Treatment of experimental autoimmune encephalomyelitis with the chemokine receptor antagonist Met-RANTES

J Neuroimmunol. 2002 Jul;128(1-2):16-22. doi: 10.1016/s0165-5728(02)00121-2.

Abstract

Specific chemokines and chemokine receptors have been implicated in inflammatory demyelinating diseases of the central nervous system (CNS), including multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). Amino-terminal modifications of chemokines can alter receptor interactions, converting agonists to specific antagonists. To examine the function in EAE of murine types 1 and 5 CC chemokine receptors (CCR1 and CCR5), we used Met-RANTES, a peptide that blocks both receptors; controls received heat-inactivated peptide. There was no effect of active treatment on acute-monophasic EAE, regardless whether compound was given at onset or in a pre-treatment regimen. Administered at disease onset, Met-RANTES modestly but significantly ameliorated fixed neurological disability at the endpoint of chronic-relapsing EAE. Met-RANTES treatment did not reduce CNS cellular infiltrates or up-regulation of CCR1 and CCR5 in affected CNS tissues. Analysis of a subset of mice suggested a trend towards reduced axonal pathology in those receiving active treatment. These data indicate that chemokine receptor blockade with Met-RANTES does not affect leukocyte trafficking in chronic-relapsing EAE. Further analysis of the effects of chemokine receptor blockade may need to focus on leukocyte activation within the affected CNS as well as trafficking events.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Axons / drug effects
  • Axons / immunology
  • Axons / pathology
  • Chemokine CCL5 / analogs & derivatives*
  • Chemokine CCL5 / pharmacology*
  • Chemokine CCL5 / therapeutic use
  • Chemokines / antagonists & inhibitors*
  • Chemokines / immunology
  • Chemokines / metabolism
  • Chemotaxis, Leukocyte / drug effects
  • Chemotaxis, Leukocyte / immunology
  • Encephalomyelitis, Autoimmune, Experimental / drug therapy*
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Encephalomyelitis, Autoimmune, Experimental / pathology
  • Female
  • Glyceraldehyde-3-Phosphate Dehydrogenases / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Multiple Sclerosis / drug therapy*
  • Multiple Sclerosis / immunology
  • Multiple Sclerosis / pathology
  • RNA, Messenger / drug effects
  • RNA, Messenger / immunology
  • RNA, Messenger / metabolism
  • Receptors, CCR1
  • Receptors, CCR5 / genetics
  • Receptors, Chemokine / antagonists & inhibitors*
  • Receptors, Chemokine / genetics
  • Receptors, Chemokine / immunology
  • Receptors, Chemokine / metabolism
  • Spinal Cord / drug effects*
  • Spinal Cord / immunology
  • Spinal Cord / pathology
  • Treatment Failure

Substances

  • Ccr1 protein, mouse
  • Chemokine CCL5
  • Chemokines
  • RANTES, Met-
  • RNA, Messenger
  • Receptors, CCR1
  • Receptors, CCR5
  • Receptors, Chemokine
  • Glyceraldehyde-3-Phosphate Dehydrogenases