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Multiple Sclerosis, Vol. 10, No. 6, 651-659 (2004)
DOI: 10.1191/1352458504ms1096oa

Pituitary adenylate cyclase-activating polypeptide (PACAP) ameliorates experimental autoimmune encephalomyelitis by suppressing the functions of antigen presenting cells

Hideki Kato

Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusaku, Nagoya 464-8601, Japan

Atsushi Ito

Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusaku, Nagoya 464-8601, Japan

Jun Kawanokuchi

Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusaku, Nagoya 464-8601, Japan

Shijie Jin

Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusaku, Nagoya 464-8601, Japan

Tetsuya Mizuno

Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusaku, Nagoya 464-8601, Japan

Kosei Ojika

Department of Neurology, Medical School, Nagoya City University, Mizuho-ku, Nagoya 467-8601, Japan

Ryuzou Ueda

Second Department of Internal Medicine, Medical School, Nagoya City University, Mizuho-ku, Nagoya 467-8601, Japan

Akio Suzumura

Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusaku, Nagoya 464-8601, Japan, suzumura{at}riem.nagoya-u.ac.jp

Pituitary adenylate cyclase-activating polypeptide (PACAP), a 38-amino acid neuropeptide belonging to the secretin-glucagon-vasoactive intestinal peptide (VIP) family, performs a variety of functions in both the nervous and immune systems. In this study, we examined the effects of PACAP on experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice. When administrated intraperitoneally every other day after immunization with myelin oligodendrocyte glycoprotein (MOG) peptide 35 -55, PACAP ameliorated both the clinical and pathological manifestations of EAE. Ex vivo examination revealed a significant inhibition of MOG35 55-specific Th1 response in mice treated with PACAP.In vitro analysis revealed that PACAP suppressed the production of inflammatory cytokines, including TNF-a, IL-1b, and IL-12, and expression of the costimulatory factor B7-2 on macrophage and microglia, which may function as antigen presenting cells (APC) in the CNS. While PACAP suppressed the differentiation of MOG35 55-specific T cells into Th1 effectors upon restimulation with MOG35 55-expressing APC, it did not affect interferon (IFN)-g production by MOG35 55-specific T cells stimulated with anti-CD3 and anti-CD28. These observations suggested that PACAP suppressed induction of EAE primarily via suppression of APC function and inflammatory cytokine production. PACAP may be useful in the future treatment of Th1-mediated autoimmune diseases, such as multiple sclerosis.

Key Words: antigen presenting cell • experimental autoimmune encephalomyelitis • microglia • multiple sclerosis • PACAP


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