Targeted delivery of immunomodulatory biologics for induction of immune privilege to allogeneic pancreatic islet grafts

项目总结 1型糖尿病(T1D)是一种慢性自身免疫性疾病，影响全球约1%的人口。 外源性胰岛素治疗是T1D的标准护理，但往往对生活质量和 在预防复发的高血糖发作和慢性并发症方面无效。最近的研究表明 人同种异体胰岛移植可以恢复长期正常血糖和胰岛素依赖性，保护严重的 免疫抑制的T1D患者的低血糖和微血管病变进展缓慢。然而， 免疫排斥和持续使用免疫抑制来控制排斥是两个主要的限制。 临床胰岛移植。标准的免疫抑制对移植物的长期存活无效 并且对移植物和移植物接受者也有显著的不良影响。因此，小说的发展 在没有慢性免疫抑制的情况下预防胰岛移植排斥反应的方法是一个重要的目标。 同种异体胰岛受到同种异体反应性T效应细胞和自身反应性T效应细胞的排斥。一个 致病T细胞和保护性T调节细胞(Treg)频率失衡是根本原因 T1D和同种异体胰岛移植排斥反应。恢复生理上的Tef和Treg平衡具有重要意义 治疗潜力。到目前为止，试图让天平向Treg细胞倾斜的方法针对的是 Teff或Treg单元单独用于调制，但成功率有限。此应用程序的主要目标是 同时针对这两种细胞类型进行调节，以获得有利于Treg细胞扩增的结果。这将是 使用创新的聚乙二醇水凝胶颗粒平台实现接枝靶向递送 以及作为Fas和IL-2R受体激动剂的两种新生物制剂的受控呈现。画眉草 被抗原激活的细胞表达Fas受体，对FasL介导的细胞凋亡变得敏感。IL-2R 信号优先使TJeff细胞对Fas诱导的细胞凋亡敏感，这也是Treg细胞所必需的 (CD4+CD25+FoxP3+)的生成、扩增和存活。因此，我们假设联合使用 Fas和IL-2R的激动剂将优先消除TJeff细胞并在体内产生/扩增Treg细胞 移植物微环境，导致诱导免疫豁免和胰岛的持续存活和功能 在没有任何免疫抑制的情况下进行异体移植。一组初步数据支持这一假设，并 为这一应用提供了很强的科学前提和可行性。这一概念将在三年内进行测试 不同同种异体胰岛移植的疗效和机制；化学性糖尿病BALB/c-to-to- 将C57BL/6小鼠、自发性糖尿病C57BL/6小鼠、人胰岛移植为人源化小鼠。这些 模型将生成与人类环境相关的关键数据。此外，有效性证明和 阐明调节有效结果的免疫机制将加速这一过程的进一步完善。 免疫调节概念及其最终移植到非人类灵长类动物作为临床试验的前奏 1型糖尿病的治疗。

PROJECT SUMMARY Type 1 diabetes (T1D) is a chronic autoimmune disorder that affects ~1% of population worldwide. Exogenous insulin treatment is the standard of care for T1D, but often negatively affects the quality of life and is ineffective in preventing recurrent hyperglycemia episodes and chronic complications. Recent studies show that human islet allografts can restore long-term normoglycemia and insulin independence, protect from severe hypoglycemia, and slow progression of microvascular lesions in immunosuppressed T1D patients. However, immune rejection and continuous use of immunosuppression to control rejection are two major limitations of clinical islet transplantation. Standard immunosuppression is ineffective in achieving long-term graft survival and also has significant adverse effects on the graft and graft recipients. Therefore, the development of novel approaches to prevent rejection of islet grafts without chronic immunosuppression is a significant goal. Allogeneic islets are subject to rejection by both alloreactive and autoreactive T effector (Teff) cells. An imbalance in the frequency of pathogenic Teff and protective T regulatory (Treg) cells is the underlying cause of T1D and allogeneic islet graft rejection. Restoring the physiological Teff and Treg balance has significant therapeutic potential. Approaches attempting to tilt the balance in favor of Treg cells have so far targeted either Teff or Treg cells individually for modulation with limited success. The primary goal of this application is to target both cell types simultaneously for modulation for an outcome in favor of Treg cell expansion. This will be achieved using innovative polyethylene glycol hydrogel particle platforms for graft-targeted delivery and controlled presentation of two novel biologics serving as agonists of Fas and IL-2R receptors. Teff cells activated by antigens express Fas receptor and become sensitive to FasL-mediated apoptosis. IL-2R signaling preferentially sensitizes Teff cells to Fas-induced apoptosis and is also required for Treg cells (CD4+CD25+FoxP3+) generation, expansion, and survival. Therefore, we hypothesize that the combined use of agonists of Fas and IL-2R will preferentially eliminate Teff cells and generate/expand Treg cells within the graft microenvironment, resulting in induced-immune privilege and sustained survival and function of islet allograft in the absence of any immunosuppression. A set of preliminary data support this hypothesis and provide strong scientific premise and feasibility for this application. This concept will be tested in three different allogeneic islet transplantation settings for efficacy and mechanisms; chemically diabetic BALB/c-to- C57BL/6 mice, spontaneously diabetic C57BL/6-to-NOD mice, and human islets into humanized mice. These models will generate critical data relevant to the human setting. Furthermore, proof-of-efficacy and the elucidation of the immune mechanisms regulating effective outcomes will expedite further refinement of this immunomodulatory concept and its eventual translation to nonhuman primates as a prelude to clinical trials for the treatment of type 1 diabetes.