Advertisement

Treatment of Autoimmunity by Inhibition of T Cell Costimulation

  • David I. Daikh
  • David Wofsy
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 490)

Abstract

Recent advances in our understanding of the mechanisms underlying immune responses have led to the development of new strategies designed to inhibit pathologic immune responses, such as autoimmunity, without severely compromising protective immune responses or causing serious toxic side effects. Many of these strategies are based on the two-signal model for T cell activation (1,2). The first signal occurs when the T cell receptor (TCR) recognizes an antigenic peptide displayed on the surface of an antigen-presenting cells (APC). The second signal is provided by other receptor-ligand pairs on T cells and APC. The presence or absence of this signal, also referred to as T cell costimulation, plays a critical role in determining whether antigen recognition through the TCR results in T cell activation or T cell unresponsiveness (1). Thus, the two-signal model implies that selective blockade of the second signal might render autoreactive T cells unresponsive in people with autoimmune diseases. As described below, this strategy has already been tested and has shown promise in animal models for autoimmunity, and it currently the subject of clinical investigation in humans.

Keywords

Systemic Lupus Erythematosus Lupus Nephritis Murine Lupus Cell Costimulation Pathologic Immune Response 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    P. Marrack and J.W. Kappler, How the immune system recognizes the body, Sci. Am. 269, 80–89 (1993).PubMedCrossRefGoogle Scholar
  2. 2.
    F.A. Harding, J.G. McArthur, J.A. Gross, D.H. Raulet, and J.P. Allison, CD28mediated signaling co-stimulates murine T cells and prevents induction of anergy in T cell clones, Nature 356, 607–610 (1992).PubMedCrossRefGoogle Scholar
  3. 3.
    P. Tan, C. Anasetti, J.A. Hansen, J. Melrose, M. Brunvand, J. Bradshaw, J.A. Ledbetter, and P.S. Linsley, 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).PubMedCrossRefGoogle Scholar
  4. 4.
    M. F. Krummel and J.P. Allison, CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation, J. Exp. Med. 182, 459–465 (1995).PubMedCrossRefGoogle Scholar
  5. 5.
    P.J. Waterhouse, M. Penninger, E. Timms, A. Wakeham, A. Shahinian, K.P. Lee, C.B. Thompson, H. Griesser, and T. Mak, Lymphoproliferative disorders with early lethality in mice deficient in CTLA-4, Science 270, 985–988 (1995).PubMedCrossRefGoogle Scholar
  6. 6.
    J. A. Bluestone, New perspectives of CD28–B7-mediated T cell costimulation, Immunity 2, 555–559 (1995).PubMedCrossRefGoogle Scholar
  7. 7.
    P.S. Linsley, W. Brady, M. Urnes, L. Gorsmaire, N.K. Damle, and J.A. Ledbetter, CTLA-4 is a second receptor for the B cell activation antigen B7, J Exp. Med. 174, 561–569 (1991).PubMedCrossRefGoogle Scholar
  8. 8.
    P.S. Linsley, P.M. Wallace, J. Johnson, M.G. Gibson, J.L. Greene, J.A. Ledbetter, C. Singh, and M.A. Tepper, Immunosuppression in vivo by a soluble form of the CTLA-4 T cell activation molecule, Science 257, 792–795 (1992).PubMedCrossRefGoogle Scholar
  9. 9.
    D. R. Milich, P.S. Linsley, J.L. Hughes, and J.E. Jones, Soluble CTLA-4 can suppress autoantibody production and elicit long term unresponsiveness in a novel transgenic model, J. Immunol. 153, 429–435 (1994).PubMedGoogle Scholar
  10. 10.
    B.K. Finck, P.S. Linsley, and D. Wofsy, Treatment of murine lupus with CTLA4Ig, Science 265, 1225–1227 (1994).PubMedCrossRefGoogle Scholar
  11. 11.
    D. I. Daikh, B.K.Finck, P.S. Linsley, D. Hollenbaugh, and D. Wofsy, Long-term inhibition of murine lupus by brief simultaneous blockade of the B7/CD28 and CD40/gp39 costimulation pathways, J. Immunol. 159, 3104–3108 (1997).PubMedGoogle Scholar
  12. 12.
    F. H. Durie, T.M. Foy, S.R. Masters, J.D. Laman, and R.J. Noelle, The role of CD40 in the regulation of humoral and cell-mediated immunity, Immunol. Today 15, 406–411 (1994).PubMedCrossRefGoogle Scholar
  13. 13.
    S.J. Klaus, I. Berberich, and E.A. Clark, CD40 and its ligand in the regulation of humoral immunity, Semin. Immunol. 6, 279–286 (1994).PubMedCrossRefGoogle Scholar
  14. 14.
    C. Mohan, Y. Shi, J.D. Laman, and S.K. Datta, Interaction between CD40 and its ligand gp39 in the development of murine lupus nephritis, J. Immunol. 154, 1470–1480 (1995).PubMedGoogle Scholar
  15. 15.
    G.S. Early, W. Zhao, and C.M. Burns, Anti-CD40 ligand antibody treatment prevents the development of lupus-like nephritis in a subset of New Zealand Black x New Zealand White mice, J. Immunol. 157, 3159–3164 (1996).PubMedGoogle Scholar
  16. 16.
    N.D. Griggs, S.S. Agersborg, R.J. Noelle, J.A. Ledbetter, P.S. Linsley, and K.S.K. Tung, The relative contribution of the CD28 and gp39 costimulatory pathways in the clonal expression and pathogenic acquisition of self reactive T cells, J Exp. Med 183, 801–810 (1996).PubMedCrossRefGoogle Scholar
  17. 17.
    J.R. Abrams, M.G. Lebwohl, C.A. Guzzo, B.V. Jegasothy, M.T. Goldfarb, B.S. Goffe, A. Menter, N.J. Lowe, G. Krueger, M.J. Brown, R.S. Weiner, M.J. Birkhofer, G.L. Warner, K.K. Berry, P.S. Linsley, J.G. Krueger, H.D. Ochs, S.L. Kelley, and S. Kang, CTLA4Ig-mediated blockade of T-cell costimulation in patients with psoriasis vulgaris, J Clin. Invest. 103, 1243–1252 (1999).PubMedCrossRefGoogle Scholar
  18. 18.
    J.C. Davis, M.C. Totoritis, T.A. Sklenar, and D. Wofsy, Results of a phase I, single-dose, dose-escalating trial of a humanized anti-CD40L monoclonal antibody (IDEC131) in patients with systemic lupus erythematosus (SLE), Arthritis Rheum. 42, S281 (1999).Google Scholar

Copyright information

© Springer Science+Business Media New York 2001

Authors and Affiliations

  • David I. Daikh
    • 1
    • 2
  • David Wofsy
    • 1
    • 2
  1. 1.Department of MedicineUniversity of CaliforniaSan FranciscoUSA
  2. 2.Department of Veterans Affairs Medical CenterSan FranciscoUSA

Personalised recommendations