Immune systems are notoriously intolerant of transplanted tissue. Although scientists have had some success in damping the immune response to prevent the rejection of animal organs, a team has now tried a more drastic strategy in mice: replace the immune system itself with the makings of one that accepts transplanted cells. The technique, reported in the latest issue of Science, will be tested next in baboons.
The most obstinate barrier to transplanting animal organs has been a carbohydrate molecule called aGal, which is attached to the surfaces of cells in all mammals except primates. When the human immune system encounters cells bearing aGal, it recognizes the transplant as foreign and begins to destroy it. John Iacomini and his colleagues at Massachusetts General Hospital and Harvard Medical School in Boston decided to tackle the aGal problem by forcing the immune system to replace its cells with ones that will tolerate aGal.
This could be done, they proposed, by drawing out a patient's bone marrow cells, then adding a gene to those cells for the enzyme galactosyltransferase (GT), which attaches aGal to the surface of the immune cells. Doctors would then reinject the GT marrow into the patient and allow the cells to form a new immune system that would recognize aGal as self, not foreign.
The researchers tested their idea with a mouse strain engineered to lack the GT gene. Like humans, these mice make an immune response to aGal. The researchers removed the animals' bone marrow, then replaced it in 12 mice with marrow cells containing the GT gene, while 13 others received marrow cells with a control gene. When the researchers measured natural antibody levels 15 weeks later, the control mice had as many antibodies to aGal as before the experiment. In contrast, mice with the GT gene made virtually no aGal antibodies--suggesting that the modified immune cells had indeed recognized aGal as self.
"This is a very significant advance," says Jeffrey Platt, an immunologist at the Mayo Clinic in Rochester, Minnesota. The finding, he says, "provides a potential avenue that would make xenotransplantation more feasible for humans." But making a human tolerate a pig heart is still years away, Iacomini says: "The first big challenge will be to get this to work in baboons."