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Journal of Virology, September 1998, p. 7542-7550, Vol. 72, No. 9
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Transient Inhibition of CD28 and CD40 Ligand Interactions Prolongs Adenovirus-Mediated Transgene Expression in the Lung and Facilitates Expression after Secondary Vector Administration

Christopher B. Wilson,1,2,* Lisa J. Embree,3 David Schowalter,3 Richard Albert,3 Alejandro Aruffo,4 Diane Hollenbaugh,4 Peter Linsley,4,dagger and Mark A. Kay1,3,5,6

Departments of Pediatrics,1 Immunology,2 Medicine,3 Pathology,5 and Biochemistry,6 University of Washington School of Medicine, Seattle, Washington 98195, and Bristol-Myers Squibb Pharmaceuticals, Seattle, Washington 981214

Received 16 January 1998/Accepted 21 May 1998

Recombinant adenovirus vectors have been used to transfer genes to the lungs in animal models, but the extent and duration of primary transgene expression and the ability to achieve expression after repeated vector administration have been limited by the development of antigen-specific immunity to the vector and, in some cases, to vector-transduced foreign proteins. To determine if focused modulation of the immune response could overcome some of these limitations, costimulatory interactions between T cells and B cells/antigen-presenting cells were transiently blocked around the time of vector administration. Systemic treatment at the time of primary-vector administration with a monoclonal antibody (MR1) against murine CD40 ligand, combined with recombinant murine CTLA4Ig and intratracheal coadministration of an adenovirus vector transducing the expression of murine CTLA4Ig, prolonged adenovirus-transduced beta -galactosidase expression in the airways for up to 28 days and resulted in persistent alveolar expression for >90 days (the duration of the experiment). Consistent with these results, this treatment regimen reduced local inflammation and markedly reduced the T-cell and T-cell-dependent antibody response to the vector. A secondary adenovirus vector, administered >90 days after the last systemic dose of MR1 and muCTLA4Ig, resulted in alkaline phosphatase expression at levels comparable to those seen with primary-vector administration. Expression of the secondary transgene persisted in the alveoli (but not in the airways) for up to 24 days (the longest period of observation) at levels similar to those observed on days 3 to 4. These results indicate that transient inhibition of costimulatory molecule interactions substantially enhanced gene transfer to the alveoli but was much less effective in the airways. This suggests that there are differences in the efficiency or nature of mechanisms limiting transgene expression in the airways and in the alveoli.

* Corresponding author. Mailing address: Department of Pediatrics, Box 356320, University of Washington, 1959 NE Pacific St., Seattle, WA 98195. Phone: (206) 543-3207. Fax: (206) 543-3184. E-mail: cbwilson{at}u.washington.edu.

dagger Present address: Rosetta Inpharmatics, Kirkland, WA 98034.

Journal of Virology, September 1998, p. 7542-7550, Vol. 72, No. 9
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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