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

Research output: Contribution to journalArticle

115 Citations (Scopus)

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

Fingerprint

Alveolar Macrophages
Phagocytes
Aerosols
Interferons
Cytokines
Lung
Monocytes
Therapeutics
Serum
Messenger RNA
Respiratory System
Inhalation
Infection
Genes

Keywords

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

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Organ specific cytokine therapy : Local activation of mononuclear phagocytes by delivery of an aerosol of recombinant interferon-γ to the human lung. / Ari Jaffe, H.; Buhl, Roland; Mastrangeli, Andrea; Holroyd, Kenneth J.; Saltini, Cesare; Czerski, Dorothy; Jaffe, Howard S.; Kramer, Susan; Sherwin, Stephen; Crystal, Ronald.

In: Journal of Clinical Investigation, Vol. 88, No. 1, 01.12.1991, p. 297-302.

Research output: Contribution to journalArticle

Ari Jaffe, H, Buhl, R, Mastrangeli, A, Holroyd, KJ, Saltini, C, Czerski, D, Jaffe, HS, 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, vol. 88, no. 1, pp. 297-302.
Ari Jaffe, H. ; Buhl, Roland ; Mastrangeli, Andrea ; Holroyd, Kenneth J. ; Saltini, Cesare ; Czerski, Dorothy ; Jaffe, Howard S. ; Kramer, Susan ; Sherwin, Stephen ; Crystal, Ronald. / Organ specific cytokine therapy : Local activation of mononuclear phagocytes by delivery of an aerosol of recombinant interferon-γ to the human lung. In: Journal of Clinical Investigation. 1991 ; Vol. 88, No. 1. pp. 297-302.
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