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.
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