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（由申请人证明）：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的胰岛胰岛中发现的胰岛素Ducingß细胞，在胰岛内的免疫调节中，胰岛在诸如NOD MITIC MICITY MICITE的胰岛中有助于T1D。，很可能在人类中。，iii）80-90％的BLE的研究报告了尸体T1D腐烂的肿块被T细胞大量渗透，但是具有显着的残留β细胞质量和实例，没有可检测到的浸润伊斯莱特炎症环境将证明T1D的最有效策略”最近，我们证明了临床前T1D通过靶向IL-2细胞ILO相关病毒（AAV）载体递送在NOD小鼠中被抑制。对于具有增强的抑制剂功能的Foxp3+Treg的特定膨胀，IL-2 Express始终避免使用SY SY的不必要的认可应用于我们的AAV载体在协同的抗炎性细胞因子中，导致通过组合ß细胞特异性细胞因子表达糖尿病的糖尿病糖尿病小鼠的YNND。 +使用人性化的小鼠直接建立表达人类胰岛病理的细胞特异性细胞因子。为了免疫疗法的目的，YTOKINE的中位数会放纵和静脉差异。