title: Dynamics of production of MIP-1alpha, MCP-1 and MIP-2 and potential role of neutralization of these chemokines in the regulation of immune responses during experimental autoimmune neuritis in Lewis rats.
abstract: Experimental autoimmune neuritis (EAN) is an inflammatory autoimmune demyelinating disease of the peripheral nervous system (PNS) and represents an animal model of Guillain-Barré syndrome (GBS), which is a major inflammatory demyelinating disease of the PNS in humans. In the present study, the dynamics of the expression of the chemokines macrophage inflammatory protein-1alpha (MIP-1alpha), MIP-2 and monocyte chemotactic protein-1 (MCP-1) were determined in the sciatic nerves of EAN rats. Additionally, the effect of neutralizing antibodies against MIP-1alpha, MIP-2 and MCP-1 on the clinical course of EAN and the chemokine expression was investigated. The maximum of MIP-1alpha positive cells in the sciatic nerves was seen on day 14 post immunization (p.i.) correlating with the development of severe clinical signs. Administration of an anti-MIP-1alpha antibody suppressed the clinical signs of EAN and inhibited inflammation and demyelination in the sciatic nerve. Peak numbers of MCP-1 positive cells in the sciatic nerves were detected on day 7 p.i. Administration of an anti-MCP-1 antibody caused a delay of onset of EAN. However, 4 of the 6 EAN rats receiving the anti-MCP-antibody showed the same degree of inflammatory cell infiltration and demyelination in the sciatic nerves as sham-treated EAN rats, whereas only 2 EAN rats had less inflammation and demyelination. The numbers of MIP-2 positive cells reached a maximum on day 21 p.i. Anti-MIP-2 antibody failed to suppress the clinical signs of EAN and the inflammation and demyelination in the sciatic nerves. Only administration of the anti-MIP-1alpha antibody resulted in a significant reduction in the number of chemokine (MIP-1alpha)-positive cells and ED1-positive macrophages in the sciatic nerves. The present results demonstrate that MIP-1alpha and MCP-1 may play a role in the immunopathogenesis of EAN, and that MIP-1alpha induced trafficking of inflammatory cells can be inhibited by immunoneutralization. Further elucidation of the regulation and coordination of MIP-1alpha and MCP-1 production may lead to new therapeutic approaches to GBS in humans.
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institute, Huddinge University Hospital (Novum KFC 4TR), Stockholm, Sweden.
authors.forename: L P
authors.initials: LP
authors.lastname: Zou
authors.forename: S H
authors.initials: SH
authors.lastname: Pelidou
authors.forename: N
authors.initials: N
authors.lastname: Abbas
authors.forename: G
authors.initials: G
authors.lastname: Deretzi
authors.forename: E
authors.initials: E
authors.lastname: Mix
authors.forename: M
authors.initials: M
authors.lastname: Schaltzbeerg
authors.forename: B
authors.initials: B
authors.lastname: Winblad
authors.forename: J
authors.initials: J
authors.lastname: Zhu
mesh_terms: D000818:Animals; D000906:Antibodies; D018932:Chemokine CCL2 / Q000096:biosynthesis* / Q000276:immunology; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D054426:Chemokine CXCL2; D018450:Disease Progression; D005620:Freund's Adjuvant; D007114:Immunization; D019402:Macrophage Inflammatory Proteins / Q000096:biosynthesis* / Q000276:immunology; D008264:Macrophages / Q000737:chemistry / Q000276:immunology; D008297:Male; D015846:Monokines / Q000096:biosynthesis* / Q000276:immunology; D009444:Neuritis, Autoimmune, Experimental / Q000276:immunology* / Q000473:pathology; D009500:Neutralization Tests; D011129:Polyradiculoneuropathy / Q000276:immunology; D051381:Rats; D011917:Rats, Inbred Lew; D012584:Sciatic Nerve / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D000906:Antibodies; D018932:Chemokine CCL2; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D054426:Chemokine CXCL2; D019402:Macrophage Inflammatory Proteins; D015846:Monokines; D005620:Freund's Adjuvant