Hydroxypropyl-β-Cyclodextrin Spikes Local Inflammation That Induces Th2 Cell and T Follicular Helper Cell Responses to the Coadministered Antigen

Cyclodextrins are commonly used as a safe excipient to enhance the solubility and bioavailability of hydrophobic pharmaceutical agents. Their efficacies and mechanisms as drug-delivery systems have been investigated for decades, but their immunological properties have not been examined. In this study, we reprofiled hydroxypropyl-β-cyclodextrin (HP-β-CD) as a vaccine adjuvant and found that it acts as a potent and unique adjuvant. HP-β-CD triggered the innate immune response at the injection site, was trapped by MARCO+ macrophages, increased Ag uptake by dendritic cells, and facilitated the generation of T follicular helper cells in the draining lymph nodes. It significantly enhanced Ag-specific Th2 and IgG Ab responses as potently as did the conventional adjuvant, aluminum salt (alum), whereas its ability to induce Ag-specific IgE was less than that of alum. At the injection site, HP-β-CD induced the temporary release of host dsDNA, a damage-associated molecular pattern. DNase-treated mice, MyD88-deficient mice, and TBK1-deficient mice showed significantly reduced Ab responses after immunization with this adjuvant. Finally, we demonstrated that HP-β-CD–adjuvanted influenza hemagglutinin split vaccine protected against a lethal challenge with a clinically isolated pandemic H1N1 influenza virus, and the adjuvant effect of HP-β-CD was demonstrated in cynomolgus macaques. Our results suggest that HP-β-CD acts as a potent MyD88- and TBK1-dependent T follicular helper cell adjuvant and is readily applicable to various vaccines.

[1]  M. Kubo,et al.  Memory B cells contribute to rapid Bcl6 expression by memory follicular helper T cells , 2014, Proceedings of the National Academy of Sciences.

[2]  C. Coban,et al.  Nonagonistic Dectin-1 ligand transforms CpG into a multitask nanoparticulate TLR9 agonist , 2014, Proceedings of the National Academy of Sciences.

[3]  S. Reed,et al.  Key roles of adjuvants in modern vaccines , 2013, Nature Medicine.

[4]  A. Gomez-Muñoz,et al.  New insights on the role of ceramide 1-phosphate in inflammation. , 2013, Biochimica et biophysica acta.

[5]  T. Kanazu,et al.  Efficacy of Repeated Intravenous Injection of Peramivir against Influenza A (H1N1) 2009 Virus Infection in Immunosuppressed Mice , 2013, Antimicrobial Agents and Chemotherapy.

[6]  O. Ohara,et al.  Distinct cellular pathways select germline-encoded and somatically mutated antibodies into immunological memory , 2012, The Journal of experimental medicine.

[7]  S. Tangye,et al.  The origins, function, and regulation of T follicular helper cells , 2012, The Journal of experimental medicine.

[8]  K. Ishii,et al.  Nucleic acid sensing at the interface between innate and adaptive immunity in vaccination , 2012, Nature Reviews Immunology.

[9]  Elizabeth E Gray,et al.  Lymph Node Macrophages , 2012, Journal of Innate Immunity.

[10]  G. Winter,et al.  Protein stabilization by cyclodextrins in the liquid and dried state. , 2011, Advanced drug delivery reviews.

[11]  C. Coban,et al.  DNA released from dying host cells mediates aluminum adjuvant activity , 2011, Nature Medicine.

[12]  E. Oviedo-Orta,et al.  Progress in understanding adjuvant immunotoxicity mechanisms. , 2011, Toxicology letters.

[13]  J. Colgan,et al.  NFIL3/E4BP4 controls type 2 T helper cell cytokine expression , 2011, The EMBO journal.

[14]  C. Coban,et al.  Silica crystals and aluminum salts regulate the production of prostaglandin in macrophages via NALP3 inflammasome-independent mechanisms. , 2011, Immunity.

[15]  F. Maxfield,et al.  Niemann‐Pick type C disease: molecular mechanisms and potential therapeutic approaches , 2011, Journal of neurochemistry.

[16]  I. Srivastava,et al.  Novel adjuvants and delivery systems for enhancing immune responses induced by immunogens , 2011, Expert review of vaccines.

[17]  Siamon Gordon,et al.  Capture of influenza by medullary dendritic cells via SIGN-R1 is essential for humoral immunity in draining lymph nodes , 2010, Nature Immunology.

[18]  S. Gordon,et al.  Scavenger receptors: role in innate immunity and microbial pathogenesis , 2009, Cellular microbiology.

[19]  P. Marrack,et al.  Towards an understanding of the adjuvant action of aluminium , 2009, Nature Reviews Immunology.

[20]  Richard A. Flavell,et al.  Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants , 2008, Nature.

[21]  N. Grubhofer.  Vaccine Adjuvants Revisited , 2008 .

[22]  Amber Vyas,et al.  Cyclodextrin based novel drug delivery systems , 2008 .

[23]  C. Coban,et al.  TANK-binding kinase-1 delineates innate and adaptive immune responses to DNA vaccines , 2008, Nature.

[24]  Thorsteinn Loftsson,et al.  Cyclodextrins as pharmaceutical solubilizers. , 2007, Advanced drug delivery reviews.

[25]  Raphael Zidovetzki,et al.  Use of cyclodextrins to manipulate plasma membrane cholesterol content: evidence, misconceptions and control strategies. , 2007, Biochimica et biophysica acta.

[26]  Cécile Viboud,et al.  Antibody response to influenza vaccination in the elderly: a quantitative review. , 2006, Vaccine.

[27]  J Fernando Bazan,et al.  IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. , 2005, Immunity.

[28]  S. Tamura,et al.  Estimation of the neuraminidase content of influenza viruses and split-product vaccines by immunochromatography. , 2005, Vaccine.

[29]  Hideo Negishi,et al.  IRF-7 is the master regulator of type-I interferon-dependent immune responses , 2005, Nature.

[30]  L. Luus,et al.  Disruption of membrane cholesterol stimulates MyD88-dependent NF-kappaB activation in immature B cells. , 2004, Cellular immunology.

[31]  G. Poland,et al.  Comparison of the safety, tolerability, and immunogenicity of a MF59-adjuvanted influenza vaccine and a non-adjuvanted influenza vaccine in non-elderly adults. , 2003, Vaccine.

[32]  U. Yamashita,et al.  Mechanisms of Enhanced Macrophage-Mediated Prostaglandin E2 Production and Its Suppressive Role in Th1 Activation in Th2-Dominant BALB/c Mice1 , 2003, The Journal of Immunology.

[33]  Kotaro Suzuki,et al.  Interleukin 21 prevents antigen-induced IgE production by inhibiting germ line Cε transcription of IL-4–stimulated B cells , 2002 .

[34]  H. Alpár,et al.  Intranasal vaccination against plague, tetanus and diphtheria. , 2001, Advanced drug delivery reviews.

[35]  S. Akira,et al.  Toll-like receptors: critical proteins linking innate and acquired immunity , 2001, Nature Immunology.

[36]  M. Borca,et al.  Adjuvant effects of sulfolipo-cyclodextrin in a squalane-in-water and water-in-mineral oil emulsions for BHV-1 vaccines in cattle. , 2000, Vaccine.

[37]  J. Hörber,et al.  Sphingolipid–Cholesterol Rafts Diffuse as Small Entities in the Plasma Membrane of Mammalian Cells , 2000, The Journal of cell biology.

[38]  J. Kline,et al.  Cutting Edge: Modulation of Airway Inflammation by CpG Oligodeoxynucleotides in a Murine Model of Asthma , 1998, The Journal of Immunology.

[39]  M. Tomasz,et al.  The mitomycin bioreductive antitumor agents: cross-linking and alkylation of DNA as the molecular basis of their activity. , 1997, Pharmacology & therapeutics.

[40]  B. Björkstén,et al.  Characterization of the Mouse and Rat IgE Antibody Responses to Timothy Pollen by Means of Crossed Radioimmunoelectrophoresis , 1982, Allergy.

[41]  Jae-Sung Lim,et al.  Comparison of the adverse events associated with MF59-adjuvanted and non-adjuvanted H1N1 vaccines in healthy young male Korean soldiers. , 2012, Japanese journal of infectious diseases.

[42]  Kotaro Suzuki,et al.  Interleukin 21 prevents antigen-induced IgE production by inhibiting germ line C(epsilon) transcription of IL-4-stimulated B cells. , 2002, Blood.

[43]  J. Kline,et al.  Modulation of airway inflammation by CpG oligodeoxynucleotides in a murine model of asthma. , 1998, Journal of immunology.