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Heat shock proteins in autoimmune disease. From causative antigen to specific therapy?

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  • Heat Shock Proteins
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Abstract

Heat shock proteins (hsp) are highly conserved from bacteria to man. Bacterial hsp, with approximate molecular weights of 60 kDa (hsp60), are immunodominant antigens that are immunologically cross-reactive with their mammalian counterparts. Hsp molecules are therefore useful in studies of fundamental questions concerning immune responses to foreign as opposed to self antigens. The finding that immune responses to hsp are associated with both experimentally-induced and spontaneous autoimmune diseases in animals has prompted intensive research to assess the role of bacterial hsp as the etiological agents involved in the development of autoimmune diseases. Recent evidence from animal models of autoimmune disease has clearly demonstrated the involvement of hsp in both the pathogenesis and the immunoregulation of autoimmune diseases. Studies with arthritogenic and diabetogenic T cell clones have identified immunogenic epitopes of hsp. These have been shown to ameliorate adjuvant arthritis in Lewis rats, and insulin-dependent diabetes mellitus (IDDM) in non-obese diabetic (NOD) mice. Such studies may have important therapeutic implications for the future treatment of human autoimmune disease.

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Literatur

  1. Atkinson, M. A., Holmes, L. A., Scharp, D. W., Lacy, P. E., and Maclaren, N. K., No evidence for serological autoimmunity to islet cell heat shock proteins in insulin dependent diabetes. J. clin. Invest.87 (1991) 721–724.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Baekkeskov, S., Aanstoot, H.-J., Christgau, S., Reetz, A., Solimena, M., Cascalho, M., Folli, F., Richter-Olesen, H., and De Camilli, P., Identification of the 64 K autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase. Nature347 (1990) 151–156.

    Article  CAS  PubMed  Google Scholar 

  3. Bahr, G. M., Rook, G. A. W., Al-Saffar, M., Van Embden, J., Stanford, J. L., and Behbehani, K., Antibody levels to mycobacteria in relation to HLA type: evidence for non-HLA-linked high levels of antibody to the 65 kDa heat shock protein ofM. bovis in rheumatoid arthritis. Clin. exp. Immun.74 (1988) 211–215.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Benoist, C., and Mathis, D., Positive selection of T cell repertoire: Where and when does it occur? Cell58 (1989) 1027–1033.

    Article  CAS  PubMed  Google Scholar 

  5. Billingham, M. E. J., Carney, S., Butler, R., and Colston, M. J., A mycobacterial 65-kD heat shock protein induces antigen-specific suppression of adjuvant arthritis, but is not itself arthritogenic. J. exp. Med.171 (1990) 339–344.

    Article  CAS  PubMed  Google Scholar 

  6. Burmester, G. R., Altstidl, U., Kalden, J. R., and Emmrich, F., Stimulatory response towards the 65 kDa heat shock protein and other mycobacterial antigens in patients with rheumatoid arthritis. J. Rheumat.18 (1991) 171–176.

    CAS  Google Scholar 

  7. Cohen, I. R., The self, the world and autoimmunity. Scient. Amer.258 (1988) 52–60.

    Article  CAS  Google Scholar 

  8. Cohen, I. R., The immunological homunculus and autoimmune disease, in: Molecular Autoimmunity, pp. 437–453. Ed. N. Talal. Academic Press, New York 1991.

    Google Scholar 

  9. Cohen, I. R., Autoimmunity to chaperonins in the pathogenesis of arthritis and diabetes. A. Rev. Immunol.9 (1991) 567–589.

    Article  CAS  Google Scholar 

  10. Cohen, I. R., and Weiner, H. L., T-cell vaccination. Immun. Today9 (1988) 332–335.

    Article  CAS  PubMed  Google Scholar 

  11. Cohen, I. R., and Young, D. B., Autoimmunity, microbial immunity and the immunological homunculus. Immun. Today12 (1991) 105–110.

    Article  CAS  PubMed  Google Scholar 

  12. Cohen, I. R., Holoshitz, J., Van Eden, W., and Frenkel, A., T lymphocyte clones illuminate pathogenesis and affect therapy of experimental arthritis. Arthrit. Rheum.28 (1985) 841–845.

    Article  CAS  Google Scholar 

  13. Custano, L., and Eisenbarth, G. S., Type-1 diabetes: a chronic autoimmune disease of human, mouse, and rat. A. Rev. Immun.8 (1990) 647–679.

    Article  Google Scholar 

  14. De Graeff-Meeder, E. R., Voorhost, M., Van Eden, W., Schuurman, H. J., Huber, J., Barkley, D., Maini, R. N., Kuis, W., Rijkers, G. T., and Zegers, B. J. M., Antibodies to the mycobacterial 65-kd heat-shock protein are reactive with synovial tissue of adjuvant arthritic rats and patients with rheumatoid arthritis and osteoarthritis. Am. J. Path.137 (1990) 1013–1017.

    PubMed  PubMed Central  Google Scholar 

  15. De Graeff-Meeder, E. R., Van der Zee, R., Rijkers, G. T., Schuurman, H.-J., Kuis, W., Bijlsma, J. W. J., Zegers, B. J. M., and Van Eden, W., Recognition of human 60 kD heat shock protein by mononuclear cells from patients with juvenile chronic arthritis. Lancet337 (1991) 1368–1372.

    Article  PubMed  Google Scholar 

  16. Deguchi, Y., Enhanced expression of heat shock protein gene in kidney lymphoid cells of lupus-prone mice during growing process. Autoimmunity10 (1991) 1–5.

    Article  CAS  PubMed  Google Scholar 

  17. Elias, D., Markovits, D., Reshef, T., Van der Zee, R., and Cohen, I. R., Induction and therapy of autoimmune diabetes in the non-obese diabetic (NOD/Lt) mouse by a 65-kDa heat shock protein. Proc. natl Acad. Sci. USA87 (1990) 1576–1580.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Elias, D., Reshef, T., Birk, O. S., Van der Zee, R., Walker, M. D., and Cohen, I. R., Vaccination against autoimmune mouse diabetes using a T cell epitope of the human 65 kDa heat shock protein. Proc. natl Acad. Sci. USA88 (1991) 3088–3091.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Feige, U., and Cohen, I. R., The 65 kDa heat shock protein (hsp65) in the pathogenesis, prevention and therapy of autoimmune arthritis and diabetes mellitus in rats and mice. Springer Semin. Immunopath.13 (1991) 99–113.

    Article  CAS  Google Scholar 

  20. Gaston, J. S. H., Life, P. F., Jenner, P. J., Colston, M. J., and Bacon, P. A., Recognition of a mycobacteria-specific epitope in the 65-kD heat-shock protein by synovial fluid-derived T cell clones. J. exp. Med.171 (1990) 831–841.

    Article  CAS  PubMed  Google Scholar 

  21. Gaston, J. S. H., Life, P. F., Van der Zee, R., Jenner, P. J., Colston, M. J., Tonks, S., and Bacon, P. A., Epitope specificity and MHC restriction of rheumatoid arthritis synovial T cell clones which recognize a mycobacterial 65 kDa heat shock protein. Int. Immun.3 (1991) 965–972.

    Article  CAS  PubMed  Google Scholar 

  22. Grandia, A. A., De Visser, H., Van Embden, J. D. A., Van der Zee, R., Van der Berg, W., and Hazenberg, M. P., Natural antibodies to 65 kDa mycobacterial heat shock protein do not correlate with susceptibility forMycobacterium tuberculosis induced adjuvant arthritis. Immunobiology182 (1991) 127–134.

    Article  CAS  PubMed  Google Scholar 

  23. Hermann, E., Lohse, A. W., Van der Zee, R., Van Eden, W., Mayet, W. J., Probst, P., Poralla, T., Meyer zum Bueschenfelde, K.-H., and Fleischer, H., Synovial fluid-derivedYersinia-reactive T cells responding to human 65-kDa heat-shock protein and heat-stressed antigen-presenting cells. Eur. J. Immun.21 (1991) 2139–2143.

    Article  CAS  Google Scholar 

  24. Holoshitz, J., Naparstek, Y., Ben-Nun, A., and Cohen, I. R., Lines of T lymphocytes induce or vaccinate against autoimmune arthritis. Science219 (1983) 56–58.

    Article  CAS  PubMed  Google Scholar 

  25. Holoshitz, J., Matitiau, A., and Cohen, I. R., Arthritis induced in rats by cloned T lymphocytes responsive to mycobacteria but not to collagen type II. J. clin. Invest.73 (1984) 211–215.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Holoshitz, J., Koning, F., Coligan, J. E., DeBruyn, J., and Strober, S., Isolation of CD4− CD8− mycobacteria-reactive T lymphocyte clones from rheumatoid arthritits synovial fluid. Nature339 (1989) 226–229.

    Article  CAS  PubMed  Google Scholar 

  27. Holoshitz, J., Kosek, J., Sibley, R., Brown, D. A., and Strober, S., T lymphocyte-synovial fibroblast interactions induced by mycobacterial proteins in rheumatoid arthritis. Arthrit. Rheum.34 (1991) 679–686.

    Article  CAS  Google Scholar 

  28. Ito, J., Krco, C., Yu, D., Luthra, H. S., and David, C. S., Preadministration of a 65 kD heat shock protein GroEL inhibits collagen induced arthritis in mice. J. cell. Biochem.15A (1991) 284.

    Google Scholar 

  29. Iwasaki, A., Yoshikai, Y., Yuuki, H., Takimoto, H., and Nomoto, K., Self-reactive T cells are activated by the 65-kDa mycobacterial heat-shock protein in neonatally thymectomized mice. Eur. J. Immun.21 (1991) 597–603.

    Article  CAS  Google Scholar 

  30. Jindal, S., Dudani, A. K., Singh, B., Harley, C. B., and Gupta, R. S., Primary structure of a human mitochondrial protein homologous to the bacterial and plant chaperonins and to the 65-kilodalton mycobacterial antigen. Molec. cell. Biol.9 (1989) 2279–2283.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Jones, D. B., Hunter, N. R., and Duff, G. W., Heat-shock protein as a beta cell antigen of insulin-dependent diabetes. Lancet336 (1990) 583–585.

    Article  CAS  PubMed  Google Scholar 

  32. Kaempe, O., Velloso, L., Andersson, A., and Karlsson, A., No role for 65 kD heat-shock protein in diabetes. Lancet336 (1990) 1250.

    Article  Google Scholar 

  33. Karlsson-Parra, A., Soederstroem, K., Ferm, M., Ivanyi, J., Kiessling, R., and Klareskog, L., Presence of human 65 kD heat shock protein (hsp) in inflamed joints and subcutaneous nodules of RA patients. Scand. J. Immun.31 (1990) 283–288.

    Article  CAS  Google Scholar 

  34. Kaufmann, S. H. E. (ed.), Heat shock proteins and immune response. Curr. Topics Microbiol. Immun.167 (1991) 1–214.

  35. Kaufmann, S. H. E., The cellular immune response to heat shock proteins. Experientia48 (1992) 640–643.

    Article  CAS  PubMed  Google Scholar 

  36. Kiessling, R., Groenberg, A., Ivanyi, J., Soederstroem, K., Ferm, M., Kleinau, S., Nilsson, E., and Klareskog, L., Role of hsp60 during autoimmune and bacterial inflammation. Immun. Rev.121 (1991) 91–111.

    Article  CAS  PubMed  Google Scholar 

  37. Kleinau, S., Soederstroem, K., Kiessling, R., and Klareskog, L., A monoclonal antibody to the mycobacterial 65 kDa heat shock protein (ML30) binds to cells in normal and arthritic joints of rats. Scand. J. Immun.33 (1991) 195–202.

    Article  CAS  Google Scholar 

  38. Lamb, J. R. and Young, D. B., T cell recognition of stress proteins. A link between infectious and autoimmune diseases. Molec. biol. Med.7 (1990) 311–321.

    CAS  PubMed  Google Scholar 

  39. Life, P. F., Bassey, E. O. E., and Gaston, J. S. H., T-cell recognition of bacterial heat-shock proteins in inflammatory arthritis. Immun. Rev.121 (1991) 113–135.

    Article  CAS  PubMed  Google Scholar 

  40. Lydyard, P. M., Rook, G. A. W., Tsuolfa, G., Sharif, M., and Smith, M., Is there a role for mycobacteria in the etiopathogenesis of rheumatoid arthritis? Immun. Rev.121 (1991) 137–154.

    Article  CAS  PubMed  Google Scholar 

  41. Matsuzaki, G., Yoshikai, Y., Harada, M., and Nomoto, K., Autoreactive T cells from normal mice recognize mycobacterial 65 kd heat-shock protein fromMycobacterium bovis. Int. Immun.3 (1990) 215–220.

    Article  Google Scholar 

  42. Burel, C., Mezger, V., Pinto, M., Rallu, M., Trigon, S., and Morange, M., Mammalian heat shock protein families. Expression and functions. Experientia48 (1992) 629–634.

    Article  CAS  PubMed  Google Scholar 

  43. Minota, S., Koyasu, S., Yahara, I., and Winfield, J., Autoantibodies to the heat-shock protein hsp90 in systemic lupus erythematosus. J. clin. Invest.81 (1988) 106–109.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Minota, S., Cameron, B., Welch, W. J., and Winfield, J. B., Autoantibodies to the constitutive 73-Kd member of the hsp70 family of heat-shock proteins in systemic lupus erythematosus. J. exp. Med.168 (1988) 1475–1480.

    Article  CAS  PubMed  Google Scholar 

  45. Mollenhauer, J., and Schulmeister, A., Humoral immune response to heat shock proteins. Experientia48 (1992) 644–649.

    Article  CAS  PubMed  Google Scholar 

  46. Monaco, J. J., Cho, S., and Attaya, M., Transport protein genes in the murine MHC: possible implications for antigen processing. Science250 (1990) 1723–1726.

    Article  CAS  PubMed  Google Scholar 

  47. Morimoto, R. I., Tissières, A., and Georgopoulos, C., (Eds), Stress proteins in biology and medicine. Cold Spring Harbor Laboratory Press, Cold Spring Harbor 1990.

    Google Scholar 

  48. Munk, M. E., Schoel, B., Modrow, S., Karr, R. W., Young, R. A., and Kaufmann, S. H. E., T lymphocytes from healthy individuals with specificity to self-epitopes shared by the mycobacterial and human 65-kilodalton heat shock protein. J. Immun.143 (1989) 2844–2849.

    Article  CAS  PubMed  Google Scholar 

  49. Nover, L., (Ed.), Heat shock response. CRC Press, Boca Raton 1991.

    Google Scholar 

  50. Ottenhoff, T. H. M., Haanen, J. B. A. G., Geluk, A., Mutis, T., Ab, B. K., Thole, J. E. R., Van Schooten, W.C. A., Van den Elsen, P. J., and De Vries, R. R. P., Regulation of mycobacterial heat-shock protein-reactive T cells by HLA class II molecules: lessons from leprosy. Immun. Rev.121 (1991) 171–191.

    Article  CAS  PubMed  Google Scholar 

  51. Pearson, C. M.: Development of arthritis, periarthritis and periostitis in rats given adjuvant. Proc. Soc. exp. Biol. Med.91 (1956) 95–101.

    Article  CAS  PubMed  Google Scholar 

  52. Pearson, C. M., and Wood, F. D., Passive transfer of adjuvant arthritis by lymph mode or spleen cells. J. exp. Med.120 (1964) 547–559.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Pope, R. M., Wallis, R. S., Sailer, D., Buchanan, T. M., and Pahlavani, M. A., T cell activation by mycobacterial antigens in inflammatory synovitis. Cell. Immun.133 (1991) 95–108.

    Article  CAS  Google Scholar 

  54. Res, P. C. M., Schaar, C. G., Breedfeld, F. C., Van Eden, W., Van Embden, J. D. A., Cohen, I. R., and De Vries, R. R. P., Synovial fluid T cell reactivity against 65 kD heat shock protein of mycobacteria in early chronic arthritis. Lancet2 (1988) 478–480.

    Article  CAS  PubMed  Google Scholar 

  55. Res, P. C. M., Telgt, D., Van Laar, J. M., Pool, M. O., Breedveld, F. C., and De Vries, R. R. P., High antigen reactivity in mononuclear cells from sites of chronic inflammation. Lancet336 (1990) 1406–1408.

    Article  CAS  PubMed  Google Scholar 

  56. Res, P. C. M., Orsini, D. L. M., Van Laar, J. M., Janson, A. A. M., Abou-Zeid, C., and De Vries, R. R. P., Diversity in antigen recognition byMycobacterium tuberculosis-reactive T cell clones from the synovial fluid of rheumatoid arthritis patients. Eur. J. Immun.21 (1991) 1297–1302.

    Article  CAS  Google Scholar 

  57. Ritossa, F., A new puffing pattern induced by temperature shock and DNP inDrosophila. Experientia18 (1962) 571–573.

    Article  CAS  Google Scholar 

  58. Selmaj, K., Brosnan, C. F., and Raine, C. S., Colocalization of lymphocytes bearing gamma/delta T-Cell receptor and heat shock protein hsp65+ oligodendrocytes in multiple sclerosis. Proc. natl Acad. Sci. USA88 (1991) 6452–6456.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Sigurdsson, E., and Baekkeskov, S., The 64-kDa Beta cell membrane autoantigen and other target molecules of humoral autoimmunity in insulin-dependent diabetes mellitus. Curr. Topics Microbiol. Immun.164 (1990) 143–168.

    CAS  Google Scholar 

  60. Sinha, A., Lopez, M. T., and McDevitt, H. O., Autoimmune disease: the failure of self-tolerance. Science248 (1990) 1380–1388.

    Article  CAS  PubMed  Google Scholar 

  61. Soederstroem, K., Halapi, E., Nilsson, E., Groenberg, A., Van Embden, J., Klareskog, J., and Kiessling, R., Synovial cells responding to a 65 kDa mycobacterial heat shock protein have a high proportion of a TcRgamma/delta subtype uncommon in peripheral blood. Scand. J. Immun.32 (1990) 503–515.

    Article  CAS  Google Scholar 

  62. Thompson, S. J., Rook, G. A. W., Brealey, R. J., Van der Zee, R., and Elson, C. J., Autoimmune reactions to heat-shock proteins in pristane-induced arthritis. Eur. J. Immun.20 (1990) 2479–2484.

    Article  CAS  Google Scholar 

  63. Tsuolfa, G., Rook, G. A. W., Bahr, G. M., Sattar, M. A., Behbehani, K., Young, D. B., Mehlert, A., Van Embden, J. D. A., Hay, F. C., Isenberg, D. A., and Lydyard, P. M., Elevated antibody levels to the mycobacterial 65-kDa heat shock protein are characteristic of patients with rheumatoid arthritis. Scand. J. Immun.30 (1989) 519–527.

    Article  Google Scholar 

  64. Van den Broek, M. F., Hogervorst, E. J. M., Van Bruggen, M. C. J., Van Eden, W., Van der Zee, R., and Van der Berg, W., Protection against streptococcal cell wall-induced arthritis by pretreatment with the 65-kD mycobacterial heat shock protein. J. exp. Med.170 (1989) 449–466.

    Article  PubMed  Google Scholar 

  65. Van der Zee, R., Van Eden, W., Meloen, R. H., Noordzij, A., and Van Embden, J. D. A., Efficient mapping and characterization of a T cell epitope by the simultaneous synthesis of multiple peptides. Eur. J. Immun.19 (1989) 43–47.

    Article  Google Scholar 

  66. Van Eden, W., Heat-shock proteins as immunogenic bacterial antigens with the potential to induce and regulate autoimmune arthritis. Immun. Rev.121 (1991) 1–27.

    Article  Google Scholar 

  67. Van Eden, W., Holoshitz, J., Nevo, Z., Frenkel, A., Klajman, A., and Cohen, I. R., Arthritis induced by a T-lymphocyte clone that responds toMycobacterium tuberculosis and to cartilage proteoglycans. Proc. natl Acad. Sci. USA82 (1985) 5117–5120.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Van Eden, W., Thole, J. E. R., Van der Zee, R., Noordzij, A., Van Embden, J. D. A., Hensen, E. J., and Cohen, I. R., Cloning of the mycobacterial epitope recognized by T lymphocytes in adjuvant arthritis. Nature331 (1988) 171–173.

    Article  PubMed  Google Scholar 

  69. Van Eden, W., Hogervorst, E. J. M., Hensen, E. J., Van der Zee, R., Van Embden, J. D. A., and Cohen, I. R., A cartilage-mimicking T-cell epitope on a 65 K mycobacterial heat-shock protein: Adjuvant arthritis as a model for human rheumatoid arthritis. Curr. Topics Microbiol. Immun.145 (1989) 27–43.

    Google Scholar 

  70. Van Schooten, W. C. A., Elferink, D. G., Van Embden, J., Anderson, D.C., and De Vries, R. R. P., DR3-restricted T cells from different HLA-DR3-positive individuals recognize the same peptide (amino acids 2–12) of the mycobacterial 65-kDa heat-shock protein. Eur. J. Immun.19 (1989) 2075–2079.

    Article  Google Scholar 

  71. Winfield, J., and Jarjour, W., Do stress proteins play a role in arthritis and autoimmunity? Immun. Rev.121 (1991) 193–220.

    Article  CAS  PubMed  Google Scholar 

  72. Yang, X.-D., Gasser, J., Riniker, B., and Feige, U., Treatment of adjuvant arthritis in rats: vaccination potential of a synthetic non-apeptide from the 65 kDa heat shock protein of mycobacteria. J. Autoimmun.3 (1990) 11–23.

    Article  CAS  PubMed  Google Scholar 

  73. Yang, X.-D., Gasser, J., and Feige, U., Prevention of adjuvant arthritis in rats by a nonapeptide from the 65 kD mycobacterial heat-shock protein. Clin. exp. Immun.81 (1990) 189–194.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Yang, X.-D., Gasser, J., and Feige, U., Prevention of adjuvant arthritis in rats by a nonapeptide from the 65 kD mycobacterial heat-shock protein. II: specificity and mechanism. Clin. exp. Immun.87 (1992) 99–104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Yang, X.-D., and Feige, U., The 65 kD heat shock protein: a key molecule mediating the development of autoimmune arthritis? Autoimmunity9 (1991) 83–88.

    Article  CAS  PubMed  Google Scholar 

  76. Young, D. B., The immune response to mycobacterial heat shock proteins. Autoimmunity7 (1990) 237–244.

    Article  CAS  PubMed  Google Scholar 

  77. Young, D. B., Ivanyi, J., Cox, J. H., and Lamb, J. R., The 65 kDa antigen of mycobacteria—a common bacterial protein? Immun. Today8 (1987) 215–219.

    Article  CAS  PubMed  Google Scholar 

  78. Young, R. A., Stress proteins and immunology. A. Rev. Immun.8 (1990) 401–420.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Microbiology and Immunology, Stanford University School of Medicine, 94305, Stanford, California, USA

    X. -D. Yang

  2. Pharmaceuticals Research Division, Department of Inflammation, Ciba-Geigy, Basel, Switzerland

    U. Feige

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Dedicated to Professor Hermann A. Moser on the occasion of his 71st birthday.

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Yang, X.D., Feige, U. Heat shock proteins in autoimmune disease. From causative antigen to specific therapy?. Experientia 48, 650–656 (1992). https://doi.org/10.1007/BF02118311

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