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CCR5+ & CXCR3+ T-Cells Are Increased In Multiple Sclerosis & Their Ligands MIP-1alpha And Ip-10 Are Expressed In DeMyelinating Brain Lesions

Konstantin E. Balashov, James B. Rottman, Howard L. Weiner, and Wayne W. Hancock
The National Academy of Sciences 0027-8424/99/966873-6
Vol. 96, Issue 12, 6873-6878, June 8, 1999

Brigham and Women's Hospital, Center for Neurologic Diseases, and Harvard Medical School, Dept of Neurology, Boston, MA 02115; LeukoSite, Inc., Cambridge, MA 02142;
and Harvard Medical School, Dept of Pathology, Boston, MA 02115
PMID# 10359806
Abstract

Multiple Sclerosis (MS) is a T-Cell-dependent chronic inflammatory disease of the Central Nervous System. The role of Chemokines in MS and its different stages is uncertain. (See: Sex Differences in AutoImmune Disease)

Recent data suggest a bias in expression of Chemokine Receptors by Th1 vs. Th2 cells; human Th1 clones express CXCR3 and CCR5 and Th2 clones express CCR3 and CCR4.

Chemokine Receptors expressed by Th1 cells may be important in MS, as increased Interferon-gamma (IFN-gamma) precedes clinical attacks, and IFN-gamma injection induces disease exacerbations.

We found CXCR3+ T-Cells increased in blood of Relapsing/Remitting MS, and both CCR5+ and CXCR3+ T-Cells increased in Progressive MS compared with controls.

Furthermore, peripheral blood CCR5+ T-Cells secreted high levels of IFN-gamma.

In the Brain, the CCR5 Ligand, MIP-1alpha, was strongly associated with Microglia/Macrophages, and the CXCR3 Ligand, IP-10, was expressed by Astrocytes in MS lesions but not unaffected White Matter of control or MS subjects.

Areas of plaque formation were infiltrated by CCR5-expressing and, to a lesser extent, CXCR3-expressing cells; InterLeukin (IL-18 and IFN-gamma were expressed in DeMyelinating lesions.

No Leukocyte expression of CCR3, CCR4, or six other Chemokines, or AntiInflammatory Cytokines IL-5, IL-10, IL-13, and Transforming Growth Factor-ß was observed.

Thus, Chemokine Receptor expression may be used for Immunologic staging of MS and potentially for other chronic AutoImmune/Inflammatory processes such as Rheumatoid Arthritis, AutoImmune Diabetes, or chronic transplant rejection.

Furthermore, these results provide a rationale for the use of agents that block CCR5 and/or CXCR3 as a therapeutic approach in the treatment of MS.

Communicated by David W. Talmage,
Univ of Colorado Health Sciences Center, Denver, CO, April 16, 1999 (received for review November 1, 1998)

§ To whom reprint requests should be addressed at:
LeukoSite, Inc., 215 First Street, Cambridge, MA 02142

Copyright 1999 by The National Academy of Sciences



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