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
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
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
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
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
NIAID supports biomedical research to prevent, diagnose and treat
illnesses such as AIDS, tuberculosis, malaria, asthma and allergies.
NIH is an agency of the U.S. Department of Health and Human Services.
Press releases, fact sheets and other NIAID-related materials are
available via the NIAID Web site at http://www.niaid.nih.gov.
Reference: TM Doherty and A Sher. IL-12 promotes drug-induced clearance
of Mycobacterium avium infection in mice. The Journal of Immunology 160,
For more information about the newly opened protocol at the NIH, call
Betsey Herpin, RN, MSN, at 1-800-772-5464 ext. 304.