Polyclonal Tregs to Promote Tolerance in Pediatric Liver Transplant Recipients

描述(申请人提供)：我们的长期目标是促进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率和死亡率风险。移植耐受可以自发地形成，并通过停用免疫抑制药物来识别。然而，数据一直表明，移植后早期的自发耐受率很低，随着时间的推移，随着多种毒性的积累，自发耐受率缓慢增加。儿童面临着特别沉重的免疫抑制负担，延长了很长的寿命。因此，迫切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细胞对自身抗原的免疫耐受是必不可少的，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的I期临床试验和正在进行的1型糖尿病的临床试验表明，调节性T细胞疗法在抑制同种免疫反应方面是安全的，并且潜在有效。在这里，我们建议进行一项开放标签的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细胞以诱导非耐受性儿童肝移植受者耐受的安全性和潜在有效性。我们还将使用从试验参与者那里收集的外周血液和活检样本进行机制研究，以提高我们对移植耐受性和调节性T细胞对人类同种免疫反应的影响的理解。我们已经建立了一个由六个临床中心和四个机械核心组成的合作网络，这些中心拥有独特和相关的专业知识，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到6年的儿童，通过高度耐受来识别不耐受的患者。 监督逐步停用免疫抑制药物。12名不耐受的患者将通过免疫抑制稳定6至12个月，然后接受自体扩增的调节性T细胞的输注。这些参与者将接受第二次免疫抑制停药尝试，以确定调节性T细胞治疗是否可以诱导耐受。将使用血液和活检样本的全球基因表达谱、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来识别耐受的生物标志物，耐受和不耐受患者之间的免疫反应差异，以及调节性T细胞对免疫反应的影响。这项提议与NIAID和CTOT-C的使命产生了强烈的共鸣，他们的使命是“促进了解，减少脆弱的儿科移植受者中免疫介导的发病率和死亡率”。

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".