Polyclonal Tregs to Promote Tolerance in Pediatric Liver Transplant Recipients

描述（由申请人提供）：我们的长期目标是促进儿科肝移植受者的移植耐受性，以便消除免疫抑制和相关的发病率和死亡率风险。移植耐受性可以自发地发展，并通过免疫抑制剂撤药来鉴定。然而，数据一致显示，移植后早期的自发耐受率较低，并且随着时间的推移随着多种毒性的累积而缓慢增加。儿童面临着免疫抑制的特别沉重的负担，这种负担会延续很长的寿命。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细胞对于对自身抗原的免疫耐受至关重要，并且可以在治疗上用于诱导移植耐受。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细胞治疗是安全的，并可能有效地抑制同种免疫反应。在此，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细胞在非耐受性儿科肝移植受者中诱导耐受的安全性和潜在疗效。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制核心组成的合作网络，这些中心拥有独特的相关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，通过高度评价肝移植的耐受性， 在监督下逐步停用免疫抑制剂。12名非耐受患者将在接受自体扩增的调节性T细胞输注之前用免疫抑制稳定6至12个月。这些受试者将接受第二次免疫抑制退出尝试，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局基因表达谱分析、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来鉴定耐受性的生物标志物、耐受性和非耐受性患者之间的免疫应答差异以及调节性T细胞对免疫应答的影响。这一建议与NIAID和CTOT-C的使命“促进理解和减少免疫介导的脆弱儿科移植受者的发病率和死亡率”产生了强烈的共鸣。

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".