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Defective post–thymic tolerance mechanisms during the chronic progressive stage of multiple sclerosis

Nature Medicine volume 2, pages 1354–1360 (1996)Cite this article

Abstract

We have recently isolated a panel of T–cell clones from chronic progressive multiple sclerosis (MS) patients that are capable of functioning as antigen–presenting cells and of expressing the costimulatory molecules B7–1 and B7–2. In this report we show that these T–cell clones are resistant to inhibitory regulation, including the induction of anergy and sensitivity to tumor growth factor–β (TGF–β)–induced growth inhibition. The resistance to anergy induction was associated with expression of B7 costimulatory molecules. These data suggest that lack of responsiveness to peripheral inhibitory signals may account for the entry of autoimmune diseases into a chronic progressive phase.

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References

  1. Sinha, A.A., Lopez, M.T. & McDevitt, H.O. Autoimmune diseases: The failure of self tolerance. Science 248, 1380–1387 (1990).

    Article  CAS  Google Scholar 

  2. Martin, R., McFarland, H.F. & McFarlin, D.E. Immunological aspects of de-myelinating diseases. Annu. Rev. Immunol. 10, 153–187 (1992).

    Article  CAS  Google Scholar 

  3. Marcos, M.A.R. et al. Mutual cell interactions and the selection of immune repertoires: Implication in autoimmunity. Immunol Today 9, 204–213 (1988).

    Article  CAS  Google Scholar 

  4. Schwartz, R.H. Acquisition of immunological self-tolerance. Cell 57, 1073–1081 (1989).

    Article  CAS  Google Scholar 

  5. Blackman, M., Kappler, J. & Marrack, P. The role of the T cell receptor in positive and negative selection of developing T cells. Science 248, 1335–1341 (1990).

    Article  CAS  Google Scholar 

  6. Blackman, M.A., Finkel, T.H., Kappler, J.W., Cambier, J. & Marrack, P. Altered antigen receptor signaling in anergic T cells from self-tolerant T-Cell receptor b-chain transgenic mice. Proc. Natl. Acad. Sci. USA 88, 6682–6686 (1991).

    Article  CAS  Google Scholar 

  7. Burns, J., Rosenzweig, A., Zweiman, B. & Lisak, R.P. Isolation of myelin basic protein-reactive T cell lines from normal human blood. Cell Immunol. 81, 435–440 (1983).

    Article  CAS  Google Scholar 

  8. Correale, J., McMillan, M., McCarthy, K., Le, T. & Weiner, L.P. Isolation and characterization of autoreactive proteolipid protein-peptide specific T-cell clones from multiple sclerosis patients. Neurology 45, 1370–1378 (1995).

    Article  CAS  Google Scholar 

  9. Kappler, J.W., Staerz, V.D., Steinmetz, M. & von Boehmer, M. Self-tolerance eliminates T cells specific for Mis-modified products of the major histocompatibility complex. Nature 332, 35–40 (1988).

    Article  CAS  Google Scholar 

  10. Karpus, W.J. & Swanborg, R.H. CD4+ suppressor cells inhibit the function of effec tor cells of experimental autoimmune encephalomyelitis through a mechanism involving transforming growth factor-beta. J. Immunol. 146, 1163–1168 (1991).

    CAS  Google Scholar 

  11. Mosmann, T.R. Cytokine secretion patterns and cross-regulation of T cell sub sets. Immunol. Res. 10, 183–188 (1991).

    Article  CAS  Google Scholar 

  12. Cohen, I.R. & Young, D.B., Immunity, microbial immunity and the im munological homunculus. Immunol Today 12, 105–110 (1991).

    Article  CAS  Google Scholar 

  13. Qin, S.X., Cobbold, S., Benjamin, R. & Waldmann, H. Induction of classical transplantation tolerance in the adult. J. Exp. Med. 169, 779–794 (1989).

    Article  CAS  Google Scholar 

  14. Mueller, D.L., Jenkins, M.K. & Schwartz, R.H. Clonal expansion versus functional clonal inactivation: A costimulatory signalling pathway determines the outcome of T Cell antigen receptor occupancy. Annu. Rev. Immunol. 7 445–480 (1989).

    Article  CAS  Google Scholar 

  15. Liu, Y. & Janeway, C.A. Jr., Interferon gamma plays a critical role in induced cell death of effector T cells: A possible third mechanism of self-tolerance. J. Exp. Med. 172, 1735–1739 (1990).

    Article  CAS  Google Scholar 

  16. Gimmi, C.D. et al. B Cell surface antigen B7 provides a costimulatory signal that induces T cell to proliferate and secrete interleukin-2. Proc. Natl Acad. Sci. USA 88, 6575–6579 (1991).

    Article  CAS  Google Scholar 

  17. Chen, C. & Nabvi, N. In vitro induction of T Cell anergy by blocking B7 and early T cell costimulatory molecule ETC-1/B7-2. Immunity 1, 147–154 (1994).

    Article  CAS  Google Scholar 

  18. Linsley, P.S. et al. Immunosuppression in vivo by a soluble form of the CTLA-4 T cell activation molecule. Science 257, 792–795 (1992).

    Article  CAS  Google Scholar 

  19. Lenschow, D.J. et al. Differential effects of anti-B7-1 and anti-B7-2 monoclonal antibody treatment on the development of diabetes in the nonobese diabetic mouse. J. Exp. Med. 181, 1145–1155 (1995).

    Article  CAS  Google Scholar 

  20. Correale, J. et al. Antigen presentation by autoreactive proteolipid protein peptide-specific T cell clones from chronic progressive multiple sclerosis patients: Roles of co-stimulatory B7 molecules and IL-12. J. Neuroimmunol. (in the press).

  21. Jenkins, M.K., Chen, C., Jung, G., Mueller, D.L. & Schwartz, R.H. Inhibition of antigen specific proliferation of type 1 murine T cell clones after stimulation with antigen and chemically modified antigen presenting cells. J Immunol. 144, 16–22 (1990).

    CAS  PubMed  Google Scholar 

  22. Williams, M.E., Shea, C.M., Lichtman, A.H. & Abbas, A.K. Antigen receptor me diated anergy in resting T lymphocytes and T cell clones. Correlation with lymphokine secretion patterns. J. Immunol. 149, 1921–1926 (1991).

    Google Scholar 

  23. O'Hehir, R.E. & Lamb, J.R. Induction of specific clonal anergy in human T lym phocytes by Staphylococcus aureus enterotoxins. Proc. Natl Acad. Sci. USA 87, 8884–8888 (1990).

    Article  CAS  Google Scholar 

  24. Jenkins, M. & Schwartz, R.H. Antigen presentation by chemically modified splenocytes induces antigen-specific T cell unresponsiveness in vitro and in vivo. J. Exp. Med. 165, 302–319 (1987).

    Article  CAS  Google Scholar 

  25. Vandenbark, A.A., Celnik, B., Vainiene, M., Miller, S.D. & Offner, H. Myelin antigen-coupled splenocytes suppress experimental autoimmune encephalomyelitis in Lewis rat through a partial reversible anergy mechanism. J. Immunol. 155, 5861–5867 (1995).

    CAS  PubMed  Google Scholar 

  26. Tan, P. et al. Induction of alloantigen-specific hyporesponsiveness in human T lymphocytes by blocking interaction of CD28 with its natural ligand B7/BB1. J. Exp. Med. 177 165–173 (1993).

    Article  CAS  Google Scholar 

  27. Sayegh, M.H. et al. CD28-B7 blockade after alloantigen challenge in vivo in hibits Thl cytokines but spares Th2. J. Exp. Med. 181, 1869–1874 (1995).

    Article  CAS  Google Scholar 

  28. Massague, J. The transforming growth factor-beta family. Annu. Rev. Cell Biol 6 597–641 (1990).

    Article  CAS  Google Scholar 

  29. Miller, S.D. et al. Evolution of the T-cell repertoire during the course of experimental immune-mediated demyelinating diseases. Immunol Rev. 144, 225–244 (1995).

    Article  CAS  Google Scholar 

  30. Olsson, T. et al. Increased numbers of T cells recognizing multiple myelin basic protein epitopes in multiple sclerosis. Eur. J. Immunol. 22, 1083–1087 (1992).

    Article  CAS  Google Scholar 

  31. Bossu, P. et al. Mature CD4+ T lymphocytes from MRL/lpr mice are resistant to receptor-mediated tolerance and apoptosis. J. Immunol. 151, 7233–7239 (1993).

    CAS  PubMed  Google Scholar 

  32. Dayan, C.M., Randall Chu, N., Londei, M., Rapoport, B. & Feldmann, M. T Cells involved in human autoimmune disease are resistant to tolerance induction. J. Immunol. 151, 1606–1613 (1993).

    CAS  PubMed  Google Scholar 

  33. Miller, S.D. et al. Blockade of CD28/B7-1 interaction prevents epitope spreading and clinical relapses of murine EAE. Immunity 3, 739–745 (1995).

    Article  CAS  Google Scholar 

  34. Kuiper, H.M., Lens, S.M.A., Hintzen, R.Q. & Van Lier, R.A.W. Lymphocyte co-stimulation: Multiple pathways, multiple functions? Res. Immunol. 146, 180–183 (1995).

    Article  CAS  Google Scholar 

  35. Van Kemenade, F.J., Kuijpers, K.C., de Waal Malefijt, R., Van Lier, R. A. W. & Miedema, F. Skewing to the LFA-3 adhesion pathway by influenza infection of antigen-presenting cells. Eur. J. Immunol. 23, 635–639 (1993).

    Article  CAS  Google Scholar 

  36. Kroemer, G. & Martinez-A, C. Mechanisms of self tolerance. Immunol. Today 13, 401–404 (1992).

    Article  CAS  Google Scholar 

  37. Racke, M.K. et al. Prevention and treatment of chronic relapsing experimental allergic encephalomyelitis by transforming growth factor beta-1. J. Immunol. 146, 3012–3017 (1991).

    CAS  PubMed  Google Scholar 

  38. Kadin, M.E. et al. Loss of receptors for transforming growth factor beta in human T cell malignancies. Proc. Natl Acad. Sci USA 91, 6002–6006 (1994).

    Article  CAS  Google Scholar 

  39. Hollsberg, P., Augobel, L.J. & Hafler, D.A. Human T cell lymphotropic virus type I-induced T cell activation: Resistance to TGF-beta-1 induced suppression. J. Immunol. 153, 566–573 (1994).

    CAS  PubMed  Google Scholar 

  40. Kurtzke, J.F. Rating neurological impairment in multiple sclerosis: An expanded disability status scale (EDSS). Neurology 33, 1444–1452 (1983).

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Neurology, University of Southern California, School of Medicine, 1333 San Pablo Street, MCK 142, Los Angeles, California, 90033, USA

    Jorge Correale, Wendy Gilmore, Jerome Lopez, Si Q. Li, Minnie McMillan & Leslie P. Weiner

  2. Department of Molecular Microbiology and Immunology, University of Southern California, School of Medicine, 1333 San Pablo Street, MCK 142, Los Angeles, California, 90033, USA

    Jorge Correale, Minnie McMillan & Leslie P. Weiner

  3. Department Cell and Neurobiology, University of Southern California, School of Medicine, 1333 San Pablo Street, MCK 142, Los Angeles, California, 90033, USA

    Wendy Gilmore

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  1. Jorge Correale
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  6. Leslie P. Weiner
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Correale, J., Gilmore, W., Lopez, J. et al. Defective post–thymic tolerance mechanisms during the chronic progressive stage of multiple sclerosis. Nat Med 2, 1354–1360 (1996). https://doi.org/10.1038/nm1296-1354

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