Reduction of CD8 ⁺ T lymphocytes in multiple sclerosis patients treated with dimethyl fumarate

Abstract

Objective:To evaluate the influence of dimethyl fumarate (DMF, Tecfidera) treatment of multiple sclerosis (MS) on leukocyte and lymphocyte subsets.Methods:Peripheral blood leukocyte and lymphocyte subsets, including CD3+, CD4+, and CD8+ T cells; CD19+ B cells; and CD56+ natural killer (NK) cells, were obtained at baseline and monitored at 3 months, 6 months, and 12 months after initiation of DMF treatment.Results:Total leukocyte and lymphocyte counts diminished after 6 months of DMF therapy. At 12 months, lymphocyte counts had decreased by 50.1% (p < 0.0001) and were below the lower limit of normal (LLN) in one-half of patients. CD3+ T lymphocyte counts fell by 44.2% (p < 0.0001). Among subsets, CD8+ T cell counts declined by 54.6% (p < 0.0001), whereas CD4+ T cell counts decreased by 39.2% (p = 0.0006). This disproportionate reduction of CD8+ T cells relative to CD4+ T cells was significant (p = 0.007) and was reflected by a 35.5% increase in the CD4/CD8 ratio (p = 0.007). A majority of CD8+ T cell counts, but not CD4+ T cell counts, were below the LLN even when total lymphocyte counts were greater than 500 cells/μL. CD19+ B cell counts were reduced by 37.5% (p = 0.035). Eosinophil levels decreased by 54.1% (p = 0.006), whereas levels of neutrophils, monocytes, basophils, and NK cells were not significantly altered.Conclusion:Subsets of peripheral blood leukocytes and lymphocytes are differentially affected by DMF treatment of MS. Reduction of CD8+ T cells is more pronounced than that of CD4+ T cells. These findings may have implications for cell-mediated antiviral immunity during DMF treatment.

Dimethyl fumarate treatment induces adaptive and innate immune modulation independent of Nrf2

“…In addition to stimulating antioxidative and potentially neuroprotective pathways with DMF, earlier studies of Fumaderm treatment in psoriasis demonstrated that FAEs also reduce lymphocyte proliferation and secretion of proinflammatory cytokines (1). Furthermore, DMF treatment caused significant reduction in inflammatory measures of disease activity in MS clinical trials (8,9), and data reported after its approval for MS indicate that sustained DMF treatment may restrict proliferation of certain lymphocyte subsets (18,19). Here, we evaluated antiinflammatory and immunomodulatory activity of DMF treatment of acute EAE in WT and Nrf2 −/− mice.…”

“…Although data suggest that continuous DMF treatment of MS may influence B cells (18,19), little is known regarding its potential immunomodulatory effects on those lymphocytes in either MS or in EAE. It is recognized that B cells serve an important role as APCs in T-cell activation and the development of acute and chronic CNS inflammation (20).…”

Lymphopenia and CD4+/CD8+ Cell Reduction under Fumaric Acid Esters

“…Spencer et al [18] , for example, showed a decrease in CD8+ cells of 54.6% compared to a 39.2% reduction in CD4+ T-cell counts over 1 year. According to the literature, alterations in blood count or haematology led to discontinuation of FAE therapy in about 2.6-12% of patients [6,11,19] .…”

“…In MS patients treated with Tecfidera ® , the CD4+ cell count dropped below 200/μL in 9% of the patients after 1 year on the drug [17,18] . The percentage of patients with CD4+ cell counts below 200/μL was much higher in our investigation, with a rate of 19.4%.…”

Dimethylfumarate in the treatment of relapsing-remitting multiple sclerosis

“…ДМФ влияет на фенотип лимфоцитов, что приводит к уменьшению клеток памяти [13]. Сни-жение абсолютного количества лимфоцитов при-мерно на 1 / 3 достигается в основном за счет сниже-ния количества CD8-и CD19-клеток [14][15][16][17].…”