Combinatorial Beta Cell-Specific Cytokine Therapy to Reverse Type I Diabetes

逆转 I 型糖尿病的β细胞特异性细胞因子组合疗法

基本信息

批准号：
9240623
负责人：
Roland M Tisch
金额：
$ 37.84万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9240623
关键词：
Address Anti-Inflammatory Agents Anti-inflammatory Antigen-Presenting Cells Apoptosis Autoimmune Diseases Autoimmune Process Autoimmunity Beta Cell CD8B1 gene Cadaver Cellular biology Chronic Clinic Cytokine Signaling Dependovirus Diabetes Mellitus Disease remission Dose Dose-Limiting Ectopic Expression Eragrostis Event FOXP3 gene Gene Delivery Goals Homeostasis Human Immunobiology Immunotherapy Impairment Inbred NOD Mice Infiltration Inflammation Insulin Insulin-Dependent Diabetes Mellitus Interleukin-2 Islets of Langerhans Maintenance Mediating Modeling Mus Nature Organ Transplantation Pancreas Pathogenicity Pathogenicity Islets Pathology Regulatory T-Lymphocyte Reporting Residual state Rodent Model Safety Self Tolerance Specificity T-Lymphocyte Testing Tissues Translating Work adeno-associated viral vector base combinatorial cytokine cytokine therapy diabetic fitness humanized mouse immunoregulation improved in vivo inflammatory milieu islet islet allograft negative affect pre-clinical prevent public health relevance purge synergism

项目摘要

DESCRIPTION (provided by applicant): Type 1 diabetes (T1D) is a T cell-mediated autoimmune disease characterized by the destruction of the insulin producing ß cells found in the pancreatic islets of Langerhans. Impaired immunoregulation within the islets contributes to T1D in rodent models such as NOD mice, and very likely in humans. In NOD mice, onset of diabetes is marked by: i) heavy infiltration of the islets by pathogenic T cells and proinflammatory antigen presenting cells, ii) a diminished pool of islet Foxp3-expressing immunoregulatory T cells (Foxp3+Treg), and iii) the loss of 80-90% of ß cell mass. The nature and effectors of islet inflammation in human T1D appear to be more variable. Studies have reported cadaveric T1D pancreases being heavily infiltrated with T cells, but subjects with significant residual ß cell mass and in some instances, no detectable islet infiltration, have als been observed. We propose that directly manipulating the islet inflammatory milieu will prove to be the most effective strategy to broadly treat "subsets" of T1D. Recently, we demonstrated that late preclinical T1D is suppressed in NOD mice by targeting IL-2 expression to ß cells in vivo via adeno-associated virus (AAV) vector gene delivery. Protection was due to islet-specific expansion of Foxp3+Treg with enhanced suppressor function. Importantly, IL-2 expression was localized to the islets thereby avoiding the unwanted complications associated with systemic delivery of a potent, pleiotropic cytokine such as IL-2. The current application proposes to use AAV vectors to co-express anti-inflammatory cytokines in the islets to promote a synergistic effect leading to robust immunoregulation. Aim 1 will focus on defining mechanisms of synergy induced via combinatorial ß cell-specific cytokine expression in recent onset diabetic NOD mice. Aim 2 will explore the in vivo effects of ectopic cytokine expression on tissue-resident human effector T cells and FOXP3+Treg using humanized mice. A human islet allograft model is also being exploited to directly establish the efficacy of ß cell-specific cytokine expression on suppressing human islet pathology. The underlying hypothesis for this proposal is that Foxp3+Treg are regulated by non-redundant cytokine signals that together act synergistically to enhance homeostasis, fitness and function. Similarly, multiple cytokine signaling events synergize to mediate distinct mechanisms of Teff tolerance. Therefore combining anti-inflammatory cytokines for the purpose of immunotherapy will induce superior and qualitatively distinct immunoregulation. This proposal will advance our general understanding of how cytokines interact to regulate Foxp3+Treg immunobiology and Teff pathogenicity.

描述（由适用提供）：1型糖尿病（T1D）是T细胞介导的自身免疫性疾病，其特征是在Langerhans的胰岛胰岛中发现了胰岛素产生的ß细胞。胰岛内的免疫调节受损在啮齿动物模型（例如NOD小鼠）中有助于T1D，并且很可能在人类中。在NOD小鼠中，糖尿病的发作标记：i）致病性T细胞和促炎性抗原呈现细胞对胰岛的大量浸润，ii）降低了表达免疫调节的T细胞（Foxp3+Treg）的胰岛液压池（Foxp3+Treg），以及III的损失80-90％的损失。人类T1D中胰岛注入的性质和影响似乎更可变。研究报告说，尸体T1D胰腺被T细胞大量浸润，但是具有显着残留β细胞肿块的受试者，在某些情况下，未观察到可检测到的胰岛浸润。我们建议直接操纵胰岛炎症环境将被证明是广泛处理T1D“子集”的最有效策略。最近，我们证明了晚期的临床前T1D通过通过腺相关病毒（AAV）载体基因递送将IL-2表达靶向ß细胞在NOD小鼠中抑制。保护是由于具有增强的抑制剂功能的Foxp3+Treg的胰岛特异性扩展。重要的是，IL-2表达位于胰岛上，从而避免了与全身传递潜在的，多效性细胞因子（如IL-2）相关的并发症。当前的应用建议使用AAV载体在胰岛中共表达抗炎细胞因子，以促进协同作用，从而导致强大的免疫调节。 AIM 1将集中在AIM 2中通过组合ß细胞特异性细胞因子表达诱导的协同作用的定义机制，将探索异位细胞因子表达对组织居住的人类效应T细胞和Foxp3+Treg的体内影响。还探索了人类胰岛同种异体移植模型，以直接建立ß细胞特异性细胞因子表达对抑制人类胰岛病理的有效性。该提案的基本假设是Foxp3+Treg受非冗余细胞因子信号的调节，这些信号共同起作用，以增强体内稳态，适应性和功能。同样，多个细胞因子信号事件合成了TEFF公差的介质不同机制。因此，为了进行免疫疗法的目的，将抗炎细胞因子结合起来将引起优越和质量上不同的免疫调节。该建议将提高我们对细胞因子如何相互作用以调节Foxp3+Treg免疫生物学和TEFF致病性的一般理解。