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

靶向递送免疫调节生物制剂以诱导同种异体胰岛移植物的免疫特权

• 批准号: 10227259
• 负责人: Andres J Garcia
• 金额: $ 42.1万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-12 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10227259
• 关键词: Acute; Adverse effects; Affect; Agonist; Allogenic; Antigens; Apoptosis; Apoptotic; Autoantigens; Autoimmune Diseases; Beta Cell; Binding; Biocompatible Materials; Biological; Biological Process; Biological Response Modifiers; C57BL/6 Mouse; CD8B1 gene; CD95 Antigens; Cell Death; Cell membrane; Chemicals; Chronic; Clinical; Clinical Treatment; Clinical Trials; Cloning; Complex; Data; Development; Engineering; Equilibrium; Eragrostis; FOXP3 gene; Failure; Formulation; Frequencies; Generations; Goals; Graft Rejection; Graft Survival; Homeostasis; Human; Hydrogels; Hyperglycemia; Hypoglycemia; IL2 gene; IL2RA gene; Immune; Immune response; Immunosuppression; Immunosuppressive Agents; Inbred BALB C Mice; Inbred NOD Mice; Individual; Innate Immune Response; Insulin; Insulin-Dependent Diabetes Mellitus; Interleukin-2; Islets of Langerhans; Islets of Langerhans Transplantation; Lead; Lesion; Life; Mediating; Membrane; Memory; Metabolic Control; Modeling; Outcome; Pathogenicity; Pathway interactions; Patients; Peripheral; Physiological; Play; Polyethylene Glycols; Population; Pre-Clinical Model; Prevention Protocols; Protocols documentation; Quality of life; Rattus; Recurrence; Regulatory T-Lymphocyte; Research; Rodent; Role; Signal Pathway; Signal Transduction; Skin; Streptavidin; Surface; T memory cell; T-Lymphocyte; Testing; Therapeutic; Time; Translations; Treatment Protocols; Tumor Necrosis Factor Ligand Superfamily Member 6; Work; alternative treatment; autoreactivity; base; cell type; chronic autoimmune disease; controlled release; design; diabetic; effective therapy; effector T cell; efficacy testing; extracellular; graft function; humanized mouse; immunoregulation; immunosuppressed; improved; innovation; islet; islet allograft; mouse model; negative affect; nonhuman primate; novel; novel strategies; particle; prevent; receptor; response; standard of care; success; synergism; targeted delivery; therapeutic target; translation to humans

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.

项目摘要 1型糖尿病（T1 D）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T1 D的标准治疗，但通常会对生活质量产生负面影响， 在预防复发性高血糖发作和慢性并发症方面是无效的。最近的研究表明 人类胰岛同种异体移植物可以恢复长期的正常血糖和胰岛素依赖性， 低血糖和免疫抑制T1 D患者微血管病变进展缓慢。然而，在这方面， 免疫排斥和连续使用免疫抑制来控制排斥是两个主要限制 临床胰岛移植。标准的免疫抑制对移植物的长期存活是无效的 并且对移植物和移植物受体也具有显著的不利影响。因此，小说的发展 在没有慢性免疫抑制的情况下防止胰岛移植物排斥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和自身反应性T效应细胞（Teff）的排斥。一个 致病性Teff和保护性调节性T（Treg）细胞频率的不平衡是根本原因 T1 D和同种异体胰岛移植物排斥反应。恢复生理Teff和Treg平衡具有显著的生物学效应。 治疗潜力迄今为止，试图使平衡倾向于Treg细胞的方法针对 Teff或Treg细胞单独进行调节，但成功有限。此应用程序的主要目标是 同时靶向两种细胞类型以调节有利于Treg细胞扩增的结果。这将 使用创新的聚乙二醇水凝胶颗粒平台实现移植物靶向递送 以及作为Fas和IL-2 R受体激动剂的两种新型生物制剂的受控呈递。Teff 被抗原激活的细胞表达Fas受体，并对FasL介导的凋亡变得敏感。IL-2R 信号传导优先使Teff细胞对Fas诱导的凋亡敏感，并且也是Treg细胞所需的 (CD4+ CD 25 + FoxP 3+）的产生、扩增和存活。因此，我们假设， Fas和IL-2 R的激动剂将优先消除Teff细胞并在细胞内产生/扩增Treg细胞。 移植物微环境，导致诱导免疫赦免和维持胰岛的存活和功能 在没有任何免疫抑制的情况下进行同种异体移植。一组初步数据支持这一假设， 为这一应用提供了强有力的科学前提和可行性。这一概念将在三个 不同的同种异体胰岛移植设置的疗效和机制;化学糖尿病BALB/c-to- C57 BL/6小鼠、自发性糖尿病C57 BL/6-to-NOD小鼠和人胰岛转化为人源化小鼠。这些 模型将产生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进一步完善这一机制。 免疫调节概念及其最终转化为非人灵长类动物作为临床试验的前奏， 1型糖尿病的治疗