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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.
- Source :
- British Journal of Pharmacology; Dec2009, Vol. 158 Issue 8, p2046-2056, 11p
- Publication Year :
- 2009
-
Abstract
- <bold>Background and Purpose: </bold>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).<bold>Experimental Approach: </bold>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.<bold>Key Results: </bold>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.<bold>Conclusions and Implications: </bold>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. [ABSTRACT FROM AUTHOR]
- Subjects :
- CHEMOKINES
ENZYME inhibitors
ENCEPHALOMYELITIS
CELL migration
CENTRAL nervous system
T cells
CELL physiology
DRUG receptors
IMMUNE response
BIOLOGICAL assay
LABORATORY mice
RNA metabolism
AMIDES
ANIMAL experimentation
CELL receptors
CELL motility
COMPARATIVE studies
DEMYELINATION
ENZYME-linked immunosorbent assay
GENE expression
RESEARCH methodology
MEDICAL cooperation
MICE
POLYMERASE chain reaction
RESEARCH
EVALUATION research
SEVERITY of illness index
QUATERNARY ammonium compounds
ANTI-HIV agents
Subjects
Details
- Language :
- English
- ISSN :
- 00071188
- Volume :
- 158
- Issue :
- 8
- Database :
- Complementary Index
- Journal :
- British Journal of Pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 64862819
- Full Text :
- https://doi.org/10.1111/j.1476-5381.2009.00528.x