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.

[1]  L. Moldawer,et al.  TNF-α Receptor Signaling and IL-10 Gene Therapy Regulate the Innate and Humoral Immune Responses to Recombinant Adenovirus in the Lung1 , 2000, The Journal of Immunology.

[2]  P. Robbins,et al.  Adenoviral transfer of the viral IL-10 gene periarticularly to mouse paws suppresses development of collagen-induced arthritis in both injected and uninjected paws. , 1999, Journal of immunology.

[3]  D. Curiel,et al.  Inhibition of tumor necrosis factor alpha decreases inflammation and prolongs adenovirus gene expression in lung and liver. , 1998, Human gene therapy.

[4]  B. Trapnell,et al.  Lung-specific expression of adenovirus E3-14.7K in transgenic mice attenuates adenoviral vector-mediated lung inflammation and enhances transgene expression. , 1998, Human gene therapy.

[5]  C. Jorgensen,et al.  Adenovirus-mediated transfer of viral IL-10 gene inhibits murine collagen-induced arthritis. , 1998, Journal of immunology.

[6]  L. Moldawer,et al.  Pharmacokinetics, immunogenicity, and efficacy of dimeric TNFR binding proteins in healthy and bacteremic baboon. , 1998, Journal of applied physiology.

[7]  Arthur S Slutsky,et al.  Adenovirus-mediated interleukin-10 gene transfer inhibits post-transplant fibrous airway obliteration in an animal model of bronchiolitis obliterans. , 1998, Human gene therapy.

[8]  H. Perlman,et al.  Adenoviral constructs encoding phosphorylation-competent full-length and truncated forms of the human retinoblastoma protein inhibit myocyte proliferation and neointima formation. , 1997, Circulation.

[9]  R. Crystal,et al.  Tumor necrosis factor α plays a central role in immune-mediated clearance of adenoviral vectors , 1997 .

[10]  A. Shaked,et al.  Adenovirus-mediated gene transfer of viral interleukin-10 inhibits the immune response to both alloantigen and adenoviral antigen. , 1997, Human gene therapy.

[11]  M. Jordana,et al.  Adenoviral vector-mediated interleukin-10 expression in vivo: intramuscular gene transfer inhibits cytokine responses in endotoxemia , 1997, Gene Therapy.

[12]  J. Banchereau,et al.  The EBV IL-10 homologue is a selective agonist with impaired binding to the IL-10 receptor. , 1997, Journal of immunology.

[13]  G. Morel,et al.  Non-receptor-mediated tissue localization of human interferon-gamma: role of heparan sulfate/heparin-like molecules. , 1996, Cytokine.

[14]  K. Olthoff,et al.  Transduction of hepatic allografts achieves local levels of viral IL-10 which suppress alloreactivity in vitro. , 1995, The Journal of surgical research.

[15]  F. Graham,et al.  Methods for construction of adenovirus vectors , 1995, Molecular biotechnology.

[16]  H. Shepard,et al.  Development and characterization of recombinant adenoviruses encoding human p53 for gene therapy of cancer. , 1994, Human gene therapy.

[17]  Ho As,et al.  Interleukin-10 and its receptor. , 1994 .

[18]  D. Rifkin,et al.  The extracellular regulation of growth factor action. , 1992, Molecular biology of the cell.

[19]  J. Banchereau,et al.  Interleukin 10 is a potent growth and differentiation factor for activated human B lymphocytes. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[20]  C. Figdor,et al.  Interleukin 10 (IL-10) and viral IL-10 strongly reduce antigen-specific human T cell proliferation by diminishing the antigen-presenting capacity of monocytes via downregulation of class II major histocompatibility complex expression , 1991, The Journal of experimental medicine.

[21]  M. Sporn,et al.  Cytokines in context , 1991, The Journal of cell biology.

[22]  R. Chanock,et al.  A mouse model for investigating the molecular pathogenesis of adenovirus pneumonia. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[23]  T. Mosmann,et al.  Isolation and expression of human cytokine synthesis inhibitory factor cDNA clones: homology to Epstein-Barr virus open reading frame BCRFI. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[24]  T. Mosmann,et al.  Interleukin 10: a novel stimulatory factor for mast cells and their progenitors , 1991, The Journal of experimental medicine.

[25]  T. Mosmann,et al.  Homology of cytokine synthesis inhibitory factor (IL-10) to the Epstein-Barr virus gene BCRFI. , 1990, Science.

[26]  T. Espevik,et al.  A highly sensitive cell line, WEHI 164 clone 13, for measuring cytotoxic factor/tumor necrosis factor from human monocytes. , 1986, Journal of immunological methods.

[27]  D. Solter,et al.  Genetic control of the cytotoxic T cell response to SV40 tumor-associated specific antigen. , 1979, Journal of immunology.

[28]  H. Ginsberg,et al.  The life and times of adenoviruses. , 1999, Advances in virus research.

[29]  R. Crystal,et al.  Innate immune mechanisms dominate elimination of adenoviral vectors following in vivo administration. , 1997, Human gene therapy.