To help rats adopt transplanted limbs as their own, researchers have harnessed a ruse that cancer cells use to hide from the immune system — effectively reprograming the animals’ defenses to ignore foreign tissue.
Rats injected with engineered microparticles tolerated a hind limb transplant from another rat for more than 200 days, even in the absence of drugs that suppress immune responses, researchers report March 13 in Science Advances.
When injected into the transplanted tissue, the microparticles release a signaling protein known as CCL22 that’s secreted from cancer cells and attracts specialized immune cells. These immune cells, called regulatory T cells, can mark the rat’s new tissue as “self” and protect it from an onslaught of immune defenses that would normally attack foreign material.
The microparticle treatment is “fundamentally different than anything that is used right now in clinical medicine simply because it doesn’t suppress the animal’s immune system,” says James Fisher, a bioengineer at the University of Pittsburgh.
Patients who receive donor organs or tissues typically spend the rest of their lives taking medication that dampens their immune responses. Without drugs, the immune system would attack and reject the donor tissue, unless it is a perfect genetic match, causing the transplant to fail.
But long-term regimens of immunosuppressive drugs can put patients at risk for things like infectious disease or cancer (SN: 10/21/18). Another approach could be to keep immune responses intact while also shielding new tissue — such as stealing techniques that cancer cells use to evade detection.
Inspired by therapies designed to block cancer’s strategies for concealment, “the thought came into my head: I wonder if we were able to synthetically mimic [what cancer cells do], could we trick the body into accepting a transplant?” says Steven Little, a chemical engineer at the University of Pittsburgh.
Little, Fisher and colleagues transplanted hind limbs from brown Norway rats onto white Lewis rats and injected CCL22-releasing microparticles into the reattached legs. The team then monitored how long the rats tolerated the new appendage without immunosuppressive drugs.
Most rats treated with microparticles maintained healthy limbs, while those that didn’t get the treatment rejected the transplant. Regulatory T cells, which act to suppress immune responses and prevent them from attacking a host’s own issue, migrated to the site of the transplant and appeared to decrease inflammation.
A rat’s tolerance for additional new tissue was also specific to the original donor. When the researchers grafted skin from a third type of rat, called Wistar Furth, onto animals that had received a new limb — but didn’t inject the animals with microparticles to train the immune system to accept the new donor — the skin was rejected and sloughed off. Skin grafts from another Lewis rat or a donor brown Norway rat, however, healed and eventually grew hair.
Skin, an animal’s protection against the outside world, hosts an abundance of immune cells ready to attack invaders or injuries — which poses a problem for successful transplants. “Anytime you throw skin into the mix, it makes things all the more difficult,” Fisher says. Since the rats could tolerate some types of skin, the rodents may also be able accept any other type of tissue.
It’s exciting to see that the rodents in the study could retain transplanted tissue, says Anita Chong, a transplant immunologist at the University of Chicago who was not involved in the work. But the technique “is far, far away” from being used in humans, she says.
While it’s clear that the rats in the study maintained their new limbs for long periods of time, some of the specific details of the mechanism are still unclear, Chong says. “But if it’s true and correct, then it’s remarkable.”
To determine the best microparticle doses to use for larger animals, the researchers next plan to try the technique in pigs — an animal that shares many physiological traits with humans.