Gr-1+ cells and the response to nematode parasites

描述（由申请人提供）：辅助性T细胞2（Th 2）效应细胞，通过Th 2细胞因子的产生，可以介导对蠕虫寄生虫感染的抗性。因此，了解导致其分化的细胞和分子相互作用对于开发促进宿主保护性免疫应答的疗法和疫苗至关重要。我们已经开始检查小鼠感染线虫寄生虫后最初产生的先天性反应，以鉴定可能在促进导致产生IL-4的Th 2细胞的适应性免疫中重要的细胞群或信号。寄生虫感染后不久引流淋巴结的全球基因表达分析显示趋化因子显著增加，包括MCP-1和CXCR 3配体。已知这两种趋化因子都募集单核细胞和粒细胞。Gr-1是这些细胞群以及浆细胞样树突状细胞共有的细胞表面标志物。引流淋巴结在接种肠道线虫寄生虫N.巴西的。用抗GR-1抗体处理引起N.接种后7 d，IL-4的表达量和寄主抗性均下降。在本研究中，我们将研究Gr 1+细胞在体内促进Th 2效应细胞发育的功能。具体来说，我们建议确定趋化因子/趋化因子受体介导的招聘Gr 1+细胞的外周淋巴结在早期阶段的免疫反应，以N。巴西的。我们还将阐明Gr 1+细胞如何抑制IFN-γ的升高，促进Th 2细胞的发展，从而导致宿主抗性的机制，通过检查Gr 1+细胞与发展中的Th 2细胞在原位的相互作用。最后，我们将在两个寄生虫模型，N。brasiliensis和H. polygyrus，Gr 1+细胞在宿主保护性初级和记忆反应的发展中的作用。

DESCRIPTION (provided by applicant): T helper 2 (Th2) effector cells, through Th2 cytokine production, can mediate resistance to helminthic parasite infection. Understanding the cell and molecular interactions that lead to their differentiation is therefore important for the development of therapies and vaccines that promote host protective immune responses. We have begun to examine the innate response that initially develops following infection of mice with nematode parasites to identify cell populations or signals that may be important in promoting adaptive immunity that leads to the developing of IL-4 producing Th2 cells. Global gene expression analyses of draining lymph nodes shortly after parasite infection showed pronounced increases in chemokines, including MCP-1 and CXCR3 ligands. Both chemokines are known to recruit monocytes and granulocytes. Gr-1 is a cell surface marker shared by these cell populations and also plasmacytoid dendritic cells. Draining lymph nodes showed pronounced increases in Gr1+ cells at 4 and 16 hours after inoculation with the intestinal nematode parasite, N. brasiliensis. Treatment with anti-GR-1 antibody caused marked increases in lymph node IFN-y expression at 18 hours after N. brasiliensis inoculation and decreased IL-4 expression and host resistance was observed at 7 days after inoculation. In the proposed studies, we will examine the function of Gr1+ cells in promoting the development of Th2 effector cells in vivo. Specifically, we propose to identify the chemokine/chemokine receptors that mediate the recruitment of Gr1+ cells to the peripheral lymph nodes at early stages of the immune response to N. brasiliensis. We will also elucidate the mechanism of how Gr1+ cells suppress IFN-y elevations and promote Th2 cell development leading to host resistance by examining Gr1+ cell interactions with developing Th2 cells in situ. Finally, we will address in two parasite models, N. brasiliensis and H. polygyrus, the role of Gr1+ cells in the development of the host protective primary and memory response.