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 此提交是对我们的父母拨款R01DK130225“公式的补充，以生成 对1型糖尿病的耐受性“ 父母摘要：目前还没有治愈自身免疫性疾病1型糖尿病(T1D)的方法，尽管事实是 青少年糖尿病研究基金会估计，大约有80人新诊断出这种疾病， 每天。由于免疫介导的对产生胰岛素的β细胞的破坏，目前对T1D的治疗仅限于 每日外源性胰岛素注射。现在需要的是选择性抑制b细胞的免疫疗法。 自身免疫在T1D防治中的作用一种方法是注射b细胞自身抗原。 抑制和耐受糖尿病效应T细胞。重要的是，这种方法避免了对 免疫力与在临床上测试的其他T1D免疫疗法相同。尽管前景看好，但基于抗原 对T1D的免疫治疗只显示了有限的临床效果。我们一直在研究可生物降解的， 缩醛葡聚糖微粒子(Ac-DEX MPS)作为递送抗原和 免疫调节药物。AC-DEX MPS具有许多非常适合应用于 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，AC-DEX议员可以 被操纵以可调节的方式在体内释放货物。我们已经表明，货物放行的时间已经 对所引起的免疫反应的性质和大小有显著影响。此外，使用这个 平台，我们最近已经证明，Ac-DEX MPS的交付封装了一种耐受剂(雷帕霉素)和 在T1D的过继T细胞转移模型中，B细胞衍生的多肽有效地预防糖尿病。因此， 本提案的重点是开发和表征Ac-DEX MPS的耐受性。 包裹免疫调节药物和b细胞衍生的多肽作为选择性抑制 糖尿病反应。我们假设MP的降解率加上 免疫调节剂提高了我们的多肽疫苗的耐受性。为了测试这一点 假设，我们提出了两个目标：特定目标1：包封雷帕霉素和抗原。 可调谐AC-DEX粒子及粒子系统的优化。在这里，我们将建立药物、剂量和 微粒的降解率，以最佳地抑制免疫反应。具体目标2：评价 Ac-DEX颗粒制剂及耐受机制在T1D动物模型中的研究为了实现这一目标，我们将 评估MPS的运输与免疫细胞摄取有关，表征潜在的免疫 由配方产生的反应，评估平台的保护和治疗效果，以及 确定治疗后导致获得性免疫丧失的结果。