People who get a kidney transplant usually face a life sentence of drugs that suppress their immune systems ? otherwise, their body will reject the new organ. A new cellular therapy could change that.
Immunosuppressant drugs can have severe side effects, increasing the risk of heart disease, infection, cancer and diabetes. So as well as saving money, dispensing with them would bring major health benefits.
Samuel Strober at Stanford University in California and colleagues seem to have worked out how to do it. Following transplant surgery, Strober's team first give patients ordinary immunosuppressive drugs, such as cyclosporine. They then apply mild radiation to the lymph nodes, spleen and thymus to further weaken the immune system. This kills some but not all of the patient's white blood cells.
They also inject antibodies which temporarily destroy the patient's most aggressive white blood cells. "We preferentially delete 'naive T cells', since they are the main subset of white blood cells that reject grafts," Strober says.
Another donation
About 10 days after the transplant, Strober injects the patient with millions of white blood cells extracted from the kidney donor. These include CD34+ stem cells, which can multiply and become part of the recipient's own immune system.
Once donor blood cells mix with recipient immune cells, they blunt the immune attack by a process called negative selection, says Strober, who has spent 30 years developing the regimen.
In negative selection, the thymus presents proteins from foreign tissue to immune cells, in effect asking them, "Do you recognise this material?" If enough immune cells recognise the tissue, those that don't are screened out and killed. Because donated immune cells recognise the foreign tissue from the transplanted kidney, the thymus gets rid of the recipient's own T-cells that could otherwise attack the kidney.
Strober monitors the recipient's blood regularly to check that the two immune systems are mixing properly, and there is no sign of rejection.
After a month, the first of two immunosuppressive drugs is withdrawn. The second is withdrawn at six months.
Three years free
Eight of Strober's 12 trial patients have now been free of immunosuppressive treatment for up to three years, although one died after three years from a heart attack unrelated to the treatment.
The other four are still on immunosuppressive drugs, but are being monitored to see if they too can break free. "So far, they've failed to meet our strict drug withdrawal criteria," says Strober.
Close match
One caveat is that all patients received donations from closely matched relatives. But Strober is confident that the regimen will work with unmatched donations too, which would greatly expand the number of organs available for the procedure. "Our preclinical lab results show that we can use mismatched recipients as well as matched, and that gives us confidence to move ahead," he says.
Although 17,000 people receive kidneys in the US each year, more than 400,000 are on the waiting list and rely on dialysis machines, so the shortage of available organs
remains acute.
Strober's procedure is not the only one to free patients from anti-rejection drugs. In 2008 a team led by David Sachs at the Massachusetts General Hospital in Boston reported a technique involving a bone marrow transplant from organ donors, which worked in four of five patients ? some of them have now been free of drugs for eight years.
Sachs says that Strober's work is encouraging, but points out that his own patients all received unmatched transplants, overcoming a greater immunological challenge. "The success rate they've reported is similar to what our studies have achieved for mismatched transplants," he says. "So it will be interesting to see the results of Strober's new trial."
One advantage of Strober's approach is that it is milder and less traumatic for the recipient than having a bone marrow transplant in addition to a kidney transplant, says Maggie Dallman, an immunologist at Imperial College London. But, like Sachs, she says that "the real test will come when this is used for mismatched organs".
Journal reference: New England Journal of Medicine, vol?365, p?1359
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