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.

摘要 本次提交是对我们的母基金R 01 DK 130225“生成的制剂”的补充 1型糖尿病的治疗方法 父母摘要：目前还没有治愈的自身免疫性疾病1型糖尿病（T1 D），尽管事实上， 青少年糖尿病研究基金会估计约有80人新诊断患有这种疾病， 日报由于免疫介导的产生胰岛素的β细胞破坏，目前T1 D的治疗仅限于 每日外源性胰岛素给药。需要的是选择性抑制B细胞的免疫疗法。 自身免疫用于预防和治疗T1 D。一种方法是施用B细胞自身抗原 以抑制和耐受致糖尿病效应T细胞。重要的是，这种方法避免了对保护性的影响。 在临床上测试的其他T1 D免疫疗法中观察到的免疫力。尽管前景看好， 针对T1 D的免疫疗法仅显示出适度的临床结果。我们一直在研究生物降解， - 缩醛化葡聚糖微粒（Ac-DEX MP）作为递送抗原的聚合物载体， 免疫调节药物。Ac-DEX MP具有许多非常适合于应用的性质。 抑制T细胞介导的自身免疫并重建自身耐受性。值得注意的是，Ac-DEX MP可以是 操纵以在体内以可调的方式释放货物。我们已经表明，货物释放的时间 对引发的免疫反应的性质和程度有显着影响。此外，使用此 在该平台上，我们最近已经表明，递送包封耐受化剂（雷帕霉素）的Ac-DEX MP和 B细胞衍生肽在T1 D的过继性T细胞转移模型中有效预防糖尿病。因此，委员会认为， 当前提案的重点是开发和表征Ac-DEX MP的致耐受性 包封免疫调节药物和B细胞衍生肽作为选择性抑制免疫调节的手段， 致糖尿病反应。我们假设MP降解率加上共包封的 免疫调节剂增强了我们基于肽的疫苗的致耐受性效力。为了验证这一 假设，我们提出了两个目标：具体目标1：包封雷帕霉素和抗原， 可调Ac-DEX粒子和粒子系统的优化。在这里，我们将建立药物，剂量， 微粒的降解速率以最佳抑制免疫应答。具体目标2：评价 Ac-DEX颗粒制剂和T1 D动物模型中的耐受性机制。为此，我们会 评估与免疫细胞摄取相关的MP的运输，表征潜在的免疫应答。 评价平台的保护和治疗功效，以及 确定治疗导致获得性免疫力丧失。