Galectin-1's effects on dendritic cell function.

描述（由申请人提供）：树突状细胞（dc）具有非凡的能力来解释环境信息，然后“决定”最合适的反应。已知它们在促进先天免疫和适应性免疫中起作用，并且越来越多的证据支持它们在稳态条件下的免疫耐受中的作用。虽然DC对外源刺激的反应研究得很好，但对激活和调节DC的内源性信号知之甚少。半乳糖凝集素-1是一种内源性半乳糖苷结合凝集素，对各种先天和适应性免疫细胞具有广泛的免疫调节能力。根据凝集素的浓度和细胞的激活状态，半乳糖凝集素-1也可以对同一细胞产生不同的影响。值得注意的是，我们的实验室最近进行了一项新的观察，发现半乳糖凝集素-1独特地激活了人类单核细胞来源的dc成熟，同时增强了它们通过细胞外基质的迁移。由于DC是一个动态群体，由处于不同分化和激活阶段的功能不同的亚群组成，我假设半乳糖凝集素-1在DC分化和成熟的不同阶段具有不同的作用。半乳糖凝集素-1对dc的免疫调节功能将在以下具体目的中进行表征：目的1：鉴定半乳糖凝集素-1诱导成熟的信号介质。我将使用生物抑制剂和敲除小鼠模型来鉴定半乳糖凝集素-1利用的关键信号分子和受体。目的2：探讨半乳糖凝集素-1在不同分化和成熟阶段对树突状细胞的免疫调节作用。我将使用体外和体内模型来评估半乳糖凝集素-1治疗的dc调节免疫反应的能力。最终，这些关于半乳糖凝集素-1在dc免疫调节功能中的作用和机制的研究将为免疫基础疾病的治疗提供新的途径。半乳糖凝集素-1在改善自身免疫性疾病方面有充分的证据。这些研究将确定半乳糖凝集素-1对DC功能的调节是否有助于促进免疫耐受和避免自身免疫。基于免疫的疾病的影响是毁灭性的，治疗具有挑战性，其复杂的症状涉及主要和多个器官系统。最近，基于树突状细胞的患者特异性治疗性疫苗取得了一些成功。提高对树突状细胞生物学及其在免疫发病机制中的作用的理解，将形成针对免疫基础疾病的新型靶向治疗的基本原理。

DESCRIPTION (provided bny applicant): Dendritic cells (DCs) have a remarkable ability to interpret environmental information and then "decide" the most appropriate response. They have known roles in promoting innate and adaptive immunity, and accumulating evidence supports their role in immune tolerance during steady state conditions. While DC responses to exogenous stimuli are well studied, less is known about endogenous signals that activate and regulate DCs. Galectin-1 is an endogenous galactoside-binding lectin that has a broad range of immunomodulatory abilities on various innate and adaptive immune cells. Galectin-1 can also have different effects on the same cell depending on the concentration of the lectin and the activation state of the cell. Notably, our laboratory recently made a novel observation that galectin-1 uniquely activates human monocyte-derived DCs to mature while enhancing their migration through extracellular matrix. Because DCs are a dynamic population consisting of functionally distinct subsets in varying stages of differentiation and activation, I posit that galectin-1 will have different effects at various stages of DC differentiation and maturation. The immunomodulatory function of galectin-1 on DCs will be characterized in the following specific aims: Aim 1: To identify the signaling mediators of galectin-1 induced maturation. I will use biological inhibitors and knock-out mouse models to identify the key signaling molecules and receptors utilized by galectin-1. Aim 2: To determine the immunomodulatory functions of galectin-1 on DCs at different stages of differentiation and maturation. I will use in vitro and in vivo models to assess the ability of galectin-1 treated DCs to regulate immune responses. Ultimately, these studies on the role and mechanism of galectin-1 on the immunomodulatory functions of DCs will lead to novel therapeutic approaches to immune-based diseases. Galectin-1 has well-documented effects on ameliorating autoimmune diseases. These studies will establish whether regulation of DC function by galectin-1 contributes to the promotion of immune tolerance and avoidance of autoimmunity. Immune-based diseases are devastating in their effects and challenging to treat, with complex symptoms involving major and multiple organ systems. Recently, there has been some success with patient-specific therapeutic vaccines based upon dendritic cells. Improved understanding of the biology of dendritic cells and their roles in immune pathogenesis will form the rationale for novel targeted therapies for immune-based diseases.