Fumaric Acid and its esters: an emerging treatment for multiple sclerosis.

Fumaric acid is an intermediate product of the citric acid cycle that is a source of intracellular energy in the form of adenosine triphosphate (ATP). It is generated by oxidation of adenylsuccinate by the enzyme succinate dehydrogenase and is then converted to maleate by the enzyme fumarase. At present, fumaric acid esters (FAE) are licensed for the treatment of psoriasis. Several lines of evidence have demonstrated immunomodulatory effects for FAE. Clinical studies in psoriasis showed a reduction of peripheral CD4(+)- and CD8(+)-T-lymphocytes due to the ability of FAE to induce apoptosis. In vitro studies with the ester dimethyl fumarate (DMF) described an inhibitory effect on nuclear factor kappa B (NF-kappaB)-dependent transcription of tumor necrosis factor-alpha (TNF-alpha) induced genes in human endothelial cells. Animal studies using a model of central nervous system demyelination, MOG-induced experimental autoimmune encephalomyelitis (EAE), revealed a reduction of microglia and macrophages in inflamed lesions. A phase II clinical study in relapsing-remitting multiple sclerosis (RRMS) patients with a modified fumaric acid ester, BG-12, showed as "proof of principle" a significant reduction in the number of gadolinium enhancing lesions after 24 weeks of treatment as compared to placebo. Further phase III studies have now started to explore the long-term efficacy of FAE.

GARP: a key receptor controlling FOXP3 in human regulatory T cells.

Recent evidence suggests that regulatory pathways might control sustained high levels of FOXP3 in regulatory CD4(+)CD25(hi) T (T(reg)) cells. Based on transcriptional profiling of ex vivo activated T(reg) and helper CD4(+)CD25(-) T (T(h)) cells we have identified GARP (glycoprotein-A repetitions predominant), LGALS3 (lectin, galactoside-binding, soluble, 3) and LGMN (legumain) as novel genes implicated in human T(reg) cell function, which are induced upon T-cell receptor stimulation. Retroviral overexpression of GARP in antigen-specific T(h) cells leads to an efficient and stable re-programming of an effector T cell towards a regulatory T cell, which involves up-regulation of FOXP3, LGALS3, LGMN and other T(reg)-associated markers. In contrast, overexpression of LGALS3 and LGMN enhance FOXP3 and GARP expression, but only partially induced a regulatory phenotype. Lentiviral down-regulation of GARP in T(reg) cells significantly impaired the suppressor function and was associated with down-regulation of FOXP3. Moreover, down-regulation of FOXP3 resulted in similar phenotypic changes and down-regulation of GARP. This provides compelling evidence for a GARP-FOXP3 positive feedback loop and provides a rational molecular basis for the known difference between natural and transforming growth factor-beta induced T(reg) cells as we show here that the latter do not up-regulate GARP. In summary, we have identified GARP as a key receptor controlling FOXP3 in T(reg) cells following T-cell activation in a positive feedback loop assisted by LGALS3 and LGMN, which represents a promising new system for the therapeutic manipulation of T cells in human disease.

[Fumaric acid and its esters in the treatment of multiple sclerosis: studies and effects]. / Fumarat in der Behandlung der Multiplen Sklerose : Mögliche Wirkmechanismen und Studien.

The currently licensed medications for relapsing-remitting multiple sclerosis (RRMS) are only partially effective and require a parenteral route of administration. Thus there is a need for new, preferably orally available therapeutics. Such a substance could be fumaric acid and its esters (FAE). These compounds are already in use for treatment of psoriasis and are known to have an immunomodulatory effect. In addition there is a potential for neuroprotective effects as suggested by in vitro studies and experiments in the animal model of experimental autoimmune encephalomyelitis. A phase II clinical study in RRMS patients with the modified fumaric acid ester BG-12 showed as "proof of principle" in a frequent MRI design that FAE significantly reduce the number of gadolinium-enhancing lesions after 24 weeks of treatment. Further phase III studies have been started to explore the long-term efficacy of this substance. The results of these studies will show if FAE can be another treatment option, maybe for combination therapy, in patients with MS.