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

• 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
• 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

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 (T1D) 是一种 T 细胞介导的自身免疫性疾病，其特征是胰岛中发现的产生胰岛素的 β 细胞遭到破坏。在啮齿类动物模型（例如 NOD 小鼠）中，胰岛内的免疫调节受损会导致 T1D，并且很可能在人类中发生。在 NOD 小鼠中，糖尿病发作的特点是：i) 胰岛被致病性 T 细胞和促炎性抗原呈递细胞严重浸润，ii) 胰岛表达 Foxp3 的免疫调节 T 细胞 (Foxp3+Treg) 池减少，以及 iii) 80-90% 的 ß 细胞质量损失。人类 T1D 中胰岛炎症的性质和效应因素似乎更加多变。研究报告称，尸体 T1D 胰腺被 T 细胞严重浸润，但也观察到受试者具有显着残留的 ß 细胞量，并且在某些情况下，没有可检测到的胰岛浸润。我们认为，直接控制胰岛炎症环境将被证明是广泛治疗“亚型”T1D 的最有效策略。最近，我们证明，通过腺相关病毒 (AAV) 载体基因递送将 IL-2 表达靶向体内 β 细胞，NOD 小鼠的晚期临床前 T1D 受到抑制。保护作用是由于 Foxp3+Treg 的胰岛特异性扩张和增强的抑制功能所致。重要的是，IL-2 表达局限于胰岛，从而避免了与全身递送强效多效性细胞因子（例如 IL-2）相关的不良并发症。目前的申请建议使用AAV载体在胰岛中共表达抗炎细胞因子，以促进协同效应，从而实现强大的免疫调节。目标 1 将重点关注在最近发病的糖尿病 NOD 小鼠中通过组合 ß 细胞特异性细胞因子表达诱导的协同机制。目标 2 将利用人源化小鼠探索异位细胞因子表达对组织驻留人类效应 T 细胞和 FOXP3+Treg 的体内影响。人类胰岛同种异体移植模型也被用来直接确定β细胞特异性细胞因子表达在抑制人类胰岛病理学方面的功效。该提议的基本假设是 Foxp3+Treg 受非冗余细胞因子信号调节，这些细胞因子信号共同协同作用以增强体内平衡、适应性和功能。同样，多种细胞因子信号传导事件协同作用，介导苔麸耐受的不同机制。因此，出于免疫治疗的目的，结合抗炎细胞因子将诱导优越且性质不同的免疫调节。该提案将增进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。