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 Sclerosis

Abstract

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 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 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.

IFN-γ-Induced Chemokines Synergize with Pertussis Toxin to Promote T Cell Entry to the Central Nervous System

“…It may be that the Abs did not access the critical CNS compartment to achieve effect, or that Ab levels were insufficient to block chemokine effects in our system. Other studies have used these same reagents to influence CNS inflammatory events (35,36), but in different model systems. Alternatively, it may simply be that CXCL10 and CCL5 are not the critical mediators driving CNS T cell entry in response to IFN-␥ and Ptx, despite their clear up-regulation.…”

“…for 5 days following administration of AdIFN␥ and Ptx. Efficacy of these reagents has been validated in studies involving blocking of chemokine-driven immune events in mouse CNS inflammation (35,36). In neither case did the blocking Ab affect infiltration of CD45 high leukocytes, as assessed by flow cytometry (data not shown).…”

“…Treatments of 0.5 ml of anti-CXCL10 antiserum (ϳ0.5 mg/ml), 250 g of R6G9, or 250 g of IgG were i.p. administered for 5 days (35,36).…”

Differential roles for CXCR3 in CD4+ and CD8+ T cell trafficking following viral infection of the CNS

“…5B). Previous studies have indicated that T cell secretion of the macrophage chemoattractant CCL5 can contribute to demyelination [14,22]. Therefore, CCL5 expression and macrophage accumulation within the CNS were evaluated following CXCR3 neutralization.…”

“…During both acute and chronic MHV infection, chemokines and chemokine receptors are expressed within the CNS, influencing host defense as well as disease by regulating inflammation within the CNS [9,14,[18][19][20][21][22][23]. Studies from our laboratory have clearly demonstrated important roles for CXCR3 ligands during both acute and chronic MHV infection of C57BL/6 mice [18,19,23].…”