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Journal of Neuropathology & Experimental Neurology:
doi: 10.1097/NEN.0000000000000069
Original Articles

Costimulatory Molecule CD40 Is Essential for Myelin Protein 0 Peptide 106–125–Induced Experimental Autoimmune Neuritis in Mice

Brunn, Anna MD; Utermöhlen, Olaf MD; Mihelcic, Mirna; Saupe, Lisa; Fiocco, Zeno; Schmidt, Annika; Carstov, Mariana; Montesinos-Rongen, Manuel PhD; Deckert, Martina MD

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Abstract

Myelin protein 0 peptide 106–125–induced murine experimental autoimmune neuritis (EAN) is a CD4-positive T cell–mediated monophasic axonal inflammatory neuropathy; interferon-γ is the key proinflammatory mediator. Experimental autoimmune neuritis is well suited for elucidating pathogenetic mechanisms underlying human acute axonal Guillain-Barré syndrome. Here, the functional role of the costimulatory molecule CD40 was defined by characterization of EAN in CD40-deficient mice. In contrast to immunized C57BL/6 mice, CD40-deficient mice were resistant to EAN owing to impaired priming of CD4-positive T-effector cells. To determine whether CD40 is a suitable candidate for the treatment of EAN, we administered monoclonal anti-CD40 antibody either before immunization or upon onset of neurologic signs. Prophylactic anti-CD40 treatment completely abolished CD4-positive T-cell priming. Therapeutic application of anti-CD40 prevented full activation of CD4-positive T cells that were in the process of priming and suppressed production of interferon-γ in peripheral lymph nodes, spleen, and serum, and of interleukin-6, interleukin-12p40, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1, which are associated with activation of the nuclear factor-κB signaling pathway. This resulted in enhanced recovery by early generation of CD25-positive, Foxp3-positive, CD4-positive regulatory T cells. Thus, these experiments highlight the crucial role of CD40 as an important costimulatory molecule in EAN and suggest that it has potential as a therapeutic target in human neuritis.

Copyright © 2014 by the American Association of Neuropathologists, Inc.

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