Novel Therapies to Improve Renal and Cardiac Allograft Outcomes

描述（由申请人提供）：提案的总体目标是开发新疗法，以改善高风险和低风险受者的肾脏和心脏移植的长期结局。1.心脏移植：我们将检验这一假设，即B细胞，通过促进间接T细胞同种异体反应性和体液同种异体免疫，在慢性移植物血管病变（CAV）的发展中发挥关键作用。我们提出了一项多中心、随机、安慰剂对照试验，300例PRA <10%的初次心脏移植受者将随机接受常规免疫抑制（他克莫司、MMF和快速类固醇减量）与抗CD 20 mAb（Rituxan）联合常规免疫抑制诱导治疗。主要终点是移植后1年通过IVUS发现的CAV发展。这项试验将与Peter Heeger博士合作进行，他还将提出一项单独的第二项试验性心脏试验，以使来自同一心脏联盟的高度致敏受体脱敏。2.肾移植：2A。我们将检验泰爱-Ig（BAFF和APRIL的融合蛋白拮抗剂）中断B细胞成熟将降低高度致敏的肾移植受者的急性排斥反应率并改善结果的假设。我们提出了一个多中心，随机，安慰剂对照试验中高度致敏（PRA >50%）死亡或活供体肾移植受者，已经经历了脱敏协议和/或接受了阴性交叉匹配的肾脏。我们将入组200例受试者，随机分为两组。所有患者将接受胸腺球蛋白和他克莫司、MMF和类固醇。实验组也将接受泰爱注射液治疗，主要终点是移植后1年活检证实的急性排斥反应率（细胞/抗体介导）。接受者将被随访24个月，以确定治疗对长期结局的影响。2B.我们将测试的假设，即策略，限制效应/记忆T细胞同种异体反应性和扩大调节性T细胞在体内将允许最小化的免疫抑制，以一个单一的代理在低风险肾移植受者。我们提出了一项初步的安全性和可行性研究，首先用胸腺球蛋白诱导，然后在移植后2-5个月每月注射（x4）低剂量胸腺球蛋白、LEA 29 Y（贝拉西普）和MMF。对照组将接受胸腺球蛋白诱导加他克莫司、霉酚酸酯和快速类固醇减量。我们计划以3：1的比例随机入组48例受试者，分别进入治疗组和对照组。主要终点是移植后6个月外周血中CD 4 + CD 25 + FOXP 3 + T细胞百分比。根据特定的临床标准，实验组的受者将在移植后1年开始停用MMF。3.对所有三项试验中的所有受试者进行广泛的机制研究，以检验上述干预性治疗方案与T细胞表型（效应/记忆和T细胞）、T细胞对供体同种异体抗原的同种异体反应性、体液同种异体免疫、T和B细胞的表型分化以及急性和慢性同种异体移植物功能障碍的分子介质的可测量变化相关的总体假设。我们将在心脏和肾移植受者中测试针对相关临床方案定制的特定假设和测定，目的是了解免疫生物学和治疗机制，并最终开发新的生物标志物来预测这些受者的短期和长期结局。 相关性：根据RFA的要求，我们在两组不同的器官移植受者（肾脏和心脏）中提出了新的治疗策略，并进行了广泛的机制研究，以更好地了解特定疾病过程的免疫生物学，我们治疗干预的作用机制，以及开发新的生物标志物。我们的研究对改善实体器官移植受者的预后具有重要意义。

DESCRIPTION (provided by applicant): The overall goal of proposal is to develop novel therapies for improvement of long-term outcomes of renal and cardiac transplants in high and low risk recipients. 1. Cardiac Transplantation: We will test the hypothesis that B cells, by promoting indirect T cell alloreactivity and humoral alloimmunity, play a critical role in development of chronic allograft vasculopathy (CAV). We propose a multicenter, randomized, and placebo controlled trial where 300 primary heart transplant recipients with a PRA of <10% will be randomized to conventional immunosuppression (tacrolimus, MMF and rapid steroid taper) versus induction therapy with anti-CD20 mAb (Rituxan) plus conventional immunosuppression. The primary endpoint is development of CAV by IVUS at one year post-transplant. This trial will be conducted in collaboration with Dr. Peter Heeger who will also be proposing a separate second pilot cardiac trail to desensitize highly sensitized recipients from the same cardiac consortium. 2. Kidney Transplantation: 2A. We will test the hypothesis that interruption of B cell maturation by TACI-lg (a fusion protein antagonist of BAFF and APRIL) will reduce acute rejection rates and improve outcome in highly sensitized renal transplant recipients. We propose a multicenter, randomized, and placebo controlled trial in highly sensitized (PRA >50%) deceased or live donor renal transplant recipients that have undergone a desensitization protocol and/or received a negative cross- matched kidney. We will enroll 200 subjects randomized into two groups. All patients will receive thymoglobulin and tacrolimus, MMF, and steroids. The experimental group will also be treated with TACI-lg. The primary endpoint will be biopsy-proven acute rejection rates (cellular/antibody mediated) at 1 year post- transplant. Recipients will be followed for 24 months to determine impact of therapy on long-term outcome. 2B. We will test the hypothesis that strategies that limit effector/memory T cell alloreactivity and expand regulatory T cells in vivo will allow minimization of immunosuppression to a single agent in low risk renal transplant recipients. We propose a pilot safety and feasibility study with initial induction with thymoglobulin followed by monthly injections (x4) of low dose thymoglobulin at months 2-5 post-transplant, LEA29Y (belatacept) and MMF. A control group will receive thymoglobulin induction plus tacrolimus, MMF and rapid steroid taper. We plan to enroll 48 subjects with 3:1 randomization in the therapeutic and control arms, respectively. The primary end point is percentage of CD4+CD25+FOXP3+ Tregs in the peripheral blood at 6 months post-transplant. Based on specific clinical criteria recipients in the experimental arm will then undergo withdrawal of MMF starting at 1 year post-transplant. 3. All subjects in all three trials will be followed with extensive mechanistic studies to test the overall hypothesis that the interventional therapeutic protocols described above are associated with measurable changes in the phenotype of T cells (effector/memory and Tregs), T cell alloreactivity against donor alloantigen, humoral alloimmunity, phenotypic differentiation of T and B cells, as well as molecular mediators of acute and chronic allograft dysfunction. We will test specific hypotheses and assays tailored to the relevant clinical protocol in cardiac and renal transplant recipients with the goal of understanding the immunobiology and mechanisms of therapy, and to ultimately develop novel biomarkers to predict short- and long-term outcomes in these recipients. Relevance: As required by the RFA we propose novel therapeutic strategies in two different groups of organ transplant recipients, kidney and heart, accompanied by extensive mechanistic studies to better understand the immunobiology of the specific disease process, the mechanisms of action of our therapeutic interventions, as well as develop novel biomarkers. Our studies have major implications for improving outcomes of solid organ transplant recipients.