Title
Mechanisms of immunotherapeutic intervention by anti-CD40L (CD154) antibody in an animal model of multiple sclerosis
Author
TNO Preventie en Gezondheid
Howard, L.M.
Miga, A.J.
Vanderlugt, C.L.
Dal Canto, M.C.
Laman, J.D.
Noelle, R.J.
Miller, S.D.
Publication year
1999
Abstract
Relapsing experimental autoimmune encephalomyelitis (R-EAE) in the SJL mouse is a Th1-mediated autoimmune demyelinating disease model for human multiple sclerosis and is characterized by infiltration of the central nervous system (CNS) by Th1 cells and macrophages. Disease relapses are mediated by T cells specific for endogenous myelin epitopes released during acute disease, reflecting a critical role for epitope spreading in the perpetuation of chronic central CNS pathology. We asked whether blockade of the CD40-CD154 (CD40L) costimulatory pathway could suppress relapses in mice with established R-EAE. Anti-CD154 antibody treatment at either the peak of acute disease or during remission effectively blocked clinical disease progression and CNS inflammation. This treatment blocked Th1 differentiation and effector function rather than expansion of myelin-specific T cells. Although T-cell proliferation and production of interleukin (IL)-2, IL-4, IL- 5, and IL-10 were normal, antibody treatment severely inhibited interferon- gamma production, myelin peptide-specific delayed-type hypersensitivity responses, and induction of encephalitogenic effector cells. Anti-CD154 antibody treatment also impaired the expression of clinical disease in adoptive recipients of encephalitogenic T cells, suggesting that CD40-CD154 interactions may be involved in directing the CNS migration of these cells and/or in their effector ability to activate CNS macrophages/microglia. Thus, blockade of CD154-CD40 interactions is a promising immunotherapeutic strategy for treatment of ongoing T cell-mediated autoimmune diseases. Chemicals/CAS: Antibodies; CD40 Ligand, 147205-72-9; Interferon Type II, 82115-62-6; Interleukins; Membrane Glycoproteins; Myelin Proteolipid Protein; Peptide Fragments; proteolipid protein 139-151; proteolipid protein 178-191, 172228-98-7
Subject
Animals
Antibodies
CD4-Positive T-Lymphocytes
CD40 Ligand
Cell Differentiation
Cell Division
Central Nervous System
Disease Models, Animal
Encephalomyelitis, Autoimmune, Experimental
Female
Hypersensitivity, Delayed
Immunotherapy
Inflammation
Interferon Type II
Interleukins
Membrane Glycoproteins
Mice
Mice, Inbred Strains
Multiple Sclerosis
Myelin Proteolipid Protein
Myelin Sheath
Peptide Fragments
Th1 Cells
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TNO identifier
234892
ISSN
0021-9738
Source
Journal of Clinical Investigation, 103 (103), 281-290
Document type
article