Immunity Without T Cells: NIAID Researchers Illuminate Role of Interleukin-12
Interleukin-12 (IL-12), a recently discovered immune protein, helps trigger an alternate line of defense that might help protect people with weakened immune systems from certain infections, according to a report from the National Institute of Allergy and Infectious Diseases (NIAID).
The NIAID study adds to growing evidence that the immune system may be able to fight certain parasitic infections even without T-helper cells, the white blood cells that normally orchestrate the body's defenses against infection. These cells are depleted in people with certain immunosuppressive conditions such as HIV disease.
Ricardo T. Gazzinelli, Ph.D., of NIAID's Laboratory of Parasitic Diseases and his colleagues report the findings, based on studies in cells and mice, in the July 1, 1993, Proceedings of the National Academy of Sciences.
Our data show that IL-12 plays a pivotal role in an alternative pathway of immunity that is independent of T-helper cells," says Dr. Gazzinelli. "These preliminary findings suggest that IL-12 could ultimately have a role in fighting opportunistic infections in immunocompromised individuals." IL-12 is a naturally occurring cytokine, a protein that serves as a messenger in the immune system for cell-to-cell communication.
Research at NIAID and elsewhere has shown that the alternative pathway involves cells known as natural killers that can be induced to secrete an infection-fighting protein, interferon gamma (INF-ç), normally produced by T-helper cells.
The current NIAID research involved both experiments in cell cultures and in severe combined immunodeficiency (SCID) mice. While lacking T cells, SCID mice do have natural killer cells. In the cell culture experiments, the investigators found that IL-12 and another cytokine, tumor necrosis factor alpha (TNF-à), are both needed for the natural killer cells to produce INF-ç. Specifically, the researchers found that when exposed to Toxoplasma gondii parasites, SCID mice spleen cells produced IL-12 and TNF-à, which in turn induced natural killer cells to produce IFN-ç.
Interferon gamma, usually produced by T cells in response to infection, is central to cell-mediated immunity, in which cells such as macrophages kill invading organisms directly," explains Alan Sher, Ph.D., chief of the Laboratory's Immunology and Cell Biology Section. "Many infectious diseases, including parasitic diseases such as leishmaniasis and schistosomiasis, are inhibited by cellular responses prompted by INF-ç. In the last few years, a number of laboratories have shown that natural killer cells also can induce INF-ç responses independently of T cells, and now our data suggest that IL-12 probably is necessary for this alternate pathway."
In their mouse experiments, the NIAID researchers found that IL-12 prolonged the survival of SCID mice infected with T. gondii, a common parasite that can cause encephalitis and death in immunosuppressed individuals. SCID mice treated with IL-12 survived more than 30 days in comparison to untreated mice that died nine to 16 days after infection.
Other laboratories have shown that IL-12 can prevent leishmaniasis in mice normally highly susceptible to that disease. "IL-12 may have a role in augmenting IFN-ç immunity to other infections as well," says Dr. Gazzinelli.
Although INF-ç itself has been used as a therapy in people, its success has been minimal because of toxicity and the large doses required.
"IL-12 might prove to be a safer, more practical approach to immunotherapy because relatively small amounts are needed," says Dr. Sher. "However, IL-12 has yet to be given to humans, and in mice there is evidence of toxicity at the doses we have tested."
In addition to its function in the natural killer cell pathway, IL-12 also may play an important role in T-cell-dependent immunity. Immunologists generally agree that T-helper cells are divided into two subsets, based primarily on the pattern of the cytokines they secrete. Th1 cells produce INF-ç and other cytokines and appear to drive cell-mediated responses. Th2 cells secrete interleukin-4 and other cytokines and stimulate the immune system's humoral response, which employs custom-made proteins called antibodies to fight infection. Recent data suggest that certain protozoa, bacteria and viruses stimulate the production of IL-12, which in turn directs T cells to differentiate into Th1 cells, which control cell-mediated immunity.
"IL-12 appears to be critical to cellular immunity via both the T-cell and natural killer cell pathways," says Dr. Gazzinelli. "It is an extraordinary molecule, with enormous implications for manipulating the immune response for therapeutic advantage."
Dr. Gazzinelli's and Sher's co-authors include Sara Hieny, M.S., and Thomas A. Lynn, Ph.D., of the Laboratory of Parasitic Diseases, and Stanley Wolf, Ph.D., of the Genetics Institute, Inc., Cambridge, Mass.
NIAID, a component of the National Institutes of Health (NIH) in Bethesda, Md., supports basic and clinical research on allergies, immunology and infectious diseases. NIH is one of eight agencies of the Public Health Service within the Department of Health and Human Services.
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