Study of Ly108 induced innate and adaptive immune responses

描述（由申请人提供）：对实验性炎症性肠病（IBD）的基因操作小鼠模型的研究已经导致了这样的理解，即免疫系统与结肠的巨大抗原负荷之间的微调平衡的扰动可能导致疾病。致病性CD 4 + T细胞（Th 1或Th 2，取决于模型）积聚在固有层中，随后是肠粘膜的炎症。由结肠细菌诱导的细菌抗原和/或小鼠抗原通过专职抗原呈递细胞（APC）呈递给T细胞。在健康小鼠中，通过CD 4 +25+ Treg细胞阻止致病性T细胞扩增，从而引发结肠炎。我们的初步研究表明，缺乏细胞表面受体Ly 108的小鼠在Th 2细胞和可能的NKT细胞发育方面存在缺陷，Ly 108-/-中性粒细胞在杀死细菌方面受损。基于Ly 108-/-小鼠的表型，我们提出了一个中心假设，即Ly 108信号传导对于处理肠道细菌和辅助性T细胞功能至关重要，因此对慢性结肠炎的发展至关重要。因此，在拟议的实验中要解决三个问题：i）从APC和CD 4 + T细胞中删除Ly 108将直接或间接影响结肠炎，并且将产生针对Ly 108的单克隆抗体或可溶性Ly 108配体（Ly 108-Fc）预防和/或治疗实验性结肠炎，ii）Ly 108如何控制T细胞信号转导途径和iii）细胞表面受体Ly 108如何影响吞噬细胞的细菌杀伤机制？在本申请中提出的实验被分组为以下具体目标，其将测试以下假设：1. T细胞、APC和中性粒细胞上的Ly 108启动参与实验性结肠炎发病机制的信号通路。2. Ly 108募集src激酶Fyn或Lck和驻留脂筏蛋白以启动CD 4+、CD 8+和NKT细胞中的信号转导。3. Ly 108受体调节吞噬细胞中的细菌杀伤。总之，这些实验应该澄清吞噬细胞，T辅助细胞和NKT细胞控制的实验性结肠炎的途径之间的相互作用。这些研究的结果应该建议可以应用于IBD患者的治疗策略。

DESCRIPTION (provided by applicant): Studies with genetically manipulated mouse models of experimental Inflammatory Bowel Diseases (IBD) have lead to an understanding that perturbations of the finely tuned balance between the immune system and the vast antigenic load of the colon can result in disease. Pathogenic CD4+ T cells, Th1 or Th2 depending on the model, accumulate in the lamina propria followed by inflammation of the intestinal mucosa. Bacterial antigens and/or mouse antigens induced by colonic bacteria are presented to the T cells by professional Antigen Presenting Cells (APC). In healthy mice the pathogenic T cells are prevented from expanding, and thus initiating colitis, by CD4+25+ Treg cells. Our preliminary studies show that mice, which lack the cell surface receptor Ly108, are defective in Th2 cell and possibly NKT cell development and Ly108-/- neutrophils are impaired in the killing of bacteria. Based on the phenotype of the Ly108-/- mouse, we propose the central hypothesis that Ly108 signaling is critical for processing commensal bacteria and for T helper cell functions and consequently to the development of chronic colitis. Therefore three questions are being addressed in the proposed experiments: i) will the deletion of Ly108 from APCs, and CD4+ T cells directly or indirectly affect colitis and will a monoclonal antibody directed against Ly108 or a soluble Ly108 ligand (Ly108-Fc) prevent and/or cure experimental colitis, ii) how does Ly108 control T cell signal transduction pathways and iii) how does the cell surface receptor Ly108 influence the bacterial killing mechanism by phagocytes? The experiments proposed in this application are grouped into the following specific aims, which will test the hypothesis that 1. Ly108 on T cells APCs and neutrophils initiates signaling pathways that are involved in the pathogenesis of experimental colitis. 2. Ly108 recruits the src-kinases Fyn or Lck and resident lipid raft proteins to initiate signal transduction in CD4+, CD8+ and NKT cells. 3. the Ly108 receptor regulates bacterial killing in phagocytes. Together these experiments should clarify the interplay between phagocytes, T helper cell and NKT cell controlled pathways to experimental colitis. The results of these studies should suggest therapeutic strategies that can be applied to IBD patients.