Journal of NeuroVirology

, Volume 12, Issue 4, pp 251–261 | Cite as

Anti-CCL2 treatment inhibits Theiler’s murine encephalomyelitis virus-induced demyelinating disease

  • William J. Karpus
  • Kevin J. Kennedy
  • Brian T. Fife
  • Jamie L. Bennett
  • Mauro C. Dal Canto
  • Steven L. Kunkel
  • Nicholas W. Lukacs


Theiler’s murine encephalomyelitis virus induces a demyelinating disease (TMEV-IDD) of the central nervous system (CNS) in susceptible mouse strains with accompanying histopathology characterized by mononuclear cell infiltrates. In susceptible strains of mice such as SJL, virus establishes a persistent infection in macrophages, induces a CNS infiltration by macrophages, T cells, and B cells, which results in chronic-progressive paralysis. In the present report the authors have investigated the functional role of CCL2 (monocyte chemotactic protein-1) in the induction and progression of demyelinating disease. Treatment of infected mice at day 0, 14, or 28 with anti-CCL2 resulted in a significant decrease in the clinical disease progression. Further analysis of anti-CCL2-treated mice revealed decreased CNS inflammation and mononuclear cell infiltration with an accompanying change in inflammatory cytokine responses. There was an overall decrease in the absolute numbers of CNS-infiltrating CD4+ T cells, macrophages, and B cells. Finally, anti-CCL2 treatment resulted in decreased viral load in the CNS. These data directly demonstrate a role for CCL2 in the pathogenesis of TMEV-IDD.


cell trafficking chemokines demyelinating disease multiple sclerosis neuroimmunology Theiler’s virus 



baby hamster kidney cell line 21


bovine serum albumin


monocyte chemotactic protein-1


macrophage inflammatory protein-1α


macrophage inflammatory protein-1β




central nervous system


macrophage inflammatory protein-2


gamma interferon inducible protein-10


hematoxylin and eosin


normal rabbit serum


Theiler’s murine encephalomyelitis virus


Theiler’s murine encephalomyelitis virus—induced demyelinating disease


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  1. Aubert C, Brahic M (1995). Early infection of the central nervous system by the GDVII and DA strains of Theiler’s virus. J Virol 69: 3197–3200.PubMedGoogle Scholar
  2. Begolka WS, Vanderlugt CL, Rahbe SM, Miller SD (1998). Differentiasl expression of inflammatory cytokines paralles progression of central nervous system pathology in two clinically distinct models of multiple sclerosis. J Immunol 16: 4437–4446.Google Scholar
  3. Bennett JL, Elhofy A, Canto MCD, Tani M, Ransohoff RM, Karpus WJ (2003). CCL2 Transgene expression in the central nervous system directs diffuse infiltration of CD4511 b+ monocytes and enhanced Theiler’s murine encephalomyelitis virus-induced demyelinating disease. J NeuroVirol 9: 623–636.PubMedGoogle Scholar
  4. Boring L, Gosling J, Chensue SW, Kunkel SL, Farese RVJ, Broxmeyer He, Charo IF (1997). Impaired monocyte migration and reduced type 1 (Th1) cytokine responses in C-C chemokine receptor 2 kinockout mice. J Clin Invest 100: 2552–2561.CrossRefPubMedGoogle Scholar
  5. Brahic M, Stroop MG, Baringer JR (1981). Theiler’ virus persists in glial cells during demyelinating disease. Cell 26: 123–128.CrossRefPubMedGoogle Scholar
  6. Butcher EC (1991). Leukocyte-endothelial cell recognition: three (or more) steps to specificity and diversity. Cell 67: 1033–1036.CrossRefPubMedGoogle Scholar
  7. Clatch RJ, Lipton HL, Miller SD (1986). Characterization of Theiler’s murine encephalomyelitis virus (TMEV)-specific delayed-type hypersensitivity responses in TMEV-induced demyelinating diseas: correlation with clinical sings. J Immunol 136: 920–927.PubMedGoogle Scholar
  8. Clatch RJ, Miller SD, Metzner R, Dal Canto MC, Lipton HL (1990). Monocytes/macrophages isolated from the mouse central nervous system contain infectious Theiler’s murine encephalomyelitis virus (TMEV). Virology 176: 244–254.CrossRefPubMedGoogle Scholar
  9. Dal Canto Mc, Lipton HL (1975). Primary demyelination in Theiler’s virus infection. An ultrastructural study. Lab Invest 33: 626–637.Google Scholar
  10. Elsner J, Petering H, Hochstetter R, Kimmig D, Wells TNC, Kapp A, Proudfoot AEJ (1997). CC chemokine antagonist Met-RANTES inhibits eosinophil effector functor functions through the chemokine receptors CCR1 and CCR3. Eur J Immunol 27: 2892–2898.CrossRefPubMedGoogle Scholar
  11. Fife BT, Kennedy KJ, Paniagua MC, Lukacs NW, Kunkel SL, Luster AD, Karpus WJ (2001a). CXCL 10 (IFN-gamma-inducible protein-10) control of encephaligtogenic CD4+ T cell accumulation in the central nervous system during experimental autoimmune encephalomyelitis. J Immunol 166: 7617–7624.PubMedGoogle Scholar
  12. Fife BT, Paniagua MC, Lukacs NW, Kunkel SL, Karpus WJ (2001b). selective CC chemokine receptor expression by central nervous system-infiltrating encephalitogenic T cells during experimental autoimmune encephalomyelitis. J Neurosci Res 66: 705–714.CrossRefPubMedGoogle Scholar
  13. Gerety SJ, Karpus WJ, Cubbon AR, Goswami RG, Rundell MK, Peterson JD, Miller SD (1994). Class II-restricted T cell responses in Theiler’s murine encephalomyelitis virus-induced dymyelinating disease. Mapping of a dominant immunopathologic VP2 T cell epitope in susceptible SJL/J mice. J Immunol 152: 908–918.PubMedGoogle Scholar
  14. Gu L, Tseng S, Horner RM, Tam C, Loda M, Rollins BJ (2000). control of TH2 polarization by the chemokine monocyte chemoattractant protein-1. Nature 404: 407–411.CrossRefPubMedGoogle Scholar
  15. Hoffman LM, Fife BT, Begolka WS, Miller SD, Karpus WJ (1999). Central nervous system chemokine expression during Theiler’s virus-induced demyelinating disease. J NeuroVirol. 5: 635–642.CrossRefPubMedGoogle Scholar
  16. Jarousse N, Syan S, Martinat C, Brahic M (1998). The neurovirulence of the DA and GDVII strains of theiler’s virus correlates with their ability To infect cultured neurons. J Virol 72: 7213–7220.PubMedGoogle Scholar
  17. Karpus WJ, Kennedy KJ, Kunkel SL, Lukacs NW (1998). Monocyte chemotactic protein 1 regulates oral tolerance induction by inhibition of T helper cell 1-related cytokines. J Exp Med 187: 733–741.CrossRefPubMedGoogle Scholar
  18. Karpus WJ, Lukacs NW, Kennedy KJ, Smith WS, Hurst SD, Barrett TA (1997). Differential CC chemokine-induced enhancement of T helper cell cytokine production. J Immunol 158: 4129–4136.PubMedGoogle Scholar
  19. Karpus WJ, Lukacs NW, McRae BL, Strieter RM, Kunkel SL, Miller SD (1995). An important role for the chemokine macrophage inflammatory protein-1α in the pathogenesis of the T cell-mediated autoimmune disease, experimental autoimmune encephalomyelitis. J Immunol 155: 5003–5010.PubMedGoogle Scholar
  20. Katz-levy Y, Neville KL, Padilla J, Rahbe S, Begolka WS, Girvin AM, Olson JK, Vanderlugt CL, Miller SD (2000). Temporal development of autoreactive Th 1 responses and endogenous presentation of self myelin epitopes by central nervous system-resident APCs in Theiler’s virus-infected mice. J Immunol 165: 5304–5314.PubMedGoogle Scholar
  21. Keeney M, Chin-Yee I, Weir K, Popma J, Nayar R, Sutherland DR (1998). Single platform flow cytometric absolute CD34 + cell counts based on the ISHAGE guidelines. Cytometry 34: 61–70.CrossRefPubMedGoogle Scholar
  22. Kennedy KJ, Strieter RM, Kunkel SL, Lukacs NW, Karpus WJ (1998). Acute and relapsing experimental autoimmune encephalomyelitis are regulated by differential expression of the CC chemokines macrophage inflammatory protein-1α and monocyte chemotactic protein-1. J Neuroimmunol 92: 98–108.CrossRefPubMedGoogle Scholar
  23. Kuziel WA, Morgan SJ, Dawson TC, Griffin S, Smithies O, Ley K, Maeda N (1997). Severe reduction in leukocyte adhesion and monocyte extravasation in mice deficient in CC chemokine receptor 2. Proc Natl Acad Sci U S A 94: 12053–12058.CrossRefPubMedGoogle Scholar
  24. Levy M, Aubert C, Brahic M (1992). Thelier’s virus replication in brain macrophages cultured in virro. J Virol 66: 3188–3193.PubMedGoogle Scholar
  25. Liang M, Mallari C, Rosser M, Ng HP, May K, Monahan S, Bauman JG, Islam I, Ghannam A, Buckman B, Shaw K, Wei GP, Xu W, Zhao Z, Ho E, Shen J, Oanh H, Subramanyam B, Vergona R, Taub D, Dunning L, Harvey Snider RM, Hesselgesser J, Morrissey MM, Perez HD (2000). Identification and characterization of a potent, selective, and orally active antagonist of the CC chemokine receptor-1. J Biol Chem 275: 19000–19008.CrossRefPubMedGoogle Scholar
  26. Lipton HL (1975). Theiler’s virus ingection in mice: An unusual biphasic disease leading to demyelination. Infect Immun 11: 1147–1155.PubMedGoogle Scholar
  27. Lipton HL, Twaddle G, Jelachivh ML (1995). The predominant virus antigen burden is present in macrophages in Theiler’s murine encephalomyelitis virus-induced demyelinating disease. J Virol 69: 2525–2533.PubMedGoogle Scholar
  28. Lu B, Rutledge BJ, Gu L, Fiorillo J, Lukacs NW, Kunkel SL, North R, Gerard C, Rollins BJ (1998), Abnormalities in monocyte recruitment and cytokine expression in monocyte chemoattractant protein 1-deficient mice. J Exp Med 187: 601–608.CrossRefPubMedGoogle Scholar
  29. Lukacs NW, Strieter RM, Elner VM, Evanoff HL, Burdick M, Kunkel SL (1994). Intercellular adhesion molecule-1 mediates the expression of monocyle-derved MIP-1α during monocyte-endothelial cell interactions. Blood 83: 1174–1178.PubMedGoogle Scholar
  30. Miller SD, Karpus WJ (1994). The immunopathogenesis and regulation of-cell-mediated demyelinating diseases. Immunol Today 15: 356–361.CrossRefPubMedGoogle Scholar
  31. Miller SD, Karpus WJ, Pope JG, Dal Canto MC, Melvold RW (1994) Theiler’s virus-induced demyelinating disease. In Autoimmune disease models, a guidebook. Cobhen IR, Miller A (eds). New York: Academic Press, pp 23–28.Google Scholar
  32. Murphy PM, Baggioline M, Charo IF, Hebert CA, Horuk R, Matsushima K, Miller LH, Oppenheim JJ, Power CA (2000). International union of pharacology, XXII. Nomenclature for chemokine receptors. Pharmacol Rev 52: 145–146.PubMedGoogle Scholar
  33. Murray PD, Krivacic K, Chemosky A, Wei T, Ransohoff RM, Rodriguez M (2000). Biphasic and regionally-restricted chemokine expression in the central nervous system in the Theiler’s virus model of multiple sclerosis. J NeuroVirol 6(Suppl 1): S44-S52.PubMedGoogle Scholar
  34. Neville KL, Padilla J, Miller SD (2002). Myelin-specific tolerance attenuates the progression of a virus-induced demyelinating disease: implications for the treatment of MS. J Neuroimmunol 123: 18–29.CrossRefPubMedGoogle Scholar
  35. Ozden S, Aubert C, Gonzalez-Dunia D, Brahic M (1991). In situ analysis of proteolipid protein gene transcripts during persistent Theiler’s virus infection. J Histochem Cytochem 39: 1305–1309.PubMedGoogle Scholar
  36. Plater-Zyberk C, Hoogewerf AJ, Proudfoot AE, Power CA, Wells TN (1997). Effect of a CC chemokine receptor antagonist on collagen induced arthritis in DBA/1 mice. Immunol Lett 57: 117–120.CrossRefPubMedGoogle Scholar
  37. Ransohoff RM, Bacon KB (2000). Chemokine receptor antagonism as a new therapy for multiple sclerosis. Expert Opin Investig Drugs 9: 1079–1097.CrossRefPubMedGoogle Scholar
  38. Rodriguez M, Leibowitz JL, Lampert PW (1983). Persistent infection of oligodendrocytes in Theiler’s virus-induced encephalomyelitis. Ann Neurol 13: 426–433.CrossRefPubMedGoogle Scholar
  39. Strieter RM, Kunkel SL, Burdick MD, Lincoln DM, Walz A (1992). The detection of a novel neutraphil-activating peptide (ENA-78) using a sensitive ELISA. Immunol Invest 21: 589–596.CrossRefPubMedGoogle Scholar
  40. Theil DJ, Tsunoda I, Libbey JE, Derfuss TJ, Fujinami RS (2000). Alterations in cytokine but not chemokine mRNA expression during three distinct Theiler’s virus infections. J Neuoimmunol 104: 22–30.CrossRefGoogle Scholar
  41. Yamada M, Zurbriggen A, Fujinami RS (1990). The relationship between viral RNA, myelin-specific mRNAs, and demyelination in central nervous system disease during Theiler’s virus infection. Am J Pathol 137: 1467–1479.PubMedGoogle Scholar
  42. Zheng L, Calenoff MA, Del Canto MC (2001). Astrocytes, not microglia, are the main cells responsible for viral persistence in Theiler’s murine encephalomyelitis virus infection leading to demyelination. J Neuroimmunol 118: 256–267.CrossRefPubMedGoogle Scholar

Copyright information

© Journal of NeuroVirology, Inc. 2006

Authors and Affiliations

  • William J. Karpus
    • 1
  • Kevin J. Kennedy
    • 1
  • Brian T. Fife
    • 1
  • Jamie L. Bennett
    • 1
  • Mauro C. Dal Canto
    • 1
  • Steven L. Kunkel
    • 2
  • Nicholas W. Lukacs
    • 2
  1. 1.Department of Pathology, Immunobiology Center, Robert H. Lurie Cancer Center, Institute for NeuroscienceNorthwestern University, Feinberg School of MedicineChicagoUSA
  2. 2.Department of PathologyUniversity of Michigan Medical SchoolAnn ArborUSA

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