USING hormones to turn adults into pre-pubescent children may sound like a bad idea. But it could provide a way to improve the safety of organ transplants.
At the moment, transplant patients must be placed on powerful immunosuppressive drugs for the rest of their lives. The drugs prevent organ rejection, but raise the risk of infections and cancers. Now David Sachs and his colleagues at the Massachusetts General Hospital in Boston are experimenting on pigs in an attempt to trick the immune system into tolerating transplanted organs, and avoid the need for long-term immune suppression.
Sachs hopes to induce immune tolerance by temporarily rejuvenating the thymus gland, a small organ beneath the breastbone that "primes" the immune system's T-cells to attack foreign cells without harming the body's own tissues. Once children reach adolescence, the sex hormones testosterone and oestrogen start to stunt the thymus, a process that continues throughout adult life. "It's big and juicy in childhood, but starts to get fatty and to wither away after puberty," says Sachs. "Although it keeps ticking over, it is never again as active in priming T-cells."
Sachs's idea is to reboot the thymus by temporarily shutting off the sex hormones with Lupron, a synthetic version of gonadotropin-releasing hormone, or GnRH, which is released from the hypothalamus in the brain and triggers puberty. The hormone is also able to rejuvenate the thymus, something that Richard Boyd and his colleagues at Monash University in Victoria, Australia, discovered in experiments on mice.
Once the thymus has been revived, Sachs will transplant a kidney and give each pig immunosuppressive drugs for a fortnight. During this period, the idea is that T-cells in the thymus will be exposed to cells and proteins from the new kidney, which they should be primed to treat as "self". After a few months, the Lupron treatment would be stopped and the pigs would return hormonally to adulthood, hopefully with the new organ fully tolerated.
Sachs has previously shown that young pigs equivalent in age to 10-year-old children can tolerate transplanted organs after only two weeks of immunosuppressive drug therapy. But this is not the case for adult pigs, or young pigs that have had their thymuses removed (Transplantation, vol 77, p 979).
These results suggest that the hormonal treatment might work in pigs. But some immunologists are sceptical that the procedure will work in people. "When you transplant organs into even small children, they reject their organs without immunosuppression, just like adults," says Maggie Dallman of Imperial College London.
Sachs agrees, but says that while most teenage transplant patients who stop taking immunosuppressive drugs do reject their new organs, some do not. "It does show that tolerance can sometimes develop naturally," says Sachs. This gives him hope that his hormonal "teen treatment" will work. He expects to have results from his pig experiments within a year. If they are positive, he will then seek approval to run a human trial.
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