The chemokine receptor antagonist, TAK‐779, decreased experimental autoimmune encephalomyelitis by reducing inflammatory cell migration into the central nervous system, without affecting T cell function

Abstract

Background and purpose:The C-C chemokine receptor CCR5, and the C-X-C chemokine receptor CXCR3 are involved in the regulation of T cell-mediated immune responses, and in the migration and activation of these cells. To determine whether blockade of these chemokine receptors modulated inflammatory responses in the central nervous sytem (CNS), we investigated the effect of a non-peptide chemokine receptor antagonist, TAK-779, in mice with experimental autoimmune encephalomyelitis (EAE). Experimental approach: EAE was induced by immunization of C57BL/6 mice with myelin oligodendrocyte glycoprotein (MOG) 35-55. TAK-779 was injected s.c. once a day after immunization. Disease incidence and severity (over 3 weeks) were monitored by histopathological evaluation and FACS assay of inflammatory cells infiltrating into the spinal cord, polymerase chain reaction quantification of mRNA expression, assay of T cell proliferation, by [

A Fusion Protein Encoding the Second Extracellular Domain of CCR5 Arrests Chemokine-Induced Cosignaling and Effectively Suppresses Ongoing Experimental Autoimmune Encephalomyelitis

“…3E). This may suggest that CCR5-Ig-based therapies may be significantly advantageous over direct blockade of CCR5 using CCR5 antagonists (46). 2) We show in this paper that blockade of these ligands inhibited CD4 + T cells migration to the CNS (Fig.…”

Antiasthmatic Drugs Targeting the Cysteinyl Leukotriene Receptor 1 Alleviate Central Nervous System Inflammatory Cell Infiltration and Pathogenesis of Experimental Autoimmune Encephalomyelitis

“…Chemokines and their receptors are well known to play roles in T cell infiltration and EAE development. For example, TAK-779, a CCR5 antagonist, decreased EAE severity by reducing inflammatory cell migration into the CNS, without affecting T cell function (45). Blocking CXCR3 by a specific Ab also inhibited T cell migration and thus the development of EAE in an adoptive transfer model (42).…”

Temporary CXCR3 and CCR5 Antagonism Following Vaccination Enhances Memory CD8 T Cell Immune Responses

“…TAK-779 administration was started from day 0 after immunization and continued for 4 wks or 8 wks for 1 or 2 immunizations, respectively. The dose of 150 μg per mouse was chosen based on previous publications showing that this dose was successfully used in experimental EAE (21) and collagen-induced arthritis (22), and approximately the same dose was used in other disease experiments, such as allograft rejection and asthma models. (20,23) For influenza virus infection, 2 wks after stopping TAK-779, sedated mice received intranasal (i.n.)…”