T and B cell Homeostasis After Induction Therapy in Kidney Transplantation

描述(由申请人提供)： 目前，大多数肾移植受者在移植时接受去淋巴抗体(如胸腺球蛋白)或非去淋巴抗体(如巴利昔单抗)。这种治疗形式被称为诱导治疗，被用作预防急性排斥反应和减少维持性免疫抑制(例如，避免或停用类固醇)的一种手段。然而，并不是所有患者都能观察到诱导治疗的有益效果，诱导治疗是否能提高同种异体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：诱导抗体是一把双刃剑：它们耗尽或阻断致病淋巴细胞，但也可以干扰自然免疫调节机制或导致同种异体反应记忆淋巴细胞的反弹。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果的关系。为了达到这些目标，我们建议在接受相同的维持性免疫抑制(霉酚酸+他克莫司+早期糖皮质激素停药)的患者中，对接受干预试验的患者进行辅助性、机械性研究，比较巴利昔单抗诱导和胸腺球蛋白诱导。具体目的是：(1)研究淋巴细胞耗竭(胸球蛋白)与非耗竭靶向IL-2R1链(巴利昔单抗)对活体供体肾移植受者T和B细胞亚群的影响；以及(2)研究这些细胞群的变化是否与急性排斥反应和早期(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细胞隔间是如何相互影响的。这项研究的创新方面包括使用移植后B细胞亚群的新的表型和功能研究，以及使用量子点结合抗体的多参数免疫荧光染色来表征人类肾移植活检中的T和B细胞浸润物。

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.