The Effect Of Fumaric Acid Esters On T Cells--Change Of Cell Phenotypes, Apoptosis Molecule And Nuclear Factors

Psoriasis is a common inflammatory cutaneous disorder with a prevalence of 0.2-3% in the general population. Treatment is difficult and relapsement rate is high. Although the pathogenesis of psoriasis is still not totally known, recent studies have shown T-cell mediated (auto-)immune response to unknown antigens plays a crucial pathogenic role. Psoriatic lesions could be induced by injecting autologous purified CD4+ T cells into uninvolved psoriatic skin transplanted to SCID mice. CD8+T cells are the main effector cells responding to antigens in the HLA-Cw*0602 binding pockets of keratinocytes in psoraisis. Therefore, CD8+ T cells are thought to be a major part in the pathogenesis of psoraisis. T cell-specific treatments such as cyclosporineA and anti CD4 antibody result in the normaliztion of the keratinocyte proliferation and epidermal thickening and lead to remission of psoriasis.Fumaric acid esters are a defined mixture of several fumaric acids. FAE has been used empirically for the systemic treatment of psoriasis patients in Germany, Netherland and Italy since 1959. In recent years the efficacy and low side-effect of FAE has been confirmed in several open and controlled clinical studies. In 1994 the drug was registered as Fumaderm? in Germany to treat severe psoriasis especiallythat is not responsive to classical treatments. Fumaderm ? is composed of dimethylfumarate, and salts of ethylhydrogenfumarate, with dimethylfumarate being the major compound. Data have shown that FAE potently modulates a number of different cells which are important in the pathogenesis of psoriasis. This partially elucidates the mechanisms of FAE in the treatment of psoriasis .FAE have been confirmed to have effect on T cells in vitro. De Jong et al showed modulation of cytokine secretion in activated T cells by monomethylfumarate which were demonstrated to increase production of interleukin (IL)-4 and IL-5 without affecting interferon-γ and IL-2 secretion, the two prominent Thl-type cytokines. By using radioactive labelled MHF and DMF the authors provided evidence of specific binding sites for MHF on T-cells. Co-culture experiments using keratinocytes from psoriasis patients and healthy controls together with HUT78 T cells revealed inhibition of IFN- y secretion and induction of IL-10 by DMF. Thus, FAE may skew the Thl -dominated immune response underlying the psoriatic tissue reaction towards a Th2-type response. By using the lympho-histocytic cell-line U937, a significant induction of apoptosis by DMF in a dose-dependent manner has been verified. Clinical observations of human peripheral blood leukocyte numbers showed a decrease mainly of T-lymphocytes equally affecting CD4+ and CD8+ cells. The decrease of lymphocytes in the peripheral blood was paralleled by the disappearence of cells of the inflammatory infiltrate within psoriatic plaques. Very recently another set of new data presented show that DMF, not MHF, however, at 10-20μ.g/ml potently induced apoptosis in human purified T-cells.The transcription factor NF-kB is implicated in the regulation of many genes that code for mediators of the immune acute phase and inflammatory responses. NFAT proteins are transcription factors that were first identified as inducers of the immune response. As demonstrated later, these proteins also play varied roles in celldifferentiation and adaptation for vascular endothelial cells. DMF was proved to inhibit NF-kB pathway in fibroblasts and endothelial cells, and subsequent work reported that NF-kB inhibition by DMF was due to an inhibition of nuclear entry of p65 protein in endothelial cells. But it is still unknown whether FAE has any effect on NF-kB and NFAT pathways in T lymphocytes.Given that activated T-cells play such an important role in the pathogenesis of psoriasis and what is more, CD4+ T cells and CD8+ T cells play different roles in the pathogenesis of psoriasis, studies are required to identify the effect by FAE on T cells and T cell subsets. Therefore in this study we investigated whether DMF and its main metabolite MHF have any ef...