A Novel Combination Therapy for Type 1 Diabetes Prevention

预防 1 型糖尿病的新型联合疗法

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

项目概要/摘要 1 型糖尿病 (T1D) 的特点是针对存在于皮肤表面或内部的自身抗原进行有针对性的自身免疫攻击。胰岛中产生胰岛素的  细胞，导致其破坏并随后丧失当前的治疗选择包括通过频繁血液进行终身疾病管理。血糖监测和注射外源性胰岛素，但迄今为止，还没有治愈或预防这种疾病的方法人类在改善患者控制 T1D 症状（即各种症状）的能力方面取得了重大进展。形式的胰岛素、连续血糖监测等），但即使有严格的血糖监测，微量和大血管疾病很常见，预期寿命缩短，再加上 T1D 护理的高昂费用，支持了这一趋势。迫切需要一种安全有效的治疗方法，可以暂时缓解这种情况。自身免疫和 T1D，但这些治疗方法与毒副作用相关，不具有抗原特异性，因此不先前的研究表明，结合短期疗程可以解决疾病的根本原因。免疫抑制剂，抗 CD3 单克隆抗体 (mAb)，每日口服转基因药物乳酸乳球菌 (L.lactis) 表达关键的 T1D 自身抗原（胰岛素原）和耐受性细胞因子 (IL-10)（乳酸乳球菌） PINS-IL-10) 通过诱导持久的抗原特异性来预防和逆转非肥胖糖尿病 (NOD) 小鼠的 T1D 免疫耐受性。乳酸乳球菌 PINS-IL-10 是非致病性、非定植性的，并且缺乏产生必需氨基酸胸苷，作为防止传播到环境中的遏制系统。创新的乳酸乳球菌技术被 FDA 普遍认为是安全的 (GRAS)，并批准用于人类然而，抗 CD3 mAb 尚未获得 FDA 批准用于人类临床。用乳酸乳球菌 PINS-IL-10 联合替代免疫抑制剂（抗- 胸腺细胞球蛋白 (ATG) 已被批准用于人类数十年，我们预计 ATG + 乳酸乳球菌。 PINS-IL-10 联合疗法将显着预防或延迟 NOD 小鼠的 T1D 发病。治疗效果，将进行治疗机制的详细研究，包括横断面分析通过流式细胞术检测肠道相关的调节性 T 细胞、辅助性 T 细胞、树突状细胞和先天性淋巴细胞淋巴组织（GALT）、靶器官（胰腺）和胰腺引流淋巴结功能测定； T 细胞自身抗原召回和调节性 T 细胞 (Treg) 抑制；以及 T1D 的体内过继转移。负责通过所提出的疗法诱导口服耐受的免疫细胞亚群的功能变化可能会提供如果有效的话，这种组合在未来的研究中作为监测治疗反应的生物标志物具有重要的用途。治疗方法可以快速转化为人类使用，并且通过修改乳酸乳球菌分泌的自身抗原，提供了潜力因此，我们预计 ATG + 乳酸乳球菌 PINS-IL-10 在其他自身免疫性疾病中的应用。联合治疗可能是预防甚至治愈 T1D 所急需的低风险干预措施。