T and B cell Homeostasis After Induction Therapy in Kidney Transplantation

肾移植诱导治疗后 T 和 B 细胞稳态

• 批准号: 8486388
• 负责人: Fadi G. Lakkis
• 金额: $ 33.88万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8486388
• 关键词: Acute; Address; Adrenal Cortex Hormones; Affect; Agreement; Allografting; Antibodies; Antithymoglobulin; B-Lymphocyte Subsets; B-Lymphocytes; Biopsy; CD8B1 gene; CDW52 gene; Cells; Chronic; Daclizumab; Enrollment; Equilibrium; Frequencies; Funding; Globulins; Goals; Graft Rejection; Homeostasis; Human; IL2RA gene; Immunofluorescence Immunologic; Immunosuppression; Incidence; Industry; Interleukin 2 Receptor; Isoantibodies; Kidney Transplantation; Lead; Living Donors; Lymphocyte; Lymphocyte Depletion; Maintenance; Mediator of activation protein; Memory; Mycophenolic Acid; Neoadjuvant Therapy; Outcome; Patients; Phenotype; Population; Preparation; Quantum Dots; Randomized; Reducing Agents; Regulatory T-Lymphocyte; Role; Staining method; Stains; Steroids; T cell response; T memory cell; T-Lymphocyte; T-Lymphocyte Subsets; Tacrolimus; Testing; Time; Transplant Recipients; Transplantation; Uncertainty; Withdrawal; antibody conjugate; basiliximab; cohort; improved; innovation; novel; prevent; prospective; reconstitution; response; stem; thymocyte; trial comparing

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.

描述（由申请人提供）： 在移植时，大多数肾脏移植受者目前接受淋巴结障碍（例如胸腺球蛋白）或非depledepleding（例如，basiliximab）抗体。这种形式的治疗被称为诱导，被用作防止急性排斥并减少维持免疫抑制（例如，避免类固醇或戒断）的一种手段。然而，在所有患者中均未观察到诱导的有益作用，并且尚不确定诱导治疗是否可以提高同种异体移植生存。这些不确定性源于诱导抗体是双刃剑：它们耗尽或阻止致病性淋巴细胞，但也可能干扰天然的免疫调节机制或导致同种反应性记忆淋巴细胞的反弹。因此，迫切需要表征诱导疗法的免疫学后果，并研究这些变化与人类的移植结果如何相关。朝向这些目标，我们建议对患者进行辅助，机械研究，以在接受相同维持免疫抑制的患者中，将大昔单抗诱导与胸腺球蛋白诱导进行比较（霉菌酸 +霉菌酸 +他的他的他的他的他的他的他的早期皮质糖粉）的疗程。具体目的是：（1）表征淋巴细胞 - 止血（胸腺球蛋白）与IL-2R1链（basiliximab）对活捐赠者肾脏肾移植者T和B细胞亚群的影响； （2）研究这些细胞群体的改变是否与急性排斥反应以及早期（1年）和晚期（3年）的移植结果相关。我们将检验以下假设：诱导后记忆和调节T和B细胞子集的分布的变化对于同种异体的结果至关重要。我们还将研究这些变化发生的机制以及T和B细胞室如何相互影响。这项研究的创新方面包括在移植后使用新的表型和功能研究，并使用多参数免疫荧光染色，用量子点点偶联抗体来表征人肾移植活检中的T和B细胞浸润​​。