Extended lung expression and increased tissue localization of viral IL-10 with adenoviral gene therapy

Extended lung expression and increased tissue localization of viral IL-10 with adenoviral gene therapy

^*Department of Surgery, University of Florida College of Medicine, P.O. Box 100286, Gainesville, FL 32610; ^†Canji, Inc., San Diego, CA 92121; and ^‡National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852

Contributed by Harold S. Ginsberg

Abstract

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.

Footnotes

↵ § Present address: 19 Proctor Road, Woods Hole, MA 02543-1534.
↵ ¶ To whom reprint requests should be addressed at: Department of Surgery, Room 6116, Shands Hospital, University of Florida College of Medicine, Gainesville, FL 32610. E-mail: moldawer{at}surgery.ufl.edu.
Article published online before print: Proc. Natl. Acad. Sci. USA, 10.1073/pnas.250489297.
Article and publication date are at www.pnas.org/cgi/doi/10.1073/pnas.250489297
Abbreviations:

Ad,

adenovirus or adenoviral;

β-gal,

β-galactosidase;

TNF-α,

tumor necrosis factor α;

IL-1α,

interleukin 1α;

hIL-10,

human IL-10;

cIL-10,

cellular IL-10;

vIL-10,

viral IL-10;

i.t.,

intratracheal(ly);

i.v.,

intravenous(ly)