Normal Th1 development following long-term therapeutic blockade of CD154-CD40 in experimental autoimmune encephalomyelitis
Laurence M. Howard, … , Mauro C. Dal Canto, Stephen D. Miller
Laurence M. Howard, … , Mauro C. Dal Canto, Stephen D. Miller
Published January 15, 2002
Citation Information: J Clin Invest. 2002;109(2):233-241. https://doi.org/10.1172/JCI14374.
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Article

Normal Th1 development following long-term therapeutic blockade of CD154-CD40 in experimental autoimmune encephalomyelitis

Abstract

Experimental autoimmune encephalomyelitis (EAE) is a Th1-mediated demyelinating disease of the CNS with similarities to multiple sclerosis. We and others have shown that a short-term course of anti-CD154 mAb treatment to block CD154-CD40 interactions can be used to prevent or even treat ongoing PLP139-151–induced relapsing EAE. However, little is known of the long-term effects of CD154 blockade on the development of antigen-specific T cell function. Here, we show that short-term treatment with anti-CD154 at the time of PLP139-151/CFA immunization inhibits clinical disease for up to 100 days after immunization. At this point, comparable numbers of Th1 cells are observed in anti-CD154 and control Ig–treated mice, as assessed by antigen-specific ELISPOT assays. Thus, the long-term Th1/Th2 balance is largely unaffected. Inflammatory responses are diminished in anti-CD154–treated mice, as indicated by reduced in vivo delayed-type hypersensitivity and reduced levels of splenic IFN-γ secretion in vitro. However, upon adoptive transfer of T cells isolated from the spleens of anti-CD154–treated mice, these cells contributed as effectively to clinical disease as those obtained from control-treated mice. Thus, anti-CD154 therapy leads to long-term therapeutic efficacy without exerting a long-term influence on Th1 development.

Authors

Laurence M. Howard, Serge Ostrovidov, Cassandra E. Smith, Mauro C. Dal Canto, Stephen D. Miller

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Short-term anti-CD154 mAb therapy causes long-term inhibition of EAE ind...
Short-term anti-CD154 mAb therapy causes long-term inhibition of EAE induction. (a) The indicated numbers of SJL mice were immunized with PLP139-151/CFA on day 0 and treated with 200 μg of either hamster IgG or anti-CD154 antibody (MR-1). Data represent combined results obtained from two separate experiments. *Disease incidence was significantly less (P < 0.0001) in anti-CD154–treated mice. (b and c) Mice immunized and treated with control Ig (b) or anti-CD154 (c) were sacrificed 105 days after immunization and sections were taken from lumbar and thoracic spinal cord sections, as described in Table 1. Sections demonstrate the continued normal appearance of spinal cord from anti-CD154–treated versus extensive immune cell infiltration, demyelination, and scarring observed in control Ig–treated mice.