Interleukin-12 therapy reduces the number of immune cells and pathology in lungs of mice infected with Mycobacterium tuberculosis.
Alternate modalities for the treatment of Mycobacterium tuberculosis are needed due to the rise in numbers of immunosuppressed individuals at risk for serious disease and the increasing prevalence of multidrug-resistant isolates. Interleukin-12 (IL-12) has been shown to improve immune responses against M. tuberculosis infection in both humans and mice. Previous studies using high-dose IL-12 in various disease models reported a paradoxical immunosuppression. We demonstrate here that exogenous administration of IL-12 for 8 weeks after an aerosolized low dose of M. tuberculosis results in increased survival and decreased pulmonary bacterial loads for CD4-T-cell-deficient mice, most likely due to an early increase in gamma interferon. IL-12 treatment did not impair or enhance the ability of the wild-type mice to control infection, as measured by bacterial numbers. Two novel findings are reported here regarding exogenous IL-12 therapy for M. tuberculosis infections: (i). IL-12 treatment resulted in decreased numbers of immune cells and reduced frequencies of lymphocytes (CD8(+), CD4(+), and NK cells) in the lungs of infected mice and (ii). IL-12 therapy reduced the pathology of M. tuberculosis-infected lungs, as granulomas were smaller and less numerous. These studies support an immunoregulatory role for IL-12 in tuberculosis.
Nolt
Dawn
D
Division of Allergy, Immunology, and Infectious Diseases, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
Flynn
JoAnne L
JL
D000276:Adjuvants, Immunologic / Q000627:therapeutic use; D000818:Animals; D015704:CD4 Antigens / Q000235:genetics / Q000378:metabolism; D006099:Granuloma / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000473:pathology; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000627:therapeutic use*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects; D018655:Lymphocyte Count; D016131:Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011994:Recombinant Proteins / Q000627:therapeutic use; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology
D000276:Adjuvants, Immunologic; D015704:CD4 Antigens; D011994:Recombinant Proteins; D018664:Interleukin-12; D007371:Interferon-gamma