REPLY
Interferon-
and Management of Infectious Diseases
Steven M. Holland, MD;
Joshua M. Farber, MD; and
John I. Gallin, MD
15 June 1996 | Volume 124 Issue 12 | Pages 1095-1096
IN RESPONSE:
We agree with Baier-Bitterlich and colleagues that the mechanism by which interferon-
acts in the setting of chronic infections such as leishmaniasis or tuberculosis is complex and may not fit neatly into the TH1/TH2 paradigm. Feedback loops, such as that which includes prostaglandin E2, are known to be down-regulatory for the destruction of intracellular pathogens at the macrophage level and are overcome by pharmacologic interferon- administration [1]. Similarly, interleukin-6 has been shown to down-regulate macrophage tumor necrosis factor-
receptor levels and to antagonize the interferon--induced up-regulation of tumor necrosis factor- receptor levels [2]. The general finding, however, has been that patients who progress to severe, disseminated infection with intracellular parasites such as Mycobacterium leprae or leishmania usually have abnormal lymphocyte proliferation and low interferon- production in response to antigen; these conditions return to normal after successful therapy [3, 4].
The broad question raised by Baier-Bitterlich and colleagues concerns the underlying mechanisms of interferon- in its pharmacologic versus its physiologic effects. Many physiologic effects of interferon- have been carefully described [5], but those that are significantly responsible for the effect of the agents in a given in vivo setting, such as an infection, remain unclear. Experiments with interferon- "knock-out" mice have confirmed the central physiologic importance of interferon- in controlling and eliminating intracellular pathogens. However, because we are still unsure of the mechanisms responsible for eliminating these infections, we cannot assess the specific critical effects of interferon- in these settings.
Many paths lead to serious infection—some host determined, some organism determined. Many paths (host-, organism-, or physician-determined) also eliminate infection. The ways in which interferon- reduces the incidence of infections in chronic granulomatous disease or assists in clearing certain mycobacterial and parasitic infections when administered therapeutically remain to be discovered.
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Author and Article Information
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National Institute of Allergy and Infectious Diseases; National Institutes of Health; Bethesda, MD 20189
1. Edwards CK 3d, Hedegaard HB, Zlotnik A, Gangadharam PR, Johnston RB Jr, Pabst MJ. Chronic infection due to Mycobacterium intracellulare in mice: association with macrophage release of prostaglandin E2 and reversal by injection of indomethacin, muramyl dipeptide, or interferon-. J Immunol. 1986; 136:1820-7.[Abstract]
2. Bermudez LE, Wu M, Petrofsky M, Young LS. Interleukin-6 antagonizes tumor necrosis factor-mediated mycobacteriostatic and mycobactericidal activities in macrophages. Infect Immunol. 1992; 60:4245-52.
3. Carvalho EM, Barral A, Pedral-Sampiao D, Barral-Netto M, Rocha H, Johnson WD Jr. Immunologic markers of clinical evolution in children recently infected with Leishmania donovani chagasi. J Infect Dis. 1992; 165:535-40.
4. Carvalho EM, Badaro R, Reed SG, Jones TC, Johnson WD Jr. Absence of interferon and interleukin 2 production during active visceral leishmaniasis. J Clin Invest. 1985; 76:2066-9.
5. Gallin JI, Farber JM, Holland SM, Nutman TB. Interferon- in the management of infectious diseases. Ann Intern Med. 1995; 123:216-24.
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