Submitted by Armen Hareyan on May 3rd, 2007
Post-Transplant Cancer
Studies in mice are shedding new light on the intricate behavior of the body's immune system following solid organ transplant, a time when patients are exceptionally vulnerable to developing life-threatening infections and disorders.
Following transplant surgery, patients almost always have to take powerful drugs to suppress their immune systems. If they didn't, their bodies would reject their new organs. But the very same drugs that can save their lives may also jeopardize them, by blocking the activity of millions of white blood cells (called T cells) that normally fend off foreign invaders like bacteria, viruses, or even cancer.
The most common cancer among transplant patients is squamous cell carcinoma of the skin. "Squamous cell carcinoma of the skin occurs 60 to 250 times more frequently in transplant patients than in the general population," says Dr. Tatiana Oberyszyn, assistant professor of pathology in the Ohio State University College of Medicine.
Oberyszyn notes that while squamous cell carcinoma is often treated successfully in healthy people, it is frequently fatal in transplant patients.
When squamous cell cancer arises, two main types of T cells spring into action, CD4 cells and CD8 cells. Earlier studies suggested that CD8 cells (also known as killer T cells) were more important than CD4 cells in blocking tumor growth.
"Transplant patients who develop squamous cell carcinoma are at a definite disadvantage because the function of their CD4 and CD8 cells is dramatically altered by immunosuppressive drugs like cyclosporin and rapamycin," says Oberyszyn, who is also a member of the Ohio State University Comprehensive Cancer Center.
Transplant patients are also exquisitely sensitive to sunlight. Physicians normally advise them to avoid the sun following surgery, because the sun's ultraviolet radiation can lead to DNA damage and set the stage for malignant growth.
"Still, we know that lots of patients do venture outside unprotected because they feel so much better with their new organ, and they just want to be out and about," says Oberyszyn. "Under the circumstances, though, it's just very risky behavior."
Hoping to understand more fully the role of T cells in the development of squamous cell carcinoma, Oberyszyn and her colleagues, Drs. Donna Kusewitt and Anne VanBuskirk, designed the experiments in mice to mimic chronic sun exposure transplant patients might normally encounter.
The researchers eliminated CD4 cells from one set of mice and CD8 cells from another group. They then exposed some members of both groups to short-term UVB radiation and others to longer-term periods of ultraviolet B radiation. They measured various factors in the animals' immune response and noted tumor development in the mice that had the longer exposure.
Surprisingly, the researchers discovered that elimination of CD4 cells " but not CD8 cells " significantly increased the intensity and the duration of the inflammatory response in the mice in the short-term exposure. In the long-term experiment, depletion of the CD4 cells resulted in more tumors.
Since there is an established link between chronic inflammation and tumor development, the researchers concluded that the increased inflammation in the skin contributed to the increased tumor development observed in the CD4 depleted mice.
The researchers also noted that when they eliminated the CD4 cells in the mice, there was a corresponding increase in the number of CD8 cells that were activated in the skin.
"This was surprising because CD8 cells normally don't infiltrate the skin in large numbers in response to ultraviolet exposure. It leads us to believe that CD4 cells may be more important than we thought in mediating normal skin function and that there may be an optimal balance between the two cell types that needs to be present to properly regulate the inflammatory response," says Oberyszyn.
The study was published in a recent issue of the Journal of Investigative Dermatology.
Oberyszyn says the study findings may offer physicians useful information as they try to gauge a patient's response to immunosuppressive therapies. "Anything we can do to help prevent the development of squamous cell skin cancer will be especially important for transplant patients," she says.
Source:
Ohio State University Medical Center 