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Earle A. Chiles Research Institute, Robert W. Franz Cancer Research Center, Providence Portland Medical Center, Portland, OR 97213;
Department of Neuroimmunology, Veterans Affairs Medical Center, Portland, OR 97201; and
Department of Neurology, Oregon Health Sciences University, Portland, OR 97201
The OX-40R is a member of the TNF receptor family and is expressed primarily on activated CD4+ T cells. When the OX-40R is engaged by the OX-40 ligand (OX-40L), a potent costimulatory signal occurs. We have identified a population of CD11b+ cells, isolated from the central nervous system (CNS) of mice with actively induced experimental allergic encephalomyelitis (EAE), that expresses OX-40L. Moreover, the expression of OX-40L was found to be associated with paralytic episodes of EAE and was reduced or absent at disease recovery. These CD11b+ cells also coexpressed B7 and MHC class II. Therefore, to address the relative contributions of OX-40R/OX-40L and CD28/B7 to the costimulation of myelin-specific T cells, blocking studies were performed using soluble OX-40R and/or soluble CTLA-4. CD11b+ cells isolated from the CNS of mice with actively induced EAE were able to present Ag to proteolipid protein 139–151-specific T cell lines in vitro. The addition of soluble OX-40R:Ig to CD11b+ brain microglia/macrophages inhibited T cell proliferation by 50–70%. The addition of CTLA-4:Ig inhibited T cell proliferation by 20–30%, and the combination inhibited T cell proliferation by 95%. In vivo administration of soluble OX-40R at the onset of actively induced or adoptively transferred EAE reduced ongoing signs of disease, and the mice recovered more quickly from acute disease. The data imply that OX-40L, expressed by CNS-derived APC, acts to provide an important costimulatory signal to EAE effector T cells found within the inflammatory lesions. Furthermore, the data suggest that agents designed to inhibit the OX-40L/OX-40R complex may be useful for treating autoimmune disease.
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L. Taylor, M. Bachler, I. Duncan, S. Keen, R. Fallon, C. Mair, T. T. McDonald, and H. Schwarz In vitro and in vivo activities of OX40 (CD134)-IgG fusion protein isoforms with different levels of immune-effector functions J. Leukoc. Biol., September 1, 2002; 72(3): 522 - 529. [Abstract] [Full Text] [PDF]
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T. De Smedt, J. Smith, P. Baum, W. Fanslow, E. Butz, and C. Maliszewski Ox40 Costimulation Enhances the Development of T Cell Responses Induced by Dendritic Cells In Vivo J. Immunol., January 15, 2002; 168(2): 661 - 670. [Abstract] [Full Text] [PDF]
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D. E. Evans, R. A. Prell, C. J. Thalhofer, A. A. Hurwitz, and A. D. Weinberg Engagement of OX40 Enhances Antigen-Specific CD4+ T Cell Mobilization/Memory Development and Humoral Immunity: Comparison of {alpha}OX-40 with {alpha}CTLA-4 J. Immunol., December 15, 2001; 167(12): 6804 - 6811. [Abstract] [Full Text] [PDF]
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L. C. Ndhlovu, N. Ishii, K. Murata, T. Sato, and K. Sugamura Critical Involvement of OX40 Ligand Signals in the T Cell Priming Events During Experimental Autoimmune Encephalomyelitis J. Immunol., September 1, 2001; 167(5): 2991 - 2999. [Abstract] [Full Text] [PDF]
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E. Baba, Y. Takahashi, J. Lichtenfeld, R. Tanaka, A. Yoshida, K. Sugamura, N. Yamamoto, and Y. Tanaka Functional CD4 T Cells after Intercellular Molecular Transfer of OX40 Ligand J. Immunol., July 15, 2001; 167(2): 875 - 883. [Abstract] [Full Text] [PDF]
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V. Malmstrom, D. Shipton, B. Singh, A. Al-Shamkhani, M. J. Puklavec, A. N. Barclay, and F. Powrie CD134L Expression on Dendritic Cells in the Mesenteric Lymph Nodes Drives Colitis in T Cell-Restored SCID Mice J. Immunol., June 1, 2001; 166(11): 6972 - 6981. [Abstract] [Full Text] [PDF]
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C. Nohara, H. Akiba, A. Nakajima, A. Inoue, C.-S. Koh, H. Ohshima, H. Yagita, Y. Mizuno, and K. Okumura Amelioration of Experimental Autoimmune Encephalomyelitis with Anti-OX40 Ligand Monoclonal Antibody: A Critical Role for OX40 Ligand in Migration, But Not Development, of Pathogenic T Cells J. Immunol., February 1, 2001; 166(3): 2108 - 2115. [Abstract] [Full Text] [PDF]
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D. J. Cua, B. Hutchins, D. M. LaFace, S. A. Stohlman, and R. L. Coffman Central Nervous System Expression of IL-10 Inhibits Autoimmune Encephalomyelitis J. Immunol., January 1, 2001; 166(1): 602 - 608. [Abstract] [Full Text] [PDF]
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J. Kjærgaard, J. Tanaka, J. A. Kim, K. Rothchild, A. Weinberg, and S. Shu Therapeutic Efficacy of OX-40 Receptor Antibody Depends on Tumor Immunogenicity and Anatomic Site of Tumor Growth Cancer Res., October 1, 2000; 60(19): 5514 - 5521. [Abstract] [Full Text]
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I. Gramaglia, A. Jember, S. D. Pippig, A. D. Weinberg, N. Killeen, and M. Croft The OX40 Costimulatory Receptor Determines the Development of CD4 Memory by Regulating Primary Clonal Expansion J. Immunol., September 15, 2000; 165(6): 3043 - 3050. [Abstract] [Full Text] [PDF]
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N. Tsukada, H. Akiba, T. Kobata, Y. Aizawa, H. Yagita, and K. Okumura Blockade of CD134 (OX40)-CD134L interaction ameliorates lethal acute graft-versus-host disease in a murine model of allogeneic bone marrow transplantation Blood, April 1, 2000; 95(7): 2434 - 2439. [Abstract] [Full Text] [PDF]
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A. D. Weinberg, M.-M. Rivera, R. Prell, A. Morris, T. Ramstad, J. T. Vetto, W. J. Urba, G. Alvord, C. Bunce, and J. Shields Engagement of the OX-40 Receptor In Vivo Enhances Antitumor Immunity J. Immunol., February 15, 2000; 164(4): 2160 - 2169. [Abstract] [Full Text] [PDF]
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H. Akiba, Y. Miyahira, M. Atsuta, K. Takeda, C. Nohara, T. Futagawa, H. Matsuda, T. Aoki, H. Yagita, and K. Okumura Critical Contribution of Ox40 Ligand to T Helper Cell Type 2 Differentiation in Experimental Leishmaniasis J. Exp. Med., January 17, 2000; 191(2): 375 - 380. [Abstract] [Full Text] [PDF]
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K. Murata, N. Ishii, H. Takano, S. Miura, L. C. Ndhlovu, M. Nose, T. Noda, and K. Sugamura Impairment of Antigen-Presenting Cell Function in Mice Lacking Expression of Ox40 Ligand J. Exp. Med., January 17, 2000; 191(2): 365 - 374. [Abstract] [Full Text] [PDF]
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P. Lane Role of Ox40 Signals in Coordinating Cd4 T Cell Selection, Migration, and Cytokine Differentiation in T Helper (Th)1 and Th2 Cells J. Exp. Med., January 17, 2000; 191(2): 201 - 206. [Full Text] [PDF]
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S. D. Pippig, C. Pena-Rossi, J. Long, W. R. Godfrey, D. J. Fowell, S. L. Reiner, M. L. Birkeland, R. M. Locksley, A. N. Barclay, and N. Killeen Robust B Cell Immunity but Impaired T Cell Proliferation in the Absence of CD134 (OX40) J. Immunol., December 15, 1999; 163(12): 6520 - 6529. [Abstract] [Full Text] [PDF]
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