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Modulating dendritic cells to optimize mucosal immunization protocols.

E Williamson1, G M Westrich, J L Viney

  • 1Department of Molecular Immunology, Immunex Corporation, Seattle WA 98101, USA. williame@immunex.com

Journal of Immunology (Baltimore, Md. : 1950)
|September 22, 1999
PubMed
Summary

Developing new mucosal vaccines requires overcoming oral tolerance. Researchers used Flt3 ligand (Flt3L) and IL-1alpha to expand and activate intestinal dendritic cells (DCs), converting tolerogenic responses into potent active immunity against fed antigens.

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Area of Science:

  • Immunology
  • Vaccinology
  • Cell Biology

Background:

  • Oral administration of antigens typically induces immune tolerance, hindering mucosal vaccine development.
  • Cholera toxin (CT) is a mucosal adjuvant but its toxicity limits clinical application.
  • Intestinal dendritic cells (DCs) present antigens but usually in a tolerogenic manner.

Purpose of the Study:

  • To investigate methods for converting tolerogenic intestinal DCs into immunogenic antigen-presenting cells (APCs).
  • To explore the potential of Flt3 ligand (Flt3L) and IL-1alpha in enhancing mucosal immune responses.
  • To develop alternative, toxin-free adjuvant systems for mucosal immunization.

Main Methods:

  • Mice were treated with Flt3 ligand (Flt3L) to expand intestinal DCs.

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  • Flt3L-expanded DCs were analyzed for co-stimulatory molecule expression (CD80, CD86) after CT immunization.
  • A combination of Flt3L and IL-1alpha was used to stimulate DCs before oral antigen administration.

    • Main Results:

    • Flt3L treatment increased intestinal DC numbers and enhanced local and systemic responses to CT.
    • CT induced up-regulation of CD80 and CD86 on Flt3L-expanded DCs.
    • Combined Flt3L and IL-1alpha treatment resulted in potent active immune responses to fed soluble antigens, overcoming normal tolerance.

    Conclusions:

    • Flt3L-expanded DCs can be modulated by inflammatory signals to promote active immunity instead of tolerance.
    • IL-1alpha acts as a potent DC-activating stimulus, enabling a toxin-free adjuvant system.
    • Flt3L holds promise as a reagent for designing effective mucosal immunization strategies.