Suppression of adenoviral-induced host immune response by TGFβ1 expression

Yi Lu, Ying Wang, Guimin Chang

Research output: Contribution to journalArticle

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Abstract

Adenoviral vector (Ad) is the most commonly used viral vector in gene therapy because of its high transduction efficiency. However, Ad has its limitation due to its transient gene expression and reduced efficacy of repeated vector administration, thanks to host cellular and humoral immune responses. Although it is well known that Ad causes immune response to secondary Ad administration and thus hampers the repeated Ad-mediated gene transfer, the systemic comparison between different viral delivery routes and the optimal elapsed time between repetitive viral deliveries has yet to be extensively studied. In this study, in order to determine (i) to what extent the host immune system attenuates the function of the secondary-administrated Ad; and (ii) whether transforming growth factor-! 1 (TGFβ1), an immune suppressor, would reduce this immune response, immune-competent C57BL/6 mice carrying subcutaneous prostate tumors were administrated by either intratumoral (i.t.) or intravenous (i.v.) injection of primary Ad (namely, the 1st viral administration: with either Ad expressing tumor suppressor gene p16, AdRSVp16, or Ad expressing reporter gene β-galactosidase, AdRSVlacZ), then followed by i.t. injection of secondary Ad (AdRSVlacZ) in the presence or absence of co-delivery of Ad expressing TGFβ1 (AdRSVTGFβ1). Sera were purified from blood samples collected at various time points. Anti-adenoviral (anti-Ad) antibody in serum and its neutralizing ability to secondary Ad infection were evaluated. No immune response was observed in mice within 3 days after fisrt viral injection regardless of i.t. or i.v. injection. After 7 days, mice by i.v. viral injection developed a strong immune response and this immune potency was increased over the time up to 8 weeks. In contrast, mice by i.t. viral injection had only a minor immune response at day 7, and this response waned in 14 days after viral injection. The immune response was mainly caused by native Ad proteins rather than by transgenes. Moreover, expression of TGFβ1 by co-delivery of AdRSVTGFβ1 with secondary AdRSVlacZ reduced anti-Ad antibody in sera and prolonged transgene lacZ expression. These results suggest that repeated administration of therapeutic Ad for solid-tumor (such as gene therapy for prostate cancer) by directly i.t. injection with reasonable intervals may provide a rational approach in a clinical setting. The addition of immune suppressor like TGFβ1 may be useful to minimize the immune response to the secondary Ad challenge. These results suggest that with reasonable and justified intervals between repeated viral administration, plus the aid of immune response suppressor, local delivery of Ad vector for solid tumor gene therapy should be efficacious with no or minimal immune response.

Original languageEnglish (US)
Pages (from-to)244-253
Number of pages10
JournalGene Therapy and Molecular Biology
Volume13
Issue number1
StatePublished - Dec 1 2009

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Injections
Intravenous Injections
Genetic Therapy
Transgenes
Anti-Idiotypic Antibodies
Serum
Galactosidases
Neoplasms
Transforming Growth Factors
Humoral Immunity
Tumor Suppressor Genes
Coinfection
Inbred C57BL Mouse
Reporter Genes
Cellular Immunity
Prostate
Immune System
Prostatic Neoplasms
Gene Expression
Genes

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology

Cite this

Suppression of adenoviral-induced host immune response by TGFβ1 expression. / Lu, Yi; Wang, Ying; Chang, Guimin.

In: Gene Therapy and Molecular Biology, Vol. 13, No. 1, 01.12.2009, p. 244-253.

Research output: Contribution to journalArticle

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