Mechanisms of immunotherapeutic intervention by anti-CD40L (CD154) antibody in an animal model of multiple sclerosis
Laurence M. Howard, … , Randolph J. Noelle, Stephen D. Miller
Laurence M. Howard, … , Randolph J. Noelle, Stephen D. Miller
Published January 15, 1999
Citation Information: J Clin Invest. 1999;103(2):281-290. https://doi.org/10.1172/JCI5388.
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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-γ 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

Laurence M. Howard, Amy J. Miga, Carol L. Vanderlugt, Mauro C. Dal Canto, Jon D. Laman, Randolph J. Noelle, Stephen D. Miller

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Figure 3

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Anti-CD154 treatment inhibits DTH responses to both the initiating and r...
Anti-CD154 treatment inhibits DTH responses to both the initiating and relapse-associated myelin epitopes. DTH responses to both the initiating PLP139-151 peptide and to the relapse-associated PLP178-191 peptide were evaluated in mice treated with either control Ig or anti-CD154 at the time of priming (a) or at the peak of acute disease (b). Data represent mean ± SD of the change in ear thickness 24 h after ear challenge with 10 μg of peptide. The numbers of mice in each group are shown below each bar. Data are representative of two experiments with similar results. DTH responses significantly less than those of control Ig-treated mice: *P < 0.05; **P < 0.01). Results shown above each bar show statistical comparisons to background ear-swelling levels, i.e., levels in naive mice challenged with each peptide. DTH, delayed-type hypersensitivity.