TY - JOUR
T1 - CD8+ T Cells Are Required For Glatiramer Acetate Therapy in Autoimmune Demyelinating Disease
AU - Tyler, Andrew F.
AU - Mendoza, Jason P.
AU - Firan, Mihail
AU - Karandikar, Nitin J.
N1 - Funding Information:
J.M. is now employed by Teva Neuroscience, the manufacturer of GA. However, these studies were conducted prior to such employment and were not supported by funding from Teva. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials.
PY - 2013/6/21
Y1 - 2013/6/21
N2 - The exact mechanism of glatiramer acetate (GA, Copaxone®), an FDA-approved immunomodulatory therapy for multiple sclerosis (MS), remains unclear after decades of research. Previously, we have shown that GA therapy of MS induces CD8+ T cell responses that can potentially suppress pathogenic CD4+ T cell responses. Using a murine model of MS, experimental autoimmune encephalomyelitis (EAE), we now demonstrate that CD8+ T cells are necessary in mediating the therapeutic effects of GA. Further, adoptive transfer of GA-induced CD8+ T cells resulted in amelioration of EAE, establishing a role as a viable immunotherapy in demyelinating disease. Generation of these cells required indoleamine-2,3-dioxygenase (IDO), while suppressive function depended on non-classical MHC class I, IFN-γ, and perforin expression. GA-induced regulatory myeloid cells, previously shown to activate CD4+ regulatory T cells in an antigen-independent manner, required CD8+ T cells for disease suppression in vivo. These studies demonstrate an essential role for CD8+ T cells in GA therapy and identify their potential as an adoptive immunotherapeutic agent.
AB - The exact mechanism of glatiramer acetate (GA, Copaxone®), an FDA-approved immunomodulatory therapy for multiple sclerosis (MS), remains unclear after decades of research. Previously, we have shown that GA therapy of MS induces CD8+ T cell responses that can potentially suppress pathogenic CD4+ T cell responses. Using a murine model of MS, experimental autoimmune encephalomyelitis (EAE), we now demonstrate that CD8+ T cells are necessary in mediating the therapeutic effects of GA. Further, adoptive transfer of GA-induced CD8+ T cells resulted in amelioration of EAE, establishing a role as a viable immunotherapy in demyelinating disease. Generation of these cells required indoleamine-2,3-dioxygenase (IDO), while suppressive function depended on non-classical MHC class I, IFN-γ, and perforin expression. GA-induced regulatory myeloid cells, previously shown to activate CD4+ regulatory T cells in an antigen-independent manner, required CD8+ T cells for disease suppression in vivo. These studies demonstrate an essential role for CD8+ T cells in GA therapy and identify their potential as an adoptive immunotherapeutic agent.
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U2 - 10.1371/journal.pone.0066772
DO - 10.1371/journal.pone.0066772
M3 - Article
C2 - 23805274
AN - SCOPUS:84879274140
SN - 1932-6203
VL - 8
JO - PloS one
JF - PloS one
IS - 6
M1 - e66772
ER -