Diversity Supplement - Formulation to Generate Tolerance Towards Type 1 Diabetes

多样性补充剂 - 产生对 1 型糖尿病耐受性的配方

• 批准号: 10560761
• 负责人: Kristy M Ainslie
• 金额: $ 11.01万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 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/10560761
• 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; Disease remission; Dose; Encapsulated; Engineering; Eragrostis; Evaluation; FOXP3 gene; Formulation; Foundations; Generations; Goals; Histocompatibility Antigens Class II; Immune; Immune mediated destruction; Immune response; Immunity; Immunology; Immunomodulators; Immunosuppressive Agents; Immunotherapy; In Vitro; Inbred NOD Mice; Incidence; Individual; Insulin; Insulin-Dependent Diabetes Mellitus; Internal Ribosome Entry Site; Islet Cell; Kinetics; Measures; Mediating; Metabolic Control; Modeling; Mouse Strains; Mus; Nature; Neuropathy; Newly Diagnosed; Non obese; Ovalbumin; Pancreas; Parents; Particle Size; Particulate; Peptides; Periodicity; Phagolysosome; Pharmaceutical Preparations; Phenotype; Play; Polymers; Prevention; Proinsulin; Property; Reading; Recurrence; Regulatory T-Lymphocyte; 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; base; biodegradable polymer; blood glucose regulation; design; diabetic; diabetogenic; effector T cell; immune function; in vivo; insulin dependent diabetes mellitus onset; lymph nodes; macrophage; mouse model; nano; nephrotoxicity; non-diabetic; novel vaccines; parent grant; particle; peptide based vaccine; peptidomimetics; pre-clinical; prevent; protective efficacy; response; trafficking; uptake

ABSTRACT This submission is a supplement to our parent grant R01DK130225 “Formulation to Generate Tolerance Towards Type 1 Diabetes” Parent Abstract: Currently no cure exists for the autoimmune disease Type 1 diabetes (T1D), despite the fact that the Juvenile Diabetes Research Foundation estimates ~80 individuals are newly diagnosed with the disease, daily. Due to immune-mediated destruction of insulin-producing β cells, current treatment of T1D is limited to daily exogenous insulin administration. What is needed are immunotherapies that selectively suppress b cell autoimmunity for the prevention and treatment of T1D. One approach is the administration of b 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 the application of 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 b 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 b 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 immune 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 immune responses generated by the formulation, evaluate the protective and therapeutic efficacy of the platform, and determine the therapy results in loss of acquired immunity.

抽象的 此提交是我们父母赠款R01DK130225的补充 对1型糖尿病的容忍度” 父母摘要：目前尚无治愈自身免疫性疾病1型糖尿病（T1D），目的地事实 少年糖尿病研究基金会估计约有80个人被新诊断出患有这种疾病， 日常的。由于免疫介导的产生胰岛素的β细胞的破坏，当前T1D的治疗仅限于 每日外源胰岛素给药。需要选择性地抑制B细胞的免疫疗法 预防和治疗T1D的自身免疫性。一种方法是给予B细胞自动抗原 重要的是，这种方法避免对保护作用 在诊所测试的其他T1D免疫疗法中可以看到免疫力。尽管很有希望，但基于抗原 T1D的免疫疗法仅显示出适中的临床结果。我们一直在研究可生物降解， 乙酰化葡萄晶微粒（AC-DEX MPS）作为聚合物载体，可输送抗原和 免疫调节药物。 AC-DEX MPS具有许多适合应用的属性 抑制T细胞介导的自身免疫性并重新建立自我耐受性。值得注意的是，AC-DEX MP可以是 操纵以可调节的方式释放体内货物。我们已经表明，货物释放的时机有 对引起的免疫反应的性质和大小的明显影响。此外，使用此 平台，我们最近表明，交付AC-DEX MP封装耐受剂（Rapamycin）和 B细胞衍生的肽有效地阻止了T1D的自适应T细胞转移模型中的糖尿病。因此， 当前建议的重点是开发和表征AC-DEX MPS的耐受性特性 封装免疫调节药物和B细胞衍生的肽作为选择性抑制的手段 糖尿病反应。我们假设MP降解速率加上 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，以最佳抑制免疫响应。特定目标2：评估 T1D动物模型中的AC-DEX粒子公式和耐受性的机理。在这个目标中，我们将 评估MPS的贩运与免疫细胞摄取有关，表征了潜在的免疫 公式产生的响应，评估平台的保护性和治疗效率，以及 确定治疗导致获得的免疫力丧失。