Bystander modulation of chemokine receptor expression on peripheral blood T lymphocytes mediated by glatiramer therapy.
BACKGROUND
Glatiramer acetate therapy is thought to be effective for multiple sclerosis (MS) by promoting T(H)2 cytokine deviation, possibly in the brain, but the exact mechanism and site of action are incompletely understood. Determining the site of action and effect of glatiramer on cell trafficking is of major importance in designing rational combination therapy clinical trials.


OBJECTIVE
To determine whether glatiramer therapy will also act in the peripheral blood through bystander modulation of chemokine receptor (CKR) expression and cytokine production on T lymphocytes.


METHODS
Before-and-after trial.


METHODS
A university MS specialty center.


METHODS
Ten patients with relapsing-remitting MS.


METHODS
Treatment with glatiramer for 12 months and serial phlebotomy.


METHODS
Cytokine production, CKR expression, and cell migration.


RESULTS
The glatiramer-reactive T cells were T(H)2 cytokine biased, consistent with previous studies. We found a significant reduction in the expression of the T(H)1 inflammation associated with the CKRs CXCR3, CXCR6, and CCR5 on glatiramer- and myelin-reactive T cells generated from patients with MS receiving glatiramer therapy vs baseline. Conversely, expression of the lymph node-homing CKR, CCR7, was markedly enhanced on the glatiramer-reactive T cells derived from patients with MS undergoing glatiramer therapy. There was a reduction in the percentage of CD4+ glatiramer-reactive T cells and an increase in the number of CD8+ glatiramer-reactive T cells.


CONCLUSIONS
Glatiramer may suppress autoreactive CD4+ effector memory T cells and enhance CD8+ regulatory responses, and bystander modulation of CKRs may occur in the periphery.
Allie
Rameeza
R
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Hu
Lina
L
Mullen
Katherine M
KM
Dhib-Jalbut
Suhayl
S
Calabresi
Peter A
PA
D024201:Bystander Effect / Q000187:drug effects* / Q000276:immunology*; D000068717:Glatiramer Acetate; D006801:Humans; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology* / Q000627:therapeutic use*; D019707:Receptors, Chemokine / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism
D010455:Peptides; D019707:Receptors, Chemokine; D000068717:Glatiramer Acetate