Costimulatory molecule CD40 is essential for myelin protein 0 peptide 106-125-induced experimental autoimmune neuritis in mice.
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.
From the Department of Neuropathology, University Hospital of Cologne (AB, MM, LS, ZF, AS, MC, MM-R, MD); Institute for Medical Microbiology, Immunology, and Hygiene, Medical Center, University of Cologne (OU); and Center for Molecular Medicine (OU), Cologne, Germany.
Anna
A
Brunn
Olaf
O
Utermöhlen
Mirna
M
Mihelcic
Lisa
L
Saupe
Zeno
Z
Fiocco
Annika
A
Schmidt
Mariana
M
Carstov
Manuel
M
Montesinos-Rongen
Martina
M
Deckert
D000595:Amino Acid Sequence; D000818:Animals; D001369:Axons / Q000276:immunology / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D019013:CD40 Antigens / Q000172:deficiency* / Q000276:immunology / Q000502:physiology*; D018836:Inflammation Mediators / Q000633:toxicity; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D018993:Myelin P0 Protein / Q000633:toxicity*; D009444:Neuritis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D010455:Peptides / Q000633:toxicity*
D019013:CD40 Antigens; D018836:Inflammation Mediators; C560546:Mpz protein, mouse; D018993:Myelin P0 Protein; D010455:Peptides; C511599:peptide 106