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：
10713401
负责人：
Kristy M Ainslie
金额：
$ 11.08万
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/10713401
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，青少年糖尿病研究还没有治愈自身免疫性疾病 1 型糖尿病 (T1D) 的方法。基金会估计，由于免疫介导，每天约有 80 人被新诊断出患有这种疾病。产生胰岛素的 β 细胞遭到破坏，目前 T1D 的治疗仅限于每日外源性胰岛素我们需要的是选择性抑制  细胞自身免疫的免疫疗法。预防和治疗 T1D 的一种方法是施用  细胞自身抗原来抑制和治疗。重要的是，这种方法避免了对糖尿病效应 T 细胞的耐受性。尽管临床上测试的其他 T1D 免疫疗法很有前景，但基于抗原的 T1D 免疫疗法已经取得进展。我们一直在研究可生物降解的乙缩醛葡聚糖微粒，仅显示出有限的临床结果。（Ac-DEX MPs）作为传递抗原和免疫调节药物的聚合物载体，具有以下特点：许多特性非常适合抑制 T 细胞介导的自身免疫和重建自我耐受。值得注意的是，我们已经证明，可以操纵 Ac-DEX MP 以可调节的方式在体内释放货物。货物释放的时间对引发的免疫反应的性质和强度有显着影响。此外，利用该平台，我们最近表明，封装耐受性的 Ac-DEX MP 的交付药物（雷帕霉素）和  细胞衍生肽在过继性 T 细胞转移模型中有效预防糖尿病因此，当前提案的重点是开发和表征 T1D 的耐受性。 Ac-DEX MPs 封装免疫调节药物和  细胞衍生肽作为选择性我们勇敢地认为 MP 降解率加上共封装。免疫调节剂增强了我们的基于肽的疫苗的耐受性效力。根据假设，我们提出了两个目标：具体目标 1：将雷帕霉素和抗原封装在可调的 Ac-DEX 颗粒和颗粒系统的优化在这里我们将建立药物、剂量和系统。微粒的降解率，以最佳地抑制自身免疫反应。具体目标 2： Ac-DEX 颗粒制剂和 T1D 动物模型耐受机制的评估。目标是，我们将评估与免疫细胞摄取相关的 MP 贩运，描述潜在的特征制剂产生的耐受性反应，评估制剂的保护和治疗功效平台，并确认该疗法对获得性免疫没有影响。