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的治疗方法，以改善高风险和低风险受体肾和心脏移植的长期预后。1. 心脏移植：我们将验证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，在慢性同种异体移植血管病变（CAV）的发展中起关键作用的假设。我们提出了一项多中心、随机、安慰剂对照试验，将300名PRA <10%的原发性心脏移植受者随机分为常规免疫抑制组（他克莫司、MMF和快速类固醇减量）和抗cd20单抗(Rituxan) +常规免疫抑制诱导组。主要终点是移植后1年IVUS发生CAV。该试验将与Peter Heeger博士合作进行，他还将提出一个单独的第二先导心脏试验，以使来自同一心脏联盟的高度敏感受者脱敏。2. 肾移植：2A。我们将验证TACI-lg （BAFF和APRIL的融合蛋白拮抗剂）中断B细胞成熟的假设，以降低急性排斥率并改善高度敏感的肾移植受者的预后。我们建议进行一项多中心、随机、安慰剂对照试验，研究对象为高度致敏（PRA >50%）的已故或活体供体肾移植受者，这些受者接受了脱敏方案和/或阴性交叉匹配肾。我们将招募200名受试者，随机分为两组。所有患者将接受胸腺球蛋白、他克莫司、MMF和类固醇治疗。实验组也将接受TACI-lg治疗。主要终点是移植后1年活检证实的急性排斥率（细胞/抗体介导）。接受者将随访24个月，以确定治疗对长期结果的影响。2 b。我们将验证这样的假设，即限制效应/记忆T细胞异体反应和扩大体内调节性T细胞的策略将使低风险肾移植受者对单一药物的免疫抑制最小化。我们建议进行一项安全性和可行性的试点研究，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、LEA29Y （belataccept）和MMF。对照组接受胸腺球蛋白诱导加他克莫司、MMF和类固醇快速减量治疗。我们计划在治疗组和对照组分别以3:1随机分组入组48名受试者。主要终点是移植后6个月外周血中CD4+CD25+FOXP3+ Tregs的百分比。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. 所有三个试验中的所有受试者都将进行广泛的机制研究，以验证上述介入治疗方案与T细胞表型（效应/记忆和treg）、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细胞和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。我们将测试针对心脏和肾脏移植受者的相关临床方案的特定假设和分析，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果。

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.