Sponsoring NCI Division:	DCB
	Grant Number:	R37CA022556-27
	Award Approved:	June 2005
	Institution:	Walter and Eliza Hall Institute for Medical Research, Victoria, Australia
	Department:	Division of Cancer and Hematology
	Scientific Abstract (CRISP) Metcalf Laboratory Literature Search on PubMed

Differentiation of Granulocytes and Macrophages

With continuous funding from NIH/NCI of more than 25 years, our studies have focused on the molecular control of white blood cell formation and function - particularly granulocytes and macrophages that are involved in innate immunity to infections.

Our major achievements include the development of most of the in vitro colony assays that allow detection and quantitation of the progenitor cells for these white blood cells, the identification, purification and, in some cases, cloning of the four major regulators of granulocyte and macrophage production and the analysis of their biological actions both in vitro and in vivo. Two of these regulators - granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte-CSF (G-CSF) have found widespread current clinical use in the treatment of cancer chemotherapy-induced neutropenia and in mobilising bone marrow stem cells into the blood. G-CSF in particular has been used in the treatment of more than 5 million patients and has led to a revolution in bone marrow transplantation.

Our more recent studies aim to understand how engagement of these molecular regulators with their cellular receptors results in intracellular signals that mediate the appropriate biological responses. Our identification and cloning of some of these key receptors (including those for GM-CSF and the cytokines interleukin-13 and interleukin-11) has revealed that they often consist of unique as well as common protein subunits and thereby often display common elements in their signalling pathways. We have also shown that antibodies to these receptor chains may be useful clinical agents and are exploring the use of antibodies to GM-CSF and IL-13 receptors to treat inflammatory and autoimmune diseases.

We also discovered a large and unique family of proteins (the suppressors of cytokine signalling-SOCS) that are themselves induced by CSFs and cytokines but then feedback to terminate the cell signalling cycle. Genetic deletion studies in mice have revealed that the negative feedback functions of individual SOCS proteins are crucial for preventing hyper-inflammatory responses to particular cytokine subsets -SOCS1 for interferon-γ, SOCS2 for growth hormone and SOCS3 for LIF, IL-6 and G-CSF. Our current studies aim to understand in more detail the molecular mechanisms whereby SOCS3 inhibits cytokine signalling and how specificity is determined at the molecular and cellular level. We envisage that these data will provide a rationale for developing therapeutics to suppress a range of inflammatory and autoimmune disorders.

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