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.
OBJECTIVE
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).


METHODS
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 [3H]-thymidine incorporation and cytokine production by enzyme-linked immunosorbent assay.


RESULTS
Treatment with TAK-779 reduced incidence and severity of EAE. It strongly inhibited migration of CXCR3/CCR5 bearing CD4+, CD8+ and CD11b+ leukocytes to the CNS. TAK-779 did not reduce proliferation of anti-MOG T cells, the production of IFN-gamma by T cells or CXCR3 expression on T cells. In addition, TAK-779 did not affect production of IL-12 by antigen-presenting cells, CCR5 induction on T cells and the potential of MOG-specific T cells to transfer EAE.


CONCLUSIONS
TAK-779 restricted the development of MOG-induced EAE. This effect involved reduced migration of inflammatory cells into the CNS without affecting responses of anti-MOG T cells or the ability of MOG-specific T cells to transfer EAE.
Ni
Jia
J
Laboratory of Immunopharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Zhu
Yi-Na
YN
Zhong
Xiang-Gen
XG
Ding
Yu
Y
Hou
Li-Fei
LF
Tong
Xian-Kun
XK
Tang
Wei
W
Ono
Shiro
S
Yang
Yi-Fu
YF
Zuo
Jian-Ping
JP
D000577:Amides / Q000494:pharmacology*; D000818:Animals; D065100:CCR5 Receptor Antagonists; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000503:physiopathology / Q000517:prevention & control*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D019713:Receptors, CCR5 / Q000378:metabolism; D054367:Receptors, CXCR3 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012720:Severity of Illness Index; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism
D000577:Amides; D065100:CCR5 Receptor Antagonists; C515188:Cxcr3 protein, mouse; D000644:Quaternary Ammonium Compounds; D012333:RNA, Messenger; D019713:Receptors, CCR5; D054367:Receptors, CXCR3; C119369:TAK 779