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-gamma to activate mononuclear phagocytes, we have evaluated strategies to use rIFN-gamma to activate human alveolar macrophages in vivo. To accomplish this, rIFN-gamma was administered to nonsmoking normals, the amounts of IFN-gamma quantified in serum and respiratory epithelial lining fluid (ELF) and the status of IFN-gamma 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-gamma. Systemic administration (subcutaneous) of maximally tolerated amounts of rIFN-gamma (250 micrograms) was followed by detectable levels of IFN-gamma 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-gamma (250-1,000 micrograms) was inhaled as an aerosol once daily for 3 d. Strikingly, while IFN-gamma 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-gamma was not associated with local or systemic adverse effects. Thus, it is feasible to use rIFN-gamma 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.
Full text
PDF





Images in this article
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Aebi M., Fäh J., Hurt N., Samuel C. E., Thomis D., Bazzigher L., Pavlovic J., Haller O., Staeheli P. cDNA structures and regulation of two interferon-induced human Mx proteins. Mol Cell Biol. 1989 Nov;9(11):5062–5072. doi: 10.1128/mcb.9.11.5062. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Badaro R., Falcoff E., Badaro F. S., Carvalho E. M., Pedral-Sampaio D., Barral A., Carvalho J. S., Barral-Netto M., Brandely M., Silva L. Treatment of visceral leishmaniasis with pentavalent antimony and interferon gamma. N Engl J Med. 1990 Jan 4;322(1):16–21. doi: 10.1056/NEJM199001043220104. [DOI] [PubMed] [Google Scholar]
- Black C. M., Catterall J. R., Remington J. S. In vivo and in vitro activation of alveolar macrophages by recombinant interferon-gamma. J Immunol. 1987 Jan 15;138(2):491–495. [PubMed] [Google Scholar]
- Chebath J., Merlin G., Metz R., Benech P., Revel M. Interferon-induced 56,000 Mr protein and its mRNA in human cells: molecular cloning and partial sequence of the cDNA. Nucleic Acids Res. 1983 Mar 11;11(5):1213–1226. doi: 10.1093/nar/11.5.1213. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Comber P. G., Rossman M. D., Rappaport E. F., Chien P., Hogarth P. M., Schreiber A. D. Modulation of human mononuclear phagocyte Fc gamma RII mRNA and protein. Cell Immunol. 1989 Dec;124(2):292–307. doi: 10.1016/0008-8749(89)90132-9. [DOI] [PubMed] [Google Scholar]
- Ezekowitz R. A., Dinauer M. C., Jaffe H. S., Orkin S. H., Newburger P. E. Partial correction of the phagocyte defect in patients with X-linked chronic granulomatous disease by subcutaneous interferon gamma. N Engl J Med. 1988 Jul 21;319(3):146–151. doi: 10.1056/NEJM198807213190305. [DOI] [PubMed] [Google Scholar]
- Fels A. O., Cohn Z. A. The alveolar macrophage. J Appl Physiol (1985) 1986 Feb;60(2):353–369. doi: 10.1152/jappl.1986.60.2.353. [DOI] [PubMed] [Google Scholar]
- Fels A. O., Nathan C. F., Cohn Z. A. Hydrogen peroxide release by alveolar macrophages from sarcoid patients and by alveolar macrophages from normals after exposure to recombinant interferons alpha A, beta, and gamma and 1,25-dihydroxyvitamin D3. J Clin Invest. 1987 Aug;80(2):381–386. doi: 10.1172/JCI113083. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fuchs H. J., Czarniecki C. W., Chiu H. H., Sniezek M., Shellito J. E. Interferon-gamma increases alveolar macrophage Ia antigen expression despite oral administration of dexamethasone to rats. Am J Respir Cell Mol Biol. 1989 Dec;1(6):525–532. doi: 10.1165/ajrcmb/1.6.525. [DOI] [PubMed] [Google Scholar]
- Gibson U. E., Kramer S. M. Enzyme-linked bio-immunoassay for IFN-gamma by HLA-DR induction. J Immunol Methods. 1989 Dec 20;125(1-2):105–113. doi: 10.1016/0022-1759(89)90083-5. [DOI] [PubMed] [Google Scholar]
- Gottlieb A. B., Luster A. D., Posnett D. N., Carter D. M. Detection of a gamma interferon-induced protein IP-10 in psoriatic plaques. J Exp Med. 1988 Sep 1;168(3):941–948. doi: 10.1084/jem.168.3.941. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gray P. W., Leung D. W., Pennica D., Yelverton E., Najarian R., Simonsen C. C., Derynck R., Sherwood P. J., Wallace D. M., Berger S. L. Expression of human immune interferon cDNA in E. coli and monkey cells. Nature. 1982 Feb 11;295(5849):503–508. doi: 10.1038/295503a0. [DOI] [PubMed] [Google Scholar]
- Gunning P., Ponte P., Okayama H., Engel J., Blau H., Kedes L. Isolation and characterization of full-length cDNA clones for human alpha-, beta-, and gamma-actin mRNAs: skeletal but not cytoplasmic actins have an amino-terminal cysteine that is subsequently removed. Mol Cell Biol. 1983 May;3(5):787–795. doi: 10.1128/mcb.3.5.787. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Haley P. J., Muggenburg B. A., Rebar A. H., Shopp G. M., Bice D. E. Bronchoalveolar lavage cytology in cynomolgus monkeys and identification of cytologic alterations following sequential saline lavage. Vet Pathol. 1989 May;26(3):265–273. doi: 10.1177/030098588902600312. [DOI] [PubMed] [Google Scholar]
- Holter W., Goldman C. K., Casabo L., Nelson D. L., Greene W. C., Waldmann T. A. Expression of functional IL 2 receptors by lipopolysaccharide and interferon-gamma stimulated human monocytes. J Immunol. 1987 May 1;138(9):2917–2922. [PubMed] [Google Scholar]
- Holter W., Grunow R., Stockinger H., Knapp W. Recombinant interferon-gamma induces interleukin 2 receptors on human peripheral blood monocytes. J Immunol. 1986 Mar 15;136(6):2171–2175. [PubMed] [Google Scholar]
- Hubbard R. C., Brantly M. L., Sellers S. E., Mitchell M. E., Crystal R. G. Anti-neutrophil-elastase defenses of the lower respiratory tract in alpha 1-antitrypsin deficiency directly augmented with an aerosol of alpha 1-antitrypsin. Ann Intern Med. 1989 Aug 1;111(3):206–212. doi: 10.7326/0003-4819-111-3-206. [DOI] [PubMed] [Google Scholar]
- Jayaram Y., Buckle A. M., Hogg N. The Fc receptor, FcRI, and other activation molecules on human mononuclear phagocytes after treatment with interferon-gamma. Clin Exp Immunol. 1989 Mar;75(3):414–420. [PMC free article] [PubMed] [Google Scholar]
- Kaplan G., Luster A. D., Hancock G., Cohn Z. A. The expression of a gamma interferon-induced protein (IP-10) in delayed immune responses in human skin. J Exp Med. 1987 Oct 1;166(4):1098–1108. doi: 10.1084/jem.166.4.1098. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kemmerich B., Rossing T. H., Pennington J. E. Comparative oxidative microbicidal activity of human blood monocytes and alveolar macrophages and activation by recombinant gamma interferon. Am Rev Respir Dis. 1987 Aug;136(2):266–270. doi: 10.1164/ajrccm/136.2.266. [DOI] [PubMed] [Google Scholar]
- Kurzrock R., Quesada J. R., Talpaz M., Hersh E. M., Reuben J. M., Sherwin S. A., Gutterman J. U. Phase I study of multiple dose intramuscularly administered recombinant gamma interferon. J Clin Oncol. 1986 Jul;4(7):1101–1109. doi: 10.1200/JCO.1986.4.7.1101. [DOI] [PubMed] [Google Scholar]
- Lipscomb M. F. Lung defenses against opportunistic infections. Chest. 1989 Dec;96(6):1393–1399. doi: 10.1378/chest.96.6.1393. [DOI] [PubMed] [Google Scholar]
- Luster A. D., Ravetch J. V. Biochemical characterization of a gamma interferon-inducible cytokine (IP-10). J Exp Med. 1987 Oct 1;166(4):1084–1097. doi: 10.1084/jem.166.4.1084. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Luster A. D., Ravetch J. V. Genomic characterization of a gamma-interferon-inducible gene (IP-10) and identification of an interferon-inducible hypersensitive site. Mol Cell Biol. 1987 Oct;7(10):3723–3731. doi: 10.1128/mcb.7.10.3723. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Luster A. D., Unkeless J. C., Ravetch J. V. Gamma-interferon transcriptionally regulates an early-response gene containing homology to platelet proteins. Nature. 1985 Jun 20;315(6021):672–676. doi: 10.1038/315672a0. [DOI] [PubMed] [Google Scholar]
- Luster A. D., Weinshank R. L., Feinman R., Ravetch J. V. Molecular and biochemical characterization of a novel gamma-interferon-inducible protein. J Biol Chem. 1988 Aug 25;263(24):12036–12043. [PubMed] [Google Scholar]
- Mistchenko A. S., Diez R. A., Falcoff R. Inhibitory effect of interferon-gamma on adenovirus replication and late transcription. Biochem Pharmacol. 1989 Jun 15;38(12):1971–1978. doi: 10.1016/0006-2952(89)90496-6. [DOI] [PubMed] [Google Scholar]
- Momburg F., Koch N., Möller P., Moldenhauer G., Butcher G. W., Hämmerling G. J. Differential expression of Ia and Ia-associated invariant chain in mouse tissues after in vivo treatment with IFN-gamma. J Immunol. 1986 Feb 1;136(3):940–948. [PubMed] [Google Scholar]
- Murray H. W., Gellene R. A., Libby D. M., Rothermel C. D., Rubin B. Y. Activation of tissue macrophages from AIDS patients: in vitro response of AIDS alveolar macrophages to lymphokines and interferon-gamma. J Immunol. 1985 Oct;135(4):2374–2377. [PubMed] [Google Scholar]
- Murray H. W. Interferon-gamma, the activated macrophage, and host defense against microbial challenge. Ann Intern Med. 1988 Apr;108(4):595–608. doi: 10.7326/0003-4819-108-4-595. [DOI] [PubMed] [Google Scholar]
- Murray H. W., Rubin B. Y., Carriero S. M., Harris A. M., Jaffee E. A. Human mononuclear phagocyte antiprotozoal mechanisms: oxygen-dependent vs oxygen-independent activity against intracellular Toxoplasma gondii. J Immunol. 1985 Mar;134(3):1982–1988. [PubMed] [Google Scholar]
- Murray H. W., Scavuzzo D., Jacobs J. L., Kaplan M. H., Libby D. M., Schindler J., Roberts R. B. In vitro and in vivo activation of human mononuclear phagocytes by interferon-gamma. Studies with normal and AIDS monocytes. J Immunol. 1987 Apr 15;138(8):2457–2462. [PubMed] [Google Scholar]
- Murray H. W., Spitalny G. L., Nathan C. F. Activation of mouse peritoneal macrophages in vitro and in vivo by interferon-gamma. J Immunol. 1985 Mar;134(3):1619–1622. [PubMed] [Google Scholar]
- Murray H. W. Survival of intracellular pathogens within human mononuclear phagocytes. Semin Hematol. 1988 Apr;25(2):101–111. [PubMed] [Google Scholar]
- Nash T. W., Libby D. M., Horwitz M. A. IFN-gamma-activated human alveolar macrophages inhibit the intracellular multiplication of Legionella pneumophila. J Immunol. 1988 Jun 1;140(11):3978–3981. [PubMed] [Google Scholar]
- Nathan C. F., Horowitz C. R., de la Harpe J., Vadhan-Raj S., Sherwin S. A., Oettgen H. F., Krown S. E. Administration of recombinant interferon gamma to cancer patients enhances monocyte secretion of hydrogen peroxide. Proc Natl Acad Sci U S A. 1985 Dec;82(24):8686–8690. doi: 10.1073/pnas.82.24.8686. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nathan C. F., Kaplan G., Levis W. R., Nusrat A., Witmer M. D., Sherwin S. A., Job C. K., Horowitz C. R., Steinman R. M., Cohn Z. A. Local and systemic effects of intradermal recombinant interferon-gamma in patients with lepromatous leprosy. N Engl J Med. 1986 Jul 3;315(1):6–15. doi: 10.1056/NEJM198607033150102. [DOI] [PubMed] [Google Scholar]
- Nathan C. F., Murray H. W., Wiebe M. E., Rubin B. Y. Identification of interferon-gamma as the lymphokine that activates human macrophage oxidative metabolism and antimicrobial activity. J Exp Med. 1983 Sep 1;158(3):670–689. doi: 10.1084/jem.158.3.670. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nathan C. F., Prendergast T. J., Wiebe M. E., Stanley E. R., Platzer E., Remold H. G., Welte K., Rubin B. Y., Murray H. W. Activation of human macrophages. Comparison of other cytokines with interferon-gamma. J Exp Med. 1984 Aug 1;160(2):600–605. doi: 10.1084/jem.160.2.600. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nathan C. F. Secretory products of macrophages. J Clin Invest. 1987 Feb;79(2):319–326. doi: 10.1172/JCI112815. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Paulnock D. M., Havlin K. A., Storer B. M., Spear G. T., Sielaff K. M., Borden E. C. Induced proteins in human peripheral mononuclear cells over a range of clinically tolerable doses of interferon-gamma. J Interferon Res. 1989 Aug;9(4):457–473. doi: 10.1089/jir.1989.9.457. [DOI] [PubMed] [Google Scholar]
- Rennard S. I., Basset G., Lecossier D., O'Donnell K. M., Pinkston P., Martin P. G., Crystal R. G. Estimation of volume of epithelial lining fluid recovered by lavage using urea as marker of dilution. J Appl Physiol (1985) 1986 Feb;60(2):532–538. doi: 10.1152/jappl.1986.60.2.532. [DOI] [PubMed] [Google Scholar]
- Rose R. M., Wasserman A. S., Weiser W. Y., Remold H. G. Deficient responses of pulmonary macrophages from healthy smokers to antiviral lymphokines in vitro. J Infect Dis. 1986 Oct;154(4):611–618. doi: 10.1093/infdis/154.4.611. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Saltini C., Hance A. J., Ferrans V. J., Basset F., Bitterman P. B., Crystal R. G. Accurate quantification of cells recovered by bronchoalveolar lavage. Am Rev Respir Dis. 1984 Oct;130(4):650–658. doi: 10.1164/arrd.1984.130.4.650. [DOI] [PubMed] [Google Scholar]
- Schaffner A., Rellstab P. Gamma-interferon restores listericidal activity and concurrently enhances release of reactive oxygen metabolites in dexamethasone-treated human monocytes. J Clin Invest. 1988 Sep;82(3):913–919. doi: 10.1172/JCI113698. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sechler J. M., Malech H. L., White C. J., Gallin J. I. Recombinant human interferon-gamma reconstitutes defective phagocyte function in patients with chronic granulomatous disease of childhood. Proc Natl Acad Sci U S A. 1988 Jul;85(13):4874–4878. doi: 10.1073/pnas.85.13.4874. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sibille Y., Reynolds H. Y. Macrophages and polymorphonuclear neutrophils in lung defense and injury. Am Rev Respir Dis. 1990 Feb;141(2):471–501. doi: 10.1164/ajrccm/141.2.471. [DOI] [PubMed] [Google Scholar]
- Thompson J. A., Cox W. W., Lindgren C. G., Collins C., Neraas K. A., Bonnem E. M., Fefer A. Subcutaneous recombinant gamma interferon in cancer patients: toxicity, pharmacokinetics, and immunomodulatory effects. Cancer Immunol Immunother. 1987;25(1):47–53. doi: 10.1007/BF00199300. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Woloszczuk W. A sensitive immunoradiometric assay for gamma interferon, suitable for its measurement in serum. Clin Chem. 1985 Jun;31(6):1090–1090. [PubMed] [Google Scholar]
- Yamamoto N., Shimokata K., Maeno K., Nishiyama Y. Effect of recombinant human interferon gamma against human cytomegalovirus. Arch Virol. 1987;94(3-4):323–329. doi: 10.1007/BF01310726. [DOI] [PubMed] [Google Scholar]