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恶性肿瘤的造血干细胞疗法的主要并发症，并且与非常高的发病率和死亡率相关。因此，开发新的方法来预防或改善这种病理学将具有很大的临床价值。本文提出的研究将调查人类NKT细胞，一群先天性T淋巴细胞，已被证明具有强大的免疫调节功能，是否可以用于抑制GVHD的发展，在人源化小鼠模型系统。在该模型系统中，将人造血干细胞与胎肝和胸腺组织一起沿着移植到严重免疫缺陷小鼠。这导致小鼠中多种人类免疫细胞谱系的分化和随后的长期持续，包括T细胞、B细胞和骨髓细胞类型。在移植后的晚期时间点（即大于100天），小鼠显示出明显类似于人造血移植患者中的慢性GVHD的病症的迹象。我们将使用这种体内模型系统来测试人NKT细胞的免疫调节作用。通过操纵参数，如CD 4+或CD 4- NKT细胞是否是优势亚群，抗原激活的强度，NKT细胞激活的内源性配体LPC的水平，和CD 1d + APC的特性，我们将深入了解决定NKT细胞的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）过继转移体外扩增的NKT细胞（CD 4 + vs. CD 4-亚群）; B）施用糖脂抗原（强vs.弱TCR激动剂）; c）增强或中断NKT细胞对LPC（与炎症相关的内源性脂质抗原）的识别; d）用PPAR？引起髓系APC上CD 1d表达上调并将其细胞因子分泌改变为较低炎症特征的激动剂。 公共卫生相关性：免疫系统癌症（白血病、淋巴瘤、骨髓瘤等）可以通过将来自健康人的骨髓来源的细胞移植到患者体内来成功治疗;然而，经常出现的严重并发症是新的免疫细胞攻击患者。这项资助将研究使用一小群称为NKT细胞的人类淋巴细胞来预防这种并发症。这些研究的积极结果可以迅速为在治疗人类癌症中实施类似方法开辟道路。

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. PUBLIC HEALTH RELEVANCE: Cancers of the immune system (leukemias, lymphomas, myelomas, etc.) can be successfully treated by transplanting bone marrow derived cells from a healthy person into the patient; however, a serious complication that frequently arises is that the new immune cells attack the patient. This grant will investigate using a small population of human lymphocytes called NKT cells to prevent this complication. Positive results from these studies could quickly open the way for implementing similar approaches in treating human cancers.