A self-adjuvanting vaccine induces cytotoxic T lymphocytes that suppress allergy

Regan J Anderson; Ching-wen Tang; Naomi J Daniels; Benjamin J Compton; Colin M Hayman; Karen A Johnston; Deborah A Knight; Olivier Gasser; Hazel C Poyntz; Peter M Ferguson; David S Larsen; Franca Ronchese; Gavin F Painter; Ian F Hermans

doi:10.1038/nchembio.1640

A self-adjuvanting vaccine induces cytotoxic T lymphocytes that suppress allergy

Nat Chem Biol. 2014 Nov;10(11):943-9. doi: 10.1038/nchembio.1640. Epub 2014 Oct 5.

Affiliations

¹ The Ferrier Research Institute, Victoria University of Wellington, Wellington, New Zealand.
² Malaghan Institute of Medical Research, Wellington, New Zealand.
³ 1] Malaghan Institute of Medical Research, Wellington, New Zealand. [2] Department of Pathology and Molecular Medicine, Wellington School of Medicine and Health Sciences, Wellington, New Zealand.
⁴ Capital and Coast District Health Board, Wellington, New Zealand.
⁵ Department of Chemistry, University of Otago, Dunedin, New Zealand.
⁶ 1] Malaghan Institute of Medical Research, Wellington, New Zealand. [2] School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand.

PMID: 25282504
DOI: 10.1038/nchembio.1640

Abstract

Epitope-based peptide vaccines encompass minimal immunogenic regions of protein antigens to allow stimulation of precisely targeted adaptive immune responses. However, because efficacy is largely determined by the functional status of antigen-presenting cells (APCs) that acquire and present peptides to cells of the adaptive immune system, adjuvant compounds are needed to enhance immunogenicity. We present here a vaccine consisting of an allergen-derived peptide conjugated to a prodrug of the natural killer-like T (NKT) cell agonist α-galactosylceramide, which is highly effective in reducing inflammation in a mouse model of allergic airway inflammation. Unlike other peptide-adjuvant conjugates that directly activate APCs through pattern recognition pathways, this vaccine encourages third-party interactions with NKT cells to enhance APC function. Therapeutic efficacy was correlated with marked increases in the number and functional activity of allergen-specific cytotoxic T lymphocytes (CTLs), leading to suppression of immune infiltration into the lungs after allergen challenge in sensitized hosts.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adjuvants, Immunologic*
Allergens / administration & dosage
Allergens / chemistry
Allergens / immunology
Animals
Anti-Inflammatory Agents / metabolism
Anti-Inflammatory Agents / pharmacology
Anti-Inflammatory Agents / therapeutic use
Antigen-Presenting Cells / drug effects
Antigen-Presenting Cells / immunology
Disease Models, Animal
Female
Galactosylceramides / metabolism
Galactosylceramides / pharmacology
Galactosylceramides / therapeutic use
Hypersensitivity / drug therapy
Hypersensitivity / immunology*
Immunoglobulin E / blood
Inflammation / drug therapy
Male
Mice
Mice, Inbred C57BL
Molecular Conformation
Natural Killer T-Cells / cytology
Natural Killer T-Cells / drug effects
Natural Killer T-Cells / immunology
Peptides / administration & dosage
Peptides / chemistry
Peptides / immunology
Prodrugs / chemistry*
Prodrugs / metabolism
T-Lymphocytes, Cytotoxic / drug effects
T-Lymphocytes, Cytotoxic / immunology*
Vaccines / administration & dosage
Vaccines / chemical synthesis
Vaccines / chemistry
Vaccines / immunology*

Substances

Adjuvants, Immunologic
Allergens
Anti-Inflammatory Agents
Galactosylceramides
Peptides
Prodrugs
Vaccines
alpha-galactosylceramide
Immunoglobulin E

Associated data

PubChem-Substance/205190589
PubChem-Substance/205190590
PubChem-Substance/205190591
PubChem-Substance/205190592
PubChem-Substance/205190593
PubChem-Substance/205190594

Grants and funding

HHSN272201300006C/PHS HHS/United States