Thursday, 8 March 2012

Cellular Cocktail Aids Organ Transplants

The immune system evolved to keep microbial invaders out. That's great if the flu is going around, but a downside is that life-saving organ transplants are typically treated with the same hostility as viruses or bacteria. As a result, most transplant patients must stay on immunosuppressive drugs for life so that their bodies don't reject the new organ. Unfortunately, these drugs can cause dangerous side effects or stop working after a few years. But new research with kidney transplant patients provides a proof of principle for a cellular therapy that may eliminate the need for antirejection drugs.

"Transplanted organs can fail even in a perfect patient, one who takes all the pills and can afford them," says Suzanne Ildstad, who directs the Institute for Cellular Therapeutics at the University of Louisville in Kentucky, noting that the drugs can cost up to $25,000 per year. In the new study, Ildstad and colleagues built on earlier attempts to use bone marrow transplants to help people receiving a new kidney.

In the first such trial, patients had their own immune cells reduced, with a combination of radiation, chemotherapy, and other treatments, before receiving a donated kidney along with bone marrow from the same donor. Because bone marrow produces immune cells, the procedure led to a brief period in which the recipient's immune system blended with that of the donor. Of 10 patients who got kidneys from genetically mismatched donors, which typically leads to organ rejection more often than matched transplants, seven successfully came off immunosuppressants. A more thorough immune system swap in which the donor's immune cells virtually take over might better ensure long-term tolerance, according to transplant surgeon Tatsuo Kawai of Massachusetts General Hospital in Boston, a co-leader of the trial. But this approach carries its own risk: The donor's immune cells may attack the recipient's body, a potentially lethal condition known as graft-versus-host disease, or GVHD.

The new study, reported online today in Science Translational Medicine, shows a way to get better organ acceptance while minimizing the GVHD risk. As part of a clinical trial conducted at Northwestern University in Chicago, Illinois, Ildstad and colleagues extracted bone marrow-producing cells from kidney donors and then removed cells likely to cause GVHD while expanding the number of "facilitating cells" that make an organ recipient's system more receptive. In the trial, eight patients with severe kidney disease initially had radiation and drug treatment to suppress their immune systems. Each patient then received a kidney from a genetically mismatched relative or unrelated donor; the concoction of donor cells processed by Ildstad's team was given a day later.

The approach resulted in a nearly complete takeover of the recipient's immune system by the donor's immune cells. But the new immune system didn't attack the recipient's body—nor did the body reject the transplanted organ. Of the eight recipients, five were completely off immunosuppressants, with no sign of GVHD, within a year, and their kidneys have continued to function well for an additional 18 months. Ildstad says the treatment seems to increase the recipient's regulatory T cells—which may serve as peacekeepers by keeping immune system activity in balance.

The results, if upheld by further research, could be transformational, Kawai says. But replacing the recipient's immune system is a drastic step, he says. "Even though there was no GVHD observed during the study period, it could develop in the future." In addition, Kawai says it will be difficult for other researchers to reproduce these findings; because the facilitating cells are patented, the method for producing them is not fully described in the paper.

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