Scientists at the National Institute of Allergy and Infectious Diseases(NIAID)have found that treating mice with interleukin-12 (IL-12) plus conventional antibiotic therapy can help control infection with Mycobacterium avium, an opportunistic infection common in people with late-stage AIDS. IL-12, a cytokine or chemical messenger produced by immune cells, helps regulate cell-mediated immunity.
These findings in immunodeficient mice suggest that combined IL-12/drug treatment may offer a highly effective strategy for managing atypical mycobacterial infections in people who have AIDS or are otherwise immunocompromised, note Mark Doherty, Ph.D., and Alan Sher, Ph.D., of NIAID's Laboratory of Parasitic Diseases, in their report published June 1 in the The Journal of Immunology. Furthermore, they postulate that the same approach might work for other opportunistic infections common in these individuals such as Toxoplasma and Histoplasma. Previous research in animals has shown that these infections also respond to IL-12 treatment.
Based on the new findings, researchers at the National Institutes of Health led by Henry Masur, M.D., recently began recruiting people with both AIDS and Mycobacterium avium complex (MAC) into a Phase I clinical trial to test IL-12 in combination with standard antibiotic treatment regimens. MAC is an infection caused by either M. avium or its close relative, M. intracellulare.
This is an excellent example of how a preclinical study can provide a model for designing a clinical trial," says Anthony S. Fauci, M.D., director of NIAID. "It's very difficult to treat this infection in AIDS patients," comments Dr. Sher. Often patients have to be treated with three or four different drugs, which can have toxic side effects so that patients become intolerant to one or more drugs. Furthermore, the bacteria that causes the infection can become resistant to one or more antibiotics. This protocol is evaluating a way we might enhance natural immunity to the infection while continuing to use antibiotic therapy."
M. avium is a ubiquitous type of bacteria found in water, mist, dust, soil and bird droppings. People usually become infected through contaminated food and water or, less often, by inhaling the organism. Healthy individuals can be infected but have no symptoms. In people who have AIDS or are otherwise immunocompromised, however, the organism can spread throughout the body, damaging tissues and causing fever, night sweats, weight loss, fatigue, or progressively severe diarrhea. In people with AIDS, M. avium infection usually occurs late in the course of the disease concurrent with low CD4+ T-cell counts. Currently, any of three drugs-rifabutin, clarithromycin and azithromycin-are approved as standard therapy to prevent MAC in HIV-infected people with CD4+ T-cell counts below 50.
Once prevention measures have failed and someone develops MAC, however, treatment is more problematic. Patients require life-long maintenance therapy with multiple antibiotics-which can lead to the development of antibiotic resistance or drug intolerance-because symptoms return if treatment is stopped. Thus, researchers are interested in new treatment options.
IL-12 both enhances the immune system's ability to kill infected cells and induces the production of interferon gamma, a protein that helps control infections like MAC. IL-12 can stimulate interferon gamma even in the absence of T cells, a potential advantage when used to treat immunocompromised patients.
Through a series of experiments conducted in immunodeficient mice, Drs. Doherty and Sher discovered that the combination of IL-12 and antibiotics has a synergistic effect, working better than either IL-12 or drugs alone. Infected mice were treated on alternate days for three sequential doses. After a two-day rest period, the animals received another three doses on the same schedule. Control animals were given saline alone. The investigators looked for evidence of bacteria in the spleens and lungs of infected mice. The first group of infected mice received high doses of IL-12 alone. These mice had significant but undramatic reductions in mycobacteria counts, and the mice displayed noticeable wasting and enlarged spleens when compared with control animals.
To try to improve the therapeutic response and reduce side effects, Drs. Doherty and Sher cut the total IL-12 dosage by half (to 500 nanograms). This dosage of IL-12 caused minimal side effects but lowered bacteria counts only slightly. However, when they combined IL-12 with clarithromycin, an antibiotic effective against M. avium in both humans and mice, the reduction in M. avium was 100-fold greater than in control animals.
Because standard clinical practice for MAC treatment involves administering multiple antibiotics, they tested the same low-dose IL-12 regimen with a second unrelated antibiotic, rifabutin. This combination also resulted in a greater than 100-fold decrease in bacteria counts when compared with using rifabutin alone.
Although they found that the activity of IL-12 depended on the stimulation of interferon gamma, when given by itself, even at a higher dose than IL-12, interferon gamma was not more effective at clearing the bacteria than antibiotics alone.
Speaking of the newly opened protocol, Dr. Sher says, "Ethically, you can't take patients off of antibiotic regimens known to be partially effective in order to test a new experimental treatment. So combined treatment is an approach that allows clinicians here at NIH to test the antimicrobial functions of IL-12 in AIDS patients without compromising standard practice."
Reference: IL-12 promotes drug-induced clearance of Mycobacterium avium infection in mice. The Journal of Immunology 160, 5428-35 (1998).
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