Belatacept in De Novo Heart Transplant

摘要 虽然在过去的十年中，心脏移植后的生存率有所提高，但长期而言， 结果仍不理想，合并症负担高得不可接受， 发病率和死亡率。其中，肾功能不全仍然处于最前沿， 慢性钙调磷酸酶抑制剂（CNI）暴露导致的移植前肾损害 导致严重的慢性肾脏疾病（肌酐> 2.5mg/dL，透析或移植）， 四分之一的心脏移植受者在10年内。同时，心脏移植 生存受到无情的免疫过程的限制，无论是先天的还是适应性的， 心脏移植物血管病变（CAV）、纤维化和移植物衰竭的发生。的 新生供体特异性抗体（dnDSA）的出现尤其预示着更糟糕的结局5- 7.临床上，高血压、高胆固醇血症和糖尿病进一步促进肾损害。 功能障碍和不良的同种异体移植结果。因此，迫切需要更多的治疗方法， 有利地调节免疫应答，同时减少共病特征。 贝拉西普（CTLA 4-IG; NULOJIX®）是由以下结构域组成的融合蛋白： 人CTLA 4和人免疫球蛋白（IG）G1的Fc结构域。通过与CD 80结合， 抗原呈递细胞（APC）上的CD 86，贝拉西普阻止CD 28介导的关键信号传导 对于i）T细胞活化和增殖，ii）T滤泡辅助细胞（Tfh）分化，iii）同源 T/B细胞相互作用和iv）负责平衡的效应器和调节机制 接受和拒绝之间。Belatacept被FDA批准用于肾移植 受体的基础上，两个随机对照试验，这表明令人印象深刻的肾 节省利益，显着减少从头供体特异性抗体（DSA），并改善 长期成果。这一提议的核心假设是， 伴随他克莫司的入组期，将在新发时保留或保护肾功能 心脏移植受者，并提供持续的长期利益。具体来说，我们假设 除了无CNI方案的肾脏保护益处外，贝拉西普还将改善 i）损害从头体液反应及其下游后果，ii） 减轻同种异体免疫记忆，和iii）减少合并症的负担。的目标 目前的R34应用程序是开发一个临床试验方案，通过1） 确定基于贝拉西普的CNI保留方案对改善肾功能的功效 和心脏移植受者的心脏移植结局，以及2）调查 贝拉西普对T细胞同种免疫、体液应答和纤维化的影响。

ABSTRACT While the last decade has seen improvements in survival following heart transplant, long-term outcomes remain suboptimal with an unacceptably high burden of comorbidities contributing to morbidity and mortality. Amongst these, renal dysfunction remains at the forefront with underlying pre-transplant renal impairment perpetuated by chronic calcineurin inhibitor (CNI) exposure leading to severe chronic kidney disease (creatinine > 2.5mg/dL, dialysis, or transplant) in almost one-quarter of heart transplant recipients within 10-years. Simultaneously, cardiac allograft survival is limited by the relentless immunological processes, both innate and adaptive that drive the development of cardiac allograft vasculopathy (CAV), fibrosis, and graft failure. The appearance of de novo donor specific antibodies (dnDSA) in particular portend a worse outcome5- 7. Clinically, hypertension, hypercholesterolemia and diabetes further contribute to renal dysfunction and adverse allograft outcomes. Thus, there is an urgent need for therapies that more favorably modulate the immune response while simultaneously reduce the comorbidity profile. Belatacept (CTLA4-Ig; NULOJIX®) is a fusion protein comprised of the extracellular domain of human CTLA4 and the Fc domain of a human immunoglobulin (Ig) G1. By binding to CD80 and CD86 on antigen presenting cells (APCs), belatacept prevents CD28 mediated signaling critical for i) T cell activation and proliferation, ii) T follicular helper cell (Tfh) differentiation, iii) cognate T/B cell interactions and iv) both effector and regulatory mechanisms responsible for the balance between acceptance and rejection. Belatacept is FDA approved for use in kidney transplant recipients on the basis of two randomized controlled trials, which demonstrated impressive renal sparing benefits, a striking reduction in de novo donor specific antibodies (DSA), and improved long-term outcomes. The core hypothesis underlying this proposal is that belatacept, combined with an entry period of concomitant tacrolimus, will preserve or protect renal function in de novo heart transplant recipients and provide sustained long-term benefit. Specifically, we hypothesize that, in addition to the renoprotective benefits of a CNI-free regimen, belatacept will improve outcomes by i) impairing de-novo humoral responses and their downstream consequences, ii) mitigating alloimmune memory, and iii) reducing the burden of comorbidities. The goal of the current R34 application is to develop a clinical trial protocol that will test our hypothesis by 1) determining the efficacy of a belatacept-based CNI sparing regimen on improving renal function and cardiac allograft outcomes in heart transplant recipients, and 2) investigating the effects of belatacept on T-cell alloimmunity, humoral responses, and fibrosis.