No Rejection of Incognito Organs

Researchers have devised a way to trick the rat immune system into ignoring--and therefore, not rejecting--transplanted organs. The new technique, described in next month's Nature Medicine, could someday be used to prevent organ rejection in people, as well as eliminate the need for lifelong immune-suppressing drugs that make most transplant recipients susceptible to infections, cancers, and nerve damage.

The immune system recognizes transplanted organs as foreign tissue by telltale proteins, called the major histocompatibility complex (MHC), that coat cell surfaces. But before immune-system fighters called T cells will attack foreign tissue, they must first get a confirmation order of sorts: a costimulatory signal. Because previous work in rats and monkeys has found that proteins that block the costimulatory signal can hold T cells at bay, Kim Olthoff, a transplant surgeon at the University of Pennsylvania Medical Center in Philadelphia, thought her team could achieve a targeted immune suppression by getting the transplanted organ itself--rather than proteins injected into the bloodstream--to block the costimulatory signal.

To do so, Olthoff and her colleagues engineered a virus to make a protein called CTLA4Ig, which blocks the costimulatory signal. Next, they soaked rat livers in a broth containing the engineered virus and transferred the organs and viral stowaways into other rats. The animals receiving these livers survived more than 4 months--even though the virus stopped producing CTLA4Ig after about 2 weeks. Rats that received regular livers and a CTLA4Ig injection also lived longer--although not as long as mice with the souped-up livers--while rats that received only the regular transplant died within 12 days after liver rejection.

This kind of work is "clearly the next frontier" in establishing localized immunity, says Lynt Johnson, director of the liver-transplant program at the University of Maryland Medical School in Baltimore. However, he says, it's unclear whether Olthoff's technique would prevent immune suppression in people.