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Immunostimulatory (CpG) DNA-Based Therapies for the Treatment of Allergic Disease

  • Tomoko Hayashi
  • Eyal Raz
Part of the Allergy Frontiers book series (ALLERGY, volume 6)

Abstract

Accumulating experimental data outline the potential use of CpG-ODN (i.e., TLR9 ligand) as an effective intervention for the prevention and treatment of allergic disorders. As discussed below, we propose that immunotherapy with CpG-ODN can be applied through two distinct strategies: (1) vaccination and (2) immunomodulation. CpG-ODN-based vaccination provides a long-term, allergen-specific, therapeutic efficacy as well as improved safety compared to conventional allergen vaccination (i.e., desensitization). In contrast, immunomodulation by CpG-ODN provides a short-term, allergen non-specific therapeutic efficacy that prevents allergic reactions in experimental models of allergic asthma, rhinitis, and conjunctivitis. The administration of CpG-ODN as immunomodulator intervenes in the sequential acquisition of allergic sensitization (e.g., Th2 phenotype spread) and organ pathology (e.g., airway remodeling). Indoleamine 2,3-dioxygenase (IDO), the rate-limiting enzyme of tryptophan catabolism, is induced by CpG-ODN and mediates, in part, these immunomodulatory and therapeutic effects. We propose that the insight gained from these two types of interventions in experimental models of allergy can help in the design of effective therapeutics for various human allergic diseases.

Keywords

Atopic Dermatitis Allergic Rhinitis Allergic Asthma Clinical Immunology Allergen Challenge 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Takeda K, Kaisho T, Akira S (2003) Toll-like receptors. Annual Review Immunology 21:335–376CrossRefGoogle Scholar
  2. 2.
    Ishii KJ, Akira S (2006) Innate immune recognition of, and regulation by, DNA. Trends in Immunology 27:525–532CrossRefPubMedGoogle Scholar
  3. 3.
    Takeda K, Akira S (2005) Toll-like receptors in innate immunity. International Immunology 17:1–14CrossRefPubMedGoogle Scholar
  4. 4.
    Ishii KJ, Uematsu S, Akira S (2006) ‘Toll’ gates for future immunotherapy. Current Pharmaceutical Design 12:4135–4142CrossRefPubMedGoogle Scholar
  5. 5.
    Tokunaga T, Yamamoto H, Shimada S, et al (1984) Antitumor activity of deoxyribonucleic acid fraction from Mycobacterium bovis BCG. I. Isolation, physicochemical characterization, and antitumor activity. Journal of the National Cancer Institute 72:955–962PubMedGoogle Scholar
  6. 6.
    Yamamoto S, Kuramoto E, Shimada S, et al (1988) In vitro augmentation of natural killer cell activity and production of interferon-alpha/beta and -gamma with deoxyribonucleic acid fraction from Mycobacterium bovis BCG. Japanese Journal of Cancer Research 79:866–873PubMedGoogle Scholar
  7. 7.
    Tokunaga T, Yano O, Kuramoto E, et al (1992) Synthetic oligonucleotides with particular base sequences from the cDNA encoding proteins of Mycobacterium bovis BCG induce interfer-ons and activate natural killer cells. Microbiology and Immunology 36:55–66PubMedGoogle Scholar
  8. 8.
    Kaisho T, Akira S (2006) Toll-like receptor function and signaling. Journal of Allergy and Clinical Immunology 117:979–987CrossRefPubMedGoogle Scholar
  9. 9.
    Hemmi H, Takeuchi O, Kawai T, et al (2000) A toll-like receptor recognizes bacterial DNA. Nature 408:740–745CrossRefPubMedGoogle Scholar
  10. 10.
    Hayashi F, Means TK, Luster AD (2003) Toll-like receptors stimulate human neutrophil function. Blood 102:2660–2669CrossRefPubMedGoogle Scholar
  11. 11.
    Lee J, Mo JH, Katakura K, et al (2006) Maintenance of colonic homeostasis by distinctive apical TLR9 signalling in intestinal epithelial cells. Nature Cell Biology 8:1327–1336CrossRefPubMedGoogle Scholar
  12. 12.
    Krieg AM, Yi AK, Matson S, et al (1995) CpG motifs in bacterial DNA trigger direct B-cell activation. Nature 374:546–549CrossRefPubMedGoogle Scholar
  13. 13.
    Klinman DM, Yi AK, Beaucage SL, et al (1996) CpG motifs present in bacteria DNA rapidly induce lymphocytes to secrete interleukin 6, interleukin 12, and interferon gamma. Proceedings of the National Academy of Sciences of the United States of America 93:2879–2883CrossRefPubMedGoogle Scholar
  14. 14.
    Van Uden J, Raz E (2000) Introduction to immunostimulatory DNA sequences. Springer Seminars in Immunopathology 22:1–9CrossRefPubMedGoogle Scholar
  15. 15.
    Roman M, Martin-Orozco E, Goodman JS, et al (1997) Immunostimulatory DNA sequences function as T helper-1-promoting adjuvants [see comments]. Nature Medicine 3:849–854CrossRefPubMedGoogle Scholar
  16. 16.
    Krieg AM (2002) CpG motifs in bacterial DNA and their immune effects. Annual Review Immunology 20:709–760CrossRefGoogle Scholar
  17. 17.
    Klaschik S, Gursel I, Klinman DM (2007) CpG-mediated changes in gene expression in murine spleen cells identified by microarray analysis. Molecular Immunology 44:1095–1104CrossRefPubMedGoogle Scholar
  18. 18.
    Howarth PH (1998) Is allergy increasing? — early life influences. Clinical and Experimental Allergy 28(Suppl 6):2–7CrossRefPubMedGoogle Scholar
  19. 19.
    Wills-Karp M, Santeliz J, Karp CL (2001) The germless theory of allergic disease: revisiting the hygiene hypothesis. Nature Reviews. Immunology 1:69–75CrossRefPubMedGoogle Scholar
  20. 20.
    Schaub B, Lauener R, von Mutius E (2006) The many faces of the hygiene hypothesis. Journal of Allergy and Clinical Immunology 117:969–977; quiz 978CrossRefPubMedGoogle Scholar
  21. 21.
    Horner AA, Raz E (2002) Immunostimulatory sequence oligodeoxynucleotide-based vaccination and immunomodulation: two unique but complementary strategies for the treatment of allergic diseases. Journal of Allergy and Clinical Immunology 110:706–712CrossRefPubMedGoogle Scholar
  22. 22.
    Hussain I, Kline JN (2003) CpG oligodeoxynucleotides: a novel therapeutic approach for atopic disorders. Current Drug Targets Inflammation and Allergy 2:199–205CrossRefPubMedGoogle Scholar
  23. 23.
    Broide D, Schwarze J, Tighe H, et al (1998) Immunostimulatory DNA sequences inhibit IL-5, eosinophilic inflammation, and airway hyperresponsiveness in mice. Journal of Immunology 161:7054–7062Google Scholar
  24. 24.
    Kline JN, Waldschmidt TJ, Businga TR, et al (1998) Modulation of airway inflammation by CpG oligodeoxynucleotides in a murine model of asthma. Journal of Immunology 160:2555–2559Google Scholar
  25. 25.
    Sur S, Wild JS, Choudhury BK, Sur N, Alam R, Klinman DM (1999) Long term prevention of allergic lung inflammation in a mouse model of asthma by CpG oligodeoxynucleotides. Journal of Immunology 162:6284–6293Google Scholar
  26. 26.
    Tighe H, Takabayashi K, Schwartz D, Marsden R, Beck L, Corbeil J, Richman DD, Eiden Jr. JJ, Spiegelberg HL, Raz E (2000) Conjugation of protein to immunostimulatory DNA results in a rapid, long-lasting and potent induction of cell-mediated and humoral immunity. European Journal of Immunology 30:1939–1947CrossRefPubMedGoogle Scholar
  27. 27.
    Bousquet J, Lockey R, Malling HJ (1998) Allergen immunotherapy: therapeutic vaccines for allergic diseases. A WHO position paper. The Journal of Allergy and Clinical Immunology 102:558–562CrossRefPubMedGoogle Scholar
  28. 28.
    Nelson HS, Lahr J, Rule R, Bock A, Leung D (1997) Treatment of anaphylactic sensitivity to peanuts by immunotherapy with injections of aqueous peanut extract. Journal of Allergy and Clinical Immunology 99:744–751CrossRefPubMedGoogle Scholar
  29. 29.
    Creticos PS, Reed CE, Norman PS, Khoury J, Adkinson Jr. NF, Buncher CR, Busse WW, Bush RK, Gadde J, Li JT, et al (1996) Ragweed immunotherapy in adult asthma. The New England Journal of Medicine 334:501–506CrossRefPubMedGoogle Scholar
  30. 30.
    Horner AA, Nguyen MD, Ronaghy A, Cinman N, Verbeek S, Raz E (2000) DNA-based vaccination reduces the risk of lethal anaphylactic hypersensitivity in mice. Journal of Allergy and Clinical Immunology 106:349–356CrossRefPubMedGoogle Scholar
  31. 31.
    Horner AA, Datta SK, Takabayashi K, Belyakov IM, Hayashi T, Cinman N, Nguyen MD, Van Uden JH, Berzofsky JH, Richman DD, Raz E (2001) Immunostimulatory DNA-based vaccines elicit multifaceted immune responses against HIV at systemic and mucosal sites. Journal of Immunology 167:1584–1591Google Scholar
  32. 32.
    Horner AA, Takabayashi K, Beck L, Sharma B, Zubeldia J, Baird S, Tuck S, Libet L, Spiegelberg HL, Liu FT, Raz E (2002) Optimized conjugation ratios lead to allergen immu-nostimulatory oligodeoxynucleotide conjugates with retained immunogenicity and minimal anaphylactogenicity. Journal of Allergy and Clinical Immunology 110:413–420CrossRefPubMedGoogle Scholar
  33. 33.
    Datta SK, Redecke V, Prilliman KR, Takabayashi K, Corr M, Tallant T, DiDonato J, Dziarski R, Akira S, Schoenberger SP, Raz E (2003) A subset of toll-like receptor ligands induces cross-presentation by bone marrow-derived dendritic cells. Journal of Immunology 170:4102–4110Google Scholar
  34. 34.
    Tighe H, Takabayashi K, Schwartz D, Van Nest G, Tuck S, Eiden JJ, Kagey-Sobotka A, Creticos PS, Lichtenstein LM, Spiegelberg HL, Raz E (2000) Conjugation of immunostimula-tory DNA to the short ragweed allergen amb a 1 enhances its immunogenicity and reduces its allergenicity. Journal of Allergy and Clinical Immunology 106:124–134CrossRefPubMedGoogle Scholar
  35. 35.
    Datta SK, Cho HJ, Takabayashi K, Horner AA, Raz E (2004) Antigen-immunostimulatory oligo-nucleotide conjugates: mechanisms and applications. Immunological Reviews 199:217–226CrossRefPubMedGoogle Scholar
  36. 36.
    Shirota H, Sano K, Hirasawa N, Terui T, Ohuchi K, Hattori T, Shirato K, Tamura G (2001) Novel roles of CpG oligodeoxynucleotides as a leader for the sampling and presentation of CpG-tagged antigen by dendritic cells. Journal of Immunology 167:66–74Google Scholar
  37. 37.
    Creticos PS (2001) The consideration of immunotherapy in the treatment of allergic asthma. Annals of Allergy, Asthma & Immunology 87:13–27CrossRefGoogle Scholar
  38. 38.
    Tulic MK, Fiset PO, Christodoulopoulos P, Vaillancourt P, Desrosiers M, Lavigne F, Eiden J, Hamid Q (2004) Amb a 1-immunostimulatory oligodeoxynucleotide conjugate immunother-apy decreases the nasal inflammatory response. Journal of Allergy and Clinical Immunology 113:235–241CrossRefPubMedGoogle Scholar
  39. 39.
    Creticos PS, Chen YH, Schroeder JT (2004) New approaches in immunotherapy: allergen vaccination with immunostimulatory DNA. Immunology and Allergy Clinics of North America 24:569–581CrossRefPubMedGoogle Scholar
  40. 40.
    Creticos PS, Schroeder JT, Hamilton RG, Balcer-Whaley SL, Khattignavong AP, Lindblad R, Li H, Coffman R, Seyfert V, Eiden JJ, Broide D (2006) Immunotherapy with a ragweed-tolllike receptor 9 agonist vaccine for allergic rhinitis. The New England Journal of Medicine 355:1445–1455CrossRefPubMedGoogle Scholar
  41. 41.
    Simons FE, Shikishima Y, Van Nest G, Eiden JJ, HayGlass KT (2004) Selective immune redirection in humans with ragweed allergy by injecting Amb a 1 linked to immunostimula-tory DNA. Journal of Allergy and Clinical Immunology 113:1144–1151CrossRefPubMedGoogle Scholar
  42. 42.
    Creticos PS, Lichtenstein LM (2003) Progress in the development of new methods of immu-notherapy: potential application of immunostimulatory DNA-conjugated to allergens for treatment of allergic respiratory conditions. Arbeiten aus them Paul-Ehrlich-Institut (Bundesamt fur Sera und Impfstoffe) zu Frankfurt A M :304–312; discussion 312–303Google Scholar
  43. 43.
    Drazen JM, Arm JP, Austen KF (1996) Sorting out the cytokines of asthma. Journal of Experimental Medicine 183:1–5CrossRefPubMedGoogle Scholar
  44. 44.
    Robinson DS, Hamid Q, Ying S Tsicopoulos A, Barkans J, Bentley AM, Corrigan C, Durham SR, Kay AB (1992) Predominant TH2-like bronchoalveolar T-lymphocyte population in atopic asthma. The New England Journal of Medicine 326:298–304PubMedGoogle Scholar
  45. 45.
    Graham LM (2002) Balancing safety and efficacy in the treatment of pediatric asthma. Journal of Allergy and Clinical Immunology 109:S560–S566CrossRefPubMedGoogle Scholar
  46. 46.
    Pullerits T, Praks L, Ristioja V, Lotvall J (2002) Comparison of a nasal glucocorticoid, antileu-kotriene, and a combination of antileukotriene and antihistamine in the treatment of seasonal allergic rhinitis. Journal of Allergy and Clinical Immunology 109:949–955CrossRefPubMedGoogle Scholar
  47. 47.
    Apter AJ, Szefler SJ (2006) Advances in adult and pediatric asthma. Journal of Allergy and Clinical Immunology 117:512–518CrossRefPubMedGoogle Scholar
  48. 48.
    Serebrisky D, Teper AA, Huang CK, Lee SY, Zhang TF, Schofield BH, Kattan M, Sampson HA, Li XM (2000) CpG oligodeoxynucleotides can reverse Th2-associated allergic airway responses and alter the B7.1/B7.2 expression in a murine model of asthma. Journal of Immunology 165:5906–5912Google Scholar
  49. 49.
    Broide DH, Stachnick G, Castaneda D, Nayar J, Miller M, Cho JY, Roman M, Zubeldia J, Hayashi T, Raz E (2001) Systemic administration of immunostimulatory DNA sequences mediates reversible inhibition of Th2 responses in a mouse model of asthma. Journal of Clinical Immunology 21:175–182CrossRefPubMedGoogle Scholar
  50. 50.
    Horner AA, Widhopf GF, Burger JA, Takabayashi K, Cinman N, Ronaghy A, Spiegelberg HL, Raz E (2001) Immunostimulatory DNA inhibits IL-4-dependent IgE synthesis by human B cells. Journal of Allergy and Clinical Immunology 108:417–423CrossRefPubMedGoogle Scholar
  51. 51.
    Lin L, Gerth AJ, Peng SL (2004) CpG DNA redirects class-switching towards “Th1-like” Ig isotype production via TLR9 and MyD88. European Journal of Immunology 34:1483–1487CrossRefPubMedGoogle Scholar
  52. 52.
    Horner AA, Raz E (2000) Immunostimulatory sequence oligodeoxynucleotide: a novel mucosal adjuvant. Clinical Immunology 95:S19–S29CrossRefPubMedGoogle Scholar
  53. 53.
    Takabayashi K, Libet L, Chisholm D, Zubeldia J, Horner AA (2003) Intranasal immuno-therapy is more effective than intradermal immunotherapy for the induction of airway allergen tolerance in Th2-sensitized mice. Journal of Immunology 170:3898–3905Google Scholar
  54. 54.
    Kitagaki K, Businga TR, Kline JN (2006) Oral administration of CpG-ODNs suppresses antigen-induced asthma in mice. Clinical and Experimental Immunology 143:249–259CrossRefPubMedGoogle Scholar
  55. 55.
    Ikeda RK, Nayar J, Cho JY, Miller M, Rodriguez M, Raz E, Broide DH (2003) Resolution of airway inflammation following ovalbumin inhalation: comparison of ISS DNA and corticos-teroids. American Journal of Respiratory Cell and Molecular Biology 28:655–663CrossRefPubMedGoogle Scholar
  56. 56.
    Elias JA, Zhu Z, Chupp G, Homer RJ (1999) Airway remodeling in asthma. Journal of Clinical Investigation 104:1001–1006CrossRefPubMedGoogle Scholar
  57. 57.
    Cho JY, Miller M, Baek KJ, Han JW, Nayar J, Rodriguez M, Lee SY, McElwain K, McElwain S, Raz E, Broide DH (2004) Immunostimulatory DNA inhibits transforming growth factor-{beta} expression and airway remodeling. American Journal of Respiratory Cell and Molecular Biology 30:651–661CrossRefPubMedGoogle Scholar
  58. 58.
    Jain VV, Businga TR, Kitagaki K, George CL, O'Shaughnessy PT, Kline JN (2003) Mucosal immunotherapy with CpG oligodeoxynucleotides reverses a murine model of chronic asthma induced by repeated antigen exposure. American Journal of Physiology. Lung cellular and Molecular Physiology 285:L1137–L1146PubMedGoogle Scholar
  59. 59.
    Banerjee B, Kelly KJ, Fink JN, Henderson Jr. JD, Bansal NK, Kurup VP (2004) Modulation of airway inflammation by immunostimulatory CpG oligodeoxynucleotides in a murine model of allergic aspergillosis. Infection and Immunity 72:6087–6094CrossRefPubMedGoogle Scholar
  60. 60.
    Lee SY, Cho JY, Miller M, McElwain K, McElwain S, Sriramarao P, Raz E, Broide DH (2006) Immunostimulatory DNA inhibits allergen-induced peribronchial angiogenesis in mice. Journal of Allergy and Clinical Immunology 117:597–603CrossRefPubMedGoogle Scholar
  61. 61.
    Youn CJ, Miller M, Baek KJ, Han JW, Nayar J, Lee SY, McElwain K, McElwain S, Raz E, Broide DH (2004) Immunostimulatory DNA reverses established allergen-induced airway remodeling. Journal of Immunology 173:7556–7564Google Scholar
  62. 62.
    Broide D (2004) Immunomodulation and reversal of airway remodeling in asthma. Current Opinion in Allergy and Clinical Immunology 4:529–532CrossRefPubMedGoogle Scholar
  63. 63.
    Fanucchi MV, Schelegle ES, Baker GL, Evans MJ, McDonald RJ, Gershwin LJ, Raz E, Hyde DM, Plopper CG, Miller LA (2004) Immunostimulatory oligonucleotides attenuate airways remodelling in allergic monkeys. American Journal of Respiratory Cell and Molecular Biology 170:1153Google Scholar
  64. 64.
    Rhee CS, Libet L, Chisholm D, Takabayashi K, Baird S, Bigby TD, Lee CH, Horner AA, Raz E (2004) Allergen-independent immunostimulatory sequence oligodeoxynucleotide therapy attenuates experimental allergic rhinitis. Immunology 113:106–113CrossRefPubMedGoogle Scholar
  65. 65.
    Hussain I, Jain V V, Kitagaki K, Businga TR, O'Shaughnessy P, Kline JN (2002) Modulation of murine allergic rhinosinusitis by CpG oligodeoxynucleotides. Laryngoscope 112:1819–1826CrossRefPubMedGoogle Scholar
  66. 66.
    Magone MT, Chan CC, Beck L, Whitcup SM, Raz E (2000) Systemic or mucosal administration of immunostimulatory DNA inhibits early and late phases of murine allergic conjunctivitis. European Journal of Immunology 30:1841–1850CrossRefPubMedGoogle Scholar
  67. 67.
    Rudikoff D, Lebwohl M (1998) Atopic dermatitis. Lancet 351:1715–1721CrossRefPubMedGoogle Scholar
  68. 68.
    Inoue J, Aramaki Y (2007) Suppression of skin lesions by transdermal application of CpG-oligodeoxynucleotides in NC/Nga mice, a model of human atopic dermatitis. Journal of Immunology 178:584–591Google Scholar
  69. 69.
    Hayashi T, Beck L, Rossetto C, Gong X, Takikawa O, Takabayashi K, Broide DH, Carson DA, Raz E (2004) Inhibition of experimental asthma by indoleamine 2,3-dioxygenase. Journal of Clinical Investigation 114:270–279PubMedGoogle Scholar
  70. 70.
    Hissong BD, Byrne GI, Padilla ML, Carlin JM (1995) Upregulation of interferon-induced indoleamine 2,3-dioxygenase in human macrophage cultures by lipopolysaccharide, muramyl tripeptide, and interleukin-1. Cellular Immunology 160:264–269CrossRefPubMedGoogle Scholar
  71. 71.
    Hayashi T, Rao SP, Takabayashi K, Van Uden JH, Kornbluth RS, Baird SM, Taylor MW, Carson DA, Catanzaro A, Raz E (2001) Enhancement of innate immunity against Mycobacterium avium infection by immunostimulatory DNA is mediated by indoleamine 2,3-dioxygenase. Infection and Immunity 69:6156–6164CrossRefPubMedGoogle Scholar
  72. 72.
    Mahanonda R, Sa-Ard-Iam N, Montreekachon P, Pimkhaokham A, Yongvanichit K, Fukuda MM, Pichyangkul S (2007) IL-8 and IDO expression by human gingival fibroblasts via TLRs. Journal of Immunology 178:1151–1157Google Scholar
  73. 73.
    Grohmann U, Orabona C, Fallarino F, Vacca C, Calcinaro F, Falorni A, Candeloro P, Belladonna ML, Bianchi R, Fioretti MC, Puccetti P (2002) CTLA-4-Ig regulates tryptophan catabolism in vivo. Nature Immunology 3:1097–1101CrossRefPubMedGoogle Scholar
  74. 74.
    Mellor AL, Munn DH (2001) Extinguishing maternal immune responses during pregnancy: implications for immunosuppression. Seminars in Immunology 13:213–218CrossRefPubMedGoogle Scholar
  75. 75.
    Babcock TA, Carlin JM (2000) Transcriptional activation of indoleamine dioxygenase by interleukin 1 and tumor necrosis factor alpha in interferon-treated epithelial cells. Cytokine 12:588–594CrossRefPubMedGoogle Scholar
  76. 76.
    Taussig LM, Wright AL, Holberg CJ, Halonen M, Morgan WJ, Martinez FD (2003) Tucson Children's Respiratory Study: 1980 to present. Journal of Allergy and Clinical Immunology 111:661–675; quiz 676CrossRefPubMedGoogle Scholar
  77. 77.
    Sears MR, Greene JM, Willan AR, Wiecek EM, Taylor DR, Flannery EM, Cowan JO, Herbison G P, Silva PA, Poulton R (2003) A longitudinal, population-based, cohort study of childhood asthma followed to adulthood. The New England Journal of Medicine 349:1414–1422CrossRefPubMedGoogle Scholar
  78. 78.
    Martinez FD (2003) Toward asthma prevention — does all that really matters happen before we learn to read? The New England Journal of Medicine 349:1473–1475CrossRefPubMedGoogle Scholar
  79. 79.
    Fasce L, Tosca MA, Olcese R, Milanese M, Erba R, Ciprandi G (2004) The natural history of allergy: the development of new sensitizations in asthmatic children. Immunology Letters 93:45–50CrossRefPubMedGoogle Scholar
  80. 80.
    Holt PG, Sly PD, Martinez FD, Weiss ST, Bjorksten B, von Mutius E, Wahn U (2004) Drug development strategies for asthma: in search of a new paradigm. Nature Immunology 5:695–698CrossRefPubMedGoogle Scholar
  81. 81.
    Reed CE (2006) The natural history of asthma. Journal of Allergy and Clinical Immunology 118:543–548CrossRefPubMedGoogle Scholar

Copyright information

© Springer 2010

Authors and Affiliations

  • Tomoko Hayashi
    • 1
  • Eyal Raz
    • 1
  1. 1.Department of Medicine 0663University of California San DiegoLa JollaUSA

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