Acute and relapsing experimental autoimmune encephalomyelitis are regulated by differential expression of the CC chemokines macrophage inflammatory protein-1α and monocyte chemotactic protein-1

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Abstract

Experimental autoimmune encephalomyelitis (EAE) is a T lymphocyte-mediated disease of the central nervous system (CNS), characterized by mononuclear cell infiltration and demyelination resulting in paralysis. We examined CC chemokine expression in the CNS throughout the entire course of the disease and found that the production of macrophage inflammatory protein (MIP)-1α correlated with increasing acute disease severity and remained elevated throughout chronic, relapsing disease. In contrast, a substantial level of monocyte chemotactic protein (MCP)-1 expression was not observed until late in acute disease and continued to be evident in the relapsing phase of the disease. MCP-1 expression correlated with increasing severity of clinical relapses. Lower levels of RANTES in the CNS were noted throughout the disease course, but showed little correlation with either acute or relapsing disease. Although RANTES expression was observed during the entire course of disease, anti-RANTES treatment had no effect on clinical disease progression. Anti-MCP-1, but not anti-MIP-1α, treatment during relapsing EAE decreased clinical severity of relapsing disease. Furthermore, anti-MCP-1 treatment reduced CNS macrophage accumulation during relapsing EAE. These results suggest that MIP-1α controls mononuclear cell accumulation during acute EAE, while MCP-1 controls mononuclear cell infiltration during relapsing EAE.

Introduction

EAE is a CD4+ T cell-mediated, inflammatory demyelinating disease of the CNS that serves as a model for the human demyelinating disease, multiple sclerosis (MS). (Arnason, 1983; Wekerle, 1991). EAE can be induced in SJL mice by immunization with proteolipid protein (PLP) or the immunodominant, encephalitogenic peptide sequence 139–151 (PLP139–151) emulsified in complete Freund's adjuvant (Tuohy et al., 1992). Alternatively, EAE can be adoptively transferred to normal recipient mice by antigen-activated PLP139–151-specific T cells (Whitham et al., 1991; Kuchroo et al., 1992). The disease is characterized by a progressive ascending clinical paralysis followed by periods of remission and subsequent relapses in the SJL/J mouse (McRae et al., 1992). Immunohistological analysis of mononuclear cell infiltration in the CNS has revealed that antigen-specific and antigen-nonspecific CD4+ and CD8+ T cells, as well as macrophages, constitute the recruited cell population (Hickey et al., 1983; Cross et al., 1990). The mechanism by which these cells traffic to the CNS and accumulate prior to and during clinical disease is not well-understood although VLA-4 (Yednock et al., 1992) and LFA-1 (Kawai et al., 1996; Willenborg et al., 1996) have been suggested as important adhesion molecules regulating the process.

Chemotactic cytokines (chemokines), such as MIP-1α, MCP-1, IL-8, and RANTES are molecules that induce leukocyte accumulation in tissue sites of inflammation (Oppenheim et al., 1991). Chemokines are potent chemoattractants that can be divided into four highly conserved, but distinct sub-families: C–x–C, C–C, C, and C–x3–C, based on the position of the first two cysteines in the amino terminus, as well as the remaining cysteines in the carboxy portion of the molecule. The C–C family members are primarily chemotactic for monocytes/macrophages, T lymphocytes, basophils and eosinophils (Davatelis et al., 1988; Schall, 1991; Taub et al., 1993). CC chemokine family members have been implicated as candidates in the immunopathology of EAE as T cell production of MIP-1α and TCA-3 was shown to be required for the adoptive transfer of EAE (Kuchroo et al., 1993). Additionally, MIP-1α and MCP-1 production in the CNS has been associated with acute disease symptoms in both rat (Hulkower et al., 1993) and murine EAE models (Ransohoff et al., 1993; Godiska et al., 1995; Hayashi et al., 1995; Karpus et al., 1995). Recently, astrocytes have been shown to express MCP-1 mRNA during relapsing EAE (Glabinski et al., 1997). These examples raise the possibility that chemokine production in the CNS of MS patients functions to drive pathogenesis of the disease through the recruitment of leukocytes into the brain.

In order to examine the regulatory role of chemokines in the pathogenesis of EAE, we studied the production and biological significance of chemokine expression in both acute and relapsing phases of EAE. In the present report, we assessed the production of CC chemokines in the CNS and the biologic roles of MIP-1α, MCP-1, RANTES, and MIP-1β in the pathogenesis of relapsing EAE in order to understand the potential mechanisms of immunopathogenesis in MS and to aid in the development of novel anti-inflammatory therapies.

Section snippets

Animals

Female SJL mice (H-2s) were purchased from Harlan Sprague Dawley (Indianapolis, IN). Mice were 6–7 weeks old at the initiation of the experiment and were maintained on standard laboratory chow and water ad libitum. Animal care was provided in accordance with the Northwestern University and NIH guidelines.

Antigens and antibodies

PLP139–151 (HSLGKWLGHPDKF) was purchased from Peptides International (Louisville, KY). The amino acid composition was verified by mass spectrometry and purity (>98%) was assessed by HPLC.

Chemokine production in the CNS following EAE induction

We previously demonstrated that following EAE induction, increasing MIP-1α concentration in the CNS correlated with increasing acute disease severity and that anti-MIP-1α administration at the time of EAE induction could ameliorate both acute and relapsing clinical EAE (Karpus et al., 1995). We now wanted to examine chemokine production in the CNS over the entire course of acute and relapsing EAE to test the hypothesis that the acute and relapsing phases of EAE were differentially regulated by

Discussion

EAE is a T cell-mediated autoimmune disease model for multiple sclerosis (MS) with the characteristic of CNS-infiltrating monocytes and lymphocytes resulting in a chronic, relapsing paralytic disease course. Regulation of disease pathogenesis includes migration of activated T cells from peripheral lymphoid tissue to the CNS, which presumably occurs in a multi-step fashion. Following activation, T cells leave the peripheral lymphoid tissue by down-regulating expression of CD62L (Springer, 1994).

Acknowledgements

This study was supported in part by USPHS grant NS34510 (WJK) and AI36302 (NWL).

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