Cancer-induced expansion and activation of CD11b+ Gr-1+ cells predispose mice to adenoviral-triggered anaphylactoid-type reactions

Kalyan Pande, Roanna Ueda, Todd Machemer, Manjiri Sathe, Van Tsai, Elena Brin, Matthew J. Delano, Nico Van Rooijen, Terrill K. McClanahan, James E. Talmadge, Lyle L. Moldawer, Joseph H. Phillips, Drake M. LaFace

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

Intravascular delivery (1.5 × 109 particles and higher) of recombinant adenovirus (rAd) induces myeloid cell mediated, self-limiting hemodynamic responses in normal mice. However, we observed anaphylactoid-type reactions and exacerbated hemodynamic events following rAd injection in mice bearing malignant 4T1 mammary carcinoma. Because 4T1 tumors induce significant CD11b+Gr-1+ myeloid cell expansion and activation, we set to determine whether this causes rAd-induced exaggerated responses. When treated with a single intravenous dose (1 × 1010 particles) of rAd, mice implanted with 4T1 carcinoma succumbed due to the anaphylactoid-type reactions. In contrast, normal mice and mice implanted with a related mammary carcinoma (66cl4) that does not induce CD11b+ Gr-1+ cell expansion, showed minimal responses. Depletion of phagocytic CD11b+Gr-1+ cells prior to rAd delivery protected 4T1 tumor-bearing animals, whereas passive transfer of CD11b+Gr-1+ cells from 4T1 tumor-bearing animals was sufficient to convey susceptibility to anaphylactoid-type reactions in normal animals. We further show that there is upregulation of nitric oxide and leukotriene signaling pathways in the 4T1 tumor-induced CD11b+Gr-1+ myeloid cells and that pretreating mice with inhibitors of nitric oxide synthetase and leukotrienes can attenuate the anaphylactoid-type reactions. These data show that malignant tumor growth can alter CD11b+Gr-1+ myeloid cells, rendering hosts susceptible to anaphylactoid-type reactions upon intravascular treatment with rAd.

Original languageEnglish (US)
Pages (from-to)508-515
Number of pages8
JournalMolecular Therapy
Volume17
Issue number3
DOIs
StatePublished - 2009

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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    Pande, K., Ueda, R., Machemer, T., Sathe, M., Tsai, V., Brin, E., Delano, M. J., Van Rooijen, N., McClanahan, T. K., Talmadge, J. E., Moldawer, L. L., Phillips, J. H., & LaFace, D. M. (2009). Cancer-induced expansion and activation of CD11b+ Gr-1+ cells predispose mice to adenoviral-triggered anaphylactoid-type reactions. Molecular Therapy, 17(3), 508-515. https://doi.org/10.1038/mt.2008.280