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Immunologie der Tuberkulose und neue Impfstoffansätze

Immunology of tuberculosis and novel vaccination strategies

  • Leitthema
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Zusammenfassung

Auch im 21. Jahrhundert stellt die Tuberkulose weltweit ein Gesundheitsproblem dar, das die WHO als „global emergency“, als globalen Notfall, einstuft. Eine hohe Durchseuchungsrate mit dem Erreger, Mycobacterium tuberculosis, der im Wirtsorganismus so lange persistiert, bis ihm ein geschwächtes Abwehrsystem die Gelegenheit zur Ausbreitung bietet, und eine aufwändige und kostenintensive Chemotherapie machen die Entwicklung eines geeigneten Impfstoffs dringend erforderlich. Hinzu kommen steigende Raten an multiresistenter Tuberkulose, u. a. in den Nachfolgestaaten der Sowjetunion und in China. Im vorliegenden Beitrag wird die Immunabwehr bei Tuberkulose vorgestellt, aus der sich verschiedene Strategien und Ansatzpunkte zur Impfstoffentwicklung ergeben.

Abstract

Even in the 21st century, tuberculosis (TB) remains one of the main health threats to mankind and is considered a global health emergency by the World Health Organization. A high infection rate by the causative agent, Mycobacterium tuberculosis, that persists in the host until a weakened immune systems allows it to spread, and an expensive and complicated anti-TB chemotherapy underline the urgent requirement for the development of an effective new vaccine. Increasing rates of multidrug resistant TB e.g. in countries of the former Soviet Union and in China aggravate the health problems caused by M. tuberculosis. This article reviews the immunology of TB in humans and presents current strategies and developments for a new vaccine.

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Literatur

  1. WHO (2004) Global tuberculosis control — surveillance, planning, financing. WHO, Genf, http://www.who.int/tb/publications/global_report/en/

  2. Means TK, Lien E, Yoshimura A et al. (1999) The CD14 ligands lipoarabinomannan and lipopolysaccharide differ in their requirement for toll-like receptors. J Immunol 163:6748–6755

    PubMed  Google Scholar 

  3. Means TK, Wang S, Lien E et al. (1999) Human toll-like receptors mediate cellular activation by Mycobacterium tuberculosis. J Immunol 163:3920–3927

    PubMed  Google Scholar 

  4. Iho S, Yamamoto T, Takahashi T et al. (1999) Oligodeoxynucleotides containing palindrome sequences with internal 5′-CpG-3′ act directly on human NK and activated T cells to induce IFN- gamma production in vitro. J Immunol 163:3642–3652

    PubMed  Google Scholar 

  5. Takeshita F, Leifer CA, Gursel I et al. (2001) Cutting edge: role of toll-like receptor 9 in CpG DNA-induced activation of human cells. J Immunol 167:3555–3558

    PubMed  Google Scholar 

  6. Armstrong JA, Hart PD (1975) Phagosome-lysosome interactions in cultured macrophages infected with virulent tubercle bacilli. Reversal of the usual nonfusion pattern and observations on bacterial survival. J Exp Med 142:1–16

    Article  PubMed  Google Scholar 

  7. Le Cabec V, Cols C, Maridonneau-Parini I (2000) Nonopsonic phagocytosis of zymosan and Mycobacterium kansasii by CR3 (CD11b/CD18) involves distinct molecular determinants and is or is not coupled with NADPH oxidase activation. Infect Immun 68:4736–4745

    Article  PubMed  Google Scholar 

  8. Losana G, Rigamonti L, Borghi I et al. (2002) Requirement for both IL-12 and IFN-gamma signaling pathways in optimal IFN-gamma production by human T cells. Eur J Immunol 32:693–700

    Article  PubMed  Google Scholar 

  9. Kaufmann SH (2001) How can immunology contribute to the control of tuberculosis? Nat Rev Immunol 1:20–30

    Article  PubMed  Google Scholar 

  10. Flynn JL (2004) Immunology of tuberculosis and implications in vaccine development. Tuberculosis (Edinb) 84:93–101

    Google Scholar 

  11. Ulrichs T, Kaufmann SH (2003) Immunology of tuberculosis: impact on the development of novel vaccines. Internist 44:1374–1384

    Article  PubMed  Google Scholar 

  12. Boros DL (1978) Granulomatous inflammations. Prog Allergy 24:183–267

    PubMed  Google Scholar 

  13. Mariano M (1995) The experimental granuloma. A hypothesis to explain the persistence of the lesion. Rev Inst Med Trop Sao Paulo 37:161–176

    PubMed  Google Scholar 

  14. Actor JK, Olsen M, Jagannath C et al. (1999) Relationship of survival, organism containment, and granuloma formation in acute murine tuberculosis. J Interferon Cytokine Res 19:1183–1193

    Article  PubMed  Google Scholar 

  15. Cardona PJ, Llatjos R, Gordillo S et al. (2000) Evolution of granulomas in lungs of mice infected aerogenically with Mycobacterium tuberculosis. Scand J Immunol 52:156–163

    Article  PubMed  Google Scholar 

  16. Turner OC, Basaraba RJ, Orme IM (2003) Immunopathogenesis of pulmonary granulomas in the guinea pig after infection with Mycobacterium tuberculosis. Infect Immun 71:864–871

    Article  PubMed  Google Scholar 

  17. Ulrichs T, Kosmiadi GA, Trusov V et al. (2004) Human tuberculous granulomas induce peripheral lymphoid follicle-like structures to orchestrate local host defence in the lung. J Pathol 204:217–228

    Article  PubMed  Google Scholar 

  18. Ulrichs T, Kosmiadi GA, Jorg S et al. (2005) Differential organization of the local immune response in patients with active cavitary tuberculosis or with nonprogressive tuberculoma. J Infect Dis 192:89–97

    Article  PubMed  Google Scholar 

  19. Lazarevic V, Nolt D, Flynn JL (2005) Long-term control of Mycobacterium tuberculosis infection is mediated by dynamic immune responses. J Immunol 175:1107–1117

    PubMed  Google Scholar 

  20. Stewart GR, Robertson BD, Young DB (2003) Tuberculosis: a problem with persistence. Nat Rev Microbiol 1:97–105

    Article  PubMed  Google Scholar 

  21. Moody DB, Ulrichs T, Muhlecker W et al. (2000) CD1c-mediated T-cell recognition of isoprenoid glycolipids in Mycobacterium tuberculosis infection. Nature 404:884–888

    Article  PubMed  Google Scholar 

  22. Ulrichs T, Anding R, Kaufmann SH et al. (2000) Numbers of IFN-gamma-producing cells against ESAT-6 increase in tuberculosis patients during chemotherapy. Int J Tuberc Lung Dis 4:1181–1183

    PubMed  Google Scholar 

  23. Ulrichs T, Munk ME, Mollenkopf H et al. (1998) Differential T cell responses to Mycobacterium tuberculosis ESAT6 in tuberculosis patients and healthy donors. Eur J Immunol 28:3949–3958

    Article  PubMed  Google Scholar 

  24. Fenhalls G, Stevens L, Moses L et al. (2002) In situ detection of Mycobacterium tuberculosis transcripts in human lung granulomas reveals differential gene expression in necrotic lesions. Infect Immun 70:6330–6338

    Article  PubMed  Google Scholar 

  25. Fenhalls G, Stevens-Muller L, Warren R et al. (2002) Localisation of mycobacterial DNA and mRNA in human tuberculous granulomas. J Microbiol Methods 51:197–208

    Article  PubMed  Google Scholar 

  26. Fenhalls G, Stevens L, Bezuidenhout J et al. (2002) Distribution of IFN-gamma, IL-4 and TNF-alpha protein and CD8 T cells producing IL-12p40 mRNA in human lung tuberculous granulomas. Immunology 105:325–335

    Article  PubMed  Google Scholar 

  27. Hernandez-Pando R, Orozco H, Mancilla R (1995) T-cell lung granulomas induced by sepharose-coupled Mycobacterium tuberculosis protein antigens: immunosuppressive phenomena reversed with cyclophosphamide and indomethacin. Immunology 86:506–511

    PubMed  Google Scholar 

  28. Hernandez-Pando R, Jeyanathan M, Mengistu G et al. (2000) Persistence of DNA from Mycobacterium tuberculosis in superficially normal lung tissue during latent infection. Lancet 356:2133–2138

    Article  PubMed  Google Scholar 

  29. Gonzalez-Juarrero M, Turner OC, Turner J et al. (2001) Temporal and spatial arrangement of lymphocytes within lung granulomas induced by aerosol infection with Mycobacterium tuberculosis. Infect Immun 69:1722–1728

    Article  PubMed  Google Scholar 

  30. Fuller CL, Flynn JL, Reinhart TA (2003) In situ study of abundant expression of proinflammatory chemokines and cytokines in pulmonary granulomas that develop in cynomolgus macaques experimentally infected with Mycobacterium tuberculosis. Infect Immun 71:7023–7034

    Article  PubMed  Google Scholar 

  31. Zhang Y (2004) Persistent and dormant tubercle bacilli and latent tuberculosis. Front Biosci 9:1136–1156

    PubMed  Google Scholar 

  32. Ulrichs T, Kaufmann SH (2002) Mycobacterial persistence and immunity. Front Biosci 7:d458–d469

    PubMed  Google Scholar 

  33. Honer zu BK, Miczak A, Swenson DL et al. (1999) Characterization of activity and expression of isocitrate lyase in Mycobacterium avium and Mycobacterium tuberculosis. J Bacteriol 181:7161–7167

    PubMed  Google Scholar 

  34. McKinney JD, Honer zu BK, Munoz-Elias EJ et al. (2000) Persistence of Mycobacterium tuberculosis in macrophages and mice requires the glyoxylate shunt enzyme isocitrate lyase. Nature 406:735–738

    Article  PubMed  Google Scholar 

  35. Glickman MS, Cox JS, Jacobs WR (2000) A novel mycolic acid cyclopropane synthetase is required for coding, persistence, and virulence of Mycobacterium tuberculosis. Mol Cell 5:717–727

    Article  PubMed  Google Scholar 

  36. Ando M, Yoshimatsu T, Ko C et al. (2003) Deletion of Mycobacterium tuberculosis sigma factor E results in delayed time to death with bacterial persistence in the lungs of aerosol-infected mice. Infect Immun 71:7170–7172

    Article  PubMed  Google Scholar 

  37. Chen P, Ruiz RE, Li Q et al. (2000) Construction and characterization of a Mycobacterium tuberculosis mutant lacking the alternate sigma factor gene, sigF. Infect Immun 68:5575–5580

    Article  PubMed  Google Scholar 

  38. Ramakrishnan L, Federspiel NA, Falkow S (2000) Granuloma-specific expression of Mycobacterium virulence proteins from the glycine-rich PE-PGRS family. Science 288:1436–1439

    Article  PubMed  Google Scholar 

  39. Sherman DR, Voskuil M, Schnappinger D et al. (2001) Regulation of the Mycobacterium tuberculosis hypoxic response gene encoding alpha-crystallin. Proc Natl Acad Sci USA 98:7534–7539

    Article  PubMed  Google Scholar 

  40. Saini DK, Malhotra V, Dey D et al. (2004) DevR-DevS is a bona fide two-component system of Mycobacterium tuberculosis that is hypoxia-responsive in the absence of the DNA-binding domain of DevR. Microbiology 150:865–875

    Article  PubMed  Google Scholar 

  41. Kaplan G, Post FA, Moreira AL et al. (2003) Mycobacterium tuberculosis growth at the cavity surface: a microenvironment with failed immunity. Infect Immun 71:7099–7108

    Article  PubMed  Google Scholar 

  42. Schluger NW (2003) The diagnosis of tuberculosis: what’s old, what’s new. Semin Respir Infect 18:241–248

    PubMed  Google Scholar 

  43. Ulrichs T, Moody DB, Grant E et al. (2003) T-cell responses to CD1-presented lipid antigens in humans with Mycobacterium tuberculosis infection. Infect Immun 71:3076–3087

    Article  PubMed  Google Scholar 

  44. Brandt L, Oettinger T, Holm A et al. (1996) Key epitopes on the ESAT-6 antigen recognized in mice during the recall of protective immunity to Mycobacterium tuberculosis. J Immunol 157:3527–3533

    PubMed  Google Scholar 

  45. Ulrichs T, Munk ME, Mollenkopf H et al. (1998) Differential T cell responses to Mycobacterium tuberculosis ESAT6 in tuberculosis patients and healthy donors [published erratum appears in Eur J Immunol 1999 Feb 29(2):725]. Eur J Immunol 28:3949–3958

    Article  PubMed  Google Scholar 

  46. Pai M, Riley LW, Colford JM Jr (2004) Interferon-gamma assays in the immunodiagnosis of tuberculosis: a systematic review. Lancet Infect Dis 4:761–776

    Article  PubMed  Google Scholar 

  47. Ulrichs T, Kaufmann SH (2002) Mycobacterial persistence and immunity. Front Biosci 7:D458–D469

    PubMed  Google Scholar 

  48. Cole ST, Brosch R, Parkhill J et al. (1998) Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 393:537–544

    Article  PubMed  Google Scholar 

  49. Stead WW (1967) Pathogenesis of a first episode of chronic pulmonary tuberculosis in man: recrudescence of residuals of the primary infection or exogenous reinfection? Am Rev Respir Dis 95:729–745

    PubMed  Google Scholar 

  50. Romeyn JA (1970) Exogenous reinfection in tuberculosis. Am Rev Respir Dis 101:923–927

    PubMed  Google Scholar 

  51. van Rie A, Warren R, Richardson M et al. (1999) Exogenous reinfection as a cause of recurrent tuberculosis after curative treatment. N Engl J Med 341:1174–1179

    Article  PubMed  Google Scholar 

  52. Feng Z, Castillo-Chavez C, Capurro AF (2000) A model for tuberculosis with exogenous reinfection. Theor Popul Biol 57:235–247

    Article  PubMed  Google Scholar 

  53. Fine PE (1989) The BCG story: lessons from the past and implications for the future. Rev Infect Dis [Suppl 2] 11:S353–S359

    Google Scholar 

  54. WHO (2005) WHO Report 2004, Global tuberculosis control, The Russian Federation. WHO, Genf, pp 105–107

  55. Kaufmann SH, McMichael AJ (2005) Annulling a dangerous liaison: vaccination strategies against AIDS and tuberculosis. Nat Med [Suppl 4] 11:S33–S44

    Google Scholar 

  56. Huygen K (2003) On the use of DNA vaccines for the prophylaxis of mycobacterial diseases. Infect Immun 71:1613–1621

    Article  PubMed  Google Scholar 

  57. Olsen AW, Williams A, Okkels LM et al. (2004) Protective effect of a tuberculosis subunit vaccine based on a fusion of antigen 85B and ESAT-6 in the aerosol guinea pig model. Infect Immun 72:6148–6150

    Article  PubMed  Google Scholar 

  58. Mollenkopf HJ, Dietrich G, Fensterle J et al. (2004) Enhanced protective efficacy of a tuberculosis DNA vaccine by adsorption onto cationic PLG microparticles. Vaccine 22:2690–2695

    Article  PubMed  Google Scholar 

  59. McShane H, Pathan AA, Sander CR et al. (2004) Recombinant modified vaccinia virus Ankara expressing antigen 85A boosts BCG-primed and naturally acquired antimycobacterial immunity in humans. Nat Med 10:1240–1244

    Article  PubMed  Google Scholar 

  60. Skeiky YA, Alderson MR, Ovendale PJ et al. (2004) Differential immune responses and protective efficacy induced by components of a tuberculosis polyprotein vaccine, Mtb72F, delivered as naked DNA or recombinant protein. J Immunol 172:7618–7628

    PubMed  Google Scholar 

  61. Fine PE (1989) The BCG story: lessons from the past and implications for the future. Rev Infect Dis [Suppl 2] 11:S353–S359

    Google Scholar 

  62. Brandt L, Skeiky YA, Alderson MR et al. (2004) The protective effect of the Mycobacterium bovis BCG vaccine is increased by coadministration with the Mycobacterium tuberculosis 72-kilodalton fusion polyprotein Mtb72F in M. tuberculosis-infected guinea pigs. Infect Immun 72:6622–6632

    Article  PubMed  Google Scholar 

  63. McShane H, Brookes R, Gilbert SC et al. (2001) Enhanced immunogenicity of CD4(+) t-cell responses and protective efficacy of a DNA-modified vaccinia virus Ankara prime-boost vaccination regimen for murine tuberculosis. Infect Immun 69:681–686

    Article  PubMed  Google Scholar 

  64. Horwitz MA, Harth G, Dillon BJ et al. (2000) Recombinant bacillus calmette-guerin (BCG) vaccines expressing the Mycobacterium tuberculosis 30-kDa major secretory protein induce greater protective immunity against tuberculosis than conventional BCG vaccines in a highly susceptible animal model. Proc Natl Acad Sci USA 97:13853–13858

    Article  PubMed  Google Scholar 

  65. Hess J, Miko D, Catic A et al. (1998) Mycobacterium bovis Bacille Calmette-Guerin strains secreting listeriolysin of Listeria monocytogenes. Proc Natl Acad Sci USA 95:5299–5304

    Article  PubMed  Google Scholar 

  66. Eddine AN, Kaufmann SH (2005) Improved protection by recombinant BCG. Microbes Infect 7:939–946

    Article  PubMed  Google Scholar 

  67. Grode L, Seiler P, Baumann S, Hess J et al. (2005) Increased vaczine efficancy against tuberculosis of recombinant mycobacterium bovis Bacille Calmette Guérin mutants that secrete listeriolysin. J Clin Invest 115 (9):2472–2479

    Article  PubMed  Google Scholar 

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Danksagung

Die Autoren danken Frau Diane Schad und Luise Fehlig für ihre wertvolle Hilfe bei der Erstellung der Graphiken.

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Authors and Affiliations

  1. Max-Planck-Institut für Infektionsbiologie, Berlin

    T. Ulrichs & S. H. E. Kaufmann

  2. Max-Planck-Institut für Infektionsbiologie, Schumannstraße 21/22, 10117, Berlin

    T. Ulrichs

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  1. T. Ulrichs
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  2. S. H. E. Kaufmann
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Correspondence to T. Ulrichs.

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Die eigene Tuberkuloseforschung wird wie folgt unterstützt: EU FP6 TB-VAC, EU FP6 MUVAPRED, BMBF Kompetenznetzwerk „structural genomics of M. tuberculosis“, BMBF Joint Project „genomics of tuberculosis“, EU Projekt XTB, DFG Schwerpunktprogramm „Neue Vakzinierungsstrategien“ und Bill and Melinda Gates Foundation „Grand Challenge 6“

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Ulrichs, T., Kaufmann, S.H.E. Immunologie der Tuberkulose und neue Impfstoffansätze. Monatsschr Kinderheilkd 154, 133–141 (2006). https://doi.org/10.1007/s00112-005-1280-5

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