The Transplant Trick
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Sachs is convinced that inducing mixed chimerism was an important step in achieving transplant success without immunosuppressants. But other researchers have doubts, though the results of their trials have done little to settle the debate. Some researchers have reported that chimeric patients have been unable to stop taking immunosuppressants, whereas others have reported that patients, without ever achieving chimerism, have gone off the drugs. Some scientists even point to Sachs’s own trial as evidence that chimerism may not be the key to tolerance. Though all of his patients were initially chimeric, their chimerism disappeared after a few weeks. “So is chimerism really necessary to achieve tolerance? I find it more and more mystifying,” says Shapiro.
Based on his work in animals, Sachs thinks chimerism may be essential initially, but that a different mechanism of organ tolerance takes over once transplant recipients cease to be chimeric. He credits T regulatory cells, which live outside the thymus, for suppressing T cells that could target the donor organ. In fact, there’s evidence that chimerism may increase the number of T regulatory cells.
But Rodolfo Alejandro, an endocrinologist at the University of Miami, thinks T regulatory cells alone, rather than chimerism, are the reason for tolerance. “It may be that chimerism is just correlated with tolerance,” Alejandro says. He points to work by immunologist Maria Grazia Roncarolo at the Fondazione San Raffaele del Monte Tabor, in Milan, and others showing that T regulatory cells are essential for establishing and maintaining transplant tolerance, and to recent studies showing that the drug rapamycin, which improves survival of transplanted organs, may work in part by helping T regulatory cells tamp down T cells that would attack the organ.
Transplant pioneer Thomas Starzl at the University of Pittsburgh has yet another explanation: a mechanism he calls microchimerism. In 1992, Starzl, who performed the first liver transplant in 1963 and developed many of today’s immunosuppressive drugs, found several patients who had received kidney or liver transplants decades earlier but had gone off immunosuppressive drugs. (This happens in fewer than 1% of transplant recipients.) “Every recipient had microchimerism,” Starzl says. “Some level of chimerism is a necessary condition for long-term tolerance.”
As Starzl defines it, microchimerism occurs when fewer than 1% of the cells in a person’s blood are donor cells. Starzl thinks the cells of microchimerism migrate from the donor organ and then hide in the lymph nodes, heart or other internal niches. After the flood of cells exhausts the body’s initial antidonor response, these cells subsequently leave their protective niches, maintaining the weakened antidonor immune response and effectively preventing rejection of the donor organ, Starzl says.
Starzl thinks microchimerism could explain why some people who go off immunosuppressive drugs do not reject their organ. He has developed a protocol to induce microchimerism in transplant recipients by killing some of their immune cells and replacing them with donor immune cells before the transplant. His results, yet to be published or peer reviewed, show that some patients are able to reduce doses of immunosuppressants and possibly to stop them entirely, at least for a few months.
Though much about chimerism and transplantation remains open to debate, most researchers agree that the MGH team’s protocol is the most innovative work under way. “It’s a landmark piece of work,” says Northwestern’s Miller, who is conducting a trial in which he gives patients stem cells after transplantation, at three-, six- and nine-month intervals, in an attempt to wean them off immunosuppression.
Sachs’s research is continuing, with a focus on extending tolerance to other organs. The MGH team is also beginning a trial of 15 patients who will receive kidneys from less-well-matched, unrelated donors. “Monkey studies suggest the results should be just as good with unrelated donors, but we won’t know for sure until we try it in humans,” Sachs says. Many organ recipients don’t have a closely matched sibling, so this work could change the prognosis—and quality of life—of many more organ recipients. “We’re hoping if we can reproduce these results and it turns out to be a protocol that will lead to tolerance on a broader scale,” Sachs says, “it would become a standard of care.”
