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 therapy does not affect the early expression of ho...
Short-term anti-CD154 therapy does not affect the early expression of homing receptors on OVA323-339–specific transgenic T cells in the draining lymph node. Five million DO11.10 transgenic OVA323-339–specific T cells were transferred to naive BALB/c recipients, and the recipients were immunized with 500 μg of OVA323-339/CFA and treated with either control Ig or anti-CD154 as described in Methods. Three days after immunization, lymph node cells were obtained and flow cytometric analysis of homing receptors evaluated ex vivo on KJ1-26 cells. Antigens critical for T cell entry into the CNS (CD44 and CD49d; a and b) and into the lymph node (CD62L; c), and IL-12–dependent homing receptors (E- and P-selectin ligands; d and e), were evaluated. Control antibody staining is indicated by the dashed line, staining in control Ig–treated mice by the black line, and staining in anti-CD154–treated mice by the gray line. Data are representative of three separate experiments.