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.
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