IL-17 AND HEMATOPOIESIS

尽管随着化疗剂量的增加，某些恶性肿瘤的反应增强，甚至完全消退，但骨髓抑制往往是癌症化疗中剂量受限的副作用。在大剂量化疗后进行干细胞挽救的患者中，不完全的造血恢复被归因于造血微环境的破坏或骨髓基质细胞(BMSC)的破坏。细胞因子/生长因子已被证明是维持正常造血的关键成分。CD4+T淋巴细胞是一种重要的造血调节细胞，其作用虽不明确，但部分通过分泌刺激性细胞因子来解释。众所周知，感染人类免疫缺陷病毒(HIV)的患者有相对较高的三系骨髓衰竭发生率，这与他们的CD4+T淋巴细胞计数呈负相关。最近发现的一种由CD4+T淋巴细胞产生的细胞因子/生长因子，在体外刺激造血，是白介素17。已有研究表明，IL-17可诱导成纤维细胞和基质细胞释放G-CSF、IL-6、IL-8等造血生长因子，支持骨髓祖细胞的体外生长。我们实验室的初步研究表明，在体内表达mIL-17可以显著刺激造血，促进粒细胞、淋巴细胞和巨核细胞的增殖。此外，我们还发现，在体内，mIL-17刺激可以诱导造血生长因子的释放。基于这些数据，我们假设IL-17的过度表达通过从BMSC释放G-CSF、GM-CSF、mIL-3、mIL-6和干细胞因子(Mscf)来刺激体内的造血。我们将通过以下特定目的来检验这一假说：特定目的1.我们的假说预测在体内表达mIL-17可以刺激粒系、淋巴系和血小板系。具体目的2。我们的假说预测，在一过性的CD4+T细胞耗竭的小鼠中，mIL-17的表达可以刺激淋巴细胞的生成，从而促进CD4+T细胞的恢复。具体目的3.我们的假设预测，mIL-17在体内的表达可以刺激局部造血细胞因子(G-CSF、GM-CSF、mIL-3、mIL-6、mSCF)的释放。具体目的4.我们的假设预测，造血细胞因子(G-CSF、GM-CSF、mIL-3、mIL-6、mSCF)的释放在mIL-17诱导的造血过程中是必不可少的。本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IL-17作为潜在的化疗剂量增强剂、治疗癌症治疗的毒性及其并发症(如感染)以及在骨髓移植中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.