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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Article

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 6

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Anti-CD154 treatment of donor mice diminishes the capacity of PLP139-151...
Anti-CD154 treatment of donor mice diminishes the capacity of PLP139-151–primed T cells to transfer R-EAE. Female SJL/J mice were primed with PLP139-151/CFA. These donor mice treated with either 250 μg of control Ig (open squares) or anti-CD154 (closed squares) on days 0, 2, 4, and 6. Draining lymph nodes were harvested on day 8 and cultured with 70 μg/ml PLP139-151 in vitro. After 4 days in culture, naive female SJL/J recipient mice were injected intravenously with 107 (a), 5 × 106 (b), or 2.5 × 106 (c) viable cells. In b, some mice received cells from anti-CD154–treated donors that were also treated with 25 μg/ml of anti-CD154 in vitro (open triangles). In addition, some mice received cells from anti-CD154–treated donors that were exposed to anti-CD154 during the in vitro activation culture and transferred into anti-CD154 treated recipients (closed triangles). Recipients treated with anti-CD154 were injected with 250 μg intraperitoneally three times a week. Mice were examined for disease severity and scored as described in Methods.