们建议研究alefacept改善COB的机制，并利用这一信息优化其使用，开发一种临床适用的治疗方法，在不使用钙调神经磷酸酶抑制剂、类固醇或总T细胞耗竭的情况下防止同种异体移植排斥反应。在制定治疗方案时，我们将专门测试alefacept消除预先存在和诱导记忆T细胞的能力，评估alefacept对同种异体和记忆T细胞以及病毒特异性记忆T细胞的绝对和相对影响。在整个研究过程中，我们将确定这种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。根据初步证据表明供者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这种方案的效果的持久性，在不改变其对保护性免疫的影响的情况下增强了同种异体特异性效应。由于该方案使用的是被批准用于临床的药物，这将提供数据支持可立即翻译的策略，以防止人类的排斥反应，并建立关于T细胞记忆在阻止基于COB的免疫调节中的作用的概括性知识。 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，尚未开发出最有效、无毒的药物方案。

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.