USE OF LOW-DOSE IL-2 TO EXPAND ENDOGENOUS REGULATORY T CELLS AND ACHIEVE TRANSPLANTATION TOLERANCE

在实验动物模型中，一组被称为调节性T细胞或Tregs的免疫细胞被证明可以调节免疫系统，并在防止器官排斥、控制自身免疫和炎症性疾病方面发挥核心作用。在移植的动物模型中，Treg是诱导免疫耐受的关键，在这种情况下，移植的器官在没有抗排斥药物的情况下被无限期地接受。使用低剂量的IL-2已被证明可以选择性和安全地增加人类Tregs的数量，但这是否可以用来诱导移植患者的耐受性从未被研究过。肝移植是一种最佳的临床环境，因为有证据表明移植耐受可以在这些患者中自发发生(尽管只在移植后多年)，而且肝移植是唯一安全的实体器官移植环境，通过故意停止所有抗排斥药物来研究耐受的发展。我们的假设是，短疗程的低剂量IL-2将暂时增加Treg的数量，并允许永久停止抗排斥药物。在目前的项目中，我们建议进行一项临床研究，在这项研究中，自发获得耐受率非常低的肝移植受者在其抗排斥药物逐渐停用期间每天接受IL-2注射。将对患者进行仔细的研究，以调查以下情况：1)IL-2是否有效地扩大了肝移植患者的Treg数量。2)Tregs在循环和/或肝脏中的扩张是否有助于抗排斥药物的成功停止。3)移植患者免疫系统中Tregs数量的增加会产生什么影响。最终，该项目将有助于澄清供者特异性Tregs是否对建立移植耐受至关重要，以及低剂量IL-2在多大程度上是促进这一现象的有效策略。这将对许多其他炎症性疾病产生影响，并将为未来的临床试验打开大门，在这些临床试验中，低剂量的IL-2可以与其他促进耐受性的药物联合使用。

A population of immune cells, called regulatory T cells or Tregs, have been shown in experimental animal models to regulate the immune system and to play a central role in preventing organ rejection and in controlling autoimmune and inflammatory diseases. In animal models of transplantation, Tregs are key to induce immunological tolerance, a situation in which the transplanted organ is indefinitely accepted in the absence of anti-rejection medication. The use of IL-2 at low doses has been shown to selectively and safely increase the number of Tregs in humans, but whether this can be used to induce tolerance in transplanted patients has never been investigated. Liver transplantation is an optimal clinical setting to do so, given that there are evidences indicating that transplantation tolerance can spontaneously occur in these patients (albeit only many years after transplantation), and that liver transplantation is the only solid organ transplantation setting in which it is safe to investigate the development of tolerance by intentionally discontinuing all anti-rejection medications. Our hypothesis is that administration of a short course of low-dose IL-2 will transiently expand the number of Tregs and allow for the permanent discontinuation of anti-rejection medication. In the current project we propose to conduct a clinical study in which liver transplant recipients who have a very low probability of achieving tolerance spontaneously will receive daily injections of IL-2 during the period of time when their anti-rejection medication is gradually withdrawn. Patients will be carefully studied to investigate the following:1) Whether IL-2 is efficacious in expanding the number of Tregs in liver transplant patients. 2) Whether the expansion of Tregs in the circulation and/or the liver facilitates the successful discontinuation of anti-rejection medication.3) What are the effects of an increased number of Tregs in the immune system of a transplanted patient. Ultimately, the project will serve to clarify whether donor-specific Tregs are essential to establish transplantation tolerance, and the extent to which low-dose IL-2 is an effective strategy to promote this phenomenon. This will have implications for a number of other inflammatory diseases, and will open the door to future clinical trials in which low-dose IL-2 could used in combination with other tolerance-promoting medications.