Polyclonal Tregs to Promote Tolerance in Pediatric Liver Transplant Recipients

多克隆 Tregs 可促进儿童肝移植受者的耐受性

• 批准号: 9005804
• 负责人: Sandy Feng
• 金额: $ 94.15万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9005804
• 关键词: Acute; Adult; Adverse effects; Age; Allografting; Antibodies; Antigens; Autoantigens; Autologous; Biological Markers; Biopsy; Biopsy Specimen; Blood specimen; Child; Childhood; Clinical; Clinical Trials; Collaborations; Data; Dose; Enrollment; Face; Flow Cytometry; Frequencies; Gene Expression Profile; Gene Expression Profiling; Goals; Health; Histocompatibility Antigens; Histology; Human; Immune; Immune Tolerance; Immune response; Immune system; Immunohistochemistry; Immunosuppression; Informed Consent; Infusion procedures; Insulin-Dependent Diabetes Mellitus; Lead; Liver; Living Donors; Longevity; Maintenance; Mediating; Mission; Monitor; Morbidity - disease rate; Multi-Institutional Clinical Trial; National Institute of Allergy and Infectious Disease; Nature; Organ Transplantation; Participant; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phase I/II Trial; Plasma; Preparation; Regulatory T-Lymphocyte; Research; Risk; Safety; Sampling; Secondary to; Self-control as a personality trait; Stream; Supervision; T cell response; T cell therapy; Testing; Time; Tissues; Toxic effect; Transplant Recipients; Transplantation; Transplantation Tolerance; Weaning; Withdrawal; chemokine; clinical investigation; cytokine; experience; graft vs host disease; improved; innovation; insulin dependent diabetes mellitus onset; liver allograft; liver transplantation; mortality; novel therapeutics; open label; peripheral blood; phase 1 study; pilot trial; predicting response; response; restoration

DESCRIPTION (provided by applicant): Our long-term goal is to promote transplant tolerance in pediatric liver transplant recipients so that immunosuppression and the associated morbidity and mortality risks can be eliminated. Transplant tolerance can spontaneously develop and be identified through immunosuppression withdrawal. However, data consistently show that rate of spontaneous tolerance is low early after transplantation and increases slowly over time as multiple toxicities accumulate. Children face a particularly onerous burden of immunosuppression, extending over a long lifespan. Therefore new therapies that facilitate tolerance induction are much needed. Research in the past 20 years has demonstrated that regulatory T cells are essential for immune tolerance to self-antigens and can be therapeutically harnessed to induce transplant tolerance. Recently concluded phase I clinical trials in graft versus host disease and an ongoing clinical trial in type 1 diabetes demonstrate that regulatory T cell therapy is safe and potentially efficacious in suppressing alloimmune responses. Here we propose to conduct an open label, phase I/II, multi-center clinical trial to determine the safety and potential efficacy of a single infusion of autologous, polyclonally expanded, regulatory T cells to induce tolerance in non- tolerant pediatric liver transplant recipients. We will also perform mechanistic studies using peripheral blood and biopsy samples collected from trial participants to improve our understanding of transplantation tolerance and the impact of regulatory T cells on alloimmune responses in humans. We have established a collaborative network of six clinical centers and four mechanistic cores that have unique and relevant expertise as well as many pre-existing collaborations to conduct this trial. We plan to enroll 25 children 2 to 6 years after liver transplantation and identify non-tolerant patients through highly supervised gradual immunosuppression withdrawal. Twelve non-tolerant patients will be stabilized with immunosuppression for 6 to 12 months before receiving an infusion of autologous expanded regulatory T cells. These participants will undergo second attempt of immunosuppression withdrawal to determine whether regulatory T cell therapy can induce tolerance. Global gene expression profiling of blood and biopsy samples, multi-parameter immunohistology of liver tissue, and multiplex plasma cytokine and chemokine analysis will be used to identify biomarkers of tolerance, differences in immune responses between tolerant and non-tolerant patients, and impact of regulatory T cells on the immune responses. This proposal is strongly resonates with the mission of NIAID and CTOT-C "to promote understanding and reduce immune-mediated morbidity and mortality in vulnerable pediatric transplant recipients".

描述（由申请人提供）：我们的长期目标是提高儿科肝移植受者的移植耐受性，从而消除免疫抑制以及相关的发病和死亡风险。移植耐受可以自发产生并通过免疫抑制撤药来识别。然而，数据一致表明，移植后早期自发耐受率较低，并且随着多种毒性的累积，随着时间的推移，自发耐受率缓慢增加。儿童面临着特别繁重的免疫抑制负担，这种负担会持续很长的一生。因此，非常需要促进耐受诱导的新疗法。过去 20 年的研究表明，调节性 T 细胞对于自身抗原的免疫耐受至关重要，并且可以在治疗上利用它来诱导移植耐受。最近结束的移植物抗宿主病 I 期临床试验和正在进行的 1 型糖尿病临床试验表明，调节性 T 细胞疗法是安全的，并且在抑制同种免疫反应方面可能有效。在这里，我们建议进行一项开放标签、I/II 期、多中心临床试验，以确定单次输注自体、多克隆扩增的调节性 T 细胞在不耐受的儿科肝移植受者中诱导耐受的安全性和潜在功效。我们还将使用从试验参与者收集的外周血和活检样本进行机制研究，以提高我们对移植耐受性以及调节性 T 细胞对人类同种免疫反应影响的理解。我们建立了一个由六个临床中心和四个机械核心组成的协作网络，这些中心拥有独特且相关的专业知识以及许多预先存在的合作来进行这项试验。我们计划招募25名肝移植后2至6年的儿童，通过高度筛选来识别不耐受的患者。 监督下逐渐停止免疫抑制。 12 名不耐受的患者将通过免疫抑制稳定病情 6 至 12 个月，然后再接受自体扩增的调节性 T 细胞输注。这些参与者将进行第二次免疫抑制撤药尝试，以确定调节性 T 细胞疗法是否可以诱导耐受。血液和活检样本的整体基因表达谱、肝组织的多参数免疫组织学以及多重血浆细胞因子和趋化因子分析将用于识别耐受性生物标志物、耐受性和非耐受性患者之间免疫反应的差异以及调节性 T 细胞对免疫反应的影响。该提案与 NIAID 和 CTOT-C 的使命产生了强烈共鸣，即“促进了解并降低弱势儿科移植受者中免疫介导的发病率和死亡率”。