Role of lipids in dendritic cell function

描述(申请人提供)：对各种病原体和抗原的充分免疫反应取决于专业抗原提呈细胞树突状细胞(DC)的有效功能。树突状细胞缺陷在各种病理条件下所描述的免疫异常或免疫反应失败中起关键作用。这对自身免疫性疾病、一些病毒和寄生虫感染以及癌症尤其重要。尽管进行了深入的研究，但DC缺陷的机制在很大程度上仍然不清楚。对这些机制的了解对于开发新的治疗方法可能非常重要。本实验室对DC功能的研究主要集中在信号转导途径、表面受体的表达和细胞因子的产生等方面。这些研究非常重要，并为DC的生物学提供了有价值的见解。然而，他们很难解释观察到的异常现象的机制。在这里，我们建议测试一个完全不同的DC功能障碍的新概念。我们认为，在不同的病理条件下观察到的DC分化和功能的良好证据的异常可能部分是由于脂质代谢异常，最终导致细胞内脂质的积聚。这种积聚阻止了正常的DC分化，并损害了已经成熟的DC的抗原提呈功能。这一假设是基于在不同的实验系统中进行的一些体外和体内的初步观察。为了验证这一假设，我们将关注一种病理疾病--癌症。具体地说，我们将研究癌症DC分化过程中脂质积累的生物学意义。具体目标1将研究肿瘤宿主树突状细胞中的脂质积累以及肿瘤衍生因子在这一过程中的作用。具体目标2将研究DC中脂质积聚的免疫学后果。如果我们的假设是正确的，这将不仅提出一个新的模型，描述癌症中抗原提呈细胞的缺陷，以及潜在的与脂质堆积相关的其他病理情况，而且还将开辟一条治疗机会的新途径。在这种情况下，将需要更详细的进一步研究。具体地说，重要的是要了解细胞质中积累的脂质的性质，导致脂质积累的上游分子机制，积累的脂质导致DC缺陷的机制，脂质积累的来源，这些发现的临床意义，以及最重要的是纠正这种情况的治疗方法。然而，如果我们不首先确定一个非常基本的事实，所有这些研究都将是无关紧要的：DC中脂质的积累在免疫上是相关的，在生物学上具有重要意义。这一提议正在寻求有限的支持，以检验这一“高风险但可能高收益”的假说。计划中的研究将探索在不同病理条件下与脂代谢异常相关的免疫系统缺陷的新机制。我们将测试新的假设，即专业抗原提呈细胞中脂质的积累阻止了这些细胞充分刺激免疫反应。这一新的机制可能会提出一种全新的方法，通过抑制脂质的积累来治疗与癌症等疾病相关的免疫缺陷。

DESCRIPTION (provided by applicant): Adequate immune responses to various pathogens and antigens depend on the effective function of professional antigen presenting cells dendritic cells (DC). Defects in DCs play critical role in immunological abnormalities or failure of immune responses described at various pathological conditions. This is especially important for autoimmune diseases, some viral and parasite infections, and cancer. Despite intensive studies the mechanisms of DC defects remain largely unclear. Understanding of these mechanisms could be very important for the development of new therapeutic approaches. Most of the studies of DC function including those from our laboratory are focused on signal transduction pathways, expression of surface receptors and cytokine production. These studies are very important and provide valuable insight into the biology of DCs. However, they struggle to explain the mechanisms of the observed abnormalities. Here, we propose to test an entirely different novel concept of DC dysfunction. We suggest that the well-documented abnormalities in DC differentiation and function observed at different pathological conditions may be caused in part by abnormal metabolism of lipids culminating in accumulation of lipids in cytoplasm of the cells. This accumulation prevents normal DC differentiation and impairs antigen-presenting function of already matured DCs. This hypothesis is based on a number of preliminary observations made in vitro and in vivo in different experimental systems. To test this hypothesis we will focus on one pathological condition - cancer. Specifically, we will investigate biological significance of accumulation of lipids during DC differentiation in cancer. Specific aim 1 will investigate lipid accumulation in DCs from tumor-bearing hosts and the role of tumor-derived factors in that process. Specific aim 2 will study the immunological consequences of lipid accumulation in DCs. If our hypothesis is correct it would suggest not only a new model describing defects in antigen presenting cells in cancer and potentially other pathological conditions associated with lipid accumulation but also open a new avenue in treatment opportunities. In this case more detailed further studies will be warranted. Specifically, it will be important to understand the nature of the lipids accumulated in cytoplasm, up-stream molecular mechanisms responsible for lipid accumulation, the mechanisms of DC defects induced by accumulating lipids, the source of lipid accumulation, clinical significance of these findings and most importantly therapeutic approaches to correct this situation. However, all these studies will be irrelevant if we do not establish first the very basic fact: accumulation of lipids in DCs is immunologically relevant and biologically significant. This proposal is seeking limited support to test this "high risk but possibly high gain" hypothesis. Proposed research will investigate novel mechanism responsible for the defects in immune system at different pathological conditions associated with abnormal lipid metabolism. We will test novel hypothesis that accumulation of lipids in professional antigen presenting cells prevents these cells from adequate stimulation of immune responses. This new mechanism may suggest an entirely new approach to the treatment of immune defects associated with such disease as cancer by inhibiting accumulation of lipids.