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Mast cell activators: a new class of highly effective vaccine adjuvants

Nature Medicine volume 14, pages 536–541 (2008)Cite this article

Abstract

Mast cells (MCs) have recently received recognition as prominent effectors in the regulation of immune cell migration to draining lymph nodes and lymphocyte activation. However, their role in the development of humoral immune responses is not clear. Here, we demonstrate that subcutaneous or nasal administration of small-molecule MC activators with vaccine antigens evokes large increases in antigen-specific serum immunoglobulin G (IgG) responses. These responses were MC dependent and correlated with increased dendritic cell and lymphocyte recruitment to draining lymph nodes. Nasal instillation of these formulations also evoked antigen-specific secretory IgA and provided protection against anthrax lethal toxin challenge in vitro and against vaccinia virus infection in vivo. Collectively, these results define the MC as an integral sensory arm of the adaptive immune system. Moreover, they highlight MC activators as a new class of vaccine adjuvants, capable of inducing protective antigen-specific immune responses through needle-free routes of administration.

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Figure 1: MC activators induce DC mobilization and DLN hypertrophy.
Figure 2: c48/80 induces MC-dependent humoral responses.
Figure 3: Adjuvant effect of nasally instilled c48/80 is mediated through activation of MCs in the nasal passages.
Figure 4: c48/80 induces a potent and long-lived IgG and IgA response.
Figure 5: c48/80-induced humoral responses confer protection against lethal challenge.

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Acknowledgements

The authors would like to acknowledge S. Kirwan for technical assistance, K. Owzar for assistance with the statistical evaluation of the immunization data for the vaccinia infection study (that is, protection against weight loss), H.-X. Liao (Laboratory of Protein Expression, Duke Human Vaccine Institute) for the recombinant B5R and M. Jenkins (University of Minnesota) for the CD11c-DTR mice used in this study. The following reagents were obtained through the BioDefense and Emerging Infections Research Repository of the National Institute of Allergy and Infectious Diseases, US National Institutes of Health: anthrax protective antigen (PA), recombinant from B. anthracis, NR-140, and anthrax lethal factor recombinant from B. anthracis, NR-570. This work was supported by US National Institutes of Health grants R37-DK50814, RO1-DK077159 and RO1-AI50021.

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Author notes

  1. James B McLachlan and Christopher P Shelburne: These authors contributed equally to this work.

Authors and Affiliations

  1. Departments of Pathology, Duke University Medical Center, Durham, 27710, North Carolina, USA

    James B McLachlan, Christopher P Shelburne, Justin P Hart, Salvatore V Pizzo, Rajen Goyal, Rhea Brooking-Dixon, Herman F Staats & Soman N Abraham

  2. Immunology, Duke University Medical Center, Durham, 27710, North Carolina, USA

    Herman F Staats & Soman N Abraham

  3. Medicine, Duke University Medical Center, Durham, 27710, North Carolina, USA

    Herman F Staats

  4. Molecular Genetics & Microbiology, Duke University Medical Center, Durham, 27710, North Carolina, USA

    Soman N Abraham

Authors
  1. James B McLachlan
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  2. Christopher P Shelburne
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Contributions

J.B.M. and C.P.S. conducted the majority of the experiments; J.P.H. provided discussions and final editing of the manuscript; S.V.P. provided discussion; R.G. assisted with the IgE titers; R.B.-D. provided the NALT micrograph; H.F.S. assisted with the IgG titers and the protection studies and in the design of the study; J.B.M., C.P.S. and S.N.A. designed the study and wrote the manuscript; and the other authors read the paper and commented on the manuscript.

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Correspondence to Soman N Abraham.

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McLachlan, J., Shelburne, C., Hart, J. et al. Mast cell activators: a new class of highly effective vaccine adjuvants. Nat Med 14, 536–541 (2008). https://doi.org/10.1038/nm1757

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