Treatment of Autoimmunity by Inhibition of T Cell Costimulation
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.
KeywordsArthritis Psoriasis Proteinuria Nephritis Bluestone
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- 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
- 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.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