Molecules in the TGF-beta pathway are known to play a role in more than 30 diseases. The newest addition is graft-vs.-host disease.

"In every type of transplantation, what you fear most is rejection," said Claude Perreault, professor of medicine at the University of Montreal. Graft-vs.-host disease, which occurs when donor T cells attack recipient organs after a bone marrow transplant, is "a very serious disease that is unfortunately quite common." He noted that more than half of all recipients have some degree of GVHD.

On the plus side, that number is not as high as it could be. Or maybe even should be. Perreault told BioWorld Today that even though there is always "some degree" of incompatibility between the donor and recipient of a bone marrow transplant, there is not always GVHD. In animal studies, even without any intervention to prevent it, GVHD only will occur in about 75% of bone marrow transplants.

That leads naturally to the question whether the remaining 25 percent are spared because of factors in the recipient, or whether there might be something about certain donors that makes their bone marrow more or less suitable for transplantation: "Maybe not all donors are created equal, but some are more dangerous than others," Perreault said.

A report on the results of gene expression studies to identify who might be such good or dangerous donors is in the Jan. 27 issue of PLoS Medicine. It comes from Perreault and his colleagues from the University of Montreal, Maisonneuve-Rosemont Hospital and the Lady Davis Institute for Medical Research in Montreal; Biosystemix Limited in Sydenham, Ontario; and the Toronto General Research Institute.

The group tested the expression patterns of roughly 19,000 genes in both killer and helper T cells from 50 donors one day prior to a bone marrow transplant. After a year, they retested the gene expression of the 40 surviving recipients of the transplants. They found 17 genes whose expression levels correlated with graft-vs.-host disease. High expression levels of some of the genes were protective, while others appeared to make matters worse.

Of the 17 genes, seven were part of the TGF-beta pathway, which is in line with the biological function of TGF-beta. Perreault said that an important role of TGF-beta is "to prevent what you might call collateral damage." During the eternal struggle of man against microbe, TGF-beta keeps the immune response from damaging host tissues.

Within the TGF-beta signaling pathway, one molecule in particular appeared to have a strong protective effect. That was SMAD3, which Perreault called "the most important player" in TGF-beta signaling. In the studies reported in PLoS Medicine, Perreault and his colleagues found that patients with high expression levels of SMAD never developed GVHD, while patients with low expression levels often, but not always, did develop GVHD.

The authors wrote that "mechanistically, this suggests that high levels of SMAD3 are sufficient (but not necessary) to prevent GVHD, while low levels are necessary (but not sufficient) for the occurrence of GVHD." The authors are putting that suggestion to the test. Perreault said that one of the projects his team is pursuing is to see whether the upregulation of SMAD3 expression is able to prevent GVHD.

The researchers are replicating their work in a larger cohort of patients, and if the work pans out, the gene signature also might be useful to identify good donor candidates. If the expression signature "can identify nondangerous donors, they will be selected" for bone marrow transplant, Perreault said.

Of course, some patients in need of a bone marrow donor have enough trouble finding any donor at all. For those patients, picking the best donor seems like a preposterous dream. But even patients who have little or no choice among donors might benefit from the knowledge that the gene signature provides. "If we can only find dangerous donors, we will preemptively adjust their immunosuppression," Perreault said.