Nature Medicine
2, 183 - 189 (1996)
doi:10.1038/nm0296-183
Selective depletion of myelin−reactive T cells with the anti−OX−40 antibody ameliorates autoimmune encephalomyelitisA.D. Weinberg1, 2, 3, D.N. Bourdette1, 3, T.J. Sullivan1, M. Lemon1, J.J. Wallin1, R. Maziarz1, 2, M. Davey1, 2, F. Palida4, W. Godfrey6, E. Engleman6, R.J. Fulton5, H. Offner1, 3
& A.A. Vandenbark1, 2, 3
1Veterans Affairs Medical Center, 3710 SW US Veteran's Hospital Road, Portland, Oregon 97207, USA
2Department of Microbiology and Immunology, Oregon Health Science University, Portland, Oregon 97201, USA
3Department of Neurology, Oregon Health Science University, Portland, Oregon 97201, USA
4PharMingen, 11555 Sorrento Valley Road, Suite E, San Diego, California 92121, USA
5Inland Laboratory, 1638 Osprey Drive, Desoto, Texas 75115, USA
6Department of Pathology, Stanford University, Palo Alto, California 94305, USA Correspondence should be addressed to A.D.W. The OX−40 protein was selectively upregulated on encephalitogenic myelin basic protein (MBP)−specific T cells at the site of inflammation during the onset of experimental autoimmune encephalomyelitis (EAE). An OX−40 immunotoxin was used to target and eliminate MBP−specific T cells within the central nervous system without affecting peripheral T cells. When injected in vivo, the OX−40 immunotoxin bound exclusively to myelin−reactive T cells isolated from the CNS, which resulted in amelioration of EAE. Expression of the human OX−40 antigen was also found in peripheral blood of patients with acute graft−versus−host disease and the synovia of patients with rheumatoid arthritis during active disease. The unique expression of the OX−40 molecule may provide a novel therapeutic strategy for eliminating autoreactive CD4+T cells that does not require prior knowledge of the pathogenic autoantigen.
REFERENCES
- Swanborg, R.H. Autoimmune effector cells. V. A monoclonal antibody specific for rat helper T lymphocytes inhibits adoptive transfer of auto-immune encephalomyelitis. J. Immunol. 130, 1503−1505 (1983). | PubMed | ISI | ChemPort |
- Cush, J.J. & Lipsky, P.E. Phenotypic analysis of synovial tissue and peripheral blood lymphocytes isolated from patients with rheumatoid arthritis. Arthritis Rheum. 31, 1230−1238 (1988). | PubMed | ISI | ChemPort |
- Caspi, R.R. et al. A new model of autoimmune disease: Experimental autoimmune uveoretinitis induced in mice with two different retinal antigens. J. Immunol. 140, 1490−1495 (1988). | PubMed | ISI | ChemPort |
- Cobbold, S.P., Nash, J.A., Prospero, T.D. & Waldmann, H. Therapy with monoclonal antibodies by elimination of T-cell subsets in vivo. Nature 312, 548−551 (1988).
- Steinman, L. Autoimmune disease. Sci. Am. 269, 106−114 (1993). | PubMed | ISI | ChemPort |
- Weinberg, A.D. et al. Target organ specific upregulation of the MRC OX-40 marker and selective production of Th1 lymphokine mRNA by encephalitogenic T helper cells isolated from the spinal cord of rats with experimental autoimmune encephalomyelitis. J. Immunol. 152, 4712−4721 (1994). | PubMed | ISI | ChemPort |
- Weinberg, A.D. et al. TGF-
 enhances the in vivo effector function and memory phenotype of Ag-specific T helper cells in EAE. J. Immunol. 148, 2109−2117 (1992). | PubMed | ISI | ChemPort |
- Weiner, H.L. et al. Double-blind pilot trial of oral tolerization with myelin antigens in MS. Science 259, 1321−1324 (1993). | PubMed | ISI | ChemPort |
- Vandenbark, A.A., Hashim, G. & Offner, H. Immunization with a synthetic T-cell receptor V-region peptide protects against experimental autoimmune encephalomyelitis. Nature 341, 541−544 (1989). | Article | PubMed | ISI | ChemPort |
- Howell, M.D. et al. Vaccination against experimental allergic encephalomyelitis with T cell receptor peptides. Science 246, 668−670 (1989). | PubMed | ISI | ChemPort |
- Weinberg, A.D. et al. The OX-40 antibody selects for autoantigen specific vb8.2+ T cells within the spinal cord of Lewis rats with autoimmune encephalomyelitis. J. Neurosci. Res. (in the press).
- Paterson, P.Y. Multiple sclerosis: An immunologic reassessment. J. Chron. Dis. 26, 119−125 (1981). | Article |
- Oksenberg, J.R. et al. Selection of T-cell receptor V-D-J gene rearrangements with specificity for a MBP peptide in brain lesions of MS. Nature 362, 68−70 (1993). | Article | PubMed | ISI | ChemPort |
- Yednock, T.A. et al. Prevention of experimental autoimmune encephalomyelitis by antibodies against
 4/l integrin. Nature 356, 63 (1992). | Article | PubMed | ChemPort |
- Jameson, B.A., McDonnel, J.M., Marini, J.C. & Korngold, R. A rationally designed CD4 analogue inhibits experimental allergic encephalomyelitis. Nature 368, 744−746 (1994). | Article | PubMed | ISI | ChemPort |
- Vandenbark, A.A., Gill, T. & Offner, H. A myelin basic protein specific T lymphocyte line which mediates EAE. J. Immunol. 135, 223−228 (1985). | PubMed | ISI | ChemPort |
- Matsumoto, Y. & Fujiwara, M. Adoptively transferred EAE in chimeric rats: Identification of transferred cells in the lesions of the CNS. Immunology 65, 23−29 (1988). | PubMed | ISI | ChemPort |
- Ortiz-Ortiz, L., Nakamura, R.M. & Weigle, W.O. T cell requirement for EAE induction in the rat. J. Immunol. 117, 576−578 (1976). | PubMed | ChemPort |
- Bourdette, D.N. et al. Myelin basic protein specific T cells in the CNS and lymph nodes of rats with EAE are different. J. Neurosci. Res. 30, 308−315 (1991). | PubMed | ISI | ChemPort |
- Hintzen, R.Q.de Jong, R., Lens, S.M.A. & van Lier, R.A.W. CD27: Marker and mediator of T-cell activation? Immunol. Today 15, 307−311 (1994). | Article | PubMed | ISI | ChemPort |
- Paterson, D.J. et al. Antigens of activated rat T lymphocytes including a molecule of 50,000 M, detected only on CD4 positive T blasts. Mol. Immunol. 24, 1281−1290 (1987). | Article | PubMed | ISI | ChemPort |
- Latza, U. et al. The human OX40 homologue: cDNA structure, expression and chromosomal assignment of the ACT35 antigen. Eur. J. Immunol. 24, 677−683 (1994). | PubMed | ISI | ChemPort |
- Baum, P.R. et al. Molecular characterization of murine and human OX-40/OX-40 ligand systems: Identification of a human OX-40 ligand as the HTLV-1-regulated protein gp34. EMBO J. 13, 3992−4001 (1994). | PubMed | ISI | ChemPort |
- Godfrey, W.R., Fagnoni, F.F., Harara, M.A., Buck, D. & Engleman, E.E. Identification of a human OX-40 ligand, a costimulator of CD4+ T cells with homology to tumor necrosis factor. J. Exp. Med. 180, 757−762 (1994). | Article | PubMed | ISI | ChemPort |
- Kruisbeek, A.M. Isolation and fractionation of mononuclear cell populations, in Current Protocols in Immunology (eds Coligan, J.E., Kruisbeek, A.M., Margulies, D.H., Shevach, E.M. & Strober, W.) 3.1.3−3.1.5 (Greene Publishing and Wiley-Interscience, New York, 1992).
- Press, O.W., Vitteta, E.S., Farr, A.G., Hansen, J.A. & Martin P.J. Evaluation of ricin A-chain immunotoxins directed against human T cells. Cell. Immunol. 102, 10−20 (1986). | PubMed | ISI | ChemPort |
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