Collaborators include scientists from Roswell Park Cancer Institute, Buffalo, N.Y.; the Tumor Immunity and Tolerance Section of the Laboratory of Molecular Immunoregulation, National Cancer Institute; and Howard Hughes Medical Institute/Memorial Sloan-Kettering Cancer Center.
"What we are showing is that testosterone seems to impede immunity," says Eugene Kwon, M.D., the Mayo Clinic urologist and immunology researcher who led the research team. "However, when testosterone is withdrawn, you get an increased host immune response indicated by the rising numbers of immune cells that are available to participate."
T-lymphocytes are cells that are vital to controlling the body's immune response. "T cells," as they are usually called by scientists, are white blood cells that can fight against tumor cells and infection. Alternatively, T cells can help other immune cells known as "B cells" make antibodies to defend the body against certain bacterial and fungal infections, and possibly against cancer. The research findings may have broad potential applications to public health. For example, knowing that testosterone levels affect T-cell response may help:
* explain why women are more prone than men to develop "autoimmune disease."
* speed the development of drugs that bolster the immune system to treat such immune-deficiency diseases as AIDS.
* improve vaccines.
* decrease the time needed to reconstitute the immune system after bone marrow transplantation.
* protect cancer patients who are receiving immunotherapy treatments or who are vulnerable to infection as a result of chemotherapy.
Significance of the Research
Researchers and physicians have known for years that there is a difference in immunity between men and women -- but they have not known why. The researchers discovered one possible mechanism driving the difference: The presence of testosterone slows or weakens the response of T-lymphocytes. Delving further to discover the mechanism behind this response, the research team found that without testosterone, the T-lymphocytes "turn-on" more quickly.
It also is possible that other sex hormones play a similar role because testosterone is just one of the hormones known as androgens.
"Females are typically more predisposed to the phenomenon of autoimmunity," says Dr. Kwon. "And of course, what's interesting about this is that females don't have significant levels of testosterone. Men, on the other hand, may have relatively blunted immune responses and have high levels of testosterone. So these results of our experiment are really very promising for unraveling this gender difference in the immune system." He emphasizes that further research is needed to validate these findings before they can be used in human patients in the clinic.
Dr. Kwon frequently cares for patients with prostate cancer. The current experiment grew out of his experience in the clinic. One of the more common forms of treatment for prostate cancer suppresses the patient's testosterone levels to increase the patient's immune attack against cancer. To test the role of testosterone on the immune system in the laboratory, the researchers removed testosterone from male mice.
"They suddenly started growing large numbers of new immune cells," Dr. Kwon says. "We also demonstrated that if you take a male mouse and treat it with chemotherapy you can prompt the mouse to recover its immune system much more quickly simply by removing androgen."
When testosterone is removed, the immune cells come back strong and aggressive, ready to attack. Says Dr. Kwon, "They become twitchy, very reactive, and in this state they can, in fact, mediate a strong immune response -- which, as physicians, is just what we want."
Collaborators and Support
In addition to Dr. Kwon, Mayo Clinic research team members include Anja C. Roden, M.D., Samuel D. Tri, Maria Mercader, Ph.D., Susan M. Kuntz, Haidong Dong, M.D., Ph.D., David J. McKean, Ph.D., Esteban Celis, M.D., and Bradley C. Leibovich, M.D. Collaborators from other institutions are: Michael T. Moser, Roswell Park Cancer Institute; Arthur A. Hurwitz, principal investigator, Tumor Immunity and Tolerance Section, Laboratory of Molecular Immunoregulation, National Cancer Institute; and James P. Allison, chairman, Immunology Program, David H. Koch Chair in Immunologic Studies, Attending Immunologist, Department of Medicine, Investigator, Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center. The work was supported by a National Institutes of Health National Cancer Institute grant; a U.S. Department of Defense grant; and the Mayo Foundation.