Faculty Opinions recommendation of Fumarates improve psoriasis and multiple sclerosis by inducing type II dendritic cells.

Fumarates improve multiple sclerosis (MS) and psoriasis, two diseases in which both IL-12 and IL-23 promote pathogenic T helper (Th) cell differentiation. However, both diseases show opposing responses to most established therapies. First, we show in humans that fumarate treatment induces IL-4–producing Th2 cells in vivo and generates type II dendritic cells (DCs) that produce IL-10 instead of IL-12 and IL-23. In mice, fumarates also generate type II DCs that induce IL-4–producing Th2 cells in vitro and in vivo and protect mice from experimental autoimmune encephalomyelitis. Type II DCs result from fumarate-induced glutathione (GSH) depletion, followed by increased hemoxygenase-1 (HO-1) expression and impaired STAT1 phosphorylation. Induced HO-1 is cleaved, whereupon the N-terminal fragment of HO-1 translocates into the nucleus and interacts with AP-1 and NF-κB sites of the IL-23p19 promoter. This interaction prevents IL-23p19 transcription without affecting IL-12p35, whereas STAT1 inactivation prevents IL-12p35 transcription without affecting IL-23p19. As a consequence, GSH depletion by small molecules such as fumarates induces type II DCs in mice and in humans that ameliorate inflammatory autoimmune diseases. This therapeutic approach improves Th1- and Th17-mediated autoimmune diseases such as psoriasis and MS by interfering with IL-12 and IL-23 production.

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Fumarates improve psoriasis and multiple sclerosis by inducing type II dendritic cells

Yearbook of Medicine ◽

10.1016/j.ymed.2012.09.024 ◽

2012 ◽

Vol 2012 ◽

pp. 36-37

Author(s):

R.S. Panush

Keyword(s):

Multiple Sclerosis ◽

Dendritic Cells ◽

Type Ii

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An Imbalance of Two Functionally and Phenotypically Different Subsets of Plasmacytoid Dendritic Cells Characterizes the Dysfunctional Immune Regulation in Multiple Sclerosis

Yearbook of Neurology and Neurosurgery ◽

10.1016/j.yneu.2010.12.026 ◽

2011 ◽

Vol 2011 ◽

pp. 94

Author(s):

A. Minagar

Keyword(s):

Multiple Sclerosis ◽

Dendritic Cells ◽

Immune Regulation ◽

Plasmacytoid Dendritic Cells

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Dexamethasone Preconditioning Improves the Response of Collagen-Induced Arthritis to Treatment with Short-Term Lipopolysaccharide-Stimulated Collagen-Loaded Dendritic Cells

Clinical and Developmental Immunology ◽

10.1155/2013/296031 ◽

2013 ◽

Vol 2013 ◽

pp. 1-7 ◽

Cited By ~ 2

Author(s):

Corina Peña ◽

David Gárate ◽

Juan Contreras-Levicoy ◽

Octavio Aravena ◽

Diego Catalán ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Cd4 T Cells ◽

Combined Treatment ◽

Type Ii Collagen ◽

Cytokine Profile ◽

Clinical Disease ◽

Type Ii ◽

Collagen Induced Arthritis ◽

Short Term

Background. Pharmacologically modulated dendritic cells (DCs) have been shown to restore tolerance in type II collagen-(CII-) induced arthritis (CIA). We examined the effect of dexamethasone (DXM) administration as a preconditioning agent, followed by an injection of lipopolysaccharide-(LPS-) stimulated and CII-loaded DCs on the CIA course.Methods. After CIA induction, mice pretreated with DXM were injected with 4-hour LPS-stimulated DCs loaded with CII (DXM/4hLPS/CII/DCs).Results. Mice injected with DXM/4hLPS/CII/DCs displayed significantly less severe clinical disease compared to animals receiving 4hLPS/CII/DCs alone or those in which only DXM was administered. Cytokine profile evaluation showed that CD4+ T cells from DXM/4hLPS/CII/DCs and 4hLPS/CII/DCs groups release higher IL-10 levels than those from mice receiving DXM alone or CIA mice. CD4+ T cells from all DC-treated groups showed less IL-17 release when compared to the CIA group. On the contrary, CD4+ T cells from DXM/4hLPS/CII/DCs and 4hLPS/CII/DCs groups released higher IFN-γlevels than those from CIA group.Conclusion. A combined treatment, including DXM preconditioning followed by an inoculation of short-term LPS-stimulated CII-loaded DCs, provides an improved strategy for attenuating CIA severity. Our results suggest that this benefit is driven by a modulation in the cytokine profile secreted by CD4+ T cells.

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CD40 in Clinical Inflammation: From Multiple Sclerosis to Atherosclerosis

Developmental Immunology ◽

10.1155/1998/69628 ◽

1998 ◽

Vol 6 (3-4) ◽

pp. 215-222 ◽

Cited By ~ 22

Author(s):

Jon D. Laman ◽

Mark De Boer ◽

Bert A. 'T Hart

Keyword(s):

Multiple Sclerosis ◽

Dendritic Cells ◽

T Cell ◽

B Cell ◽

Antibody Production ◽

Memory Formation ◽

Isotype Switching ◽

Cell Responses ◽

Clinical Conditions ◽

Antigen Presenting

The interactions of CD40 and CD40L have been known for some time to critically regulate B-cell responses with respect to proliferation, isotype switching, antibody production, and memory formation. More recent findings demonstrated that CD40 can be expressed on several other antigen-presenting cell (APC) types such as macrophages, dendritic cells, and fibroblasts. This expression of CD40 regulates T-cell-APC interaction and is centrally involved in a wide array of inflammatory events. Here, currently available data are reviewed demonstrating that CD40- CD40L interactions are operational in two chronic inflammatory clinical conditions, namely, multiple sclerosis and atherosclerosis. The functional correlates of these interactions are discussed in the light of recent other findings, shedding light on the multiple effects of CD40- CD40L interactions.

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