IL-17 AND HEMATOPOIESIS

尽管随着化疗剂量的加强，一些恶性肿瘤的反应增加，甚至完全消退，但骨髓抑制通常是癌症化疗中的剂量限制性副作用。在高剂量化疗后接受干细胞拯救的患者中，造血恢复不完全归因于造血微环境或骨髓基质细胞（BMSC）的损伤。细胞因子/生长因子已被证明是维持正常造血的关键组分。一个重要的，但定义不明确的作用，作为造血调节有CD 4 + T淋巴细胞，这是部分解释通过分泌刺激细胞因子。众所周知，感染人类免疫缺陷病毒（HIV）的患者具有相对较高的三系骨髓衰竭发生率，这与其CD 4 + T淋巴细胞计数呈负相关。最近发现的一种由CD 4 + T淋巴细胞产生的刺激体外造血的细胞因子/生长因子是白细胞介素-17。有报道称，IL-17可诱导成纤维细胞和基质细胞释放造血生长因子如G-CSF、IL-6和IL- 8，其可支持骨髓祖细胞的体外生长。我们实验室的初步研究表明，mIL-17的体内表达显著刺激造血，粒细胞，淋巴细胞和巨核细胞的增殖。此外，我们发现mIL-17在体内刺激诱导造血生长因子的释放。基于这些数据，我们假设IL-17的过表达通过从BMSC释放G-CSF、GM-CSF、mIL-3、mIL-6和干细胞因子（mSCF）来刺激体内造血。我们将通过以下具体目标来检验这一假设：具体目标1。我们的假设预测在体内mIL-17的表达，刺激粒细胞生成，淋巴细胞生成和血小板生成。具体目标2。我们的假设预测mIL-17的表达在短暂的CD 4 + T细胞耗竭小鼠刺激淋巴细胞生成，从而导致增强的CD 4 + T细胞恢复。具体目标3。我们的假设预测mIL-17在体内的表达刺激造血细胞因子（G-CSF、GM-CSF、mIL-3、mIL-6、mSCF）的局部释放。具体目标4。我们的假设预测造血细胞因子（G-CSF、GM-CSF、mIL-3、mIL-6、mSCF）的释放对于mIL-17诱导的造血是必需的。这项研究的结果不仅有助于我们进一步了解IL-17的体内生物学，而且可能为开发IL-17作为化疗剂量强化、癌症治疗诱导的毒性及其并发症（例如感染）的潜在药物以及在骨髓移植后的可能作用提供平台。

Despite increased responses and even complete regression of some malignancies with dose intensification of chemotherapy, myelosuppression is often a dose-limiting side effect in cancer chemotherapy. In patients with stem cell rescue after high dose chemotherapy, incomplete hematopoietic recovery has been attributed to damage of the hematopoietic microenvironment or to bone marrow stroma cells (BMSC). Cytokines/growth factors have been shown to be critical components to the maintenance of normal hematopoiesis. A significant, although poorly defined role as regulator of hematopoiesis have CD4+T-lymphocytes which is in part explained through secretion of stimulatory cytokines. It is well established that patients infected with the human immunodeficiency virus (HIV) have a relatively high incidence of trilineage bone marrow failure, which is inversely related to their CD4+T-lymphocyte counts. One recently discovered cytokine/growth factor made by CD4+ T- lymphocytes, which stimulates in vitro hematopoiesis, is Interleukin-17. It has been reported that IL-17 can induce the release of hematopoietic growth factors such as G-CSF, IL-6 and IL- 8 from fibroblasts and stroma cells, which can support the growth of bone marrow progenitor cells in vitro. Preliminary studies from our laboratory demonstrate that in vivo expression of mIL-17 markedly stimulates hematopoiesis with proliferation of granulocytes, lymphocytes and megakaryocytes. Moreover, we found that mIL-17 stimulates induces the release of hematopoietic growth factors in vivo. Based on these data we hypothesize that overexpression of IL-17 stimulates hematopoiesis in vivo through the release of G-CSF, GM-CSF, mIL-3, mIL-6, and stem cell factor (mSCF) from BMSC. We will test this hypothesis through the following Specific Aims: Specific Aim 1. Our hypothesis predicts in vivo mIL-17 expression to stimulate granulopoiesis, lymphopoiesis and thrombopoiesis. Specific Aim 2. Our hypothesis predicts mIL-17 expression in transiently CD4+ T-cell depleted mice to stimulate lymphopoiesis and thus to result in enhanced CD4+ T-cell restoration. Specific Aim 3. Our hypothesis predicts that expression of mIL-17 in vivo stimulates local release of hematopoietic cytokines (G-CSF, GM-CSF, mIL-3, mIL-6, mSCF). Specific Aim 4. Our hypothesis predicts that release of hematopoietic cytokines (G-CSF, GM-CSF, mIL-3, mIL-6, mSCF) is essential for mIL-17 induced hematopoiesis. The results of this study will not only aid us in further understanding the in vivo biology of IL-17, but may provide the platform for the development of IL-17 as potential agent for dose intensification of chemotherapy, for cancer treatment induced toxicities and their complications (e.g. infections) and a possible role in engraftment after bone marrow.