Formulation to Generate Tolerance Towards Type 1 Diabetes

产生对 1 型糖尿病耐受性的配方

• 批准号: 10436981
• 负责人: Kristy M Ainslie
• 金额: $ 38.18万
• 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/10436981
• 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; 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; particle; peptide based vaccine; peptidomimetics; pre-clinical; prevent; protective efficacy; response; trafficking; uptake

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.

摘要 目前还没有治愈自身免疫性疾病1型糖尿病（T1 D）的方法。青少年糖尿病研究 基金会估计，每天约有80人被新诊断患有这种疾病。由于免疫介导 破坏产生胰岛素的β细胞，目前T1 D的治疗仅限于每日外源性胰岛素 局所需要的是选择性地抑制免疫细胞自身免疫的免疫疗法， T1 D的预防和治疗一种方法是施用抗肿瘤细胞自身抗原以抑制和抑制肿瘤细胞的增殖。 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免疫的影响， 在临床上测试的其他T1 D免疫疗法。虽然有希望，但T1 D的基于抗原的免疫疗法 仅显示出适度的临床结果。我们一直在研究可生物降解的缩醛化葡聚糖微粒 本发明提供了一种用于递送抗原和免疫调节药物的聚合物载体（Ac-DEX MP）。Ac-DEX议员有一个 许多特性非常适合于抑制T细胞介导的自身免疫和重建自身耐受性。 值得注意的是，Ac-DEX MP可以被操纵以在体内以可调的方式释放货物。我们已经证明 货物释放的时间对所引发的免疫应答的性质和强度具有显著影响。 此外，使用这个平台，我们最近已经表明，递送包封耐受性的Ac-DEX MP， 在过继性T细胞转移模型中， 的T1 D。因此，当前提案的重点是开发和表征致耐受性特性 包封免疫调节药物和胰岛细胞衍生肽的Ac-DEX MP作为选择性地 抑制致糖尿病反应。我们假设MP降解率加上共包封率 免疫调节剂的加入增强了我们的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自身免疫应答。具体目标二： Ac-DEX颗粒制剂和T1 D动物模型中耐受性机制的评价。在这 目的是，我们将评估与免疫细胞摄取相关的MP的运输，表征潜在的 通过测定由制剂产生的致耐受性应答，评价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。