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. 1993 Oct;61(10):4225–4231. doi: 10.1128/iai.61.10.4225-4231.1993

Modulation of adjuvant arthritis in Lewis rats by recombinant vaccinia virus expressing the human 60-kilodalton heat shock protein.

J A López-Guerrero 1, J P López-Bote 1, M A Ortiz 1, R S Gupta 1, E Páez 1, C Bernabeu 1
PMCID: PMC281148  PMID: 8406810

Abstract

The immune response to the mycobacterial 65-kDa heat shock protein (hsp65) is considered an important event in the induction of adjuvant arthritis (AA) in rats; this induction probably occurs through a molecular mimicry mechanism involving cross-reactivity against the rat homolog hsp60. To analyze the role of mammalian molecule hsp60 in arthritis, we generated a recombinant vaccinia virus (hsp60-VV) carrying the human hsp60 gene inserted into the thymidine kinase locus under the control of the 7.5k vaccinia virus promoter. Human hsp60 is almost identical to its rat homolog (97.4% linear amino acid homology) and shares about 50% of amino acid positions with Mycobacterium tuberculosis hsp65. The latter supposedly carries a critical epitope for AA induction that is not present in human hsp60. Infections with hsp60-VV of monkey cell cultures led to the expression of the human hsp60 molecule, as evidenced by immunoblotting analysis with specific monoclonal antibodies. Also, Lewis rats infected with hsp60-VV produced specific antibodies, demonstrating the in vivo expression of human hsp60 in the infected animals. Therefore, we used hsp60-VV to analyze whether the delivery of hsp60 could affect the induction of AA in Lewis rats. hsp60-VV clearly reduced and retarded arthritic symptoms when administered to rats at day 7 after AA induction. In contrast, inoculation of rats with a control recombinant vaccinia virus did not affect the course of the disease. The improvement in AA with hsp60-VV administration was associated with a specific immune response, as determined by the presence of antibodies to hsp60 in the sera and the proliferation induced by hsp60 of T cells from popliteal lymph nodes. These results support a critical role for immunity to heat shock proteins in AA. Since the protective construct is virtually identical to rat homolog hsp60, we conclude that immunity directed to conserved areas of this family of proteins is directly involved in the pathogenesis of AA.

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Selected References

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  1. Bennink J. R., Yewdell J. W. Recombinant vaccinia viruses as vectors for studying T lymphocyte specificity and function. Curr Top Microbiol Immunol. 1990;163:153–184. doi: 10.1007/978-3-642-75605-4_6. [DOI] [PubMed] [Google Scholar]
  2. Billingham M. E., Carney S., Butler R., 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. 1990 Jan 1;171(1):339–344. doi: 10.1084/jem.171.1.339. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Boog C. J., de Graeff-Meeder E. R., Lucassen M. A., van der Zee R., Voorhorst-Ogink M. M., van Kooten P. J., Geuze H. J., van Eden W. Two monoclonal antibodies generated against human hsp60 show reactivity with synovial membranes of patients with juvenile chronic arthritis. J Exp Med. 1992 Jun 1;175(6):1805–1810. doi: 10.1084/jem.175.6.1805. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Brideau R. J., Carter P. B., McMaster W. R., Mason D. W., Williams A. F. Two subsets of rat T lymphocytes defined with monoclonal antibodies. Eur J Immunol. 1980 Aug;10(8):609–615. doi: 10.1002/eji.1830100807. [DOI] [PubMed] [Google Scholar]
  5. Chakrabarti S., Brechling K., Moss B. Vaccinia virus expression vector: coexpression of beta-galactosidase provides visual screening of recombinant virus plaques. Mol Cell Biol. 1985 Dec;5(12):3403–3409. doi: 10.1128/mcb.5.12.3403. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Cohen I. R. Autoimmunity to chaperonins in the pathogenesis of arthritis and diabetes. Annu Rev Immunol. 1991;9:567–589. doi: 10.1146/annurev.iy.09.040191.003031. [DOI] [PubMed] [Google Scholar]
  7. Cohen I. R. The cognitive paradigm and the immunological homunculus. Immunol Today. 1992 Dec;13(12):490–494. doi: 10.1016/0167-5699(92)90024-2. [DOI] [PubMed] [Google Scholar]
  8. Cohen I. R., Young D. B. Autoimmunity, microbial immunity and the immunological homunculus. Immunol Today. 1991 Apr;12(4):105–110. doi: 10.1016/0167-5699(91)90093-9. [DOI] [PubMed] [Google Scholar]
  9. De Graeff-Meeder E. R., van der Zee R., Rijkers G. T., Schuurman H. J., Kuis W., Bijlsma J. W., Zegers B. J., van Eden W. Recognition of human 60 kD heat shock protein by mononuclear cells from patients with juvenile chronic arthritis. Lancet. 1991 Jun 8;337(8754):1368–1372. doi: 10.1016/0140-6736(91)93057-g. [DOI] [PubMed] [Google Scholar]
  10. Gaston J. S. Heat shock proteins and autoimmunity. Semin Immunol. 1991 Jan;3(1):35–42. [PubMed] [Google Scholar]
  11. Gaston J. S., Life P. F., Bailey L. C., Bacon P. A. In vitro responses to a 65-kilodalton mycobacterial protein by synovial T cells from inflammatory arthritis patients. J Immunol. 1989 Oct 15;143(8):2494–2500. [PubMed] [Google Scholar]
  12. Gaston J. S., Life P. F., Jenner P. J., Colston M. J., 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. 1990 Mar 1;171(3):831–841. doi: 10.1084/jem.171.3.831. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Gutierrez-Ramos J. C., Andreu J. L., Revilla Y., Viñuela E., Martinez C. Recovery from autoimmunity of MRL/lpr mice after infection with an interleukin-2/vaccinia recombinant virus. Nature. 1990 Jul 19;346(6281):271–274. doi: 10.1038/346271a0. [DOI] [PubMed] [Google Scholar]
  14. Gutierrez-Ramos J. C., Moreno de Alboran I., Martínez C. In vivo administration of interleukin-2 turns on anergic self-reactive T cells and leads to autoimmune disease. Eur J Immunol. 1992 Nov;22(11):2867–2872. doi: 10.1002/eji.1830221117. [DOI] [PubMed] [Google Scholar]
  15. Hermann E., Lohse A. W., Van der Zee R., Van Eden W., Mayet W. J., Probst P., Poralla T., Meyer zum Büschenfelde K. H., Fleischer B. Synovial fluid-derived Yersinia-reactive T cells responding to human 65-kDa heat-shock protein and heat-stressed antigen-presenting cells. Eur J Immunol. 1991 Sep;21(9):2139–2143. doi: 10.1002/eji.1830210923. [DOI] [PubMed] [Google Scholar]
  16. Hogervorst E. J., Boog C. J., Wagenaar J. P., Wauben M. H., Van der Zee R., Van Eden W. T cell reactivity to an epitope of the mycobacterial 65-kDa heat-shock protein (hsp 65) corresponds with arthritis susceptibility in rats and is regulated by hsp 65-specific cellular responses. Eur J Immunol. 1991 May;21(5):1289–1296. doi: 10.1002/eji.1830210529. [DOI] [PubMed] [Google Scholar]
  17. Hogervorst E. J., Schouls L., Wagenaar J. P., Boog C. J., Spaan W. J., van Embden J. D., van Eden W. Modulation of experimental autoimmunity: treatment of adjuvant arthritis by immunization with a recombinant vaccinia virus. Infect Immun. 1991 Jun;59(6):2029–2035. doi: 10.1128/iai.59.6.2029-2035.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hogervorst E. J., Wagenaar J. P., Boog C. J., van der Zee R., van Embden J. D., van Eden W. Adjuvant arthritis and immunity to the mycobacterial 65 kDa heat shock protein. Int Immunol. 1992 Jul;4(7):719–727. doi: 10.1093/intimm/4.7.719. [DOI] [PubMed] [Google Scholar]
  19. JOKLIK W. K. The purification fo four strains of poxvirus. Virology. 1962 Sep;18:9–18. doi: 10.1016/0042-6822(62)90172-1. [DOI] [PubMed] [Google Scholar]
  20. Jarjour W. N., Jeffries B. D., Davis J. S., 4th, Welch W. J., Mimura T., Winfield J. B. Autoantibodies to human stress proteins. A survey of various rheumatic and other inflammatory diseases. Arthritis Rheum. 1991 Sep;34(9):1133–1138. doi: 10.1002/art.1780340909. [DOI] [PubMed] [Google Scholar]
  21. Jefferies W. A., Green J. R., Williams A. F. Authentic T helper CD4 (W3/25) antigen on rat peritoneal macrophages. J Exp Med. 1985 Jul 1;162(1):117–127. doi: 10.1084/jem.162.1.117. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Jindal S., Dudani A. K., Singh B., Harley C. B., Gupta R. S. Primary structure of a human mitochondrial protein homologous to the bacterial and plant chaperonins and to the 65-kilodalton mycobacterial antigen. Mol Cell Biol. 1989 May;9(5):2279–2283. doi: 10.1128/mcb.9.5.2279. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Kleinau S., Söderström K., Kiessling R., Klareskog L. A monoclonal antibody to the mycobacterial 65 kDa heat shock protein (ML 30) binds to cells in normal and arthritic joints of rats. Scand J Immunol. 1991 Feb;33(2):195–202. doi: 10.1111/j.1365-3083.1991.tb03749.x. [DOI] [PubMed] [Google Scholar]
  24. Li S. G., Quayle A. J., Shen Y., Kjeldsen-Kragh J., Oftung F., Gupta R. S., Natvig J. B., Førre O. T. Mycobacteria and human heat shock protein-specific cytotoxic T lymphocytes in rheumatoid synovial inflammation. Arthritis Rheum. 1992 Mar;35(3):270–281. doi: 10.1002/art.1780350305. [DOI] [PubMed] [Google Scholar]
  25. McKenzie K. R., Adams E., Britton W. J., Garsia R. J., Basten A. Sequence and immunogenicity of the 70-kDa heat shock protein of Mycobacterium leprae. J Immunol. 1991 Jul 1;147(1):312–319. [PubMed] [Google Scholar]
  26. Moore M. W., Carbone F. R., Bevan M. J. Introduction of soluble protein into the class I pathway of antigen processing and presentation. Cell. 1988 Sep 9;54(6):777–785. doi: 10.1016/s0092-8674(88)91043-4. [DOI] [PubMed] [Google Scholar]
  27. Morrison L. A., Lukacher A. E., Braciale V. L., Fan D. P., Braciale T. J. Differences in antigen presentation to MHC class I-and class II-restricted influenza virus-specific cytolytic T lymphocyte clones. J Exp Med. 1986 Apr 1;163(4):903–921. doi: 10.1084/jem.163.4.903. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. PEARSON C. M. Development of arthritis, periarthritis and periostitis in rats given adjuvants. Proc Soc Exp Biol Med. 1956 Jan;91(1):95–101. doi: 10.3181/00379727-91-22179. [DOI] [PubMed] [Google Scholar]
  29. Paterson D. J., Jefferies W. A., Green J. R., Brandon M. R., Corthesy P., Puklavec M., Williams A. F. Antigens of activated rat T lymphocytes including a molecule of 50,000 Mr detected only on CD4 positive T blasts. Mol Immunol. 1987 Dec;24(12):1281–1290. doi: 10.1016/0161-5890(87)90122-2. [DOI] [PubMed] [Google Scholar]
  30. Pope R. M., Lovis R. M., Gupta R. S. Activation of synovial fluid T lymphocytes by 60-kd heat-shock proteins in patients with inflammatory synovitis. Arthritis Rheum. 1992 Jan;35(1):43–48. doi: 10.1002/art.1780350107. [DOI] [PubMed] [Google Scholar]
  31. Singh B., Gupta R. S. Expression of human 60-kD heat shock protein (HSP60 or P1) in Escherichia coli and the development and characterization of corresponding monoclonal antibodies. DNA Cell Biol. 1992 Jul-Aug;11(6):489–496. doi: 10.1089/dna.1992.11.489. [DOI] [PubMed] [Google Scholar]
  32. Thompson S. J., Rook G. A., Brealey R. J., Van der Zee R., Elson C. J. Autoimmune reactions to heat-shock proteins in pristane-induced arthritis. Eur J Immunol. 1990 Nov;20(11):2479–2484. doi: 10.1002/eji.1830201118. [DOI] [PubMed] [Google Scholar]
  33. Towbin H., Staehelin T., Gordon J. Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc Natl Acad Sci U S A. 1979 Sep;76(9):4350–4354. doi: 10.1073/pnas.76.9.4350. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Trentham D. E., Townes A. S., Kang A. H. Autoimmunity to type II collagen an experimental model of arthritis. J Exp Med. 1977 Sep 1;146(3):857–868. doi: 10.1084/jem.146.3.857. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Van Vollenhoven R. F., Soriano A., McCarthy P. E., Schwartz R. L., Garbrecht F. C., Thorbecke G. J., Siskind G. W. The role of immunity to cartilage proteoglycan in adjuvant arthritis. Intravenous injection of bovine proteoglycan enhances adjuvant arthritis. J Immunol. 1988 Aug 15;141(4):1168–1173. [PubMed] [Google Scholar]
  36. Venner T. J., Gupta R. S. Nucleotide sequence of rat hsp60 (chaperonin, GroEL homolog) cDNA. Nucleic Acids Res. 1990 Sep 11;18(17):5309–5309. doi: 10.1093/nar/18.17.5309. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Williams A. F., Barclay A. N., Clark S. J., Paterson D. J., Willis A. C. Similarities in sequences and cellular expression between rat CD2 and CD4 antigens. J Exp Med. 1987 Feb 1;165(2):368–380. doi: 10.1084/jem.165.2.368. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Yang X. D., Gasser J., Feige U. Prevention of adjuvant arthritis in rats by a nonapeptide from the 65-kD mycobacterial heat shock protein: specificity and mechanism. Clin Exp Immunol. 1992 Jan;87(1):99–104. doi: 10.1111/j.1365-2249.1992.tb06420.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Yang X. D., Gasser J., Feige U. Prevention of adjuvant arthritis in rats by a nonapeptide from the 65-kD mycobacterial heat-shock protein. Clin Exp Immunol. 1990 Aug;81(2):189–194. doi: 10.1111/j.1365-2249.1990.tb03316.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Zinkernagel R. M., Cooper S., Chambers J., Lazzarini R. A., Hengartner H., Arnheiter H. Virus-induced autoantibody response to a transgenic viral antigen. Nature. 1990 May 3;345(6270):68–71. doi: 10.1038/345068a0. [DOI] [PubMed] [Google Scholar]
  41. van Eden W. Heat-shock proteins as immunogenic bacterial antigens with the potential to induce and regulate autoimmune arthritis. Immunol Rev. 1991 Jun;121:5–28. doi: 10.1111/j.1600-065x.1991.tb00821.x. [DOI] [PubMed] [Google Scholar]
  42. van Eden W., Hogervorst E. J., Hensen E. J., van der Zee R., van Embden J. D., Cohen I. R. A cartilage-mimicking T-cell epitope on a 65K mycobacterial heat-shock protein: adjuvant arthritis as a model for human rheumatoid arthritis. Curr Top Microbiol Immunol. 1989;145:27–43. doi: 10.1007/978-3-642-74594-2_3. [DOI] [PubMed] [Google Scholar]
  43. van Eden W., Holoshitz J., Cohen I. Antigenic mimicry between mycobacteria and cartilage proteoglycans: the model of adjuvant arthritis. Concepts Immunopathol. 1987;4:144–170. [PubMed] [Google Scholar]
  44. van Eden W., Holoshitz J., Nevo Z., Frenkel A., Klajman A., Cohen I. R. Arthritis induced by a T-lymphocyte clone that responds to Mycobacterium tuberculosis and to cartilage proteoglycans. Proc Natl Acad Sci U S A. 1985 Aug;82(15):5117–5120. doi: 10.1073/pnas.82.15.5117. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. van Eden W., Thole J. E., van der Zee R., Noordzij A., van Embden J. D., Hensen E. J., Cohen I. R. Cloning of the mycobacterial epitope recognized by T lymphocytes in adjuvant arthritis. Nature. 1988 Jan 14;331(6152):171–173. doi: 10.1038/331171a0. [DOI] [PubMed] [Google Scholar]
  46. van den Broek M. F., Hogervorst E. J., Van Bruggen M. C., Van Eden W., van der Zee R., van den Berg W. B. Protection against streptococcal cell wall-induced arthritis by pretreatment with the 65-kD mycobacterial heat shock protein. J Exp Med. 1989 Aug 1;170(2):449–466. doi: 10.1084/jem.170.2.449. [DOI] [PMC free article] [PubMed] [Google Scholar]

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