Skip to main content
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1994 May 24;91(11):5085–5088. doi: 10.1073/pnas.91.11.5085

Prevention of autoimmune lysis by T cells with specificity for a heat shock protein by antisense oligonucleotide treatment.

U Steinhoff 1, U Zügel 1, A Wand-Württenberger 1, H Hengel 1, R Rösch 1, M E Munk 1, S H Kaufmann 1
PMCID: PMC43936  PMID: 7910966

Abstract

T lymphocytes with specificity for the bacterial heat shock protein (hsp) 60 recognize stressed host cells, thus possibly promoting pathogenesis of certain infectious and autoimmune diseases. Here, we show that autoimmune destruction of stressed Schwann cells and macrophages by cytotoxic T lymphocytes raised against mycobacterial hsp60 can be inhibited by the use of hsp60-specific antisense oligodeoxynucleotides (A-ODNs). The inhibitory effect of hsp60 A-ODNs was specific because lysis of murine cytomegalovirus-infected host cells by virus-specific cytotoxic lymphocytes was not affected. Immunoblot analysis and immunoprecipitation studies suggest that different forms of stress increase hsp60 synthesis in Schwann cells and that this neosynthesis is reduced by hsp60 A-ODNs. These findings (i) provide evidence for participation of endogenous hsp60 in the recognition of stressed host cells by mycobacterial hsp60-crossreactive T cells and (ii) suggest the feasibility of inhibiting autoimmune reactions by target-cell treatment with specific A-ODNs.

Full text

PDF

Images in this article

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Acha-Orbea H., Mitchell D. J., Timmermann L., Wraith D. C., Tausch G. S., Waldor M. K., Zamvil S. S., McDevitt H. O., Steinman L. Limited heterogeneity of T cell receptors from lymphocytes mediating autoimmune encephalomyelitis allows specific immune intervention. Cell. 1988 Jul 15;54(2):263–273. doi: 10.1016/0092-8674(88)90558-2. [DOI] [PubMed] [Google Scholar]
  2. Akhtar S., Kole R., Juliano R. L. Stability of antisense DNA oligodeoxynucleotide analogs in cellular extracts and sera. Life Sci. 1991;49(24):1793–1801. doi: 10.1016/0024-3205(91)90480-y. [DOI] [PubMed] [Google Scholar]
  3. 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]
  4. Elias D., Reshef T., Birk O. S., van der Zee R., Walker M. D., Cohen I. R. Vaccination against autoimmune mouse diabetes with a T-cell epitope of the human 65-kDa heat shock protein. Proc Natl Acad Sci U S A. 1991 Apr 15;88(8):3088–3091. doi: 10.1073/pnas.88.8.3088. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Ellis J. Proteins as molecular chaperones. 1987 Jul 30-Aug 5Nature. 328(6129):378–379. doi: 10.1038/328378a0. [DOI] [PubMed] [Google Scholar]
  6. Flesch I., Kaufmann S. H. Mycobacterial growth inhibition by interferon-gamma-activated bone marrow macrophages and differential susceptibility among strains of Mycobacterium tuberculosis. J Immunol. 1987 Jun 15;138(12):4408–4413. [PubMed] [Google Scholar]
  7. 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]
  8. Kaufmann S. H. Heat shock proteins and the immune response. Immunol Today. 1990 Apr;11(4):129–136. doi: 10.1016/0167-5699(90)90050-j. [DOI] [PubMed] [Google Scholar]
  9. Kaufmann S. H., Schoel B., van Embden J. D., Koga T., Wand-Württenberger A., Munk M. E., Steinhoff U. Heat-shock protein 60: implications for pathogenesis of and protection against bacterial infections. Immunol Rev. 1991 Jun;121:67–90. doi: 10.1111/j.1600-065x.1991.tb00823.x. [DOI] [PubMed] [Google Scholar]
  10. Koga T., Wand-Württenberger A., DeBruyn J., Munk M. E., Schoel B., Kaufmann S. H. T cells against a bacterial heat shock protein recognize stressed macrophages. Science. 1989 Sep 8;245(4922):1112–1115. doi: 10.1126/science.2788923. [DOI] [PubMed] [Google Scholar]
  11. Lallier T., Bronner-Fraser M. Inhibition of neural crest cell attachment by integrin antisense oligonucleotides. Science. 1993 Jan 29;259(5095):692–695. doi: 10.1126/science.8430321. [DOI] [PubMed] [Google Scholar]
  12. Lamb J. R., Bal V., Mendez-Samperio P., Mehlert A., So A., Rothbard J., Jindal S., Young R. A., Young D. B. Stress proteins may provide a link between the immune response to infection and autoimmunity. Int Immunol. 1989;1(2):191–196. doi: 10.1093/intimm/1.2.191. [DOI] [PubMed] [Google Scholar]
  13. Leamon C. P., Low P. S. Delivery of macromolecules into living cells: a method that exploits folate receptor endocytosis. Proc Natl Acad Sci U S A. 1991 Jul 1;88(13):5572–5576. doi: 10.1073/pnas.88.13.5572. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Lindquist S. The heat-shock response. Annu Rev Biochem. 1986;55:1151–1191. doi: 10.1146/annurev.bi.55.070186.005443. [DOI] [PubMed] [Google Scholar]
  15. Lisziewicz J., Sun D., Klotman M., Agrawal S., Zamecnik P., Gallo R. Specific inhibition of human immunodeficiency virus type 1 replication by antisense oligonucleotides: an in vitro model for treatment. Proc Natl Acad Sci U S A. 1992 Dec 1;89(23):11209–11213. doi: 10.1073/pnas.89.23.11209. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Munk M. E., Schoel B., Modrow S., Karr R. W., Young R. A., Kaufmann S. H. T lymphocytes from healthy individuals with specificity to self-epitopes shared by the mycobacterial and human 65-kilodalton heat shock protein. J Immunol. 1989 Nov 1;143(9):2844–2849. [PubMed] [Google Scholar]
  17. Rajagopalan S., Zordan T., Tsokos G. C., Datta S. K. Pathogenic anti-DNA autoantibody-inducing T helper cell lines from patients with active lupus nephritis: isolation of CD4-8- T helper cell lines that express the gamma delta T-cell antigen receptor. Proc Natl Acad Sci U S A. 1990 Sep;87(18):7020–7024. doi: 10.1073/pnas.87.18.7020. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Reddehase M. J., Koszinowski U. H. Significance of herpesvirus immediate early gene expression in cellular immunity to cytomegalovirus infection. Nature. 1984 Nov 22;312(5992):369–371. doi: 10.1038/312369a0. [DOI] [PubMed] [Google Scholar]
  19. Renneisen K., Leserman L., Matthes E., Schröder H. C., Müller W. E. Inhibition of expression of human immunodeficiency virus-1 in vitro by antibody-targeted liposomes containing antisense RNA to the env region. J Biol Chem. 1990 Sep 25;265(27):16337–16342. [PubMed] [Google Scholar]
  20. Selmaj K., Brosnan C. F., 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 U S A. 1991 Aug 1;88(15):6452–6456. doi: 10.1073/pnas.88.15.6452. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. 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]
  22. Steinhoff U., Kaufmann S. H. Specific lysis by CD8+ T cells of Schwann cells expressing Mycobacterium leprae antigens. Eur J Immunol. 1988 Jun;18(6):969–972. doi: 10.1002/eji.1830180622. [DOI] [PubMed] [Google Scholar]
  23. Steinhoff U., Schoel B., Kaufmann S. H. Lysis of interferon-gamma activated Schwann cell by cross-reactive CD8+ alpha/beta T cells with specificity for the mycobacterial 65 kd heat shock protein. Int Immunol. 1990;2(3):279–284. doi: 10.1093/intimm/2.3.279. [DOI] [PubMed] [Google Scholar]
  24. Urban J. L., Horvath S. J., Hood L. Autoimmune T cells: immune recognition of normal and variant peptide epitopes and peptide-based therapy. Cell. 1989 Oct 20;59(2):257–271. doi: 10.1016/0092-8674(89)90288-2. [DOI] [PubMed] [Google Scholar]
  25. Urban J. L., Kumar V., Kono D. H., Gomez C., Horvath S. J., Clayton J., Ando D. G., Sercarz E. E., Hood L. Restricted use of T cell receptor V genes in murine autoimmune encephalomyelitis raises possibilities for antibody therapy. Cell. 1988 Aug 12;54(4):577–592. doi: 10.1016/0092-8674(88)90079-7. [DOI] [PubMed] [Google Scholar]
  26. Volkmer H., Bertholet C., Jonjić S., Wittek R., Koszinowski U. H. Cytolytic T lymphocyte recognition of the murine cytomegalovirus nonstructural immediate-early protein pp89 expressed by recombinant vaccinia virus. J Exp Med. 1987 Sep 1;166(3):668–677. doi: 10.1084/jem.166.3.668. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Wahlestedt C., Golanov E., Yamamoto S., Yee F., Ericson H., Yoo H., Inturrisi C. E., Reis D. J. Antisense oligodeoxynucleotides to NMDA-R1 receptor channel protect cortical neurons from excitotoxicity and reduce focal ischaemic infarctions. Nature. 1993 May 20;363(6426):260–263. doi: 10.1038/363260a0. [DOI] [PubMed] [Google Scholar]
  28. Wand-Württenberger A., Schoel B., Ivanyi J., Kaufmann S. H. Surface expression by mononuclear phagocytes of an epitope shared with mycobacterial heat shock protein 60. Eur J Immunol. 1991 Apr;21(4):1089–1092. doi: 10.1002/eji.1830210437. [DOI] [PubMed] [Google Scholar]
  29. Young D., Lathigra R., Hendrix R., Sweetser D., Young R. A. Stress proteins are immune targets in leprosy and tuberculosis. Proc Natl Acad Sci U S A. 1988 Jun;85(12):4267–4270. doi: 10.1073/pnas.85.12.4267. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Young R. A. Stress proteins and immunology. Annu Rev Immunol. 1990;8:401–420. doi: 10.1146/annurev.iy.08.040190.002153. [DOI] [PubMed] [Google Scholar]
  31. 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]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES