Dynamics of production of MIP-1 alpha, MCP-1 and MIP-2 and potential role of neutralization of these chemokines in the regulation of immune responsesduring experimental autoimmune neuritis in Lewis rats

Experimental autoimmune neuritis (EAN) is an inflammatory autoimmune demyel inating disease of the peripheral nervous system (PNS) and represents an an imal model of Guillain-Barre syndrome (GBS), which is a major inflammatory demyelinating disease of the PNS in humans. In the present study, the dynam ics of the expression of the chemokines macrophage inflammatory protein-1 a lpha (MIP-1 alpha), MIP-2 and monocyte chemotactic protein-1 (MCP-1) were d etermined in the sciatic nerves of EAN rats. Additionally, the effect of ne utralizing antibodies against MIP-1 alpha, MIP-2 and MCP-1 on the clinical course of EAN and the chemokine expression was investigated. The maximum of MIP-1 alpha positive cells in the sciatic nerves was seen on day 14 post i mmunization (pi.) correlating with the development of severe clinical signs . Administration of an anti-MIP-1 alpha antibody suppressed the clinical si gns of EAN and inhibited inflammation and demyelination in the sciatic nerv e. 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 o nset of EAN. However, 4 of the 6 EAN rats receiving the anti-MCP-1 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 ha d 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 sciati c nerves. Only administration of the anti-MLP-1 alpha antibody resulted in a significant reduction in the number of chemokine (MIP-1 alpha)-positive c ells and ED1-positive macrophages in the sciatic nerves. The present result s demonstrate that MIP-1 alpha and MCP-1 may play a role in the immunopatho genesis of EAN, and that MIP-1 alpha induced trafficking of inflammatory ce lls can be inhibited by immunoneutralization. Further elucidation of the re gulation and coordination of MIP-1 alpha and MCP-1 production may lead to n ew therapeutic approaches to GBS in humans. (C) 1999 Elsevier Science B.V. All rights reserved.