Formulation to Generate Tolerance Towards Type 1 Diabetes

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。青少年糖尿病的研究进展 基金会估计，每天大约有80名新诊断出患有这种疾病的人。由于免疫介导的 破坏产生胰岛素的β细胞，目前对T1D的治疗仅限于每日外源性胰岛素 行政管理。需要的是选择性抑制细胞自身免疫的免疫疗法 T1D的防治。一种方法是使用细胞自身抗原来抑制和 耐受糖尿病效应T细胞。重要的是，这种方法避免了对保护性免疫的影响 在临床上测试的其他T1D免疫疗法。尽管T1D基于抗原的免疫疗法前景看好，但它已经 仅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 (AC-DEX MPS)作为运送抗原和免疫调节药物的聚合物载体。AC-DEX议员有一个 一些特性非常适合于抑制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 MPS可以被操纵来以可调节的方式在体内释放货物。我们已经证明了 货物放行的时间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，我们最近已经表明，AC-DEX MPS的交付封装了一种耐受性 药物(雷帕霉素)和细胞衍生肽在过继T细胞转移模型中有效预防糖尿病 T1D。因此，当前提案的重点是开发和表征致耐受特性 包裹免疫调节药物的Ac-DEX MPS和细胞衍生多肽作为选择性治疗的手段 抑制糖尿病的反应。我们假设MP降解率加上共胶囊化 免疫调节剂的使用增强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，以最佳地抑制自身免疫反应。具体目标2： Ac-DEX颗粒制剂及其耐受机制在T1D动物模型中的评价。在这 目的，我们将评估MPS的运输与免疫细胞摄取有关，表征潜在的 所产生的耐受性反应，评价该制剂的保护和治疗效果 平台，并确认该疗法对获得性免疫没有影响。

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.