Journal of Clinical Immunology

, Volume 27, Issue 4, pp 363–371 | Cite as

Toll or Toll-Free Adjuvant Path Toward the Optimal Vaccine Development

Original Article

Abstract

Successful vaccines contain an adjuvant component that activates the innate immune system, thereby eliciting antigen-specific immune responses. Many adjuvants appear to be ligands for toll-like receptors (TLR), which are thus promising targets for the development of novel adjuvants to elicit vaccine immunogenicity. However, recent evidence suggests that some adjuvants activate the innate immune system in a TLR-independent manner possibly through other pattern recognition receptors and signaling machinery. In particular, newly identified intracellular retinoic-acid-inducible gene (RIG)-like receptors, NOD-like receptors, or even as yet unknown recognition machinery for the adjuvant may regulate TLR-independent vaccine immunogenicity. To develop optimal vaccines, it will be critical to understand how TLR-dependent and TLR-independent innate immune activation, by various adjuvants, control the consequent adaptive immune responses to vaccine.

KEY WORDS:

Innate immunity adaptive immunity toll-like receptor (TLR) vaccine adjuvant dendritic cells monophosphoryl lipid A (MPL) outer-surface lipoprotein (OspA) Hib-OMPC NOD desmuramylpeptides (DMP) muramyldipeptide (MDP) complete Freund's adjuvant (CFA) incomplete Freund's adjuvant (IFA) bacille calmette guerin (BCG) flagellin DNA vaccine ICE protease activating factor (IPAF) neuronal apoptosis inhibitory protein 5 (NAIP5) dsRNA Poly-I:C retinoic-acid-inducible gene I (RIG-I) melanoma-differentiation-associated gene 5 (MDA5) IPS-1 ssRNA interferon B-DNA Z-DNA CpG DNA 

References

  1. 1.
    Janeway CA, Jr., Medzhitov R: Innate immune recognition. Annu Rev Immunol. 20:197–216, 2002PubMedCrossRefGoogle Scholar
  2. 2.
    Akira S, Uematsu S, Takeuchi O: Pathogen recognition and innate immunity. Cell 124:783–801, 2006PubMedCrossRefGoogle Scholar
  3. 3.
    Beutler B, Jiang Z, Georgel P, Crozat K, Croker B, Rutschmann S, Du X, Hoebe K: Genetic analysis of host resistance: Toll-like receptor signaling and immunity at large. Annu Rev Immunol 24:353–389, 2006PubMedCrossRefGoogle Scholar
  4. 4.
    Gavin AL, Hoebe K, Duong B, Ota T, Martin C, Beutler B, Nemazee D: Adjuvant-enhanced antibody responses in the absence of toll-like receptor signaling. Science 314:1936–1938, 2006PubMedCrossRefGoogle Scholar
  5. 5.
    Janssen E, Tabeta K, Barnes MJ, Rutschmann S, McBride S, Bahjat KS, Schoenberger SP, Theofilopoulos AN, Beutler B, Hoebe K: Efficient T cell activation via a Toll-Interleukin 1 receptor-independent pathway. Immunity 24:787–799, 2006PubMedCrossRefGoogle Scholar
  6. 6.
    Lopez CB, Moltedo B, Alexopoulou L, Bonifaz L, Flavell RA, Moran TM: TLR-independent induction of dendritic cell maturation and adaptive immunity by negative-strand RNA viruses. J Immunol 173:6882–6889, 2004PubMedGoogle Scholar
  7. 7.
    Creagh EM, O’Neill LA: TLRs, NLRs and RLRs: A trinity of pathogen sensors that co-operate in innate immunity. Trends Immunol 27:352–357, 2006PubMedCrossRefGoogle Scholar
  8. 8.
    Meylan E, Tschopp J, Karin M: Intracellular pattern recognition receptors in the host response. Nature 442:39–44, 2006PubMedCrossRefGoogle Scholar
  9. 9.
    Ishii KJ, Akira S: Innate immune recognition of, and regulation by, DNA. Trends Immunol 27:525–532, 2006PubMedCrossRefGoogle Scholar
  10. 10.
    Kaisho T, Akira S: Toll-like receptors as adjuvant receptors. Biochim Biophys Acta 1589:1–13, 2002PubMedCrossRefGoogle Scholar
  11. 11.
    van Duin D, Medzhitov R, Shaw AC: Triggering TLR signaling in vaccination. Trends Immunol 27:49–55, 2006PubMedCrossRefGoogle Scholar
  12. 12.
    O’Hagan DT, Valiante NM: Recent advances in the discovery and delivery of vaccine adjuvants. Nat Rev Drug Discov 2:727–735, 2003PubMedCrossRefGoogle Scholar
  13. 13.
    Pashine A, Valiante NM, Ulmer JB: Targeting the innate immune response with improved vaccine adjuvants. Nat Med 11:S63–S68, 2005PubMedCrossRefGoogle Scholar
  14. 14.
    Ishii KJ, Coban C, Akira S: Manifold mechanisms of toll-like receptor-ligand recognition. J Clin Immunol 25:511–521, 2005PubMedCrossRefGoogle Scholar
  15. 15.
    Ishii KJ, Akira S: Innate immune recognition of nucleic acids: Beyond toll-like receptors. Int J Cancer 117:517–523, 2005PubMedCrossRefGoogle Scholar
  16. 16.
    Blander JM, Medzhitov R: On regulation of phagosome maturation and antigen presentation. Nat Immunol 7:1029–1035, 2006PubMedCrossRefGoogle Scholar
  17. 17.
    Masihi KN, Lange W, Brehmer W, Ribi E: Immunobiological activities of nontoxic lipid A: Enhancement of nonspecific resistance in combination with trehalose dimycolate against viral infection and adjuvant effects. Int J Immunopharmacol 8:339–345, 1986PubMedCrossRefGoogle Scholar
  18. 18.
    Cluff CW, Baldridge JR, Stover AG, Evans JT, Johnson DA, Lacy MJ, Clawson VG, Yorgensen VM, Johnson CL, Livesay MT, Hershberg RM, Persing DH: Synthetic toll-like receptor 4 agonists stimulate innate resistance to infectious challenge. Infect Immun 73:3044–3052, 2005PubMedCrossRefGoogle Scholar
  19. 19.
    Pasare C, Medzhitov R: Toll-dependent control mechanisms of CD4 T cell activation. Immunity 21:733–741, 2004PubMedCrossRefGoogle Scholar
  20. 20.
    Pasare C, Medzhitov R: Control of B-cell responses by toll-like receptors. Nature 438:364–368, 2005PubMedCrossRefGoogle Scholar
  21. 21.
    Evans JT, Cluff CW, Johnson DA, Lacy MJ, Persing DH, Baldridge JR: Enhancement of antigen-specific immunity via the TLR4 ligands MPL adjuvant and Ribi. 529. Expert Rev Vaccines 2:219–229, 2003PubMedCrossRefGoogle Scholar
  22. 22.
    Hoffman ES, Smith RE, Renaud RC, Jr.: From the analyst's couch: TLR-targeted therapeutics. Nat Rev Drug Discov 4:879–880, 2005PubMedCrossRefGoogle Scholar
  23. 23.
    Takeuchi O, Kawai T, Muhlradt PF, Morr M, Radolf JD, Zychlinsky A, Takeda K, Akira S: Discrimination of bacterial lipoproteins by toll-like receptor 6. Int Immunol 13:933–940, 2001PubMedCrossRefGoogle Scholar
  24. 24.
    Takeuchi O, Sato S, Horiuchi T, Hoshino K, Takeda K, Dong Z, Modlin RL, Akira S: Cutting edge: Role of toll-like receptor 1 in mediating immune response to microbial lipoproteins. J Immunol 169:10–14, 2002PubMedGoogle Scholar
  25. 25.
    Patel M, Xu D, Kewin P, Choo-Kang B, McSharry C, Thomson NC, Liew FY: TLR2 agonist ameliorates established allergic airway inflammation by promoting Th1 response and not via regulatory T cells. J Immunol 174:7558–7563, 2005PubMedGoogle Scholar
  26. 26.
    Borsutzky S, Kretschmer K, Becker PD, Muhlradt PF, Kirschning CJ, Weiss S, Guzman CA: The mucosal adjuvant macrophage-activating lipopeptide-2 directly stimulates B lymphocytes via the TLR2 without the need of accessory cells. J Immunol 174:6308–6313, 2005PubMedGoogle Scholar
  27. 27.
    Alexopoulou L, Thomas V, Schnare M, Lobet Y, Anguita J, Schoen RT, Medzhitov R, Fikrig E, Flavell RA: Hyporesponsiveness to vaccination with Borrelia burgdorferi OspA in humans and in. Nat Med 8:878–884, 2002PubMedGoogle Scholar
  28. 28.
    Yoder A, Wang X, Ma Y, Philipp MT, Heilbrun M, Weis JH, Kirschning CJ, Wooten RM, Weis JJ: Tripalmitoyl-S-glyceryl-cysteine-dependent OspA vaccination of toll-like receptor 2-deficient mice results in effective protection from Borrelia burgdorferi challenge. Infect Immun 71:3894–3900, 2003PubMedCrossRefGoogle Scholar
  29. 29.
    Latz E, Franko J, Golenbock DT, Schreiber JR: Haemophilus influenzae type b-outer membrane protein complex glycoconjugate vaccine induces cytokine production by engaging human toll-like receptor 2 (TLR2) and requires the presence of TLR2 for optimal immunogenicity. J Immunol 172:2431–2438, 2004PubMedGoogle Scholar
  30. 30.
    Inohara N, Chamaillard M, McDonald C, Nunez G: NOD-LRR proteins: Role in host-microbial interactions and inflammatory disease. Annu Rev Biochem 74:355–383, 2005PubMedCrossRefGoogle Scholar
  31. 31.
    Fritz JH, Ferrero RL, Philpott DJ, Girardin SE: NOD-like proteins in immunity, inflammation and disease. Nat Immunol 7:1250–1257, 2006PubMedCrossRefGoogle Scholar
  32. 32.
    Ellouz F, Adam A, Ciorbaru R, Lederer E: Minimal structural requirements for adjuvant activity of bacterial peptidoglycan derivatives. Biochem Biophys Res Commun 59:1317–1325, 1974PubMedCrossRefGoogle Scholar
  33. 33.
    Kufer TA, Sansonetti PJ: Sensing of bacteria: NOD a lonely job. Curr Opin Microbiol 2006Google Scholar
  34. 34.
    Tada H, Aiba S, Shibata K, Ohteki T, Takada H: Synergistic effect of NOD1 and NOD2 agonists with toll-like receptor agonists on human dendritic cells to generate interleukin-12 and T helper type 1 cells. Infect Immun 73:7967–7976, 2005PubMedCrossRefGoogle Scholar
  35. 35.
    Fremond CM, Yeremeev V, Nicolle DM, Jacobs M, Quesniaux VF, Ryffel B: Fatal mycobacterium tuberculosis infection despite adaptive immune response in the absence of MyD88. J Clin Invest 114:1790–1799, 2004PubMedCrossRefGoogle Scholar
  36. 36.
    Hayashi F, Smith KD, Ozinsky A, Hawn TR, Yi EC, Goodlett DR, Eng JK, Akira S, Underhill DM, Aderem A: The innate immune response to bacterial flagellin is mediated by toll-like receptor 5. Nature 410:1099–1103, 2001PubMedCrossRefGoogle Scholar
  37. 37.
    Uematsu S, Jang MH, Chevrier N, Guo Z, Kumagai Y, Yamamoto M, Kato H, Sougawa N, Matsui H, Kuwata H, Hemmi H, Coban C, Kawai T, Ishii KJ, Takeuchi O, Miyasaka M, Takeda K, Akira S: Detection of pathogenic intestinal bacteria by toll-like receptor 5 on intestinal CD11c+ lamina propria cells. Nat Immunol 7:868–874, 2006PubMedCrossRefGoogle Scholar
  38. 38.
    Applequist SE, Rollman E, Wareing MD, Liden M, Rozell B, Hinkula J, Ljunggren HG: Activation of innate immunity, inflammation, and potentiation of DNA vaccination through mammalian expression of the TLR5 agonist flagellin. J Immunol 175:3882–3891, 2005PubMedGoogle Scholar
  39. 39.
    Honko AN, Sriranganathan N, Lees CJ, Mizel SB: Flagellin is an effective adjuvant for immunization against lethal respiratory challenge with Yersinia pestis. Infect Immun 74:1113–1120, 2006PubMedCrossRefGoogle Scholar
  40. 40.
    Molofsky AB, Byrne BG, Whitfield NN, Madigan CA, Fuse ET, Tateda K, Swanson MS: Cytosolic recognition of flagellin by mouse macrophages restricts Legionella pneumophila infection. J Exp Med 203:1093–1104, 2006PubMedCrossRefGoogle Scholar
  41. 41.
    Zamboni DS, Kobayashi KS, Kohlsdorf T, Ogura Y, Long EM, Vance RE, Kuida K, Mariathasan S, Dixit VM, Flavell RA, Dietrich WF, Roy CR: The Birc1e cytosolic pattern-recognition receptor contributes to the detection and control of Legionella pneumophila infection. Nat Immunol 7:318–325, 2006PubMedCrossRefGoogle Scholar
  42. 42.
    Franchi L, Amer A, Body-Malapel M, Kanneganti TD, Ozoren N, Jagirdar R, Inohara N, Vandenabeele P, Bertin J, Coyle A, Grant EP, Nunez G: Cytosolic flagellin requires Ipaf for activation of caspase-1 and interleukin 1beta in salmonella-infected macrophages. Nat Immunol 7:576–582, 2006PubMedCrossRefGoogle Scholar
  43. 43.
    Miao EA, Alpuche-Aranda CM, Dors M, Clark AE, Bader MW, Miller SI, Aderem A: Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1beta via Ipaf. Nat Immunol 7:569–575, 2006PubMedCrossRefGoogle Scholar
  44. 44.
    Robinson RA, DeVita VT, Levy HB, Baron S, Hubbard SP, Levine AS: A phase I-II trial of multiple-dose polyriboinosic-polyribocytidylic acid in patieonts with leukemia or solid tumors. J Natl Cancer Inst 57:599–602, 1976PubMedGoogle Scholar
  45. 45.
    Adams M, Navabi H, Jasani B, Man S, Fiander A, Evans AS, Donninger C, Mason M: Dendritic cell (DC) based therapy for cervical cancer: use of DC pulsed with tumour lysate and matured with a novel synthetic clinically non-toxic double stranded RNA analogue poly [I]:poly [C(12)U] (Ampligen R). Vaccine 21:787–790, 2003PubMedCrossRefGoogle Scholar
  46. 46.
    Schulz O, Diebold SS, Chen M, Naslund TI, Nolte MA, Alexopoulou L, Azuma YT, Flavell RA, Liljestrom P, Reis e Sousa C: Toll-like receptor 3 promotes cross-priming to virus-infected cells. Nature 433:887–892, 2005PubMedCrossRefGoogle Scholar
  47. 47.
    Zaks K, Jordan M, Guth A, Sellins K, Kedl R, Izzo A, Bosio C, Dow S: Efficient immunization and cross-priming by vaccine adjuvants containing TLR3 or TLR9 agonists complexed to cationic liposomes. J Immunol 176:7335–7345, 2006PubMedGoogle Scholar
  48. 48.
    Yoneyama M, Kikuchi M, Natsukawa T, Shinobu N, Imaizumi T, Miyagishi M, Taira K, Akira S, Fujita T: The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat Immunol 5:730–737, 2004PubMedCrossRefGoogle Scholar
  49. 49.
    Yoneyama M, Kikuchi M, Matsumoto K, Imaizumi T, Miyagishi M, Taira K, Foy E, Loo YM, Gale M, Jr., Akira S, Yonehara S, Kato A, Fujita T: Shared and unique functions of the DExD/H-Box helicases RIG-I, MDA5, and LGP2 in antiviral innate immunity. J Immunol 175:2851–2858, 2005PubMedGoogle Scholar
  50. 50.
    Kawai T, Akira S: Innate immune recognition of viral infection. Nat Immunol 7:131–137, 2006PubMedCrossRefGoogle Scholar
  51. 51.
    Kato H, Takeuchi O, Sato S, Yoneyama M, Yamamoto M, Matsui K, Uematsu S, Jung A, Kawai T, Ishii KJ, Yamaguchi O, Otsu K, Tsujimura T, Koh CS, Reis e Sousa C, Matsuura Y, Fujita T, Akira S: Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 441:101–105, 2006PubMedCrossRefGoogle Scholar
  52. 52.
    Gitlin L, Barchet W, Gilfillan S, Cella M, Beutler B, Flavell RA, Diamond MS, Colonna M: Essential role of mda-5 in type I IFN responses to polyriboinosinic:polyribocytidylic acid and encephalomyocarditis picornavirus. Proc Natl Acad Sci USA 103:8459–8464, 2006PubMedCrossRefGoogle Scholar
  53. 53.
    Kariko K, Bhuyan P, Capodici J, Weissman D: Small interfering RNAs mediate sequence-independent gene suppression and induce immune activation by signaling through toll-like receptor 3. J Immunol 172:6545–6549, 2004PubMedGoogle Scholar
  54. 54.
    Ishii KJ, Akira S: TLR ignores methylated RNA? Immunity 23:111–113, 2005PubMedCrossRefGoogle Scholar
  55. 55.
    Sugiyama T, Gursel M, Takeshita F, Coban C, Conover J, Kaisho T, Akira S, Klinman DM, Ishii KJ: CpG RNA: Identification of novel single-stranded RNA that stimulates human CD14+CD11c+ monocytes. J Immunol 174:2273–2279, 2005PubMedGoogle Scholar
  56. 56.
    Koski GK, Kariko K, Xu S, Weissman D, Cohen PA, Czerniecki BJ: Cutting edge: Innate immune system discriminates between RNA containing bacterial versus eukaryotic structural features that prime for high-level IL-12 secretion by dendritic cells. J Immunol 172:3989–3993, 2004PubMedGoogle Scholar
  57. 57.
    Diebold SS, Massacrier C, Akira S, Paturel C, Morel Y, Reis e Sousa C: Nucleic acid agonists for toll-like receptor 7 are defined by the presence of uridine ribonucleotides. Eur J Immunol 36:3256–3267, 2006PubMedCrossRefGoogle Scholar
  58. 58.
    Hemmi H, Kaisho T, Takeuchi O, Sato S, Sanjo H, Hoshino K, Horiuchi T, Tomizawa H, Takeda K, Akira S: Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat Immunol 3:196–200, 2002PubMedCrossRefGoogle Scholar
  59. 59.
    Diebold SS, Kaisho T, Hemmi H, Akira S, Reis e Sousa C: Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 303:1529–1531, 2004PubMedCrossRefGoogle Scholar
  60. 60.
    Heil F, Hemmi H, Hochrein H, Ampenberger F, Kirschning C, Akira S, Lipford G, Wagner H, Bauer S: Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science 303:1526–1529, 2004PubMedCrossRefGoogle Scholar
  61. 61.
    Gorden KB, Gorski KS, Gibson SJ, Kedl RM, Kieper WC, Qiu X, Tomai MA, Alkan SS, Vasilakos JP: Synthetic TLR agonists reveal functional differences between human TLR7 and TLR8. J Immunol 174:1259–1268, 2005PubMedGoogle Scholar
  62. 62.
    Horsmans Y, Berg T, Desager JP, Mueller T, Schott E, Fletcher SP, Steffy KR, Bauman LA, Kerr BM, Averett DR: Isatoribine, an agonist of TLR7, reduces plasma virus concentration in chronic hepatitis C infection. Hepatology 42:724–731, 2005PubMedCrossRefGoogle Scholar
  63. 63.
    McInturff JE, Modlin RL, Kim J: The role of toll-like receptors in the pathogenesis and treatment of dermatological disease. J Invest Dermatol 125:1–8, 2005PubMedCrossRefGoogle Scholar
  64. 64.
    Stockfleth E, Trefzer U, Garcia-Bartels C, Wegner T, Schmook T, Sterry W: The use of toll-like receptor-7 agonist in the treatment of basal cell carcinoma: An overview. Br J Dermatol 149(Suppl 66):53–56, 2003PubMedCrossRefGoogle Scholar
  65. 65.
    Lysa B, Tartler U, Wolf R, Arenberger P, Benninghoff B, Ruzicka T, Hengge UR, Walz M: Gene expression in actinic keratoses: Pharmacological modulation by imiquimod. Br J Dermatol 151:1150–1159, 2004PubMedCrossRefGoogle Scholar
  66. 66.
    Wille-Reece U, Flynn BJ, Lore K, Koup RA, Kedl RM, Mattapallil JJ, Weiss WR, Roederer M, Seder RA: HIV Gag protein conjugated to a toll-like receptor 7/8 agonist improves the magnitude and quality of Th1 and CD8+ T cell responses in nonhuman primates. Proc Natl Acad Sci USA 102:15190–15194, 2005PubMedCrossRefGoogle Scholar
  67. 67.
    Kato H, Sato S, Yoneyama M, Yamamoto M, Uematsu S, Matsui K, Tsujimura T, Takeda K, Fujita T, Takeuchi O, Akira S: Cell type-specific involvement of RIG-I in antiviral response. Immunity 23:19–28, 2005PubMedCrossRefGoogle Scholar
  68. 68.
    Hornung V, Ellegast J, Kim S, Brzozka K, Jung A, Kato H, Poeck H, Akira S, Conzelmann KK, Schlee M, Endres S, Hartmann G: 5′-Triphosphate RNA is the ligand for RIG-I. Science 314:994–997, 2006PubMedCrossRefGoogle Scholar
  69. 69.
    Pichlmair A, Schulz O, Tan CP, Naslund TI, Liljestrom P, Weber F, Reis e Sousa C: RIG-I-mediated antiviral responses to single-stranded RNA bearing 5′-phosphates. Science 314:997–1001, 2006PubMedCrossRefGoogle Scholar
  70. 70.
    Klinman DM: Immunotherapeutic uses of CpG oligodeoxynucleotides. Nat Rev Immunol 4:249–258, 2004PubMedCrossRefGoogle Scholar
  71. 71.
    Wagner H: The immunobiology of the TLR9 subfamily. Trends Immunol 25:381–386, 2004PubMedCrossRefGoogle Scholar
  72. 72.
    Krieg AM: Therapeutic potential of toll-like receptor 9 activation. Nat Rev Drug Discov 5:471–484, 2006PubMedCrossRefGoogle Scholar
  73. 73.
    Broide DH: Immunostimulatory sequences of DNA and conjugates in the treatment of allergic rhinitis. Curr Allergy Asthma Rep 5:182–185, 2005PubMedCrossRefGoogle Scholar
  74. 74.
    Vollmer J: TLR9 in health and disease. Int Rev Immunol 25:155–181, 2006PubMedCrossRefGoogle Scholar
  75. 75.
    Gurunathan S, Klinman DM, Seder RA: DNA vaccines: Immunology, application, and optimization*. Annu Rev Immunol 18:927–974, 2000PubMedCrossRefGoogle Scholar
  76. 76.
    Hemmi H, Takeuchi O, Kawai T, Kaisho T, Sato S, Sanjo H, Matsumoto M, Hoshino K, Wagner H, Takeda K, Akira S: A toll-like receptor recognizes bacterial DNA. Nature 408:740–745, 2000PubMedCrossRefGoogle Scholar
  77. 77.
    Spies B, Hochrein H, Vabulas M, Huster K, Busch DH, Schmitz F, Heit A, Wagner H: Vaccination with plasmid DNA activates dendritic cells via toll-like receptor 9 (TLR9) but functions in TLR9-deficient mice. J Immunol 171:5908–5912, 2003PubMedGoogle Scholar
  78. 78.
    Babiuk S, Mookherjee N, Pontarollo R, Griebel P, van Drunen Littel-van den Hurk S, Hecker R, Babiuk L: TLR9−/− and TLR9+/+ mice display similar immune responses to a DNA vaccine. Immunology 113:114–120, 2004PubMedCrossRefGoogle Scholar
  79. 79.
    Tudor D, Dubuquoy C, Gaboriau V, Lefevre F, Charley B, Riffault S: TLR9 pathway is involved in adjuvant effects of plasmid DNA-based vaccines. Vaccine 23:1258–1264, 2005PubMedCrossRefGoogle Scholar
  80. 80.
    Suzuki K, Mori A, Ishii KJ, Saito J, Singer DS, Klinman DM, Krause PR, Kohn LD: Activation of target-tissue immune-recognition molecules by double-stranded polynucleotides. Proc Natl Acad Sci USA 96:2285–2290, 1999PubMedCrossRefGoogle Scholar
  81. 81.
    Ishii KJ, Suzuki K, Coban C, Takeshita F, Itoh Y, Matoba H, Kohn LD, Klinman DM: Genomic DNA released by dying cells induces the maturation of APCs. J Immunol 167:2602–2607, 2001PubMedGoogle Scholar
  82. 82.
    Kawane K, Fukuyama H, Yoshida H, Nagase H, Ohsawa Y, Uchiyama Y, Okada K, Iida T, Nagata S: Impaired thymic development in mouse embryos deficient in apoptotic DNA degradation. Nat Immunol 4:138–144, 2003PubMedCrossRefGoogle Scholar
  83. 83.
    Ishii KJ, Coban C, Kato H, Takahashi K, Torii Y, Takeshita F, Ludwig H, Sutter G, Suzuki K, Hemmi H, Sato S, Yamamoto M, Uematsu S, Kawai T, Takeuchi O, Akira S: A toll-like receptor-independent antiviral response induced by double-stranded B-form DNA. Nat Immunol 7:40–48, 2006PubMedCrossRefGoogle Scholar
  84. 84.
    Stetson DB, Medzhitov R: Recognition of cytosolic DNA activates an IRF3-dependent innate immune response. Immunity 24:93–103, 2006PubMedCrossRefGoogle Scholar
  85. 85.
    Spohn R, Buwitt-Beckmann U, Brock R, Jung G, Ulmer AJ, Wiesmuller KH: Synthetic lipopeptide adjuvants and toll-like receptor 2—structure-activity relationships. Vaccine 22:2494–2499, 2004PubMedCrossRefGoogle Scholar
  86. 86.
    Rharbaoui F, Drabner B, Borsutzky S, Winckler U, Morr M, Ensoli B, Muhlradt PF, Guzman CA: The Mycoplasma-derived lipopeptide MALP-2 is a potent mucosal adjuvant. Eur J Immunol 32:2857–2865, 2002PubMedCrossRefGoogle Scholar
  87. 87.
    Becker PD, Bertot GM, Souss D, Ebensen T, Guzman CA, Grinstein S: Intranasal vaccination with recombinant CD protein and adamantylamide dipeptide as mucosal adjuvant enhances pulmonary clearance of Moraxella catarrhalis in a murine experimental model. Infect Immun 2006Google Scholar
  88. 88.
    Alexopoulou L, Holt AC, Medzhitov R, Flavell RA: Recognition of double-stranded RNA and activation of NF-kappaB by toll-like receptor 3. Nature 413:732–738, 2001PubMedCrossRefGoogle Scholar
  89. 89.
    Ren T, Zamboni DS, Roy CR, Dietrich WF, Vance RE: Flagellin-deficient Legionella mutants evade caspase-1—and Naip5-mediated macrophage immunity. PLoS Pathog 2:e18, 2006PubMedCrossRefGoogle Scholar
  90. 90.
    Wille-Reece U, Flynn BJ, Lore K, Koup RA, Miles AP, Saul A, Kedl RM, Mattapallil JJ, Weiss WR, Roederer M, Seder RA: Toll-like receptor agonists influence the magnitude and quality of memory T cell responses after prime-boost immunization in nonhuman primates. J Exp Med 203:1249–1258, 2006PubMedCrossRefGoogle Scholar
  91. 91.
    Westwood A, Elvin SJ, Healey GD, Williamson ED, Eyles JE: Immunological responses after immunisation of mice with microparticles containing antigen and single stranded RNA (polyuridylic acid). Vaccine 24:1736–1743, 2006PubMedCrossRefGoogle Scholar
  92. 92.
    Coban C, Ishii KJ, Sullivan DJ, Kumar N: Purified malaria pigment (hemozoin) enhances dendritic cell maturation and modulates the isotype of antibodies induced by a DNA vaccine. Infect Immun 70:3939–3943, 2002PubMedCrossRefGoogle Scholar
  93. 93.
    Coban C, Ishii KJ, Kawai T, Hemmi H, Sato S, Uematsu S, Yamamoto M, Takeuchi O, Itagaki S, Kumar N, Horii T, Akira S: Toll-like receptor 9 mediates innate immune activation by the malaria pigment hemozoin. J Exp Med 201:19–25, 2005PubMedCrossRefGoogle Scholar
  94. 94.
    Fleck J, Mock M, Tytgat F, Nauciel C, Minck R: Adjuvant activity in delayed hypersensitivity of the peptidic part of bacterial peptidoglycans. Nature 250:517–518, 1974PubMedCrossRefGoogle Scholar
  95. 95.
    Takada H, Uehara A: Enhancement of TLR-mediated innate immune responses by peptidoglycans through NOD signaling. Curr Pharm Des 12:4163–4172, 2006PubMedCrossRefGoogle Scholar
  96. 96.
    Martinon F, Agostini L, Meylan E, Tschopp J: Identification of bacterial muramyl dipeptide as activator of the NALP3/cryopyrin inflammasome. Curr Biol 14:1929–1934, 2004PubMedCrossRefGoogle Scholar
  97. 97.
    Kanneganti TD, Ozoren N, Body-Malapel M, Amer A, Park JH, Franchi L, Whitfield J, Barchet W, Colonna M, Vandenabeele P, Bertin J, Coyle A, Grant EP, Akira S, Nunez G: Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3. Nature 440:233–236, 2006PubMedCrossRefGoogle Scholar
  98. 98.
    Mariathasan S, Weiss DS, Newton K, McBride J, O’Rourke K, Roose-Girma M, Lee WP, Weinrauch Y, Monack DM, Dixit VM: Cryopyrin activates the inflammasome in response to toxins and ATP. Nature 440:228–232, 2006PubMedCrossRefGoogle Scholar
  99. 99.
    Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J: Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440:237–241, 2006PubMedCrossRefGoogle Scholar
  100. 100.
    Gupta RK: Aluminum compounds as vaccine adjuvants. Adv Drug Deliv Rev 32:155–172, 1998CrossRefGoogle Scholar
  101. 101.
    Aucouturier J, Ascarateil S, Dupuis L: The use of oil adjuvants in therapeutic vaccines. Vaccine 24(Suppl 2):S2–S5, 2006PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  1. 1.Exploratory Research for Advanced Technology (ERATO)Japan Science and Technology Agency (JST), Osaka UniversitySuitaJapan
  2. 2.Departments of Host Defense, and Molecular ProtozoologyThe 21st Century Center of Excellence (COE), Combined Program on Microbiology and Immunology, Research Institute for Microbial Diseases, Osaka UniversitySuitaJapan

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