Formulation to Generate Tolerance Towards Type 1 Diabetes

产生对 1 型糖尿病耐受性的配方

基本信息

批准号：
10615119
负责人：
Kristy M Ainslie
金额：
$ 38.16万
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：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10615119
关键词：
Abbreviations Acetals Acids Affect American Animal Model Antibodies Antigen Presentation Antigen Targeting Antigen-Presenting Cells Antigens Autoantigens Autoimmune Diseases Autoimmune Responses Autoimmunity B-Lymphocytes Beta Cell CD4 Positive T Lymphocytes Cells Cellular Immunity Child Chromogranin A Clinic Clinical Clinical Research Coupled Cyclosporine DNA cassette Data Dendritic Cells Dependence Dexamethasone Dextrans Diabetes Mellitus Disease Dose Encapsulated Engineering Eragrostis Evaluation FOXP3 gene Formulation Foundations Generations Goals Histocompatibility Antigens Class II Immune Immune mediated destruction Immune response Immunity Immunology Immunosuppressive Agents Immunotherapy In Vitro Inbred NOD Mice Incidence Individual Insulin Insulin-Dependent Diabetes Mellitus Internal Ribosome Entry Site Islet Cell Kidney Diseases Kinetics Macrophage Measures Mediating Metabolic Control Modeling Mouse Strains Mus Nature Neuropathy Newly Diagnosed Non obese Ovalbumin Pancreas Particle Size Particulate Patients Peptides Periodicity Phagolysosome Pharmaceutical Preparations Phenotype Play Polymers Prevention Proinsulin Property Qualifying Reading Recurrence Regulatory T-Lymphocyte Remission Induction Research Retinal Diseases Role Self Tolerance Sirolimus System T cell regulation T cell therapy T-Cell Receptor T-Lymphocyte Testing Transgenic Mice Transgenic Organisms Treatment Efficacy Vascular Diseases acquired immunity biodegradable polymer blood glucose regulation design diabetic diabetogenic effector T cell immune function immune modulating agents in vivo insulin dependent diabetes mellitus onset lymph nodes mouse model nano nephrotoxicity novel vaccines particle particle therapy peptide based vaccine peptidomimetics pre-clinical prevent programs protective efficacy response trafficking uptake

项目摘要

ABSTRACT Currently no cure exists for the autoimmune disease Type 1 diabetes (T1D). The Juvenile Diabetes Research Foundation estimates ~80 individuals are newly diagnosed with the disease, daily. Due to immune-mediated destruction of the insulin-producing β cells, current treatment of T1D is limited to daily exogenous insulin administration. What is needed are immunotherapies that selectively suppress  cell autoimmunity for the prevention and treatment of T1D. One approach is the administration of  cell autoantigen to suppress and tolerize diabetogenic effector T cells. Importantly, this approach avoids effects on protective immunity seen with other T1D immunotherapies tested in the clinic. Although promising, antigen-based immunotherapy for T1D has shown only modest clinical results. We have been studying biodegradable, acetalated dextran microparticles (Ac-DEX MPs) as a polymeric vehicle to deliver antigen and immunomodulatory drugs. Ac-DEX MPs have a number of properties well suited for suppressing T cell-mediated autoimmunity and reestablishing self-tolerance. Notably, Ac-DEX MPs can be manipulated to release cargo in vivo in a tunable manner. We have shown that timing of cargo release has marked effects on the nature and magnitude of the immune response that is elicited. Furthermore, using this platform, we have recently shown that delivery of Ac-DEX MPs encapsulating a tolerizing agent (rapamycin) and a  cell-derived peptide effectively prevents diabetes in an adoptive T cell transfer model of T1D. Accordingly, the focus of the current proposal is to develop and characterize the tolerogenic properties of Ac-DEX MPs encapsulating immunomodulatory drugs and  cell-derived peptides as a means to selectively suppress the diabetogenic response. We hypothesize that the rate of MP degradation plus the co-encapsulation of immunomodulatory agent enhances the tolerogenic potency of our peptide-based vaccine. To test this hypothesis, we have proposed two Aims: Specific Aim 1: Encapsulation of rapamycin and antigens in tunable Ac-DEX particles and optimization of particle system. Here we will establish drug, dosing, and degradation rate of the microparticles for optimum inhibition of the autoimmune response. Specific Aim 2: Evaluation of Ac-DEX particle formulation and mechanism of tolerance in animal models of T1D. In this Aim, we will evaluate the trafficking of the MPs as related to immune cell uptake, characterizing the underlying tolerogenic responses generated by the formulation, evaluate the protective and therapeutic efficacy of the platform, and confirm that the therapy has no effect on acquired immunity.

抽象的目前尚无治愈1型糖尿病（T1D）的自身免疫性疾病。少年糖尿病研究基金会估计，每天新诊断出约80个人。由于免疫介导胰岛素产生的β细胞的破坏，T1D的当前治疗仅限于每日外源胰岛素行政。需要选择性地抑制细胞自动免疫的免疫疗法 T1D的预防和处理。一种方法是给予细胞自动抗原以抑制和耐受性糖尿病效应T细胞。重要的是，这种方法避免对看到的保护性免疫的影响在诊所测试的其他T1D免疫疗法。尽管很有希望，但基于抗原的T1D免疫疗法具有仅显示适度的临床结果。我们一直在研究可生物降解的乙酰葡萄糖微粒（AC-DEX MPS）作为提供抗原和免疫调节药物的聚合物。 AC-DEX MPS有一个适合抑制T细胞介导的自身免疫和重新建立自我耐受性的属性数量。值得注意的是，可以操纵AC-DEX MPS以可调的方式在体内释放货物。我们已经表明货物释放的时机对引起的免疫反应的性质和大小有明显的影响。此外，使用此平台，我们最近表明，AC-DEX MP的交付封装了公差剂（雷帕霉素）和细胞衍生的肽有效防止被采用的T细胞转移模型中的糖尿病 T1D。彼此之间，当前建议的重点是发展和表征耐受性特性封装免疫调节药物和细胞衍生的肽的AC-DEX MPS的一种方法抑制糖尿病的反应。我们假设MP降解的速率加共同服免疫调节剂增强了基于肽的疫苗的耐受性效力。测试这个假设，我们提出了两个目的：特定目的1：雷帕霉素和抗原的封装可调的AC-DEX颗粒和粒子系统的优化。在这里，我们将建立药物，给药，并微粒的降解速率，以最佳抑制自身免疫反应。具体目标2：评估T1D动物模型中AC-DEX颗粒制剂和耐受性的机制。在这个目的，我们将评估MPS的贩运与免疫细胞摄取相关，表征了基础公式产生的耐受性反应，评估平台，并确认该疗法对获得的免疫力没有影响。