Bone marrow and stem cell transplantation rejection averted by UV light exposure

One of the unfortunate side effects of bone marrow and stem cell transplantation is that the newly implanted cells often stage an internal attack against the patient they're intended to help. Stanford University School of Medicine researchers now have a better grasp of this phenomenon, known as graft-versus-host disease, or GVHD, and have proposed a possible method of prevention: simple ultraviolet light.

In a new animal study, researchers identified the principal culprit in skin GVHD: an immune cell in the skin known as a Langerhans cell. These cells normally function as flag posts for the immune system, signaling infection-fighting T-cells to come to a particular site to fight off a virus or bacteria. But in transplants, they do patients a great disservice, alerting T-cells to attack the patient's own tissues, researchers found.

The researchers were able to effectively eliminate the Langerhans cells in transplanted mice by exposing them to ultraviolet light, giving the animals mild sunburn. Transplanted mice that received this treatment experienced no skin GVHD while those that didn't showed severe signs of the disease, said Edgar Engleman, MD, professor of pathology and medicine and senior author of the study.

"The experiment not only provided the proof that these cells cause graft-versus-host disease, but also provides a way of thinking about how you might prevent it," said Engleman, who also directs the Stanford Blood Center. The study appears in the May issue of the journal Nature Medicine.

Bone marrow or stem cell transplants are commonly used to treat patients with cancers of the blood system, such as leukemia, lymphoma or myeloma. Patients first receive radiation treatment to wipe out their defective immune systems, which then are replaced by healthy donor cells.

Sometimes, however, the process fails as GVHD sets in. The effects of the disease are most commonly seen in the skin as a reddish rash or, in more severe cases, as skin that blisters and peels.

The Stanford scientists first suspected that Langerhans cells might have a major role in skin GVHD after their earlier experiments showed these cells were resistant to radiation and persisted in the skin for a long time, said Miriam Merad, MD, PhD, a former postdoctoral scholar in Engelman's lab and the first author of the study. The discovery was "shocking," Engleman said, as all other white blood cells have a short half-life and are frequently replaced. The Langerhans cells don't change unless they're disturbed in some way, say by inflammation, he said.

The scientists surmised that these cells might linger in the skin of a transplant patient and instigate trouble. Their latest experiments bore this out.

The researchers tested their theory in two different sets of mice. In one group, the animals had their own Langerhans cells intact. When these animals were transplanted, the Langerhans cells triggered a response and the mice developed severe GVHD in the skin. In a second group, the scientists replaced the animals' Langerhans cells with other cells. When these mice underwent transplant, they remained protected from skin GVHD.

The scientists took it a step further. They exposed the vulnerable mice - those with their own Langerhans cells - to ultraviolet light using a sunlamp. The sun exposure depleted the Langerhans cells and effectively protected the mice from the disease, said Merad, who is now based at the Mount Sinai School of Medicine.

The researchers said the results present a promising option for transplant patients and could be the basis for clinical trials in which patients are exposed to ultraviolet light before treatment.

"What we would do is try to eliminate the host Langerhans cells before the transplant, as we did in the mice," Merad said. She noted that dermatologists now use ultraviolet light to treat some skin diseases, administering it to patients inside a chamber under controlled circumstances to avoid burning.

Engleman said the ultraviolet treatment would have to be carefully administered to patients before bone marrow or stem cell transplantation to avoid harmful side effects. "The trick is deplete the host Langerhans cells in a manner that doesn't cause other unwanted effects," he said.

Other Stanford researchers in the study include Petra Hoffman, PhD; Erik Ranheim, MD, PhD; Markus G. Manz, MD; Irving Weissman, MD; and Samuel Strober, MD. Other collaborators included Sarah Slaymaker and Israel Charo, MD, PhD, of UCSF; Sergio A. Lira, MD, PhD, of Mount Sinai; and Donald N. Cook, MD, of Duke University.
The study was funded by the National Institutes of Health and by a grant from the Irene Diamond Fund.