Mechanisms of immunotherapeutic intervention by anti-CD40L (CD154) antibody in an animal model of multiple sclerosis.

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.

• Authors: L M Howard, A J Miga, C L Vanderlugt, M C Dal Canto, J D Laman, R J Noelle, S D Miller
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 103 Issue 2 Pg. 281-90 (Jan 1999) ISSN: 0021-9738 [Print] United States
• PMID: 9916140 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antibodies
• Interleukins
• Membrane Glycoproteins
• Myelin Proteolipid Protein
• Peptide Fragments
• myelin proteolipid protein (139-151)
• CD40 Ligand
• myelin proteolipid protein (178-191)
• Interferon-gamma

Topics

• Animals
• Antibodies (therapeutic use)
• CD4-Positive T-Lymphocytes (immunology)
• CD40 Ligand
• Cell Differentiation (immunology)
• Cell Division (immunology)
• Central Nervous System (immunology, pathology)
• Disease Models, Animal
• Encephalomyelitis, Autoimmune, Experimental (immunology)
• Female
• Hypersensitivity, Delayed (immunology)
• Immunotherapy (methods)
• Inflammation (immunology)
• Interferon-gamma (immunology)
• Interleukins (immunology)
• Membrane Glycoproteins (immunology)
• Mice
• Mice, Inbred Strains
• Multiple Sclerosis (immunology)
• Myelin Proteolipid Protein (immunology)
• Myelin Sheath (immunology)
• Peptide Fragments (immunology)
• Th1 Cells (immunology)