Analysis of human NKT cells in GVHD in vivo

描述（由申请人提供）：移植物抗宿主病（GVHD）是目前用于治疗血液系统恶性肿瘤的造血干细胞疗法的主要并发症，具有非常高的发病率和死亡率。因此，开发新的方法来预防或改善这种病理将具有很大的临床价值。这里提出的研究将探讨人类NKT细胞，一群先天T淋巴细胞，已被证明具有强大的免疫调节功能，是否可以用来抑制人源化小鼠模型系统中GVHD的发展。在该模型系统中，将严重免疫缺陷小鼠与胎儿肝脏和胸腺组织一起移植人造血干细胞。这导致小鼠体内多种人类免疫细胞的分化和随后的长期持续存在，包括T细胞、B细胞和骨髓细胞类型。在移植后的后期时间点（即大于100天），小鼠表现出明显类似于人类造血移植患者慢性GVHD的症状。我们将使用这种体内模型系统来测试人类NKT细胞的免疫调节作用。通过操纵诸如CD4+或CD4- NKT细胞是主要亚群、抗原激活强度、内源性配体LPC对NKT细胞的激活水平以及CD1d+ apc的特征等参数，我们将深入了解决定NKT细胞免疫调节作用的因素。具体目的如下：评估以下治疗对GVHD发展的影响：a)过继性转移体外扩增的NKT细胞（CD4+与CD4-亚群）；b)给予糖脂抗原（强/弱TCR激动剂）；c)增强或中断NKT细胞对LPC（一种与炎症相关的内源性脂质抗原）的识别；d) PPAR治疗？引起髓系apc上CD1d表达上调并改变其细胞因子分泌以减少炎症的激动剂。

DESCRIPTION (provided by applicant): Graft-vs-host disease (GVHD) is the major complication of hematopoietic stem cell therapies that are currently used to treat hematological malignancies, and is associated with very high rates of morbidity and mortality. Therefore, the development of new approaches to prevent or ameliorate this pathology would be of great clinical value. The studies proposed here will investigate whether human NKT cells, a population of innate T lymphocytes that has been shown to have potent immunoregulatory functions, can be used to inhibit the development of GVHD in a humanized mouse model system. In this model system, severely immune deficient mice are transplanted with human hematopoietic stem cells, along with fetal liver and thymic tissue. This results in the differentiation and subsequent long-term persistence of multiple lineages of human immune cells in the mice, including T cells, B cells, and myeloid cell types. At late time points after transplantation (i.e. greater than 100 days) the mice show signs of a condition that markedly resembles chronic GVHD in human hematopoietic transplant patients. We will use this in vivo model system to test the immunoregulatory impact of human NKT cells. By manipulating parameters such as whether CD4+ or CD4- NKT cells are the dominant subset, the strength of antigenic activation, the level of NKT cell activation by the endogenous ligand LPC, and the characteristics of CD1d+ APCs, we will gain insight into the factors that determine the immunoregulatory effects of NKT cells. The specific aims are as follows: Assess the impact of the following treatments on the development of GVHD: a) adoptively transferring in vitro expanded NKT cells (CD4+ vs. CD4- subsets); b) administering glycolipid antigens (strong vs. weak TCR agonists); c) augmenting or interrupting NKT cell recognition of LPC (an endogenous lipid antigen associated with inflammation); d) treatment with a PPAR? agonist that causes up-regulation of CD1d expression on myeloid APCs and alters their cytokine secretion to a less inflammatory profile.