Delayed-type hypersensitivity response to high doses of adenoviral vectors

Thomas J. Russi, Edward A. Hirschowitz, Ronald Crystal

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

The present study evaluates the hypothesis that delayed-type hypersensitivity (DTH) contributes to the inflammatory reaction observed when high-dose adenoviral (Ad) vectors are administered to a previously immunized animal. Immunocompetent C57BL/6 mice immunized intraperitoneally with 109 pfu AdCMV. Null [an E1-, E3- Ad vector with a cytomegalovirus (CMV) promoter but no transgene] and challenged intradermally to the footpad with the same vector demonstrated significant footpad swelling 24 hr after challenge with 109 pfu, but not with a lower dose. Footpad histology revealed a mononuclear-granulocytic cellular infiltrate typical of that seen in DTH. Evaluation of the same doses of vector in immunodeficient mice nu/nu and RAG-2- on the C57BL/6 background, and nu/nu and severe combined immunodeficiency (SCID) on the BALB/c background demonstrated suppression of footpad swelling. However, the footpad response remained intact inβ2-microglobulin deficient (β2-m-) mice, suggesting minimal or no role of major histocompatibility complex (MHC) class I-mediated mechanisms for the region of localized inflammation. Challenge with an Ad expressing the interleukin-2 cDNA to immunized C57BL/6 mice demonstrated augmented footpad swelling response. Finally, pretreatment with cyclosporin resulted in a 69% inhibition of the response compared to controls, whereas other immunosuppressants (cyclophosphamide, methotrexate, and hydrocortisone) had no inhibitory effect. These findings provide further insight into the dynamic interplay of immune processes ultimately leading to inflammation when high-dose Ad vectors are administered to a target organ.

Original languageEnglish
Pages (from-to)323-330
Number of pages8
JournalHuman Gene Therapy
Volume8
Issue number3
DOIs
Publication statusPublished - 10 Feb 1997
Externally publishedYes

    Fingerprint

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this