Sher A, Doherty TM; Keystone Symposia on Molecular and Cellular Biology:1998 Opportunistic Infections in AIDS.
Keyst Symp Mol Cell Biol Keyst Symp Mol Cell Biol. 1998 Apr 2-8; 108 (abstract no. 021).
Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
Unlike many other opportunistic pathogens, Mycobacterium avium is often difficult to manage in AIDS patients using conventional chemotherapeutic strategies. We have therefore considered the possibility of immunologic intervention utilizing host resistance pathways which might remain intact in CD4+ T cell deficient HIV+ individuals. A mouse experimental model was established employing i.v. inoculation of a virulent strain (SmT) of the bacterium. The resulting infections are characterized by an initial increase in tissue (liver, lung and spleen) bacterial loads during the first 3-4 weeks followed by a gradual leveling off and decline in CFU in subsequent months. In contrast in IL-12 and IFN-gamma deficient animals, bacterial loads continue to increase during the chronic phase while T deficient SCID mice show an intermediate phenotype. The latter findings suggested that an IL-12 dependent, T lymphocyte independent mechanism exists which can limit the growth of M. avium in immunocompromised hosts. Indeed, treatment of SCID mice with rIL-12 caused a significant lowering of bacterial recoveries. More importantly when SCID mice infected with M. avium were simultaneously given both rIL-12 and antibiotic (clarithromycin or rifabutin) a marked synergy was observed allowing us to lower the dose of both agents while obtaining superior control of in vivo bacterial growth. The effect of IL-12 in this synergy was found to be IFN-gamma dependent. Taken together these observations suggest that combined antibiotic-cytokine treatment may offer a strategy for improving management of M. avium infection in AIDS patients while lowering the dose of drugs administered. In contrast to direct cytokine therapy, such a combined protocol could be tested clinically without the risks of complete removal from ongoing chemotherapy.
Publication Types:
Keywords:
- Animals
- Anti-Bacterial Agents
- Antibiotics, Antitubercular
- CD4-Positive T-Lymphocytes
- Clarithromycin
- Cytokines
- Humans
- Interleukin-12
- Mice
- Mice, Inbred BALB C
- Mice, Inbred C57BL
- Mice, SCID
- Mycobacterium avium
- Mycobacterium avium Complex
- Mycobacterium avium-intracellulare Infection
- Rifabutin
- Spleen
- T-Lymphocytes
Other ID:
UI: 102236488
From Meeting Abstracts