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(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，其特征是朗格汉斯胰岛中发现的胰岛素产生细胞被破坏。在NOD小鼠等啮齿动物模型中，胰岛免疫调节受损导致T1D，很可能在人类中也是如此。在NOD小鼠中，糖尿病的发病特点是：1)致病T细胞和前炎性抗原提呈细胞对胰岛的大量渗透；2)表达Foxp3的免疫调节性T细胞池减少(Foxp3+Treg)；3)失去80%-90%的？细胞团。人类T1D胰岛炎症的性质和影响因素似乎更具变异性。已有研究报道身体T1D胰腺中大量T细胞渗透，但仍可观察到有显著残余细胞团块的受试者以及在某些情况下未检测到胰岛浸润的ALS。我们认为，直接操纵胰岛炎症环境将被证明是广泛治疗T1D“亚组”的最有效的策略。最近，我们通过腺相关病毒(AAV)载体的基因传递，在体内将IL-2的表达靶向？细胞，从而抑制了NOD小鼠的晚期临床前T1D。这种保护是由于Foxp3+Treg的胰岛特异性扩增和增强的抑制功能所致。重要的是，IL-2的表达定位于胰岛，从而避免了全身注射强大的、多功能的细胞因子如IL-2所引起的不必要的并发症。目前的应用建议使用AAV载体在胰岛中共表达抗炎细胞因子，以促进协同效应，从而实现强大的免疫调节。目的1将重点研究在新近发病的糖尿病NOD小鼠中，通过细胞特异性细胞因子的组合表达而诱导协同作用的机制。目的2利用人源化小鼠，探讨异位表达细胞因子对组织驻留的人效应T细胞和FOXP3+Treg的影响。人类同种异体胰岛移植模型也被用来直接确定细胞特异性细胞因子表达在抑制人类胰岛病理方面的有效性。这一提议的基本假设是，Foxp3+Treg受非冗余细胞因子信号的调控，这些信号共同协同作用，增强体内平衡、健康和功能。类似地，多个细胞因子信号事件协同作用，调节不同的TJeff耐受机制。因此，结合抗炎细胞因子用于免疫治疗，将会产生优越的、定性的免疫调节。这一建议将促进我们对细胞因子如何相互作用来调节Foxp3+Treg免疫生物学和TEF致病性的总体理解。