Contributions
Abstract: EP1479
Type: ePoster
Abstract Category: Pathology and pathogenesis of MS - 15 Immunology
Dimethyl fumarate (DMF) is a disease modifying therapy licensed as a first line therapy for relapsing remitting multiple sclerosis (RRMS). The exact mechanism of action of DMF is not clear, although it has been proposed to exert both anti-inflammatory and antioxidant effects on immune cells, and to cause apoptosis in T cells. Pro-inflammatory T cells such as Th1 and Th17 cells are proposed to have a pathogenic role in MS, whereas regulatory T (Treg) cells suppress pathogenic T cells and prevent autoimmunity. We examined the immunomodulatory effects of DMF treatment in RRMS patients, comparing baseline, 1, 3 and 6 months post treatment. We used multi-parameter flow cytometry to determine the frequency and phenotype of peripheral CD4 T cells. Preliminary data indicated a significant reduction in the frequency and absolute numbers of memory CD4 T cells, with a corresponding increase in the naïve compartment after 6 months of treatment. Pro-inflammatory cytokines IL-17, IFN-γ, TNF, GM-CSF production by CD4 T cells was not altered by DMF treatment, however there was a significant reduction in the expression of the CD161 Th17 lineage marker after 6 months. In addition we observed a significant increase in the frequency of IL-2 producing T cells after 3 and 6 months relative to baseline. There was a non-significant trend towards an increase in Treg cells in response to DMF treatment, however the proportion of memory Treg cells was significantly reduced after 6 months.
In summary, DMF therapy appears to specifically target memory CD4 T cells within both the effector and Treg compartments, resulting in a reciprocal increase in the proportion of naïve CD4 T cells. The increase in IL-2 production may reflect a decrease in effector memory T cells which have a reduced capacity for IL-2 production. The reduction in CD161 expression in response to DMF therapy suggests that DMF may specifically target Th17 lineage cells, however no corresponding reduction in IL-17 cytokine was observed and increased patient numbers need to be analysed. Finally DMF therapy for 3 or 6 months significantly decreased the CD161+ Th17:Treg cell ratio suggesting that DMF therapy may in part exert its effects via reciprocal effects on Th17 and Treg cells.
Disclosure:
BM has no disclosures.
N McNicholas has received a Newman fellowship sponsored by Biogen.
K O'Connell has received travel and educational grants from Biogen, Novartis, Abvie, Teva and Merck Serono.
C McGuigan has received honoraria, participated in advisory boards and/or received research funding from Biogen, Merck Serono, Novartis, Roche, Genzyme and Bayer.
JMF has received honoraria from Novartis and served on their Advisory Board, and received research grant funding from Abbvie.
Abstract: EP1479
Type: ePoster
Abstract Category: Pathology and pathogenesis of MS - 15 Immunology
Dimethyl fumarate (DMF) is a disease modifying therapy licensed as a first line therapy for relapsing remitting multiple sclerosis (RRMS). The exact mechanism of action of DMF is not clear, although it has been proposed to exert both anti-inflammatory and antioxidant effects on immune cells, and to cause apoptosis in T cells. Pro-inflammatory T cells such as Th1 and Th17 cells are proposed to have a pathogenic role in MS, whereas regulatory T (Treg) cells suppress pathogenic T cells and prevent autoimmunity. We examined the immunomodulatory effects of DMF treatment in RRMS patients, comparing baseline, 1, 3 and 6 months post treatment. We used multi-parameter flow cytometry to determine the frequency and phenotype of peripheral CD4 T cells. Preliminary data indicated a significant reduction in the frequency and absolute numbers of memory CD4 T cells, with a corresponding increase in the naïve compartment after 6 months of treatment. Pro-inflammatory cytokines IL-17, IFN-γ, TNF, GM-CSF production by CD4 T cells was not altered by DMF treatment, however there was a significant reduction in the expression of the CD161 Th17 lineage marker after 6 months. In addition we observed a significant increase in the frequency of IL-2 producing T cells after 3 and 6 months relative to baseline. There was a non-significant trend towards an increase in Treg cells in response to DMF treatment, however the proportion of memory Treg cells was significantly reduced after 6 months.
In summary, DMF therapy appears to specifically target memory CD4 T cells within both the effector and Treg compartments, resulting in a reciprocal increase in the proportion of naïve CD4 T cells. The increase in IL-2 production may reflect a decrease in effector memory T cells which have a reduced capacity for IL-2 production. The reduction in CD161 expression in response to DMF therapy suggests that DMF may specifically target Th17 lineage cells, however no corresponding reduction in IL-17 cytokine was observed and increased patient numbers need to be analysed. Finally DMF therapy for 3 or 6 months significantly decreased the CD161+ Th17:Treg cell ratio suggesting that DMF therapy may in part exert its effects via reciprocal effects on Th17 and Treg cells.
Disclosure:
BM has no disclosures.
N McNicholas has received a Newman fellowship sponsored by Biogen.
K O'Connell has received travel and educational grants from Biogen, Novartis, Abvie, Teva and Merck Serono.
C McGuigan has received honoraria, participated in advisory boards and/or received research funding from Biogen, Merck Serono, Novartis, Roche, Genzyme and Bayer.
JMF has received honoraria from Novartis and served on their Advisory Board, and received research grant funding from Abbvie.