"Immunology memory helps us understand much about skin diseases, many of which result in the inappropriate activation of these T-cells that live in the skin," according to Thomas S. Kupper, MD, the Thomas Fitzpatrick Professor of Dermatology, Harvard Medical School, and chief of dermatology, Dana Farber Cancer Institute and Brigham and Women’s Hospital, Boston.
A patient with cutaneous T-cell lymphoma receives a strong blast of a monoclonal antibody that depletes all T-cells and B-cells from his blood, which leads to a complete response to his disease. Despite the presumed absence of T-cells, he develops a drug-eruption rash several days later.
How was this possible since dermatologists know that T-cells are required to trigger such a skin rash? Kupper explained the mechanism behind this phenomenon during the Marion B. Sulzberger, MD, Memorial Lecture recently at the 2011 annual meeting of the American Academy of Dermatology (AAD) in New Orleans.
"Five years ago, we would have been scratching our heads over the mechanism," he says. "Now we know why this really isn’t a puzzle but actually a logical outcome. A powerful leukemia drug, alemtuzumab, did clear the malignant and normal T-cells from the patient’s blood but did not clear the vast majority of normal T-cells that reside in his skin."
During his lecture, he set the stage for explaining this process by addressing the history of key discoveries about T-cells and immunity. Once the prevailing notion was that T-cell memory, a cardinal feature of the immune system, was carried by T-cells that circulate in the blood and through lymph nodes. A skin challenge would prompt the recruitment of T-cells from the blood, resulting in an immune response.
"What we really couldn’t explain based on that older paradigm was what happened to T-cells after they got into skin," Kupper says. "Also, diseases like fixed-drug eruption or psoriasis with fixed plaques tend to occur in the same place, even after successful treatment. It didn’t make sense that T-cells from the bloodstream would know exactly where to go when they were circulating out of the blood into skin."
In the early 1990s, investigators learned that T-cells were designed to travel to different tissues, including skin. A population of memory T-cells was discovered to be specific for homing and trafficking to skin.
In recent years, an experiment on a mouse has also shed light on the recurrent psoriasis dynamic at work. From a psoriasis patient, a sample of cleared, normal-looking skin with no psoriatic plaque was placed onto a mouse that had no immune system. The transplanted normal skin on that mouse soon turned psoriatic, which should have been impossible in the immune-free mouse, indicating that a mechanism was at play in the skin that had been transplanted onto the mouse.
During that same time frame, experiments in Kupper’s laboratory soon revealed the probable mechanism—memory T-cells residing in the skin. An investigator in his lab at the time, Rachael Clark, MD, PhD, developed a new method to extract T-cells from skin, and in parallel applied a histopathological stain to pieces of normal skin. She and fellow investigators counted the cells and then extrapolated the count to the surface area of the human body. They discovered twice as many T-cells in normal skin compared to those circulating in blood, which Kupper described as "a staggering observation that was really paradigm-shifting."
Now an independent investigator, Clark went on to show that more than 95% of cells with skin-homing markers are living in the skin at any given moment and not circulating through the blood. The groundbreaking discovery of this work is that skin immunology memory actually resides in T-cells that live in the skin.
"Our strategies for treating immune skin diseases will evolve based on these observations," he says. "This really helps us understand potential new therapies based on where the disease-causing T-cells live. The flip side is that immunology memory also helps us understand much about skin diseases, many of which result in the inappropriate activation of these T-cells that live in the skin."