Blocking OX-40/OX-40 ligand interaction in vitro and in vivo leads to decreased T cell function and amelioration of experimental allergic encephalomyelitis

Andrew D. Weinberg, Keith W. Wegmann, Castle Funatake, Ruth Whitham

Research output: Contribution to journalArticle

210 Citations (Scopus)

Abstract

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 H. 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.

Original languageEnglish (US)
Pages (from-to)1818-1826
Number of pages9
JournalJournal of Immunology
Volume162
Issue number3
StatePublished - Feb 1 1999

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Autoimmune Experimental Encephalomyelitis
Ligands
T-Lymphocytes
Neurologic Mutant Mice
Central Nervous System
Cell Proliferation
Tumor Necrosis Factor Receptors
Microglia
Acute Disease
Myelin Sheath
In Vitro Techniques
Autoimmune Diseases
Macrophages
Cell Line
Brain
Population

ASJC Scopus subject areas

  • Immunology

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Blocking OX-40/OX-40 ligand interaction in vitro and in vivo leads to decreased T cell function and amelioration of experimental allergic encephalomyelitis. / Weinberg, Andrew D.; Wegmann, Keith W.; Funatake, Castle; Whitham, Ruth.

In: Journal of Immunology, Vol. 162, No. 3, 01.02.1999, p. 1818-1826.

Research output: Contribution to journalArticle

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abstract = "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 H. 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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