Structure of GM-CSF

GM-CSF is a polypeptide of 144 amino acids with a 17-amino acid leader sequence. It is heterogeneously glycosylated. GM-CSF has a molecular weight of 14 to 35 kDa, depending on the degree of glycosylation. Interestingly, removal of the carbohydrate moiety, either by synthesis in bacteria or mutagenesis, actually increases the specific activity of GM-CSF.

Major sites of production of GM-CSF GM-CSF can be synthesized by a variety of cell types in response to specific activating signals

(see Table 58-4) T cells, macrophages, mast cells, endothelial cells, and fibroblasts can be induced to accumulate GM-CSF mRNA and secrete GM-CSF protein. If one considers the potential physiologic role of GM-CSF in enhancing host defense, production of this factor by cells that are sensitive to immune challenge is certainly teleologically consistent.

GM-CSF receptor

The GM-CSF receptor is a type I cytokine receptor with α- and β-chains. The β chain is shared by IL-3 and IL-5. The receptor is expressed by mononuclear phagocytes, neutrophils, endothelial cells, eosinophils, and fibroblasts.

Major biologic activities of GM-CSF

GM-CSF stimulates proliferation of multi-lineage progenitors and the growth of BFU-E, granulocyte, macrophage, and eosinophil colonies. GM-CSF also enhances the functional activity of most phagocytes, including neutrophils, macrophages, and eosinophils. In GM-CSF-deficient mice, the major morbidity results from the absence of normal phagocytic function rather than from a failure to produce phagocytes. Indeed, there is no compelling evidence that GM-CSF alone induces neutrophilic differentiation in the absence of G-CSF. It is, therefore, likely that the neutrophilic leukocytosis seen after GM-CSF treatment reflects the ability of GM-CSF to induce other growth factors, such as IL-1, which then stimulates production of G-CSF.

Experimental overexpression of GM-CSF protein has been achieved using transgenic mice or by insertion of retroviral vectors expressing GM-CSF into the bone marrow of mice. The transgenic mice exhibit blindness (caused by accumulation of macrophages in the eye) and infiltration of macrophages into striated muscles. Thus, the local presence of high concentrations of GM-CSF during development of the mouse embryo appears to be pathologic. Humans treated with GM-CSF do not develop these complications. Overexpression of GM-CSF in bone marrow cells infected with retroviruses carrying the murine GM-CSF cDNA leads to a myeloproliferative syndrome that is fatal, although non-neoplastic.⁸ Expression of the GM-CSF gene itself does not lead to neoplastic transformation as determined by subsequent transplantation of cells into normal mice.

A number of reports have also substantiated GM-CSF-induced growth of various tumor cell lines of nonhematopoietic origin: small cell carcinoma of the lung and colon adenocarcinoma.

GM-CSF in human illness

Autocrine expression of GM-CSF in myeloid leukemia cells and cell lines has been proposed to play a role in neoplasia.⁹ Autonomous production by the tumor of GM-CSF (or G-CSF) has also been implicated as one possible pathophysiologic mechanism underlying leukemoid reactions in cancer patients.¹⁰ In addition, the presence of GM-CSF biologic activity in synovial fluid from patients with rheumatoid arthritis suggests that it may enhance the tissue destruction associated with this disorder.

Clinical indications for GM-CSF

GM-CSF has been shown to be safe and effective in the treatment of patients with acute myelogenous leukemia (AML) who are undergoing induction therapy. This molecule shortens the neutropenic period and decreases the rate of serious infections in older individuals. GM-CSF is also indicated for accelerating myeloid reconstitution after allogeneic bone marrow transplantations (BMTs). This molecule also enhances survival in patients who experience engraftment failure or delay after allogeneic or autologous transplantation. Finally, peripheral blood stem cells mobilized in the presence of GM-CSF yield significantly higher colony counts than those mobilized without this molecule and, after transplantation, recipients of GM-CSF–mobilized progenitors have quicker neutrophil, platelet, and red blood cell recovery and shorter hospital stays.

Although the use of GM-CSF to alleviate mucositis has been proposed, a double-blind study in which GM-CSF was administered topically failed to demonstrate salutary activity in this condition.¹¹