Year XVI -Issue 06 - 2000

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macrophage formation that have yet to be discovered and this general conclusion is true also for regulation in the eosinophil and megakaryocytic lineages. For example only three regulators are known to stimulate macrophage formation (MCSF, GMCSF and MultiCSF) yet deletion of both GMCSF and MCSF does not reduce macrophage numbers to zero and if MultiCSF removal does not deplete macrophage numbers then one or more other macrophage-active factors must await detection. In the case of granulocyte production, combined deletion of GCSF and GMCSF again does not reduce granulocyte numbers to zero. Here, however, stem cell factor deletion is known to reduce granulocyte levels somewhat (58) and this factor plus IL6 might represent the missing factors.

The alternative again is that at least one other granulocyte-active factor remains to be identified. It cannot simply be assumed that the detection of these missing factors is not of much importance because we already possess active CSFs able to be used clinically.

The missing factors might have qualitatively distinct or unexpected actions on macrophages or granulocytes not able to be achieved by the existing CSFs.

Results from the whole field of gene deletion have one unifying theme - there are so far no true examples of a redundant gene and each gene product does play a unique role somewhere in controlling the production or function of cells.

Consequences of Excessive CSF Stimulation

With the exception of aberrant CSF production by some tumors, leading to hyperplasia of target hemopoietic cells, there are no known examples in clinical medicine of sustained excess levels of CSF. As mentioned earlier, excess CSF production need not be systemic and it has so far proved impractical to establish whether local excess production of CSF might on occasion occur in restricted local sites and cause disease.

Most of our information on the long-term consequences of greatly excessive levels of CSF has come from the generation of mice with genetic manipulations to achieve sustained elevations of one CSF or another.

It was initially speculated that excessive stimulation of cell proliferation by CSFs might lead to leukemia development.

However this has proved not to be the outcome. Excessive stimulation leads only to severe hyperplasia not leukemia development. The hematopoietic reserve is normally sufficient to compensate for such distortions and they do not lead to deficient cell production in other lineages.

What has emerged as a consequence of excessive stimulation are a variety of inflammatory states that are likely to be based on excessive stimulation of the production, and particularly the activation, of mature cells. Thus, excess levels of GMCSF lead to massive overproduction and activation of macrophages and the development of inflammatory, locally destructive, lesions due to the production of toxic products by activated macrophages (59, 60). Similarly, excess MultiCSF levels lead to mast cell hyperplasia and tissue damage from mast cell products (61).

These dramatic systemic models raise the possibility that local excess production of agents like GMCSF or MultiCSF could be involved as causative factors in a variety of local inflammatory states.

Clinical Use of the CSFs

In terms of absolute numbers of patients treated, the most frequent current use of GCSF and GMCSF is to promote the regeneration of granulocytic and monocytic cells in cancer patients who have received prior chemotherapy (62, 63).

This usually results in a shortening of leukopenic periods with some improvement in the frequency of associated infections and the ability to administer subsequent courses of chemotherapy (Figure 2).

In much less numerous patients with congenital or cyclic neutropenia, continuous GCSF treatment has achieved a notable reduction in infections and morbidity (64).

Of increasing practical importance is the use of CSF-elevated peripheral blood stem cells (PBSC) in place of marrow cells as a superior cell population for transplantation. Most such transplants in cancer patients are now performed using PBSC often without the necessity for hospital admission, a remarkable change in transplantation medicine (65).

CSF-elicited populations of mature blood cells are also in increasing use in patients in the acute phase of leukopenia following chemotherapy. Worthy of further exploration is the use locally of GMCSF to promote wound and chronic ulcer healing.

The powerful ability of GMCSF to stimulate dendritic cell function (66) and thus to improve the effectiveness of vaccines involving weak antigens (67, 68) needs to be properly exploited.