T and B cell Homeostasis After Induction Therapy in Kidney Transplantation

描述（由申请人提供）： 大多数肾移植受者目前接受淋巴细胞清除（例如，胸腺球蛋白）或非消耗性（例如，巴利昔单抗）抗体。这种形式的治疗被称为诱导，并被用作预防急性排斥和减少维持免疫抑制的手段（例如，类固醇回避或戒断）。然而，诱导治疗的有益效果并没有在所有患者中观察到，诱导治疗是否能提高移植物的长期存活率仍不确定。这些不确定性源于这样一个事实，即诱导抗体是双刃剑：它们消耗或阻断致病淋巴细胞，但也可以干扰天然免疫调节机制或导致同种异体反应性记忆淋巴细胞反弹。因此，迫切需要描述诱导治疗的免疫学后果，并研究这些变化与人类移植结局的关系。为了实现这些目标，我们建议对即将参加干预性试验的患者进行辅助机制研究，比较接受相同维持免疫抑制（麦考酚酸+他克莫司+早期皮质类固醇停药）的患者的巴利昔单抗诱导与Thymoglobulin诱导。具体目标是：（1）描述淋巴细胞耗竭（Thymoglobulin）与非耗竭靶向IL-2 R1链（Basiliximab）对活体供肾移植受者T和B细胞亚群的影响;（2）研究这些细胞群的改变是否与急性排斥反应以及早期（1年）和晚期（3年）移植结果相关。我们将检验这一假设，即诱导后记忆和调节性T和B细胞亚群的分布变化是同种异体移植结果的核心。我们还将研究这些变化发生的机制以及T和B细胞区室如何相互影响。这项研究的创新方面包括使用新的表型和功能研究的B细胞亚群移植后和表征T和B细胞浸润在人类肾移植活检使用多参数免疫荧光染色与量子点共轭抗体。

DESCRIPTION (provided by applicant): The majority of kidney transplant recipients currently receive lymphodepleting (e.g., Thymoglobulin) or non-depleting (e.g., Basiliximab) antibodies at the time of transplantation. This form of therapy is known as induction and is employed as a means to prevent acute rejection and reduce maintenance immunosuppression (e.g., steroid avoidance or withdrawal). However, the salutary effects of induction are not observed in all patients and it remains uncertain whether induction therapy improves long-term allograft survival. These uncertainties stem from the fact that induction antibodies are double-edged swords: they deplete or block pathogenic lymphocytes but can also interfere with natural immunoregulatory mechanisms or lead to the rebound of alloreactive memory lymphocytes. Therefore, there is a critical need to characterize the immunological consequences of induction therapy and investigate how these changes relate to graft outcomes in humans. Towards these goals, we propose to perform ancillary, mechanistic studies on patients to be enrolled in an interventional trial comparing Basiliximab induction to Thymoglobulin induction in patients receiving identical maintenance immunosuppression (mycophenolic acid + Tacrolimus + early corticosteroid withdrawal). The specific aims are to: (1) characterize the effects of lymphocyte-depletion (Thymoglobulin) vs. non-depleting targeting of the IL-2R1 chain (Basiliximab) on T and B cell subsets in living donor renal transplant recipients; and (2) investigate whether alterations in these cell populations correlate with acute rejection and early (1-yr) and late (3-yr) graft outcomes. We will test the hypothesis that changes in the distribution of memory and regulatory T and B cell subsets after induction are central to allograft outcome. We will also investigate the mechanisms by which these changes come about and how the T and B cell compartments influence each other. Innovative aspects of the study include the use of novel phenotypic and functional studies of B cell subsets after transplantation and characterizing T and B cell infiltrates in human kidney transplant biopsies using multiparametric immunofluorescence staining with quantum dot-conjugated antibodies.