Polymeric biomaterial-based microparticle vaccine for amelioration of Type 1 diab

描述(申请人提供)：1型糖尿病(T1D)被认为是自我耐受性崩溃的结果，其特征是T细胞介导的对胰腺中产生胰岛素的细胞的破坏。最终，葡萄糖代谢中断，导致心脏病和肾功能衰竭等威胁生命的并发症的发展。在T1D的实验系统中，已知有许多因素可以促进有利的免疫细胞反应。然而，这些制剂的系统性给药往往会导致严重的有害偏离目标。 效果。我们开创了一种新型的、基于生物材料的颗粒疫苗系统，用于体内递送促耐受因子和胰岛素抗原，目标是一种关键的免疫细胞类型-树突状细胞(DC)。树突状细胞是专职的抗原提呈细胞，直接参与T细胞和B细胞免疫，包括维持对自身抗原的耐受。此外，某些免疫调节剂对DC的外源性调节可诱导出支持耐受的DC表型，并改善T1D。用DC靶向微粒(MPS)接种有望纠正T1D自身免疫反应，关键是不需要基于DC的细胞治疗所需的昂贵的体外操作。我们的长期目标是开发一种易于注射的颗粒疫苗，能够预防和逆转人类的T1D。这种方法极大地增强了广泛使用的潜力。这一第一阶段提案的目标是完成临床前研究，证明我们最有希望的粒子疫苗配方用于人类的可行性。更具体地说，我们希望在T1D的临床前模型中评估颗粒疫苗的生物分布、生物利用度、毒性和潜在有害的ff-靶效应。我们的初步数据有力地表明，这种基于生物材料的颗粒疫苗系统有望纠正T1D的自身免疫反应。此外，我们与佛罗里达大学生物医学工程系、医学院和糖尿病卓越中心的战略合作提高了我们完成预期目标的能力。

DESCRIPTION (provided by applicant): Type 1 Diabetes (T1D) is thought to result from a breakdown of self-tolerance that is characterized by T cell-mediated destruction of the insulin-producing ¿-cells in the pancreas. Ultimately, glucose metabolism is interrupted, resulting in the development of life-threatening complications such as heart disease and renal failure. A number of factors are known to promote advantageous immune cell responses in experimental systems for T1D. However, systemic delivery of these agents often results in significant harmful off-target effects. We have pioneered a novel, biomaterial-based, particle vaccine system for in vivo delivery of pro- tolerance factors and insulin antigen, targeted to a key immune cell type, dendritic cells (DCs). Dendritic cells are professional antigen presenting cells (APCs), directly involved in T cell and B cell immunity, including the maintenance of tolerance to self-antigens. Moreover, exogenous conditioning of DCs with certain immuno-modulatory agents has been shown to induce a pro- tolerance DC phenotype as well as ameliorate T1D. Vaccination with DC-targeting microparticles (MPs) holds promise to correct T1D autoimmune responses, critically, without the costly ex vivo manipulations required of DC-based cellular therapy. Our long term goal is to develop an easily injectable, particle vaccine capable of prevention and reversal of T1D in humans. This approach greatly enhances the potential for widespread use. The objective of this Phase I proposal is to complete preclinical studies that demonstrate the feasibility of our most promising particle vaccine formulation for use in humans. More specifically, we want to assess biodistribution, bioavailability, toxicity and potentially harmful ff-target effects of the particle vaccine in preclinical models of T1D. Our preliminary data strongly suggests that this biomaterial-based, particle vaccine system holds promise for correcting autoimmune responses in T1D. Additionally, our strategic collaborations with the Biomedical Engineering Department, College of Medicine and Diabetes Center of Excellence at the University of Florida boost our capability to complete the desired goals.