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Gene transfer is also significantly curtailed following a second dose of virus. In an effort to reduce adenovirus-associated inflammation, capsids of first-generation vectors were modified with various activated monomethoxypolyethylene glycols. Cytotoxic T-lymphocyte production was significantly reduced in C57BL\/6 mice after a single intratracheal administration of modified vectors, and length of gene expression was extended from 4 to 42 days. T-cell subsets from mice exposed to the conjugated vectors demonstrated a marked decrease in Th1 responses and slight enhancement of Th2 responses compared to animals dosed with native virus. Neutralizing antibodies (NAB) against adenovirus capsid proteins were reduced in serum and bronchoalveolar lavage fluid of animals after a single dose of modified virus, allowing significant levels of gene expression upon rechallenge with native adenovirus. Modification with polyethylene glycol (PEG) also allowed substantial gene expression from the new vectors in animals previously immunized with unmodified virus. However, gene expression was significantly reduced after two doses of the same PEG-conjugated vector. Alternating the activation group of PEG between doses did produce significant gene expression upon readministration. This technology in combination with second-generation or helper-dependent adenovirus could produce dosing strategies which promote successful readministration of vector in clinical trials and marked expression in patients with significant anti-adenovirus NAB levels and reduce the possibility of immune reactions against viral vectors for gene therapy.<\/jats:p>","DOI":"10.1128\/jvi.75.10.4792-4801.2001","type":"journal-article","created":{"date-parts":[[2002,7,27]],"date-time":"2002-07-27T05:58:35Z","timestamp":1027749515000},"page":"4792-4801","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":202,"title":["\u201cStealth\u201d Adenoviruses Blunt Cell-Mediated and Humoral Immune Responses against the Virus and Allow for Significant Gene Expression upon Readministration in the Lung"],"prefix":"10.1128","volume":"75","author":[{"given":"Maria A.","family":"Croyle","sequence":"first","affiliation":[{"name":"<!--label omitted: 1-->Institute for Human Gene Therapy and Department of Molecular and Cellular Engineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104,1and"},{"name":"<!--label omitted: 2-->Division of Pharmaceutics, The University of Texas at Austin College of Pharmacy, Austin, Texas 787122"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Narendra","family":"Chirmule","sequence":"additional","affiliation":[{"name":"<!--label omitted: 1-->Institute for Human Gene Therapy and Department of Molecular and Cellular Engineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104,1and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Zhang","sequence":"additional","affiliation":[{"name":"<!--label omitted: 1-->Institute for Human Gene Therapy and Department of Molecular and Cellular Engineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104,1and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James M.","family":"Wilson","sequence":"additional","affiliation":[{"name":"<!--label omitted: 1-->Institute for Human Gene Therapy and Department of Molecular and Cellular Engineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104,1and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.71.3.2408-2416.1997"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1089\/hum.1997.8.1-15"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0958-1669(99)00007-5"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI115761"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.1998.463"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.72.7.6138-6145.1998"},{"key":"e_1_3_2_8_2","doi-asserted-by":"crossref","first-page":"448","DOI":"10.4049\/jimmunol.163.1.448","article-title":"Repeated administration of adenoviral vectors in lungs of human CD4 transgenic mice treated with a non-depleting CD4 antibody","volume":"163","author":"Chirmule N.","year":"1999","unstructured":"Chirmule N. 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