Human dendritic cell (DC)-based anti-infective therapy: Engineering DCs to secrete functional IFN-γ and IL-12

Seema S. Ahuja, Srinivas Mummidi, Harry L. Malech, Sunil K. Ahuja

Research output: Contribution to journalArticlepeer-review

49 Scopus citations

Abstract

An imbalance in the Th1- and Th2-type cytokine responses may allow certain microbes to modify the host response to favor their own persistence. We now show that infection/pulsing of human CD34+ peripheral blood hemopoietic progenitor cell-derived dendritic cells (DCs) with Leishmania donovani promastigotes, Histoplasma capsulatum, and Mycobacterium kansasii impairs the constitutive production of IL-12 from these cells. Thus, strategies aimed at modulating a dysregulated Th1/Th2 response to infection would be of great interest. To both augment the host immune response and deliver potent immunomodulatory cytokines such as IL-12 and IFN-γ, our goal is to develop a therapeutic strategy using genetically modified, microbial Ag-pulsed DCs. Toward developing such immunotherapies, we used retrovirus- mediated somatic gene transfer techniques to engineer human DCs to secrete biologically active IL-12 and IFN-γ. DCs pulsed with microbial antigens (e.g., leishmania and histoplasma Ags) were capable of inducing proliferative responses in autologous CD4+ lymphocytes. CD4+ lymphocytes cocultured with IL-12-transduced autologous DCs had enhanced Ag-specific proliferative responses compared with CD4+ lymphocytes cocultured with nontransduced or IFN-γ-transduced DCs. In this cell culture model system we demonstrate that IL-12 has a negative effect on IL-4 secretion that is independent of its ability to induce IFN-γ secretion. Taken together, these results indicate that IL-12-transduced DCs may be specifically suited in inducing or down- modulating Ag-specific Th1 or Th2 responses, respectively, and thus may be useful as adjunctive therapy in those intracellular infections in which a dominant Th1 response is critical for the resolution of infection.

Original languageEnglish (US)
Pages (from-to)868-876
Number of pages9
JournalJournal of Immunology
Volume161
Issue number2
StatePublished - Jul 15 1998

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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