Determinants of donor-specific T cell tolerance in kidney transplantation in non-sensitized recipients

非致敏受者肾移植中供体特异性 T 细胞耐受的决定因素

• 批准号: 10622059
• 负责人: Xunrong Luo
• 金额: $ 109.12万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10622059
• 关键词: Anti-Inflammatory Agents; Antigens; Antithymoglobulin; Award; B cell clonality; B-Lymphocytes; Bar Codes; Biological; COVID-19 pandemic; Carbodiimides; Cell Therapy; Cells; Chemicals; Chronic; Clinical; Clonal Anergy; Clonal Deletion; Clonal Evolution; Clonality; Crosslinker; Cytomegalovirus; Cytomegalovirus Infections; Data Analytics; Environment; Future; Ganciclovir; Gene Expression; Genes; Immune; Immune Tolerance; Immunity; Immunosuppression; Impairment; Infection; Infusion procedures; Injections; Islets of Langerhans Transplantation; Kidney; Kidney Transplantation; Knowledge; Leukocytes; Living Donors; Lymphocyte; Lymphoid Tissue; Macaca mulatta; Maintenance; Maps; Modeling; Molecular; Mus; Opportunistic Infections; Organ; Output; Pattern; Phenotype; Population; Positioning Attribute; Predisposition; Regimen; Regulation; Reperfusion Injury; Resistance; Rhesus; Risk; Shapes; Sirolimus; Splenocyte; Sterility; T cell clonality; T-Lymphocyte; Technology; Testing; Therapeutic; Thymus Gland; Transplant Recipients; Transplantation; Transplantation Tolerance; Vaccines; Vascularization; Viremia; Virus; Virus Diseases; anergy; antiviral immunity; combinatorial; dynamical evolution; efficacy evaluation; efficacy testing; first-in-human; imprint; innovation; islet; islet allograft; isoimmunity; kidney allograft; living kidney donor; mouse model; multidimensional data; pathogen; pathogenic virus; post-transplant; preservation; prophylactic; single cell technology; transplant model

Studies from our current NHPCSG U19 revealed that induction with depletional thymoglobulin in combination with maintenance with co-stimulation blockade plus rapamycin (ATG/CoB/Rapa) is a highly effective regimen in repopulating the post-depletional lymphocyte repertoire with a naïve and CoB-sensitive phenotype. In this application, we hypothesize that this newly repopulated repertoire is now susceptible to donor-specific manipulation by an innovative cellular therapy using ECDI-treated, ex vivo expanded donor B cells to induce donor-specific transplantation tolerance via donor-specific deletion, anergy and regulation. To test our hypothesis, we will (1) deliver donor ECDI-B cells in the context of ATG/CoB/Rapa and determine its efficacy on the induction of donor-specific tolerance; (2) apply the cutting-edge technology of rhesus macaque single cell immune repertoire sequencing (scIRS) pioneered by our collaborator Dr. Peng at NCSU to investigate and precisely quantify donor-specific deletion, anergy or regulation at a single cell level. As infections have been brought into sharp focus by the recent SARS-CoV2 pandemic and have been shown to have a profound effect on the susceptibility and stability of immune tolerance, we propose to further interrogate the interaction between anti-viral immunity and donor-specific immune tolerance at a molecular level. We propose to use cytomegalovirus (CMV) as a model pathogen as it is commonly encountered in transplant recipients. With these goals in mind, we constructed three specific aims for this Project: Aim 1 will determine the efficacy of transplantation tolerance by donor ECDI-B cell infusions in the presence of ATG/CoB/Rapa in rhesus kidney transplantation, modeling both deceased donor as well as living donor kidney transplantation; Aim 2 will determine the effect of CVM exposures on the induction and maintenance of transplantation tolerance in rhesus macaques; and Aim 3 will employ cutting edge technologies including scIRS and the expertise in high- dimensional data analytics provided by the CIC to examine lymphocyte repertoire and functionality under tolerance conditions with or without concurrent CMV infection. At the completion of this project, we will: 1) establish a clinically feasible and effective regimen for transplantation tolerance induction in rhesus macaques using a combination of depletional induction and infusions of ECDI-fixed donor leukocytes; 2) understand the cellular and molecular mechanisms of this tolerance approach; 3) determine the effective components of therapeutic strategies to preserve transplantation tolerance in settings of unexpected viral infections. These advances will ultimately position us to conduct a first-in-human kidney transplant tolerance trial testing the optimized combinatorial regimen of donor ECDI-B cell infusions in the context of ATG/CoB/Rapa.

我们目前的NHPCSG U19的研究表明， 联合维持与共刺激阻断加雷帕霉素（ATG/CoB/Rapa）是一种非常有效的 方案在用幼稚和CoB敏感表型重新填充耗竭后淋巴细胞库中的作用。 在这个应用中，我们假设这个新重新填充的库现在对供体特异性免疫应答敏感。 通过使用ECDI处理的、离体扩增的供体B细胞的创新细胞疗法来诱导 供体特异性移植耐受通过供体特异性缺失、无反应性和调节实现。来测试我们 假设，我们将（1）在ATG/CoB/Rapa的背景下递送供体ECDI-B细胞，并确定其对 供体特异性耐受的诱导;（2）应用猕猴单细胞移植的前沿技术 免疫谱系测序（scIRS）由我们的合作者NCSU的Peng博士首创，用于研究和 在单细胞水平上精确定量供体特异性缺失、无反应性或调节。由于感染已经 最近的SARS-CoV 2大流行使其成为人们关注的焦点，并已被证明具有深远的影响 关于免疫耐受的敏感性和稳定性，我们建议进一步询问 分子水平上的抗病毒免疫和供体特异性免疫耐受。我们建议使用 巨细胞病毒（CMV）作为模型病原体，因为它通常在移植受体中遇到。与这些 考虑到这些目标，我们为这个项目制定了三个具体目标：目标1将决定 在存在ATG/CoB/Rapa的情况下通过供体ECDI-B细胞输注在恒河猴肾中的移植耐受 移植，模拟死亡供体以及活体供体肾移植; Aim 2将 确定CVM暴露对恒河猴移植耐受诱导和维持的影响 Aim 3将采用包括scIRS在内的尖端技术， CIC提供的多维数据分析，以检查淋巴细胞库和功能， 有或没有并发CMV感染的耐受性条件。在本项目完成后，我们将：1） 建立一种临床可行有效恒河猴移植耐受诱导方案 使用消耗诱导和输注ECDI固定的供体白细胞的组合; 2）了解 这种耐受方法的细胞和分子机制; 3）确定有效成分 在意外病毒感染的情况下保持移植耐受性的治疗策略。这些 这些进展将最终使我们能够进行首次人体肾移植耐受性试验， 在ATG/CoB/Rapa背景下供体ECDI-B细胞输注的优化组合方案。