Cell growth factor: use with caution.

Cell growth factor: Use With caution

A cell-stimulating growth factor that has shown promise in patients with shortages of white blood cells can also cause blindness and death in mice, according to new research. There are significant methodological differences between the new study and previous trials on humans, making it difficult to draw parallels between the two types of studies. But the researchers warn that excess stimulation by the factor "may lead to the development of serious disease states . . . [that] could be of importance in the context of current clinical trials.'

The researchers looked at mice that had been genetically engineered to produce excess qualtities of granulocyte-macrophage colony stimulating factor (GM-CSF). Normally present in the blood in small quantities, GM-CSF stimulates the proliferation and function of certain white blood cells. When given intravenously in moderate amounts to patients with AIDS, it has stimulated increased production of disease-fighting white blood cells (SN: 9/12/87, p.165).

Working at research institutes in Melbourne and Parkville, Australia, and at the Duke University Eye Center in Durham, N.C., the researchers used a retrovirus to transfer an extra GM-CSF gene into male and female mice and examined the mouse progeny for effects of increased production of the cell growth factor. They found that GM-CSF blood levels were at least 40-fold higher than in normal mice, but along with that increase came a number of problems.

Most strikingly, all of the transgenic mice has opaque eyes. Tissue samples showed that the eyes had been ravaged by an overabundance of macrophages--a variety of white blood cell that is especially activated by GM-CSF. Degeneration of the lens and retina was apparent, along with varying degrees of retinal detachment. Other parts of the mice were heavily infiltrated with macrophages--many of them larger than normal and containing two to 18 nuclei instead of one. The overgrowth of macrophages was accompanied by tissue destruction in all 81 recombinant mice, and within five months most of them died.

It's likely, the researchers say, that the increase in macrophages was a consequence of the growth-promoting properties of GM-CSF, and that the tissue destruction was a direct consequence of the accumulation of those cells. Macrophages are known to secrete chemical factors that can destroy muscle tissue while attracting a variety of reactive, inflammatory cells. Surprisingly, however, there was no evidence of GM-CSF production in the bone marrow of the transgenic mice, where, under normal circumstances, GM-CSF exerts its proliferative effects on progenitor white blood cells. Further tests led the researchers to conclude that in the genealtered mice, the macrophages themselves were both producing and reacting to the stimulating factor.

"The macrophages in these transgenic mice may be autocrine [self] stimulated,' the researchers say. "Furthermore, CSF is probably produced in the transgene very early in development, while therapeutic use would be more likely to involve short-term exposure in adults.'

Those differences, say the authors and others, are significant. According to H. Franklin Bunn, a hematologist from Brigham and Women's Hospital in Boston, the new research "means uncontrolled release of GM-CSF could lead to problems. But keep in mind that you have to interpret it very carefully in how it applies to clinical application. This transgenic model is very different because the gene is being expressed in tissues where it normally wouldn't be expressed,' Bunn told SCIENCE NEWS.

Nevertheless, the researchers warn, the findings "highlight the need for careful toxicological studies before these agents are used for prolonged periods in the treatment of chronic conditions.'