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用于治疗各种免疫学疾病的新型分子靶标的鉴定。由于共刺激途径被认为是T细胞活化和分化所必需的，因此操纵抗原遇到的T细胞上的共刺激信号已被认为是诱导抗原特异性耐受的有吸引力的方法。在诱导耐受性方面，有两种方法被广泛采用。首先，使用阻断抗体或可溶性受体破坏T细胞活化通常诱导对抗原的耐受性。第二种方法是通过利用T细胞负调节因子的信号传导。在活化的T细胞上显著上调的负调节因子在过去几年中一直受到关注。CTLA-4、PD-1和BTLA是作为诱导T细胞耐受性的靶标鉴定和探索的三种主要的T细胞负调节剂。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参与。我们和其他人已经在体外和体内成功地证明了这一点。设计用于这种共连接的灵活且有效的系统是实现使用共刺激控制作为临床使用的抗原特异性耐受诱导策略的目标的下一步。我们的假设是，使T细胞上的多个负调节因子与抗原特异性T细胞上的TCR一起沿着将是必要的并且足以诱导有效的抗原特异性耐受。我们建议制备可注射的可生物降解的微球，其包覆有重组MHC-肽和T细胞负调节因子的配体作为致耐受性抗原呈递系统，以诱导抗原特异性T细胞耐受。本研究的目的是：1）使用TCR转基因小鼠测试微球结合的MHC-二聚体肽复合物和负调节配体在诱导有效的抗原特异性耐受中的潜力，和2）使用NOD小鼠模型探索基于致耐受性微球的抗原呈递系统在预防和治疗自身免疫性糖尿病中的潜力。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.