Organ specific cytokine therapy. Local activation of mononuclear phagocytes by delivery of an aerosol of recombinant interferon-gamma to the human lung.
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.
Jaffe
H A
HA
Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892.
Buhl
R
R
Mastrangeli
A
A
Holroyd
K J
KJ
Saltini
C
C
Czerski
D
D
Jaffe
H S
HS
Kramer
S
S
Sherwin
S
S
Crystal
R G
RG
D000199:Actins / Q000235:genetics; D000328:Adult; D000336:Aerosols; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000008:administration & dosage / Q000032:analysis / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008262:Macrophage Activation / Q000187:drug effects*; D008297:Male; D009928:Organ Specificity; D012333:RNA, Messenger / Q000032:analysis; D011994:Recombinant Proteins
D000199:Actins; D000336:Aerosols; D012333:RNA, Messenger; D011994:Recombinant Proteins; D007371:Interferon-gamma