Cyclophosphamide diminishes inflammation and prolongs transgene expression following delivery of adenoviral vectors to mouse liver and lung.

Published

Journal Article

Immune responses to adenovirus-mediated gene transfer contribute to the problems of transient recombinant gene expression, inflammation, and difficulties with vector readministration. Activation of CD4+ T cells is required for full realization of effector function of both CD8+ T cells (i.e., cytotoxic T cells) and B cells (i.e., neutralizing antibody). We evaluate in this study the effectiveness of a short course of high-dose cyclophosphamide to block immune responses in mice administered vector into lung and liver of C57BL/6 mice. Administration of cyclophosphamide with vector directed to liver blocked activation and mobilization of both CD4+ and CD8+ T cells. As a result, transgene expression was prolonged, inflammation was reduced, and, at the higher doses of cyclophosphamide, formation of neutralizing antibody was prevented and the vector was successfully readministered. Similar studies in the lung demonstrated an effective blockade of T and B cell responses. In contrast to the liver, where it was easier to stabilize transgene expression than to prevent neutralizing antibody, cyclophosphamide prevented the formation of neutralizing antibodies at all doses in the lung, whereas stabilization of transgene expression was only achieved at the highest dose. These experiments begin to define the parameters by which cyclophosphamide could be used as an adjunct in gene therapy.

Full Text

Duke Authors

Cited Authors

  • Jooss, K; Yang, Y; Wilson, JM

Published Date

  • August 1996

Published In

Volume / Issue

  • 7 / 13

Start / End Page

  • 1555 - 1566

PubMed ID

  • 8864756

Pubmed Central ID

  • 8864756

Electronic International Standard Serial Number (EISSN)

  • 1557-7422

International Standard Serial Number (ISSN)

  • 1043-0342

Digital Object Identifier (DOI)

  • 10.1089/hum.1996.7.13-1555

Language

  • eng