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Pesce, Isabella (2008) Immunological events induced by intrapulmonary administration of LTK63 or CpG in mice. [Ph.D. thesis]

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Abstract (english)

Summary

The synthetic oligodeoxynucleotides containing unmethylated CpG dinucleotides (CpG ODNs) and LTK63, a detoxified mutant of the E. coli the heat labile enterotoxin (LT), are potent mucosal adjuvants. In addition, CpG ODNs and LTK63 provide generic protection, in the absence of co-administered antigen, to respiratory infections. CpG ODNs act through a well-defined molecular pathway, but little is known about immune modulation induced by CpG ODNs in the lung. Similarly, it is clear that LTK63 is immunogenic and functions efficiently as adjuvant, but the mechanism of action in both adjuvanticity and in generic protection is largely unknown. In order to study ex vivo and compare the immunological events induced by CpG ODNs and LTK63, the B-type CpG 1826 or LTK63 were administered intrapulmonary in BALB/c mice. Lungs, sera and spleens were monitored from 3 hours to 14 days after intrapulmonary administration by combining different approaches, comprising multiplex analysis of cytokine protein expression and flow cytometric analysis of lung immune cell populations. In addition, alveolar macrophage (AM) sensitivity to CpG ODNs and the effect of LTK63 on DC recruitment into the lung and on the function of DCs isolated from LTK63 treated and control mice were tested.

The cytokine analysis of lung homogenates shows that CpG ODNs induce an early cytokine response and that the earliest cytokines detected in the lung are KC at 1 hr followed by IL-1a and b, IL-12(p40) and IL-6 at 3 hrs and by G-CSF, MCP-1, MIP-1a and b, and RANTES at 6 hrs. Most but not all of these cytokines are found systemically in the serum in a narrow peak at slightly later time points compared to their appearance in the organ, suggesting a spillover from the lung into the blood, and several of those cytokines are released by AMs after in vitro stimulation with CpG ODNs. Flow cytometric analysis of lung immune cells shows that intrapulmonary administration of CpG ODN induces activation of plasmacytoid DCs (pDCs), myeloid DCs (mDCs), CD4 T cells, CD8 T cells and NK cells in a time period of 12 hours to 4 days after treatment, as well as recruitment into the lung of pDCs at 2 days and of mDC starting at 4 days, respectively.

LTK63 treatment, in contrast, acts more slowly and induces two phases of activation in the lung: an early phase, which extends from 1 to 2 days, and a second phase, which extends from 6 to 8 days. In the first phase, LTK63 intrapulmonary administration induces up-regulation of IL-1b, G-CSF and KC, which represent granulocyte chemoattractants and growth factors, and consistent with this, accumulation of granulocytes and mDCs in the lung is observed. In the second phase, LTK63 induces in the lung the up-regulation of a complex mixture of cytokines involved in inflammation and cell recruitment, which are produced in part by CD11c+ cells, as shown in in vitro experiments with these cells isolated from the lungs of LTK63 treated mice. Flow cytometric analysis of lung immune cells shows that at 6-8 days after LTK63 treatment, the number of mDCs and pDCs, CD8+ and CD4+ T cells, granulocytes, NK cells and B cells increase, and CD8+ and CD4+ T cell subsets are activated. In vivo migration assays indicate that at least part of the LTK63-induced increase in mDC numbers is due to the recruitment of differentiated DCs from the blood. In order to understand the nature of the increased immune responsiveness in the lung, the T cell stimulatory ability of lung myeloid cells was analyzed. The studies of the mixed population of total lung CD11c+ cells show that cells isolated from LTK63 treated mice are more efficient at stimulating allogeneic T cell responses than those from untreated mice. When we tested the T cell stimulatory ability of cells sorted into CD11c+MHC-IIhigh mDCs and CD11chighMHC-IIint cells comprising alveolar macrophages and immature mDCS, we found no difference on a per cell basis between LTK63 treated and control mice. Since I find a strong accumulation of CD11c+MHC-IIhigh mDCs after LTK63 treatment, I conclude that the enhanced immune responsiveness induced by LTK63 is partly due to increased numbers of CD11c+MHC-IIhigh mDCs with a strong potential to prime T cells.

In conclusion, while both CpG ODNs and LTK63 studied here appear to act mainly through APCs such as AMs and DCs, the kinetics of this process greatly differ between the two. The response to CpG ODNs is much faster, probably due to the direct activation of receptor-bearing innate immune cells present in the lung, among which mDCs and pDCs. The earliest event in the response to LTK63, in contrast, is detectable only after 24 hrs, which suggests either that the initial steps are too subtle to be detected here, and that chemokine production and cell influx observed at 1 to 2 days has to be considered the distal result of a sequence of small events preceding those detected here. Alternatively, due to the nature of the interaction between LTK63 and target cells, the phenomena observed at 24 hrs may in fact be the very first to take place, which would suggest a very slow onset of cell activation by LTK63. On the other hand, the response to LTK63 lasts longer, and a second wave of events are observed at 6-8 days. The explanation that is most plausible and compatible with known kinetics of immune responses is that this second wave is driven at least partly by the adaptive immune response to LTK63 and that in fact, LTK63 acts by mimicking infection by a pathogen. At 8 days, we do not detect any response to CpG ODNs anymore, which again would be compatible with the fact that in the absence of a protein Ag component, the immune response is limited to the initial innate phase and not prolonged. This is in line with the studies on generic protection indicating that this protective effect is less durable for CpG ODNs than for LTK63.


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EPrint type:Ph.D. thesis
Tutor:Montecucco, Cesare
Supervisor:Wack, Andreas
Ph.D. course:Ciclo 20 > Scuole per il 20simo ciclo > BIOSCIENZE > BIOLOGIA CELLULARE
Data di deposito della tesi:07 January 2008
Anno di Pubblicazione:07 January 2008
Key Words:lung, LTK63, CpG ODNs, innate immunity, adaptive immunity,
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/04 Patologia generale
Struttura di riferimento:Dipartimenti > pre 2012 - Dipartimento di Scienze Biomediche Sperimentali
Codice ID:667
Depositato il:25 Sep 2008
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Le url contenute in alcuni riferimenti sono raggiungibili cliccando sul link alla fine della citazione (Vai!) e tramite Google (Ricerca con Google). Il risultato dipende dalla formattazione della citazione.

1. Martin TR, Frevert CW. Innate immunity in the lungs. Proc Am Thorac Soc. 2005;2:403-411. Cerca con Google

2. Zhang P, Summer WR, Bagby GJ, Nelson S. Innate immunity and pulmonary host defense. Immunol Rev. 2000;173:39-51. Cerca con Google

3. Lehrer RI. Primate defensins. Nat Rev Microbiol. 2004;2:727-738. Cerca con Google

4. Iwasaki A. Mucosal dendritic cells. Annu Rev Immunol. 2007;25:381-418. Cerca con Google

5. Sibille Y, Reynolds HY. Macrophages and polymorphonuclear neutrophils in lung defense and injury. Am Rev Respir Dis. 1990;141:471-501. Cerca con Google

6. Reynolds HY. Immunologic system in the respiratory tract. Physiol Rev. 1991;71:1117-1133. Cerca con Google

7. Underhill DM, Ozinsky A, Hajjar AM, et al. The Toll-like receptor 2 is recruited to macrophage phagosomes and discriminates between pathogens. Nature. 1999;401:811-815. Cerca con Google

8. Diamond G, Legarda D, Ryan LK. The innate immune response of the respiratory epithelium. Immunol Rev. 2000;173:27-38. Cerca con Google

9. Becker MN, Diamond G, Verghese MW, Randell SH. CD14-dependent lipopolysaccharide-induced beta-defensin-2 expression in human tracheobronchial epithelium. J Biol Chem. 2000;275:29731-29736. Cerca con Google

10. Platz J, Beisswenger C, Dalpke A, et al. Microbial DNA induces a host defense reaction of human respiratory epithelial cells. J Immunol. 2004;173:1219-1223. Cerca con Google

11. Lefrancois L, Puddington L. Intestinal and pulmonary mucosal T cells: local heroes fight to maintain the status quo. Annu Rev Immunol. 2006;24:681-704. Cerca con Google

12. Mellman I, Steinman RM. Dendritic cells: specialized and regulated antigen processing machines. Cell. 2001;106:255-258. Cerca con Google

13. Bender A, Albert M, Reddy A, et al. The distinctive features of influenza virus infection of dendritic cells. Immunobiology. 1998;198:552-567. Cerca con Google

14. Feng H, Zhang D, Palliser D, et al. Listeria-infected myeloid dendritic cells produce IFN-beta, priming T cell activation. J Immunol. 2005;175:421-432. Cerca con Google

15. Gerna G, Percivalle E, Lilleri D, et al. Dendritic-cell infection by human cytomegalovirus is restricted to strains carrying functional UL131-128 genes and mediates efficient viral antigen presentation to CD8+ T cells. J Gen Virol. 2005;86:275-284. Cerca con Google

16. Lambrecht BN, Pauwels RA, Fazekas De St Groth B. Induction of rapid T cell activation, division, and recirculation by intratracheal injection of dendritic cells in a TCR transgenic model. J Immunol. 2000;164:2937-2946. Cerca con Google

17. van Rijt LS, Jung S, Kleinjan A, et al. In vivo depletion of lung CD11c+ dendritic cells during allergen challenge abrogates the characteristic features of asthma. J Exp Med. 2005;201:981-991. Cerca con Google

18. Lambrecht BN, Salomon B, Klatzmann D, Pauwels RA. Dendritic cells are required for the development of chronic eosinophilic airway inflammation in response to inhaled antigen in sensitized mice. J Immunol. 1998;160:4090-4097. Cerca con Google

19. Bellini A, Vittori E, Marini M, Ackerman V, Mattoli S. Intraepithelial dendritic cells and selective activation of Th2-like lymphocytes in patients with atopic asthma. Chest. 1993;103:997-1005. Cerca con Google

20. van den Heuvel MM, Vanhee DD, Postmus PE, Hoefsmit EC, Beelen RH. Functional and phenotypic differences of monocyte-derived dendritic cells from allergic and nonallergic patients. J Allergy Clin Immunol. 1998;101:90-95. Cerca con Google

21. Probst HC, Tschannen K, Odermatt B, Schwendener R, Zinkernagel RM, Van Den Broek M. Histological analysis of CD11c-DTR/GFP mice after in vivo depletion of dendritic cells. Clin Exp Immunol. 2005;141:398-404. Cerca con Google

22. Miller MJ, Wei SH, Parker I, Cahalan MD. Two-photon imaging of lymphocyte motility and antigen response in intact lymph node. Science. 2002;296:1869-1873. Cerca con Google

23. Bousso P, Robey E. Dynamics of CD8+ T cell priming by dendritic cells in intact lymph nodes. Nat Immunol. 2003;4:579-585. Cerca con Google

24. Sumen C, Mempel TR, Mazo IB, von Andrian UH. Intravital microscopy: visualizing immunity in context. Immunity. 2004;21:315-329. Cerca con Google

25. Holt PG, Haining S, Nelson DJ, Sedgwick JD. Origin and steady-state turnover of class II MHC-bearing dendritic cells in the epithelium of the conducting airways. J Immunol. 1994;153:256-261. Cerca con Google

26. Vermaelen K, Pauwels R. Pulmonary dendritic cells. Am J Respir Crit Care Med. 2005;172:530-551. Cerca con Google

27. McWilliam AS, Nelson D, Thomas JA, Holt PG. Rapid dendritic cell recruitment is a hallmark of the acute inflammatory response at mucosal surfaces. J Exp Med. 1994;179:1331-1336. Cerca con Google

28. Stumbles PA, Thomas JA, Pimm CL, et al. Resting respiratory tract dendritic cells preferentially stimulate T helper cell type 2 (Th2) responses and require obligatory cytokine signals for induction of Th1 immunity. J Exp Med. 1998;188:2019-2031. Cerca con Google

29. Vermaelen KY, Carro-Muino I, Lambrecht BN, Pauwels RA. Specific migratory dendritic cells rapidly transport antigen from the airways to the thoracic lymph nodes. J Exp Med. 2001;193:51-60. Cerca con Google

30. Hammad H, de Heer HJ, Soullie T, Hoogsteden HC, Trottein F, Lambrecht BN. Prostaglandin D2 inhibits airway dendritic cell migration and function in steady state conditions by selective activation of the D prostanoid receptor 1. J Immunol. 2003;171:3936-3940. Cerca con Google

31. Legge KL, Braciale TJ. Accelerated migration of respiratory dendritic cells to the regional lymph nodes is limited to the early phase of pulmonary infection. Immunity. 2003;18:265-277. Cerca con Google

32. Lawrence CW, Braciale TJ. Activation, differentiation, and migration of naïve virus-specific CD8+ T cells during pulmonary influenza virus infection. J Immunol. 2004;173:1209-1218. Cerca con Google

33. Medzhitov R, Janeway CA, Jr. Innate immune induction of the adaptive immune response. Cold Spring Harb Symp Quant Biol. 1999;64:429-435. Cerca con Google

34. MacLean JA, Sauty A, Luster AD, Drazen JM, De Sanctis GT. Antigen-induced airway hyperresponsiveness, pulmonary eosinophilia, and chemokine expression in B cell-deficient mice. Am J Respir Cell Mol Biol. 1999;20:379-387. Cerca con Google

35. Tsitoura DC, DeKruyff RH, Lamb JR, Umetsu DT. Intranasal exposure to protein antigen induces immunological tolerance mediated by functionally disabled CD4+ T cells. J Immunol. 1999;163:2592-2600. Cerca con Google

36. Akbari O, DeKruyff RH, Umetsu DT. Pulmonary dendritic cells producing IL-10 mediate tolerance induced by respiratory exposure to antigen. Nat Immunol. 2001;2:725-731. Cerca con Google

37. Brimnes MK, Bonifaz L, Steinman RM, Moran TM. Influenza virus-induced dendritic cell maturation is associated with the induction of strong T cell immunity to a coadministered, normally nonimmunogenic protein. J Exp Med. 2003;198:133- 144. Cerca con Google

38. Eisenbarth SC, Piggott DA, Huleatt JW, Visintin I, Herrick CA, Bottomly K. Lipopolysaccharide-enhanced, toll-like receptor 4-dependent T helper cell type 2 responses to inhaled antigen. J Exp Med. 2002;196:1645-1651. Cerca con Google

39. Havenith CE, Breedijk AJ, Betjes MG, Calame W, Beelen RH, Hoefsmit EC. T cell priming in situ by intratracheally instilled antigen-pulsed dendritic cells. Am J Respir Cell Mol Biol. 1993;8:319-324. Cerca con Google

40. Kuipers H, Hijdra D, De Vries VC, et al. Lipopolysaccharide-induced suppression of airway Th2 responses does not require IL-12 production by dendritic cells. J Immunol. 2003;171:3645-3654. Cerca con Google

41. Sallusto F, Lenig D, Forster R, Lipp M, Lanzavecchia A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature. 1999;401:708-712. Cerca con Google

42. Freytag LC, Clements JD. Mucosal adjuvants. Vaccine. 2005;23:1804-1813. Cerca con Google

43. Holmgren J, Czerkinsky C, Eriksson K, Mharandi A. Mucosal immunisation and adjuvants: a brief overview of recent advances and challenges. Vaccine. 2003;21 Suppl 2:S89-95. Cerca con Google

44. Klinman DM. Immunotherapeutic uses of CpG oligodeoxynucleotides. Nat Rev Immunol. 2004;4:249-258. Cerca con Google

45. Yamamoto S, Yamamoto T, Kataoka T, Kuramoto E, Yano O, Tokunaga T. Unique palindromic sequences in synthetic oligonucleotides are required to induce IFN [correction of INF] and augment IFN-mediated [correction of INF] natural killer activity. J Immunol. 1992;148:4072-4076. Cerca con Google

46. Krieg AM, Yi AK, Matson S, et al. CpG motifs in bacterial DNA trigger direct Bcell activation. Nature. 1995;374:546-549. Cerca con Google

47. Klinman DM, Yi AK, Beaucage SL, Conover J, Krieg AM. CpG motifs present in bacteria DNA rapidly induce lymphocytes to secrete interleukin 6, interleukin 12, and interferon gamma. Proc Natl Acad Sci U S A. 1996;93:2879-2883. Cerca con Google

48. Hemmi H, Takeuchi O, Kawai T, et al. A Toll-like receptor recognizes bacterial DNA. Nature. 2000;408:740-745. Cerca con Google

49. Takeshita F, Leifer CA, Gursel I, et al. Cutting edge: Role of Toll-like receptor 9 in CpG DNA-induced activation of human cells. J Immunol. 2001;167:3555-3558. Cerca con Google

50. Bauer S, Kirschning CJ, Hacker H, et al. Human TLR9 confers responsiveness to bacterial DNA via species-specific CpG motif recognition. Proc Natl Acad Sci U S A. 2001;98:9237-9242. Cerca con Google

51. Ishii KJ, Takeshita F, Gursel I, et al. Potential role of phosphatidylinositol 3 kinase, rather than DNA-dependent protein kinase, in CpG DNA-induced immune activation. J Exp Med. 2002;196:269-274. Cerca con Google

52. Takeshita F, Ishii KJ, Ueda A, Ishigatsubo Y, Klinman DM. Positive and negative regulatory elements contribute to CpG oligonucleotide-mediated regulation of human IL-6 gene expression. Eur J Immunol. 2000;30:108-116. Cerca con Google

53. Yamamoto M, Sato S, Mori K, et al. Cutting edge: a novel Toll/IL-1 receptor domain-containing adapter that preferentially activates the IFN-beta promoter in the Toll-like receptor signaling. J Immunol. 2002;169:6668-6672. Cerca con Google

54. Takeshita F, Klinman DM. CpG ODN-mediated regulation of IL-12 p40 transcription. Eur J Immunol. 2000;30:1967-1976. Cerca con Google

55. Hacker H, Vabulas RM, Takeuchi O, Hoshino K, Akira S, Wagner H. Immune cell activation by bacterial CpG-DNA through myeloid differentiation marker 88 and tumor necrosis factor receptor-associated factor (TRAF)6. J Exp Med. 2000;192:595-600. Cerca con Google

56. Aderem A, Ulevitch RJ. Toll-like receptors in the induction of the innate immune response. Nature. 2000;406:782-787. Cerca con Google

57. Gursel M, Verthelyi D, Gursel I, Ishii KJ, Klinman DM. Differential and competitive activation of human immune cells by distinct classes of CpG oligodeoxynucleotide. J Leukoc Biol. 2002;71:813-820. Cerca con Google

58. Hornung V, Rothenfusser S, Britsch S, et al. Quantitative expression of toll-like receptor 1-10 mRNA in cellular subsets of human peripheral blood mononuclear cells and sensitivity to CpG oligodeoxynucleotides. J Immunol. 2002;168:4531- 4537. Cerca con Google

59. Kadowaki N, Ho S, Antonenko S, et al. Subsets of human dendritic cell precursors express different toll-like receptors and respond to different microbial antigens. J Exp Med. 2001;194:863-869. Cerca con Google

60. Demedts IK, Bracke KR, Maes T, Joos GF, Brusselle GG. Different roles for human lung dendritic cell subsets in pulmonary immune defense mechanisms. Am J Respir Cell Mol Biol. 2006;35:387-393. Cerca con Google

61. Iwasaki A, Medzhitov R. Toll-like receptor control of the adaptive immune responses. Nat Immunol. 2004;5:987-995. Cerca con Google

62. Kerkmann M, Costa LT, Richter C, et al. Spontaneous formation of nucleic acidbased nanoparticles is responsible for high interferon-alpha induction by CpG-A in plasmacytoid dendritic cells. J Biol Chem. 2005;280:8086-8093. Cerca con Google

63. Hartmann G, Weeratna RD, Ballas ZK, et al. Delineation of a CpG phosphorothioate oligodeoxynucleotide for activating primate immune responses in vitro and in vivo. J Immunol. 2000;164:1617-1624. Cerca con Google

64. Vollmer J, Weeratna R, Payette P, et al. Characterization of three CpG oligodeoxynucleotide classes with distinct immunostimulatory activities. Eur J Immunol. 2004;34:251-262. Cerca con Google

65. Hartmann G, Krieg AM. Mechanism and function of a newly identified CpG DNA motif in human primary B cells. J Immunol. 2000;164:944-953. Cerca con Google

66. Sparwasser T, Koch ES, Vabulas RM, et al. Bacterial DNA and immunostimulatory CpG oligonucleotides trigger maturation and activation of murine dendritic cells. Eur J Immunol. 1998;28:2045-2054. Cerca con Google

67. Sparwasser T, Miethke T, Lipford G, et al. Macrophages sense pathogens via DNA motifs: induction of tumor necrosis factor-alpha-mediated shock. Eur J Immunol. 1997;27:1671-1679. Cerca con Google

68. Lipford GB, Bauer M, Blank C, Reiter R, Wagner H, Heeg K. CpG-containing synthetic oligonucleotides promote B and cytotoxic T cell responses to protein antigen: a new class of vaccine adjuvants. Eur J Immunol. 1997;27:2340-2344. Cerca con Google

69. Davis HL, Weeratna R, Waldschmidt TJ, Tygrett L, Schorr J, Krieg AM. CpG DNA is a potent enhancer of specific immunity in mice immunized with recombinant hepatitis B surface antigen. J Immunol. 1998;160:870-876. Cerca con Google

70. Moldoveanu Z, Love-Homan L, Huang WQ, Krieg AM. CpG DNA, a novel immune enhancer for systemic and mucosal immunization with influenza virus. Vaccine. 1998;16:1216-1224. Cerca con Google

71. Elkins KL, Rhinehart-Jones TR, Stibitz S, Conover JS, Klinman DM. Bacterial DNA containing CpG motifs stimulates lymphocyte-dependent protection of mice against lethal infection with intracellular bacteria. J Immunol. 1999;162:2291-2298. Cerca con Google

72. Gramzinski RA, Doolan DL, Sedegah M, Davis HL, Krieg AM, Hoffman SL. Interleukin-12- and gamma interferon-dependent protection against malaria conferred by CpG oligodeoxynucleotide in mice. Infect Immun. 2001;69:1643- 1649. Cerca con Google

73. Krieg AM, Love-Homan L, Yi AK, Harty JT. CpG DNA induces sustained IL-12 expression in vivo and resistance to Listeria monocytogenes challenge. J Immunol. 1998;161:2428-2434. Cerca con Google

74. Zimmermann S, Egeter O, Hausmann S, et al. CpG oligodeoxynucleotides trigger protective and curative Th1 responses in lethal murine leishmaniasis. J Immunol. 1998;160:3627-3630. Cerca con Google

75. Horner AA, Ronaghy A, Cheng PM, et al. Immunostimulatory DNA is a potent mucosal adjuvant. Cell Immunol. 1998;190:77-82. Cerca con Google

76. McCluskie MJ, Davis HL. Oral, intrarectal and intranasal immunizations using CpG and non-CpG oligodeoxynucleotides as adjuvants. Vaccine. 2000;19:413-422. Cerca con Google

77. Pal S, Davis HL, Peterson EM, de la Maza LM. Immunization with the Chlamydia trachomatis mouse pneumonitis major outer membrane protein by use of CpG oligodeoxynucleotides as an adjuvant induces a protective immune response against an intranasal chlamydial challenge. Infect Immun. 2002;70:4812-4817. Cerca con Google

78. Bozza S, Gaziano R, Lipford GB, et al. Vaccination of mice against invasive aspergillosis with recombinant Aspergillus proteins and CpG oligodeoxynucleotides as adjuvants. Microbes Infect. 2002;4:1281-1290. Cerca con Google

79. Jain VV, Kitagaki K, Businga T, et al. CpG-oligodeoxynucleotides inhibit airway remodeling in a murine model of chronic asthma. J Allergy Clin Immunol. 2002;110:867-872. Cerca con Google

80. Choudhury BK, Wild JS, Alam R, et al. In vivo role of p38 mitogen-activated protein kinase in mediating the anti-inflammatory effects of CpG oligodeoxynucleotide in murine asthma. J Immunol. 2002;169:5955-5961. Cerca con Google

81. Hayashi T, Beck L, Rossetto C, et al. Inhibition of experimental asthma by indoleamine 2,3-dioxygenase. J Clin Invest. 2004;114:270-279. Cerca con Google

82. Broide D, Schwarze J, Tighe H, et al. Immunostimulatory DNA sequences inhibit IL-5, eosinophilic inflammation, and airway hyperresponsiveness in mice. J Immunol. 1998;161:7054-7062. Cerca con Google

83. Juffermans NP, Leemans JC, Florquin S, et al. CpG oligodeoxynucleotides enhance host defense during murine tuberculosis. Infect Immun. 2002;70:147-152. Cerca con Google

84. Edwards L, Williams AE, Krieg AM, Rae AJ, Snelgrove RJ, Hussell T. Stimulation via Toll-like receptor 9 reduces Cryptococcus neoformans-induced pulmonary inflammation in an IL-12-dependent manner. Eur J Immunol. 2005;35:273-281. Cerca con Google

85. Deng JC, Moore TA, Newstead MW, Zeng X, Krieg AM, Standiford TJ. CpG oligodeoxynucleotides stimulate protective innate immunity against pulmonary Klebsiella infection. J Immunol. 2004;173:5148-5155. Cerca con Google

86. Harandi AM, Eriksson K, Holmgren J. A protective role of locally administered immunostimulatory CpG oligodeoxynucleotide in a mouse model of genital herpes infection. J Virol. 2003;77:953-962. Cerca con Google

87. Raghavan S, Nystrom J, Fredriksson M, Holmgren J, Harandi AM. Orally administered CpG oligodeoxynucleotide induces production of CXC and CC chemokines in the gastric mucosa and suppresses bacterial colonization in a mouse model of Helicobacter pylori infection. Infect Immun. 2003;71:7014-7022. Cerca con Google

88. Rappuoli R, Pizza M, Douce G, Dougan G. Structure and mucosal adjuvanticity of cholera and Escherichia coli heat-labile enterotoxins. Immunol Today. 1999;20:493-500. Cerca con Google

89. Katz JM, Lu X, Young SA, Galphin JC. Adjuvant activity of the heat-labile enterotoxin from enterotoxigenic Escherichia coli for oral administration of inactivated influenza virus vaccine. J Infect Dis. 1997;175:352-363. Cerca con Google

90. Marinaro M, Riccomi A, Rappuoli R, et al. Mucosal delivery of the human immunodeficiency virus-1 Tat protein in mice elicits systemic neutralizing antibodies, cytotoxic T lymphocytes and mucosal IgA. Vaccine. 2003;21:3972- 3981. Cerca con Google

91. Zurbriggen R, Metcalfe IC, Gluck R, Viret JF, Moser C. Nonclinical safety evaluation of Escherichia coli heat-labile toxin mucosal adjuvant as a component of a nasal influenza vaccine. Expert Rev Vaccines. 2003;2:295-304. Cerca con Google

92. Giuliani MM, Del Giudice G, Giannelli V, et al. Mucosal adjuvanticity and immunogenicity of LTR72, a novel mutant of Escherichia coli heat-labile enterotoxin with partial knockout of ADP-ribosyltransferase activity. J Exp Med. 1998;187:1123-1132. Cerca con Google

93. Pizza M, Giuliani MM, Fontana MR, et al. Mucosal vaccines: non toxic derivatives of LT and CT as mucosal adjuvants. Vaccine. 2001;19:2534-2541. Cerca con Google

94. Baudner BC, Balland O, Giuliani MM, et al. Enhancement of protective efficacy following intranasal immunization with vaccine plus a nontoxic LTK63 mutant delivered with nanoparticles. Infect Immun. 2002;70:4785-4790. Cerca con Google

95. Baudner BC, Giuliani MM, Verhoef JC, Rappuoli R, Junginger HE, Giudice GD. The concomitant use of the LTK63 mucosal adjuvant and of chitosan-based delivery system enhances the immunogenicity and efficacy of intranasally administered vaccines. Vaccine. 2003;21:3837-3844. Cerca con Google

96. Beignon AS, Briand JP, Rappuoli R, Muller S, Partidos CD. The LTR72 mutant of heat-labile enterotoxin of Escherichia coli enhances the ability of peptide antigens to elicit CD4(+) T cells and secrete gamma interferon after coapplication onto bare skin. Infect Immun. 2002;70:3012-3019. Cerca con Google

97. Ugozzoli M, Santos G, Donnelly J, O'Hagan DT. Potency of a genetically detoxified mucosal adjuvant derived from the heat-labile enterotoxin of Escherichia coli (LTK63) is not adversely affected by the presence of preexisting immunity to the adjuvant. J Infect Dis. 2001;183:351-354. Cerca con Google

98. Ugozzoli M, Mariani M, Del Giudice G, Soenawan E, O'Hagan DT. Combinations of protein polysaccharide conjugate vaccines for intranasal immunization. J Infect Dis. 2002;186:1358-1361. Cerca con Google

99. Tierney R, Beignon AS, Rappuoli R, Muller S, Sesardic D, Partidos CD. Transcutaneous immunization with tetanus toxoid and mutants of Escherichia coli heat-labile enterotoxin as adjuvants elicits strong protective antibody responses. J Infect Dis. 2003;188:753-758. Cerca con Google

100. Jakobsen H, Adarna BC, Schulz D, Rappuoli R, Jonsdottir I. Characterization of the antibody response to pneumococcal glycoconjugates and the effect of heat-labile enterotoxin on IGg subclasses after intranasal immunization. J Infect Dis. 2001;183:1494-1500. Cerca con Google

101. Bonenfant C, Dimier-Poisson I, Velge-Roussel F, et al. Intranasal immunization with SAG1 and nontoxic mutant heat-labile enterotoxins protects mice against Toxoplasma gondii. Infect Immun. 2001;69:1605-1612. Cerca con Google

102. Peppoloni S, Ruggiero P, Contorni M, et al. Mutants of the Escherichia coli heatlabile enterotoxin as safe and strong adjuvants for intranasal delivery of vaccines. Expert Rev Vaccines. 2003;2:285-293. Cerca con Google

103. Simmons CP, Hussell T, Sparer T, Walzl G, Openshaw P, Dougan G. Mucosal delivery of a respiratory syncytial virus CTL peptide with enterotoxin-based adjuvants elicits protective, immunopathogenic, and immunoregulatory antiviral CD8+ T cell responses. J Immunol. 2001;166:1106-1113. Cerca con Google

104. Ryan EJ, McNeela E, Murphy GA, et al. Mutants of Escherichia coli heat-labile toxin act as effective mucosal adjuvants for nasal delivery of an acellular pertussis vaccine: differential effects of the nontoxic AB complex and enzyme activity on Th1 and Th2 cells. Infect Immun. 1999;67:6270-6280. Cerca con Google

105. Stephenson I, Zambon MC, Rudin A, et al. Phase I evaluation of intranasal trivalent inactivated influenza vaccine with nontoxigenic Escherichia coli enterotoxin and novel biovector as mucosal adjuvants, using adult volunteers. J Virol. 2006;80:4962-4970. Cerca con Google

106. Di Tommaso A, Saletti G, Pizza M, et al. Induction of antigen-specific antibodies in vaginal secretions by using a nontoxic mutant of heat-labile enterotoxin as a mucosal adjuvant. Infect Immun. 1996;64:974-979. Cerca con Google

107. Douce G, Fontana M, Pizza M, Rappuoli R, Dougan G. Intranasal immunogenicity and adjuvanticity of site-directed mutant derivatives of cholera toxin. Infect Immun. 1997;65:2821-2828. Cerca con Google

108. Jakobsen H, Bjarnarson S, Del Giudice G, Moreau M, Siegrist CA, Jonsdottir I. Intranasal immunization with pneumococcal conjugate vaccines with LT-K63, a nontoxic mutant of heat-Labile enterotoxin, as adjuvant rapidly induces protective immunity against lethal pneumococcal infections in neonatal mice. Infect Immun. 2002;70:1443-1452. Cerca con Google

109. Baudner BC, Morandi M, Giuliani MM, et al. Modulation of immune response to group C meningococcal conjugate vaccine given intranasally to mice together with the LTK63 mucosal adjuvant and the trimethyl chitosan delivery system. J Infect Dis. 2004;189:828-832. Cerca con Google

110. Ryan EJ, McNeela E, Pizza M, Rappuoli R, O'Neill L, Mills KH. Modulation of innate and acquired immune responses by Escherichia coli heat-labile toxin: distinct pro- and anti-inflammatory effects of the nontoxic AB complex and the enzyme activity. J Immunol. 2000;165:5750-5759. Cerca con Google

111. Simmons CP, Mastroeni P, Fowler R, et al. MHC class I-restricted cytotoxic lymphocyte responses induced by enterotoxin-based mucosal adjuvants. J Immunol. 1999;163:6502-6510. Cerca con Google

112. Neidleman JA, Vajdy M, Ugozzoli M, Ott G, O'Hagan D. Genetically detoxified mutants of heat-labile enterotoxin from Escherichia coli are effective adjuvants for induction of cytotoxic T-cell responses against HIV-1 gag-p55. Immunology. 2000;101:154-160. Cerca con Google

113. Williams AE, Edwards L, Humphreys IR, et al. Innate imprinting by the modified heat-labile toxin of Escherichia coli (LTK63) provides generic protection against lung infectious disease. J Immunol. 2004;173:7435-7443. Cerca con Google

114. Walzl G, Tafuro S, Moss P, Openshaw PJ, Hussell T. Influenza virus lung infection protects from respiratory syncytial virus-induced immunopathology. J Exp Med. 2000;192:1317-1326. Cerca con Google

115. Chen HD, Fraire AE, Joris I, Brehm MA, Welsh RM, Selin LK. Memory CD8+ T cells in heterologous antiviral immunity and immunopathology in the lung. Nat Immunol. 2001;2:1067-1076. Cerca con Google

116. Karrer HE. The ultrastructure of mouse lung: the alveolar macrophage. J Biophys Biochem Cytol. 1958;4:693-700. Cerca con Google

117. Lutz MB, Kukutsch N, Ogilvie AL, et al. An advanced culture method for generating large quantities of highly pure dendritic cells from mouse bone marrow. J Immunol Methods. 1999;223:77-92. Cerca con Google

118. Krieg AM. CpG motifs in bacterial DNA and their immune effects. Annu Rev Immunol. 2002;20:709-760. Cerca con Google

119. Suzuki K, Suda T, Naito T, Ide K, Chida K, Nakamura H. Impaired toll-like receptor 9 expression in alveolar macrophages with no sensitivity to CpG DNA. Am J Respir Crit Care Med. 2005;171:707-713. Cerca con Google

120. Lappin MB, Weiss JM, Delattre V, et al. Analysis of mouse dendritic cell migration in vivo upon subcutaneous and intravenous injection. Immunology. 1999;98:181- 188. Cerca con Google

121. Kirby AC, Raynes JG, Kaye PM. CD11b regulates recruitment of alveolar macrophages but not pulmonary dendritic cells after pneumococcal challenge. J Infect Dis. 2006;193:205-213. Cerca con Google

122. Vermaelen K, Pauwels R. Accurate and simple discrimination of mouse pulmonary dendritic cell and macrophage populations by flow cytometry: methodology and new insights. Cytometry A. 2004;61:170-177. Cerca con Google

123. Krieg AM, Davis HL. Enhancing vaccines with immune stimulatory CpG DNA. Curr Opin Mol Ther. 2001;3:15-24. Cerca con Google

124. Li J, Ma Z, Tang ZL, Stevens T, Pitt B, Li S. CpG DNA-mediated immune response in pulmonary endothelial cells. Am J Physiol Lung Cell Mol Physiol. 2004;287:L552-558. Cerca con Google

125. Chen L, Arora M, Yarlagadda M, et al. Distinct responses of lung and spleen dendritic cells to the TLR9 agonist CpG oligodeoxynucleotide. J Immunol. 2006;177:2373-2383. Cerca con Google

126. Luster AD. The role of chemokines in linking innate and adaptive immunity. Curr Opin Immunol. 2002;14:129-135. Cerca con Google

127. Khader SA, Partida-Sanchez S, Bell G, et al. Interleukin 12p40 is required for dendritic cell migration and T cell priming after Mycobacterium tuberculosis infection. J Exp Med. 2006;203:1805-1815. Cerca con Google

128. Nakano H, Yanagita M, Gunn MD. CD11c(+)B220(+)Gr-1(+) cells in mouse lymph nodes and spleen display characteristics of plasmacytoid dendritic cells. J Exp Med. 2001;194:1171-1178. Cerca con Google

129. Asselin-Paturel C, Boonstra A, Dalod M, et al. Mouse type I IFN-producing cells are immature APCs with plasmacytoid morphology. Nat Immunol. 2001;2:1144- 1150. Cerca con Google

130. Bangs SC, McMichael AJ, Xu XN. Bystander T cell activation--implications for HIV infection and other diseases. Trends Immunol. 2006;27:518-524. Cerca con Google

131. Hemmi H, Kaisho T, Takeuchi O, et al. Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat Immunol. 2002;3:196-200. Cerca con Google

132. Jurk M, Heil F, Vollmer J, et al. Human TLR7 or TLR8 independently confer responsiveness to the antiviral compound R-848. Nat Immunol. 2002;3:499. Cerca con Google

133. Zuniga EI, McGavern DB, Pruneda-Paz JL, Teng C, Oldstone MB. Bone marrow plasmacytoid dendritic cells can differentiate into myeloid dendritic cells upon virus infection. Nat Immunol. 2004;5:1227-1234. Cerca con Google

134. Colonna M, Trinchieri G, Liu YJ. Plasmacytoid dendritic cells in immunity. Nat Immunol. 2004;5:1219-1226. Cerca con Google

135. Tritto E, Muzzi A, Pesce I, et al. The acquired immune response to the mucosal adjuvant LTK63 imprints the mouse lung with a protective signature. J Immunol. 2007;179:5346-5357. Cerca con Google

136. Chapman TJ, Castrucci MR, Padrick RC, Bradley LM, Topham DJ. Antigenspecific and non-specific CD4+ T cell recruitment and proliferation during influenza infection. Virology. 2005;340:296-306. Cerca con Google

137. Roman E, Miller E, Harmsen A, et al. CD4 effector T cell subsets in the response to influenza: heterogeneity, migration, and function. J Exp Med. 2002;196:957-968. Cerca con Google

138. Yamamoto N, Suzuki S, Shirai A, et al. Dendritic cells are associated with augmentation of antigen sensitization by influenza A virus infection in mice. Eur J Immunol. 2000;30:316-326. Cerca con Google

139. Gill MA, Palucka AK, Barton T, et al. Mobilization of plasmacytoid and myeloid dendritic cells to mucosal sites in children with respiratory syncytial virus and other viral respiratory infections. J Infect Dis. 2005;191:1105-1115. Cerca con Google

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