A Novel Combination Therapy for Type 1 Diabetes Prevention

预防 1 型糖尿病的新型联合疗法

• 批准号: 9331929
• 负责人: Olivia A Bailey
• 金额: $ 3.87万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-16 至 2020-05-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9331929
• 关键词: Adoptive Transfer; Adverse effects; Antigen-Presenting Cells; Antigens; Antithymoglobulin; Area; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Bacteria; Biological Assay; Biological Markers; Biological Preservation; Biomedical Engineering; Blood Glucose; CD3 Antigens; CD4 Positive T Lymphocytes; Caring; Cells; Clinical; Clinical Trials; Combined Modality Therapy; Complex; Containment; Crohn' s disease; Cross-Sectional Studies; Dendritic Cells; Dependence; Development; Diabetes Mellitus; Diabetes prevention; Disease; Disease Management; Dose; Engineering; Environment; Environmental Risk Factor; Essential Amino Acids; Eukaryota; Expenditure; FDA approved; Flow Cytometry; Food; Frequencies; Future; Gastrointestinal tract structure; Genetic; Genetic Engineering; Genetic Predisposition to Disease; Goals; Growth; Gut associated lymphoid tissue; Helper-Inducer T-Lymphocyte; Human; Human body; Hypoglycemia; Immune; Immune Tolerance; Immune response; Immune system; Immunoglobulin G; Immunosuppression; Immunosuppressive Agents; In Vitro; Inbred NOD Mice; Incidence; Income; Individual; Infection; Injectable; Injection of therapeutic agent; Insulin; Insulin-Dependent Diabetes Mellitus; Interleukin-10; Interruption; Intervention; Investigation; Islets of Langerhans; Lactococcus lactis; Life; Life Expectancy; Lymphocyte antigen; Lymphoid Cell; Malignant Neoplasms; Measures; Mediating; Medical; Mesentery; Monitor; Monoclonal Antibodies; Monoclonal Antibody HuM291; Oral; Oral Administration; Organ; Pancreas; Patients; Phenotype; Population; Prevention; Process; Production; Proinsulin; Proteins; Recombinants; Regulatory T-Lymphocyte; Research; Risk; Symptoms; System; T-Lymphocyte; Technology; Testing; Therapeutic; Therapeutic Uses; Thymidine; Time; To autoantigen; Translating; Treatment Efficacy; Vascular Diseases; blood glucose regulation; combinatorial; commensal microbes; cost; cytokine; effective therapy; efficacy testing; experimental study; glucose monitor; improved; in vivo; innovation; insulin dependent diabetes mellitus onset; interest; lymph nodes; mouse model; novel; oral tolerance; prevent; social; standard care; treatment response

Project Summary/Abstract Type 1 Diabetes (T1D) is characterized by a targeted autoimmune attack against self-antigens present on or within the insulin-producing  cells of the pancreatic islets of Langerhans, resulting in their destruction and subsequent loss of systemic blood glucose homeostasis. Current treatment options include lifelong disease management via frequent blood glucose monitoring and injections with exogenous insulin, but to date, there is no cure or means to prevent the disease in humans. Significant progress has been made improving patients' ability to manage their T1D symptoms (i.e., various forms of insulin, continuous glucose monitoring, and more), but even with rigorous glycemic monitoring, micro- and macro-vascular disease are common and life expectancy reduced. This, combined with high cost of T1D care, supports a pressing need for a safe and effective therapy. Systemic immunosuppression can offer a temporary reprieve from autoimmunity and T1D, but these treatments, associated with toxic side effects, are not antigen specific and thus, do not address the underlying cause of the disease. Previous studies have shown that combining a short course immunosuppressant, anti-CD3 monoclonal antibody (mAb), with daily oral administration of genetically modified Lactococcus lactis (L. lactis) expressing a key T1D autoantigen (proinsulin) and a tolerogenic cytokine (IL-10) (L. lactis PINS-IL-10) prevents and reverses T1D in non-obese diabetic (NOD) mice by inducing lasting antigen-specific immunological tolerance. L. lactis PINS-IL-10 is non-pathogenic, non-colonizing, and lacks the ability to produce the essential amino acid thymidine which serves as a containment system to prevent dissemination into the environment. This innovative L. lactis technology is generally regarded as safe (GRAS) by the FDA and approved for use in humans for the treatment of Crohn’s disease. However, anti-CD3 mAb is not FDA approved for human clinical use. Herein, we propose oral treatment of NOD mice with L. lactis PINS-IL-10 combined with an alternative immunosuppressive agent, anti- thymocyte globulin (ATG), which has been approved for use in humans for decades. We expect that ATG + L. lactis PINS-IL-10 combination therapy will significantly prevent or delay T1D onset in NOD mice. In addition to studies of treatment efficacy, detailed investigations of therapeutic mechanism will be performed including cross-sectional analysis of regulatory T cells, helper T cells, dendritic cells, and innate lymphoid cells by flow cytometry of the gut associated lymphoid tissues (GALT), the target organ (pancreas), and pancreatic draining lymph nodes; functional assays measuring T cell autoantigen recall and regulatory T cell (Treg) suppression; and in vivo adoptive transfer of T1D. Phenotypic or functional changes in the immune cell subsets responsible for oral tolerance induction by the proposed therapy might offer important utility as biomarkers for monitoring therapeutic response in future studies. If effective, this combinatorial treatment can quickly be translated for human use and by modifying the autoantigen secreted by L. lactis, offers potential application in additional autoimmune diseases beyond T1D. Thus, we expect that ATG + L. lactis PINS-IL-10 combination therapy may present a much-needed low-risk intervention to prevent or even cure T1D.

项目摘要/摘要 1型糖尿病（T1D）的特征是针对存在或内部的自身免疫性攻击 产生胰岛素的胰岛细胞的胰岛胰岛细胞，导致其破坏并随后丧失 全身血糖稳态。当前的治疗选择包括经常血液的终身疾病管理 葡萄糖监测和注射外源性胰岛素，但迄今 人类。已经取得了重大进展，提高了患者管理其T1D症状的能力（即各种 胰岛素的形式，连续的葡萄糖监测等等），但即使进行严格的血糖监测，微型和微型 宏 - 血管疾病很常见，预期寿命降低。加上高昂的T1D护理成本，支持A 迫切需要安全有效的疗法。系统性免疫抑制可以提供暂时的缓刑 自身免疫性和T1D，但这些与有毒副作用相关的治疗方法不是抗原特异性的，因此不要 解决该疾病的根本原因。先前的研究表明，结合简短的课程 免疫抑制剂，抗CD3单克隆抗体（MAB），每天口服一般修饰 乳酸乳酸乳酸（L.乳酸）表达钥匙T1D自动抗原（促硫素）和耐受性细胞因子（IL-10）（L.乳酸乳杆菌） PIN-IL-10）通过诱导的持久抗原特异 免疫耐受性。乳酸乳杆菌PIN-IL-10是非致病性的，非殖民化的，并且缺乏产生的能力 必需的氨基酸胸苷，可作为阻止环境传播的遏制系统。这 FDA通常认为创新的乳酸乳杆菌技术被认为是安全的（GRA），并批准用于人类 克罗恩病的治疗。但是，抗CD3 MAB未获得FDA批准用于人类临床使用。在这里，我们建议 口服乳酸乳杆菌销子-IL-10与替代免疫抑制剂，抗 - 胸腺细胞球蛋白（ATG）已被批准用于人类数十年。我们希望ATG + L.乳酸 PINS-IL-10组合疗法将显着预防或延迟NOD小鼠的T1D发作。除了研究 治疗效率，将对治疗机制进行详细研究，包括横截面分析 调节性T细胞，辅助T细胞，树突状细胞和先天淋巴样细胞通过肠道相关的流式细胞仪 淋巴组织（GALT），靶器官（胰腺）和胰腺排干淋巴结；功能测定测量 T细胞自动抗原召回和调节性T细胞（TREG）抑制；和T1D的体内自适应转移。表型或 拟议疗法负责口服耐受性诱导口服耐受性的免疫细胞子集的功能变化可能会提供 重要的效用作为在未来研究中监测治疗反应的生物标志物。如果有效，该组合 可以快速翻译治疗以供人类使用，并通过修改L.乳酸分泌的自动抗原，提供潜在的潜力 在T1D以外的其他自身免疫性疾病中应用。那就是我们预计ATG + L.乳酸杆菌销钉IL-10 联合疗法可能会提供急需的低风险干预措施，以预防甚至治愈T1D。