Adenoviral-Mediated Gene Transfer of Interleukin-6 in Rat Lung Enhances Antiviral Immunoglobulin A and G Responses in Distinct Tissue Compartments

doi:10.1006/bbrc.1999.0644

Biochemical and Biophysical Research Communications

Volume 258, Issue 2, 10 May 1999, Pages 332-335

https://doi.org/10.1006/bbrc.1999.0644 Get rights and content

Abstract

The effect of IL-6 transgene expression following lung gene transfer on anti-adenovirus humoral responses of immunoglobulin (Ig) G and A both in the lung and peripheral blood was investigated. Lung infection by a control adenovirus caused an increased level of circulating anti-adenoviral IgG antibodies. However, the magnitude of this response was many times higher in the peripheral blood of rats receiving an adenovirus engineered to express IL-6 transgene. In comparison, much lower levels of anti-adenoviral IgG were detected in the bronchoalveolar fluids of rats receiving either virus. In contrast, there was no detectable level of anti-adenoviral IgA in the peripheral blood in any cases, yet significantly detectable levels of anti-adenoviral IgA were measured in the lung. The levels of this IgA were much higher in the lung of rats expressing IL-6 than in the lung of control animals (15 times higher by day 14). Our findings thus provide evidence that IL-6 plays a significant role in enhancing specific airways mucosal IgA and systemic IgG responses during local lung viral infection, and provide the rationale for using IL-6 locally at mucosa sites as an immune adjuvant for antiviral vaccination program.

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Systemic interleukin-6 responses following administration of adenovirus gene transfer vectors to humans by different routes
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Citation Excerpt :
Many cell types, including monocytes, alveolar macrophages, endothelial cells, fibroblasts, mesangial cells, keratinocytes, B and T lymphocytes, and dendritic cells, produce IL-6 in response to a variety of stimuli [18–20,23]. Among the diverse functions of IL-6 include regulation of the terminal steps of B-cell differentiation, stimulation of B-cell IgG synthesis, stimulation of T-cell proliferation and induction of cytotoxic T-lymphocyte activity by peripheral and thymic T-cell precursors [20,23,31,32]. Studies in experimental animals have demonstrated that, following Ad vector-mediated gene transfer to several organs, a combination of innate and acquired host immune responses preclude stable gene expression [4–19].
Administration of adenovirus (Ad) vectors to animals induces innate immune responses, typified by elevated interleukin-6 (IL-6). To assess innate responses to Ad vectors in humans, we evaluated serum IL-6 following administration of E1⁻ E3⁻ Ad vectors to different human hosts and the relationship among peak IL-6 and peak anti-Ad neutralizing antibodies. We administered: 1) Ad_GVCFTR.10, a vector carrying the normal human CFTR cDNA (3×10⁷ to 2×10¹⁰ particle units (pu)) to airways of individuals with cystic fibrosis (CF); 2) Ad_GVVEGF121.10, a vector carrying the normal human vascular endothelial growth factor (VEGF)121 cDNA, to the myocardium (4×10⁸ to 4×10¹⁰ pu) of individuals with coronary artery disease (CAD) and to lower extremity muscles (4×10⁸ to 4×10^9.5 pu) of individuals with peripheral vascular disease (PVD); and 3) Ad_GVCD.10, a vector carrying the Escherichia coli cytosine deaminase gene to skin (7×10⁷ to 7×10⁹ pu) and airways (7×10⁸ to 7×10¹⁰ pu) of normal individuals and to liver metastasis (4×10⁸ to 4×10⁹ pu) of individuals with colon carcinoma. IL-6 increased mildly (up to 220 pg/ml) following vector administration to skin and lung airways of normal individuals and of individuals with CF, and to muscle and liver metastasis of individuals with PVD and colon cancer, respectively. IL-6 responses were higher (up to 1100 pg/ml) following myocardial administration. Control individuals who had chest surgery and bronchoscopy, but no vector administration, had comparable IL-6 increases. Thus, both administration of Ad vectors of humans up to 10¹⁰ pu and the procedures used to administer the vectors elicit systemic IL-6 responses. There was no correlation among peak IL-6 and peak anti-Ad antibodies. These observatio ns indicate that the innate host responses following administration of Ad vectors to humans may result from the procedures used to administer the vector, and from the vector per se.
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Methods. Male Lewis rats were transfected with 1 × 10⁹ pfu/mL of E1-deleted Ad5CMVLacZ vector transtracheally. Rats were randomly assigned to receive daily intraperitoneal triple immunosuppression regimen consisting of cyclosporine (15 mg/kg per day), azathioprine (6 mg/kg per day), and methylprednisolone (2.5 mg/kg per day), or normal saline solution. Retransfection was performed 35 days later to all nonimmunosuppressed animals, whereas immunosuppressed rats were further randomized to receive retransfection or phosphate-buffered saline. Animals were sacrificed on days 1, 2, 7, 35, 42, and 49 after the initial transfection. β-Galactosidase activity was measured on lung homogenates. Interferon-γ, tumor necrosis factor-α, and antiadenoviral immunoglobin G were measured from the serum.
Results. Enhanced and prolonged transgene expression was observed in immunosuppressed animals, especially after retransfection. Concentrations of serum tumor necrosis factor-α in both groups were less than 12 pg/mL throughout the study. A significant increase in serum interferon-γ levels was observed in nonimmunosuppressed animals after retransfection; this was not seen in the immunosuppressed animals. Serum antiadenoviral immunoglobin G titers in both groups were sharply elevated on day 1, and declined to basal levels by day 7, reflecting a preexisting level of humoral immunity to adenovirus. The titer in nonimmunosuppressed rats was significantly increased after retransfection, but remained at very low level in immunosuppressed animals.
Conclusions. Inhibition of interferon-γ and antiadenoviral immunoglobin G production by triple immunosuppressants may be part of the mechanisms that lead to enhanced and prolonged transgene expression after retransfection.
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^☆: Kelly, J.

¹: To whom correspondence and reprint requests should be addressed at Rm. 4H13, Health Science Centre, Department of Pathology, McMaster University, Hamilton, Ontario, L8N 3Z5 Canada. Fax: 905-522-6750. E-mail:[email protected].

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Biochemical and Biophysical Research Communications

Regular ArticleAdenoviral-Mediated Gene Transfer of Interleukin-6 in Rat Lung Enhances Antiviral Immunoglobulin A and G Responses in Distinct Tissue Compartments☆

Abstract

Immunol. Today

Cytokines of the Lung

J. Immunol.

J. Immunol.

Systemic interleukin-6 responses following administration of adenovirus gene transfer vectors to humans by different routes

Transplant immunosuppression enhances efficiency of adenoviral-mediated gene retransfection: Inhibition of interferon-γ and immunoglobin G

Pseudomonas aeruginosa LasB protease impairs innate immunity in mice and humans by targeting a lung epithelial cystic fibrosis transmembrane regulator-IL-6-antimicrobial-repair pathway

Cigarette Smoke Decreases Pulmonary Dendritic Cells and Impacts Antiviral Immune Responsiveness

Gene therapy and gene transfer approaches for acute lung injury

Use of gene transfer to study lung: Cytokine biology

Regular Article
Adenoviral-Mediated Gene Transfer of Interleukin-6 in Rat Lung Enhances Antiviral Immunoglobulin A and G Responses in Distinct Tissue Compartments☆