Current and future clinical applications of interferon-gamma in host antimicrobial defense

The T cell-derived macrophage-activating lymphokine, interferon-gamma (IFN-gamma), is the most broadly acting antimicrobial-inducing and host defense-enhancing cytokine thus far identified in experimental models of infectious diseases. The activity induced by IFN-gamma encompasses all classes of non-viral pathogens including intracellular and extracellular parasites, fungi and bacteria. In man, treatment with immuno-enhancing doses of IFN-gamma is safe, well-tolerated and stimulates the antimicrobial mechanisms of blood monocytes, circulating neutrophils and tissue macrophages. Aerosol administration activates alveolar macrophages in a compartmentalized fashion. Monocytes from IFN-gamma-treated patients with cancer, leprosy, and AIDS all respond with the activated phenotype, and suppressed monocyte HLA-DR expression in trauma patients can be up-regulated by IFN-gamma therapy. Thus far, IFN-gamma has been recognized as effective in the prophylaxis of chronic granulomatous disease and as adjunctive treatment in at least one systemic intracellular infection, visceral leishmaniasis. Additional trials suggest beneficial effects as prophylaxis in trauma and as treatment in leprosy, cutaneous leishmaniasis, and HIV- and non-HIV-related disseminated atypical mycobacterial infection. IFN-gamma is also being tested as a prophylaxis in patients with burns and advanced HIV infection and as an adjunct in drug-resistant tuberculosis. Future antimicrobial applications for IFN-gamma include: a) long-term prophylaxis in T cell-deficient states, b) short-term prophylaxis in patients with a reversible host defense defect such as granulocytopenia or immune response suppression induced by trauma or burn injury, and c) adjunctive treatment along with conventional antibiotic therapy for i) nosocomial pneumonia (aerosol administration), ii) opportunistic infections in general, iii) infections which typically respond poorly to available treatment and iv) for infections which require prolonged therapy for cure. In the latter, the addition of IFN-gamma may accelerate the response to conventional therapy and permit a clinically important reduction in the duration of treatment while preserving efficacy.