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Model of Multiple Sclerosis and Reduced Neurologic Disease in A Antibody Targeting of the CC Chemokine Ligand 5 Results in Diminished Leukocyte Infiltration into the Central Nervous System and Reduced Neurologic Disease in a Viral This information is current as Model of Multiple Sclerosis of September 25, 2021. William G. Glass, Michelle J. Hickey, Jenny L. Hardison, Michael T. Liu, Jerry E. Manning and Thomas E. Lane J Immunol 2004; 172:4018-4025; ; doi: 10.4049/jimmunol.172.7.4018 Downloaded from http://www.jimmunol.org/content/172/7/4018 References This article cites 52 articles, 22 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/172/7/4018.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 25, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2004 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Antibody Targeting of the CC Chemokine Ligand 5 Results in Diminished Leukocyte Infiltration into the Central Nervous System and Reduced Neurologic Disease in a Viral Model of Multiple Sclerosis1 William G. Glass,2,3† Michelle J. Hickey,3† Jenny L. Hardison,† Michael T. Liu,† Jerry E. Manning,*† and Thomas E. Lane4*† Intracerebral infection of mice with mouse hepatitis virus, a member of the Coronaviridae family, reproducibly results in an acute encephalomyelitis that progresses to a chronic demyelinating disease. The ensuing neuropathology during the chronic stage of disease is primarily immune mediated and similar to that of the human demyelinating disease multiple sclerosis. Secretion of Downloaded from chemokines within the CNS signals the infiltration of leukocytes, which results in destruction of white matter and neurological impairment. The CC chemokine ligand (CCL)5 is localized in white matter tracts undergoing demyelination, suggesting that this chemokine participates in the pathogenesis of disease by attracting inflammatory cells into the CNS. In this study, we administer a mAb directed against CCL5 to mice with established mouse hepatitis virus-induced demyelination and impaired motor skills. Anti-CCL5 treatment decreased T cell accumulation within the CNS based, in part, on viral Ag specificity, indicating the ability to differentially target select populations of T cells. In addition, administration of anti-CCL5 improved neurological function and http://www.jimmunol.org/ significantly (p < 0.005) reduced the severity of demyelination and macrophage accumulation within the CNS. These results demonstrate that the severity of CNS disease can be reduced through the use of a neutralizing mAb directed against CCL5 in a viral model of demyelination. The Journal of Immunology, 2004, 172: 4018–4025. ultiple sclerosis (MS)5 is a human neuroinflammatory 6). Numerous chemokines have been detected within the CNS of disease that is characterized by demyelinated axons MS patients as well as within active plaque lesions, suggesting that M and often associated with chronic inflammation of the these molecules contribute to demyelination by attracting targeted CNS (1–3). Although the immunopathology of MS lesions is com- populations of leukocytes into the CNS (7–9). One chemotactic plex and varied, trafficking and accumulation of immune cells factor considered important to leukocyte trafficking is the CC che- by guest on September 25, 2021 within the CNS are thought to play an important role in the estab- mokine ligand (CCL)5, which has been shown to be expressed lishment and progression of disease (1, 4). In many instances, the within the CNS of MS patients (7, 9). For example, samples of pathology associated with MS is thought to be mediated by the cerebral spinal fluid isolated from MS patients undergoing clinical presence of T cells and activated macrophages, all of which are relapse contain significantly higher levels of CCL5 compared with presumably responding to chemotactic signals derived within the control populations (9). CCL5 transcripts are also expressed in CNS (4). Although the mechanisms regulating leukocyte entry into lesions of active demyelination in samples of postmortem brain the CNS are not well understood, emerging evidence points to an tissue from MS patients, and peripheral T cells isolated from MS important role for chemokines in participating in this process (5, patients exhibited enhanced migration in response to CCL5 (8, 10, 11). These observations have led to the hypothesis that selective neutralization of CCL5 signaling may reduce the severity of neu- *Center for Immunology and †Department of Molecular Biology and Biochemistry, roinflammation and disease (12, 13). University of California, Irvine, CA 92697 Infection of the CNS of susceptible mice with mouse hepatitis Received for publication March 27, 2003. Accepted for publication January 22, 2004. virus (MHV), a positive-strand RNA virus and a member of the The costs of publication of this article were defrayed in part by the payment of page Coronaviridae family, reproducibly results in an acute encephalo- charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. myelitis followed by a demyelinating disease that is similar to the 1 human demyelinating disease MS (14–16). MHV infection ini- This work was supported by National Institutes of Health Grant 41249 and National ϩ Multiple Sclerosis Society Grant 3278-A-3 (to T.E.L.). W.G.G. was supported by tiates a robust cell-mediated response in which both CD4 and National Institutes of Health Training Grant A107319-12. M.J.H. is a Roman Reed CD8ϩ T cells are essential in controlling viral replication and Fellow and supported by Roman Reed Predoctoral Fellowship RR02-032. spread (17–21). However, viral clearance is incomplete, and viral 2 Current address: Laboratory of Host Defenses, National Institute of Allergy and RNA and protein can persist within white matter tracts. These Infectious Diseases, National Institutes of Health, Building 10, Room 11N111, Be- thesda, MD 20892. areas of viral persistence are often associated with demyelinating 3 W.G.G. and M.J.H. contributed equally to this study. lesions, and recent studies have indicated an important role for 4 Address correspondence and reprint requests to Dr. Thomas E. Lane, Department of both T cells and macrophages in contributing to myelin destruction Molecular Biology and Biochemistry, 3205 McGaugh Hall, University of California, (17, 22–25). CCR5 and its primary ligand CCL5 are important Irvine, CA 92697-3900. E-mail address: [email protected] contributors to the trafficking of leukocytes into the CNS of MHV- 5 Abbreviations used in this paper: MS, multiple sclerosis; MHV, mouse hepatitis infected mice (17, 25–27). In support of this is the demonstration virus; CCL, CC chemokine ligand; CXCL, CXC chemokine ligand; p.i., postinfec- tion; i.c., intracranial(ly); S, surface glycoprotein; M, transmembrane protein; RPA, that administration of neutralizing antisera to CCL5 during the RNase protection assay; LFB, Luxol fast blue. acute stage of disease resulted in decreased T cell and macrophage Copyright © 2004 by The American Association of Immunologists, Inc. 0022-1767/04/$02.00 The Journal of Immunology 4019 infiltration, which correlated with significantly reduced levels of lowing anesthetization by inhalation of methoxyflurane (Pitman-Moore, demyelination in the CNS (17). During the chronic stage of dis- Washington Crossing, NJ), mice were injected i.c. with 1000 PFU of MHV ␮ ease, continued infiltration of T lymphocytes and macrophages suspended in 30 l of sterile saline (35). Control (sham) animals were injected with 30 ␮l of sterile saline alone. Animals were sacrificed at de- into the CNS results in extensive myelin destruction and neuro- fined time points, and brains and spinal cords were removed for analysis in logical impairment. T cells infiltrating into the CNS of MHV-in- studies described. One-half of each brain at each time point was either fected mice express CCL5, which presumably serves to attract stored at Ϫ80°C for RNA isolation or used for FACS analysis. Immune activated leukocytes and activated macrophages (17). splenocytes were obtained from C57BL/6 mice injected i.p. with MHV- JHM at day 7 p.i. and used for analysis of virus-specific T cells as de- The current study evaluates the functional contributions of scribed below. CCL5 in participating in inflammation and demyelination in mice persistently infected with MHV. In this study, we demonstrate that Ab administration treatment with a neutralizing mAb specific for mouse CCL5 results Beginning day 12 p.i., MHV-infected C57BL/6 mice were treated via i.p. in 1) improved neurological function, 2) decreased infiltration of T injection with 250 ␮g of either anti-CCL5 Ab (R6G9) or an IgG1 isotype- cells and macrophages into the CNS, and 3) a significant ( p Յ matched control Ab (Sigma-Aldrich, St. Louis, MO) suspended in 500 ␮l 0.005) reduction in demyelination. Additionally, anti-CCL5 treat- of sterile PBS. Mice received treatment on days 12, 14, 16, 18, and 20 p.i. ment selectively targeted T cell subsets based, in part, on their viral for a total of five injections. Ag specificity, indicating an ability to differentially target T cells Clinical disease during chronic disease in this model. Taken together, these results further implicate CCL5 as an active participant in the maintenance Clinical disease was assessed using a previously described scale (17).
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