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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

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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 4

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Myelin epitope-specific in vitro proliferative responses of spleen and l...
Myelin epitope-specific in vitro proliferative responses of spleen and lymph node cells from mice treated with anti-CD154 during disease induction or at the peak of acute disease. Splenic and lymph node lymphocytes from three mice each treated with control Ig or anti-CD154 either at the time of priming were harvested at day 10 after immunization (a and b) or at the peak of acute disease were harvested at day 25 after immunization (c and d). A total of 5 × 105 viable cells per well were cultured with varying concentrations of PLP139-151 or PLP178-191 for 4 days. Cultures were pulsed with 3H-TdR 18–24 h before harvest. Data are presented as ΔCPM (3H-TdR incorporation in cultures containing peptide antigen – 3H-TdR incorporation in cultures containing medium). Data shown are representative of two experiments. Mean ± SD of viable lymphocytes recovered from each treatment group (minimum of three mice each from three separate experiments) is shown in the legend (*P < 0.05). Stimulation indices (S.I.) are shown for each treatment group at the concentration of peptide that stimulated optimal proliferation. An S.I. ≥3 is considered significant.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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Referenced in 8 patents
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