People who get a kidney transplant usually face a life sentence of drugs that suppress their immune systems 鈥� 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.
at Stanford University in California and colleagues seem to have worked out how to do it. Following transplant surgery, Strober鈥檚 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鈥檚 white blood cells.
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They also inject antibodies which temporarily destroy the patient鈥檚 most aggressive white blood cells. 鈥淲e preferentially delete 鈥榥aive T cells鈥�, since they are the main subset of white blood cells that reject grafts,鈥� 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鈥檚 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, 鈥淒o you recognise this material?鈥� If enough immune cells recognise the tissue, those that don鈥檛 are screened out and killed. Because donated immune cells recognise the foreign tissue from the transplanted kidney, the thymus gets rid of the recipient鈥檚 own T-cells that could otherwise attack the kidney.
Strober monitors the recipient鈥檚 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After a month, the first of two immunosuppressive drugs is withdrawn. The second is withdrawn at six months.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鈥檚 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. 鈥淪o far, they鈥檝e failed to meet our strict drug withdrawal criteria,鈥� 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. 鈥淥ur preclinical lab results show that we can use mismatched recipients as well as matched, and that gives us confidence to move ahead,鈥� 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鈥檚 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 from organ donors, which worked in four of five patients 鈥� some of them have now been free of drugs for eight years.
Sachs says that Strober鈥檚 work is encouraging, but points out that his own patients all received unmatched transplants, overcoming a greater immunological challenge. 鈥淭he success rate they鈥檝e reported is similar to what our studies have achieved for mismatched transplants,鈥� he says. 鈥淪o it will be interesting to see the results of Strober鈥檚 new trial.鈥�
One advantage of Strober鈥檚 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 , an immunologist at Imperial College London. But, like Sachs, she says that 鈥渢he real test will come when this is used for mismatched organs鈥�.
Journal reference: , vol聽365, p聽1359
