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: 8610243
• 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/8610243
• 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; 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; cytokine; experience; graft vs host disease; improved; innovation; insulin dependent diabetes mellitus onset; liver allograft; liver transplantation; mortality; open label; peripheral blood; phase 1 study; pilot trial; public health relevance; 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）：我们的长期目标是促进小儿肝移植接受者的移植耐受性，以便可以消除免疫抑制以及相关的发病率和死亡风险。可以通过免疫抑制戒断来自发发展和识别移植耐受性。但是，数据始终表明，移植后自发耐受的速率很低，并且随着多种毒性的积累，随着时间的推移会慢慢增加。孩子们面临着特别繁重的免疫抑制负担，延长了漫长的寿命。因此，急需促进耐受性的新疗法。在过去的20年中，研究表明，调节性T细胞对于免疫对自我抗原的耐受性至关重要，并且可以在治疗上利用以诱导移植耐受性。最近在移植物与宿主疾病的I期临床试验中结束了，1型糖尿病中正在进行的临床试验表明，调节性T细胞疗法是安全的，并且有效地抑制了同种免疫反应。在这里，我们建议进行开放标签，I/II期，多中心临床试验，以确定单一输注自体，多克隆扩展的调节性T细胞的安全性和潜在疗效，以诱导非耐受性儿科肝移植者的耐受性。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械研究，以提高我们对移植耐受性的理解以及调节性T细胞对人类同种免疫反应的影响。我们已经建立了一个由六个临床中心和四个具有独特和相关专业知识的机械核心的协作网络，以及许多先前存在的合作来进行此试验。我们计划在肝移植后2至6年招募25名儿童，并通过高度识别非耐受性患者 监督逐渐的免疫抑制戒断。在接受自体膨胀的调节性T细胞输注之前，十二名非耐受性患者将用免疫抑制稳定6至12个月。这些参与者将进行第二次免疫抑制戒断的尝试，以确定调节性T细胞疗法是否可以诱导耐受性。血液和活检样本的全球基因表达分析，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鉴定耐受性的生物标志物，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。该建议与NIAID和CTOT-C的使命具有强烈的共鸣，以促进脆弱的小儿移植受者的理解和减少免疫介导的发病率和死亡率”。