IL-17 and Hematopoiesis

描述(申请人提供)：尽管确切的机制尚不清楚，但CD4+T淋巴细胞被认为是重要的造血调节因子。CD4+T细胞耗竭综合征通常与严重的造血功能障碍和微生物宿主防御功能受损有关。尽管中性粒细胞计数通常正常，但在CD4+T细胞计数下降的患者中，细菌宿主防御严重受损，提示在这种情况下中性粒细胞功能障碍。以往的工作已经证实，IL-17是体内重要的T淋巴细胞来源的造血调节因子和关键的宿主防御细胞因子。IL-17是中性粒细胞募集、刺激和扩增造血器官原始前体细胞所必需的，尤其是在造血祖细胞系。因此，可以合理地得出结论，推测仅有CD4+T细胞衍生因子IL-17可能与CD4+T细胞缺陷有关，这些缺陷与造血和宿主防御受损有关。该项目的长期目标是了解和更好地确定IL-17在体内的作用和功能。IL-17的靶细胞是骨髓和炎症组织中的间质细胞，释放次级细胞因子和趋化因子。在下一个授权期将评估的假说是，在组织炎症期间，这些次级细胞因子和趋化因子是足够的粒细胞生成和中性粒细胞支持所必需的。如果这一假设是正确的，那么有可能开发IL-17作为一种治疗支持细胞因子，用于治疗急性或慢性细胞毒性的造血器官损伤，或治疗T细胞缺陷或耗竭患者的免疫受损状态。我们将通过以下特定目标来验证这一假说：特定目标1将在体内研究IL-17介导的粒细胞生成的机制，并确定与G-CSF和SCF协同作用的基质细胞衍生细胞因子的作用。具体目标2将探讨IL-17作为骨髓基质细胞及其前体细胞的主要生长因子的假说，其机制涉及bFGF的上调。具体目标3将检验这一假设，即在细菌组织炎症期间，CD4+和CD8+T细胞都产生IL-17，并且IL-17刺激次级细胞因子，而次级细胞因子是充足供应和支持粒细胞所必需的。具体目标4将检验这样的假设：(A)IL-17是细胞毒性损伤后充分的造血恢复所必需的，以及(B)IL-17具有促进造血恢复的治疗潜力。所提出的特定目标的成功完成将加深我们对IL-17在体内作用机制的理解，这将为设计新的治疗策略提供基础。

DESCRIPTION (provided by applicant): CD4+T-lymphocytes are recognized as important regulators of hematopoiesis although the exact mechanisms are poorly defined. CD4+T-cell depletion syndromes are often associated with serious impairment of hematopoiesis as well as of microbial host defense. In spite of often-normal neutrophil counts, bacterial host defense is severely compromised in patients with decreased CD4+T-cell counts suggestive of neutrophil dysfunction in this setting. Previous work has established that IL-17 is an important T-lymphocyte derived regulator of hematopoiesis and a critical host defense cytokine in vivo. IL-17 is required for neutrophil recruitment and for stimulation and expansion of primitive precursor cells in hematopoietic organs, specifically of the myelopoietic lineage. Therefore it is reasonable to conclude that the presumed exclusively CD4+T-cell derived factor IL-17 may be associated with CD4+T-cell deficiency related to impaired hematopoiesis and host defense. The long-term objective of this project is to understand and better define the role and function of IL-17 in vivo. The target cells for IL-17 are stroma cells in bone marrow and inflamed tissue, which release secondary cytokines and chemokines. The hypothesis to be evaluated in the next grant period is that these secondary cytokines and chemokines are required for adequate granulopoiesis and neutrophil support during tissue inflammation. If this hypothesis is correct, then it may be possible to develop IL-17 as a therapeutic support cytokine to treat acute or chronic cytotoxic insults of the blood forming organs or to treat the immunocompromised state of otherwise T-cell deficient or depleted patients. We will test this hypothesis through the following Specific Aims: Specific Aim 1 will investigate the mechanism of IL-17 mediated granulopoiesis in vivo and determine the role of stroma cell derived cytokines that act synergistically with G-CSF and SCF. Specific Aim 2 will investigate the hypothesis that IL-17 acts as a primary growth factor for bone marrow stroma cells and their precursors via a mechanism involving up-regulation of bFGF. Specific Aim 3 will examine the hypothesis that both CD4+ and CD8+ T-cells produce IL-17 during bacterial tissue inflammation and that IL-17 stimulates secondary cytokines, which are required for adequate supply and support of granulocytes. Specific Aim 4 will test the hypothesis that (A) IL-17 is required for adequate hematopoietic restoration after cytotoxic insult and (B) that IL-17 has a therapeutic potential to accelerate hematopoietic recovery. The successful completion of the proposed specific aims will enhance our understanding of the IL-17 in vivo mechanism of action, which will provide the foundation for the design of novel therapeutic strategies.