Extended lung expression and increased tissue localization of viral IL-10 with adenoviral gene therapy.
IL-10 is a pleiotropic cytokine that acts as an important regulator of macrophage, T cell, and natural killer cell functions. Human IL-10 (hIL-10) has both stimulatory and inhibitory effects on a wide variety of cell types. Viral IL-10 (vIL-10) possesses only a subset of hIL-10's activities, predominantly its suppression of cytokine synthesis by T helper type 1 clones. In the present report, we evaluated tissue accumulation and biological activity of hIL-10 and vIL-10 in vivo in individual organs by using a first-generation adenoviral (Ad) vector administered intratracheally and intravenously. We report the observation that Ad vectors delivering vIL-10, but not hIL-10, are associated with prolonged expression in the lung (>42 days) when delivered intratracheally. In contrast, there was no prolongation in vIL-10 expression when Ad vectors were intravenously administered, although vIL-10 levels in the tissue, but not serum, were markedly increased relative to hIL-10. Moreover, we report an augmented capacity of expressed vIL-10 versus hIL-10 to suppress the acute inflammatory responses in the lung to intratracheal administration of Ad. These findings confirm fundamental differences in Ad-induced expression of vIL-10 and hIL-10 when administered to the lungs. The results further suggest that Ad vectors expressing vIL-10 may have a role as anti-inflammatory agents in the treatment of acute and chronic lung inflammation.
Minter
R M
RM
Department of Surgery, University of Florida College of Medicine, P.O. Box 100286, Gainesville, FL 32610, USA.
Ferry
M A
MA
Rectenwald
J E
JE
Bahjat
F R
FR
Oberholzer
A
A
Oberholzer
C
C
La Face
D
D
Tsai
V
V
Ahmed
C M
CM
Hutchins
B
B
Copeland
E M
EM
Ginsberg
H S
HS
Moldawer
L L
LL
D000256:Adenoviridae / Q000235:genetics* / Q000276:immunology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D000914:Antibodies, Viral / Q000097:blood / Q000276:immunology; D002460:Cell Line; D005260:Female; D015967:Gene Expression Regulation, Viral; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000473:pathology / Q000628:therapy; D007275:Injections, Intravenous; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000493:pharmacokinetics; D007442:Intubation, Intratracheal; D008099:Liver / Q000378:metabolism / Q000821:virology; D008168:Lung / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D009500:Neutralization Tests; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000493:pharmacokinetics; D013997:Time Factors; D014161:Transduction, Genetic; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000493:pharmacokinetics
D000893:Anti-Inflammatory Agents; D000914:Antibodies, Viral; D011994:Recombinant Proteins; D014764:Viral Proteins; D016753:Interleukin-10