Microsphere based Tolerogenic antigen presentation system

描述（由申请人提供）：对T细胞活化和共刺激机制的理解导致了治疗各种免疫疾病的新分子靶点的鉴定。由于共刺激通路被认为是T细胞活化和分化的必要条件，操纵抗原遇到的T细胞上的共刺激信号被认为是诱导抗原特异性耐受的一种有吸引力的方法。有两种方法可以很好地诱导耐受性。首先，使用阻断抗体或可溶性受体破坏T细胞活化通常会诱导对抗原的耐受性。第二种方法是利用T细胞负调节因子的信号传导。负调节因子在活化T细胞上的显著上调是近年来备受关注的分子。CTLA-4、PD-1和BTLA是三种主要的T细胞负调节因子，被确定并探索作为诱导T细胞耐受的靶点。在活化的T细胞上还有其他具有未知负调节因子的配体。抗原特异性耐受的诱导依赖于T细胞受体（TCR）和这些负调节因子的同时作用。我们和其他人已经成功地在体外和体内证明了这一点。为这种共连接设计灵活有效的系统是实现将共刺激控制作为抗原特异性耐受诱导策略用于临床的下一步。我们的假设是，在T细胞上加入多种负调节因子以及抗原特异性T细胞上的TCR将是诱导有效抗原特异性耐受的必要和充分条件。我们提出制备可注射的可生物降解微球，包被重组mhc肽和T细胞负调节配体作为耐受性抗原提呈系统，以诱导抗原特异性T细胞耐受。本研究旨在：1)利用tcr转基因小鼠检测微球结合mhc -二聚肽复合物和负调节配体诱导有效抗原特异性耐受性的潜力；2)利用NOD小鼠模型探索耐受性微球抗原提呈系统预防和治疗自身免疫性糖尿病的潜力。这项研究的结果将帮助我们设计一种有效的抗原特异性免疫治疗方法，可用于治疗或预防自身免疫性疾病，如儿童1型糖尿病和其他免疫介导的疾病，通过耐受性诱导和调节性T细胞诱导。

DESCRIPTION (provided by applicant): Understanding of T cell activation and costimulatory mechanisms have led to the identification of novel molecular targets for the treatment of various immunological disorders. Since costimulatory pathways are considered to be essential for T cell activation and differentiation, manipulating co-stimulatory signals on antigen encountered T cells has been considered as an attractive approach for inducing antigen specific tolerance. Two approaches are well adopted in inducing tolerance. Firstly, disrupting T cell activation using blocking antibodies or soluble receptors has often induced tolerance to antigens. Second approach is through exploiting the signaling of T cell negative regulators. Negative regulators that are upregulated significantly on activated T cells have been the molecules of attention in last several years. CTLA-4, PD-1 and BTLA are the three major T cell negative regulators identified and explored as the targets for inducing T cell tolerance. There are other ligands with unknown negative regulators on activated T cells. Induction of antigen specific tolerance depends on concurrent engagement of the T cell receptor (TCR) and these negative regulators. We and others have successfully demonstrated this both in vitro and in vivo. Designing flexible and effective system for this co-ligation is the next step towards achieving the goal of using costimulatory control as antigen specific tolerance induction strategy for clinical use. Our hypothesis is that engaging multiple negative regulators on T cells along with TCR on antigen specific T cells will be necessary and sufficient to induce effective antigen specific tolerance. We propose to generate injectable biodegradable microspheres coated with recombinant MHC-peptides and ligands of T cell negative regulators as tolerogenic antigen presenting system to induce antigen specific T cell tolerance. This study will be aimed at: 1) testing the potential of microsphere bound MHC-dimer peptide complex and negative regulatory ligands in inducing effective antigen specific tolerance using TCR-transgenic mice, and 2) exploring the potential of tolerogenic microsphere based antigen presenting system in preventing and treating autoimmune diabetes using NOD mouse model. The results from this study will help us design an effective antigen specific immunotherapeutic approach that can be used to treat or prevent autoimmune diseases, like childhood type 1 diabetes and other immune mediated disorders through tolerance induction and regulatory T cell induction.