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

逆转 I 型糖尿病的组合 β 细胞特异性细胞因子疗法

• 批准号: 8911506
• 负责人: Roland M Tisch
• 金额: $ 39.14万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 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/8911506
• 关键词: Address; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Antigen-Presenting Cells; Apoptosis; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Beta Cell; Biology; CD8B1 gene; Cells; Chronic; Clinic; Cytokine Signaling; Dependovirus; Diabetes Mellitus; Disease remission; Dose; Dose-Limiting; Ectopic Expression; Eragrostis; Event; Gene Delivery; Goals; Health; Homeostasis; Human; Immunobiology; Immunotherapy; Inbred NOD Mice; Infiltration; Inflammation; Inflammatory; Insulin; Insulin-Dependent Diabetes Mellitus; Interleukin-2; Islets of Langerhans; Maintenance; Mediating; Modeling; Mus; Nature; Organ Transplantation; Pancreas; Pathogenicity; 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; immunoregulation; improved; in vivo; islet; islet allograft; pre-clinical; prevent; purge; synergism

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（由申请人提供）：1型糖尿病（T1 D）是一种T细胞介导的自身免疫性疾病，其特征在于胰岛中发现的胰岛素产生细胞的破坏。胰岛内的免疫调节受损导致啮齿动物模型（如NOD小鼠）中的T1 D，并且很可能在人类中。在NOD小鼠中，糖尿病的发作以以下为标志：i）致病性T细胞和促炎性抗原呈递细胞对胰岛的严重浸润，ii）表达胰岛Foxp 3的免疫调节T细胞（Foxp 3 +Treg）的池减少，和iii）80-90%的胰岛细胞质量损失。人类T1 D中胰岛炎症的性质和效应物似乎更多变。研究已经报道了尸体T1 D胰腺被T细胞严重浸润，但是也观察到具有显著残余胰岛细胞团块的受试者，并且在某些情况下，没有可检测的胰岛浸润。我们建议直接操纵胰岛炎症环境将被证明是广泛治疗T1 D“亚群”的最有效策略。最近，我们证明了通过腺相关病毒（AAV）载体基因递送将IL-2表达靶向到体内T1 D细胞来抑制NOD小鼠中的晚期临床前T1 D。保护作用是由于Foxp 3 +Treg的胰岛特异性扩增以及增强的抑制功能。重要的是，IL-2表达定位于胰岛，从而避免了与全身递送强效多效性细胞因子如IL-2相关的不希望的并发症。当前的申请提出使用腺相关病毒载体在胰岛中共表达抗炎细胞因子，以促进协同效应，从而实现强大的免疫调节。目的1将集中于定义协同机制诱导通过组合的胰岛细胞特异性细胞因子的表达在新近发病的糖尿病NOD小鼠。目的2将使用人源化小鼠探索异位细胞因子表达对组织驻留的人效应T细胞和FOXP 3 +Treg的体内影响。人胰岛同种异体移植物模型也被用于直接建立胰岛细胞特异性细胞因子表达对抑制人胰岛病理学的功效。该提议的基本假设是Foxp 3 +Treg受非冗余细胞因子信号调节，这些信号一起协同作用以增强稳态、适应性和功能。类似地，多种细胞因子信号传导事件协同作用以介导Teff耐受性的不同机制。因此，为了免疫治疗的目的而组合抗炎细胞因子将诱导上级和质量上不同的免疫调节。这一建议将促进我们对细胞因子如何相互作用以调节Foxp 3 +Treg免疫生物学和Teff致病性的一般理解。