Organ specific cytokine therapy: Local activation of mononuclear phagocytes by delivery of an aerosol of recombinant interferon-γ to the human lung

H. Ari Jaffe, Roland Buhl, Andrea Mastrangeli, Kenneth J. Holroyd, Cesare Saltini, Dorothy Czerski, Howard S. Jaffe, Susan Kramer, Stephen Sherwin, Ronald Crystal

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Abstract

In the context of the central role of the alveolar macrophage in host defense of the respiratory epithelial surface, and the ability of IFN-γ to activate mononuclear phagocytes, we have evaluated strategies to use rIFN-γ to activate human alveolar macrophages in vivo. To accomplish this, rIFN-γ was administered to nonsmoking normals, the amounts of IFN-γ quantified in serum and respiratory epithelial lining fluid (ELF) and the status of IFN-γ related activation of blood monocytes and alveolar macrophages was evaluated by quantifying the expression of mRNA transcripts of IP-10, a gene induced specifically by IFN-γ. Systemic administration (subcutaneous) of maximally tolerated amounts of rIFN-γ (250 μg) was followed by detectable levels of IFN-γ in serum but not ELF, the expression of IP-10 transcripts in blood monocytes but not alveolar macrophages, and multiple systemic adverse effects. To circumvent the inability of systemic administration to reach respiratory ELF and activate alveolar macrophages, rIFN-γ (250-1,000 μg) was inhaled as an aerosol once daily for 3 d. Strikingly, while IFN-γ was not detected in serum it was detectable in respiratory ELF in a dose-dependent fashion. Further, alveolar macrophages, but not blood monocytes, expressed IP-10 mRNA transcripts and, importantly, inhalation of aerosolized rIFN-γ was not associated with local or systemic adverse effects. Thus, it is feasible to use rIFN-γ to activate alveolar macrophages by targeting the cytokine directly to the lung. These data suggest a potential strategy for targeted cytokine therapy, without systemic side effects, to augment respiratory tract defenses in individuals at risk for or with lung infection.

Original languageEnglish
Pages (from-to)297-302
Number of pages6
JournalJournal of Clinical Investigation
Volume88
Issue number1
Publication statusPublished - 1 Dec 1991
Externally publishedYes

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Keywords

  • Bronchoalveolar lavage
  • Gene
  • Immune defense
  • IP-10
  • Macrophage

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Ari Jaffe, H., Buhl, R., Mastrangeli, A., Holroyd, K. J., Saltini, C., Czerski, D., Jaffe, H. S., Kramer, S., Sherwin, S., & Crystal, R. (1991). Organ specific cytokine therapy: Local activation of mononuclear phagocytes by delivery of an aerosol of recombinant interferon-γ to the human lung. Journal of Clinical Investigation, 88(1), 297-302.