British Journal of Dermatology 1998; 139: 390–395.
`
`The antipsoriatic agent dimethylfumarate immunomodulates
`T-cell cytokine secretion and inhibits cytokines of the psoriatic
`cytokine network
`
`Summary
`
`H.M.OCKENFELS, T.SCHULTEWOLTER, G.OCKENFELS, R.FUNK AND M.GOOS
`Department of Dermatology, University of Essen, 45122 Essen, Germany
`
`Accepted for publication 4 April 1998
`
`Interactions between infiltrating T cells and keratinocytes via the secretion of the TH1 cytokines
`interleukin (IL) 2 and interferon ␥ (INF-␥), the keratinocyte growth factor transforming growth
`factor ␣ (TGF-␣) and the cytokines IL-6 and IL-8 are thought to be the predominant mechanisms
`inducing skin lesions in psoriatic patients. Systemic treatment of psoriasis with fumaric acid
`derivatives (FAEs) has been reported to be effective in the treatment of psoriasis, but the mode of
`action is still unknown. To clarify this phenomenon, keratinocytes from psoriatic patients as well as
`from healthy volunteers were mono- and cocultured with HUT 78 T cells with/without the addition
`of FAEs; the cytokine concentrations were then measured in the culture supernatants. Furthermore,
`mRNA expression was determined in epidermal growth factor (EGF) -activated keratinocytes as well
`as in phytohaemagglutinin (PHA)-activated HUT 78 T cells. Only dimethylfumarate (DMF) dimin-
`ished IL-6 and TGF-␣ secretion in the psoriatic cocultures. However, it did not have this effect on
`cocultures from control subjects or on monocultures. DMF suppresses EGF-induced TGF-␣ mRNA
`induction in psoriatic keratinocytes. DMF inhibited INF-␥ secretion in all cultures but stimulated the
`IL-10 secretion. This immunomodulation away from the TH1 cytokine IFN-␥ to the TH2 cytokine IL-
`10 was confirmed in HUT 78 T cells by Northern blot analysis. An increased number of eosinophils is
`a known side-effect in patients treated with this drug, suggesting a clinical relevance of this
`immunomodulation in vivo. This immunomodulation and the suppression of cytokines from the
`psoriatic cytokine network could be responsible for the beneficial effect of DMF in the treatment of a
`hyperproliferative and TH1 cytokine-mediated skin disease.
`
`Psoriasis is a common inflammatory cutaneous disorder
`with a prevalence of 2–3% in the general population.
`Recent findings support a central role for immunologi-
`cal mechanisms in the aetiology of psoriasis. Early
`psoriatic lesions are predominantly infiltrated by
`CD4 þ T cells. These T cells produce high amounts of
`the so-called T-helper 1 (TH1) cytokines interferon ␥
`(IFN-␥) and interleukin (IL) 2 and of other inflamma-
`tory cytokines (e.g.
`IL-6). The effectiveness of
`the
`immunosuppressive drug cyclosporin A or of anti-CD4
`monoclonal antibodies in the treatment of psoriasis
`underlines the central role of
`immunocompetent T
`cells in the pathogenesis of this disease.1–3
`
`Correspondence: Dr med. Hans Michael Ockenfels, Department of
`Dermatology and Allergy, Klinikum Hanau, Leimenstr. 20, 63450
`Hanau, Germany.
`The paper contains data from the doctoral thesis of Gabriele Ockenfels.
`Some of this work was presented in a lecture given at the congress
`‘Psoriasis: from gene to clinic’, London, 5–7 December 1996.
`
`In addition to these TH1 cytokines, the proinflamma-
`tory cytokines IL-6 and IL-8, as well as the keratinocyte
`growth factor (transforming growth factor alpha; TGF-
`␣), are found to be highly elevated in the psoriatic skin
`lesion. Consequently, an idea prevalent among the
`hypotheses proposed to explain the inflammatory and
`hyperproliferative psoriatic skin lesions is that keratino-
`cytes and skin-infiltrating T cells elaborate a specific
`cytokine network including these five mentioned cyto-
`kines.2,4 In some western European countries, a new
`(old) systemic therapy of psoriasis with fumaric acid
`esters (FAEs) is increasingly playing a major part in the
`treatment of psoriasis. More than 30 years have passed
`since the biochemist Schweckendick5 reported the suc-
`cessful treatment of his own psoriatic lesions with
`fumaric acid.
`Although fumaric acid was widely used outside the
`field of dermatology for more than 20 years, FAEs have
`now been reintroduced in the dermatological clinics,
`
`390
`
`䉷 1998 British Association of Dermatologists
`
`Sawai (IPR2019-00789), Ex. 1021, p. 001
`
`

`

`DIMETHYLFUMARATE, CYTOKINES AND PSORIASIS
`
`391
`
`and many double-blind, placebo-controlled studies have
`proved the efficacy of these.6 The current fumaric acid
`therapy for psoriasis is the oral administration of
`dimethylfumarate (DMF) combined with salts (magne-
`sium, calcium and zinc) of monoethyl fumarate (MEF).
`Because almost nothing was known about the antipsor-
`iatic mechanisms of FAEs at the cellular level, we
`investigated the effect of FAEs on the psoriatic cytokine
`network. Therefore, keratinocytes were mono- or cocul-
`tured in a recently described coculture model7,8 with/
`without FAEs and cytokine mRNA induction in the cells;
`cytokine levels in the culture supernatants were also
`determined.
`
`Materials and methods
`
`Patients
`
`Skin biopsies were taken from the lesional plaques of
`nine patients with psoriasis (six men and three women;
`mean age 45 years, range 23–65 years) and from 14
`healthy volunteers (nine men and five women; mean
`age 53 years, range 25–75 years), who served as the
`control group. All the patients had severe psoriasis with
`more than 20% of the skin surface affected. None of
`these patients had received any topical (e.g. calcipotriol
`or dithranol) therapy 6 weeks before or systemic immu-
`nosuppressive therapy 6 months before the study.
`
`Cocultures of keratinocytes with HUT 78 T cells
`
`Keratinocyte cultures were performed with standard
`methods in RPMI-1640 medium supplemented with
`10% heat-inactivated fetal calf serum (FCS) in view of
`the coculture conditions. In passages 4–5, keratino-
`cytes were cocultivated with HUT 78 T cells as
`described previously.7,8 HUT 78 T cells (ATCC, Rock-
`ville, MD, U.S.A.) are a continuously activated T-cell
`lymphoma cell line growing in RPMI-1640 supple-
`mented with 10% FCS.9 HUT 78 T cells are known to
`be capable of binding to non-cytokine-pretreated ker-
`atinocytes and were first described in coculture with
`keratinocytes by Stoof et al.9 in 1992. These cells are
`known to produce cytokines of the TH1 group (IL-2
`and IFN-␥) as well as cytokines of the TH2 group (IL-4,
`IL-5 and IL-10).8,10,11
`Briefly, keratinocytes (105/mL) were seeded in 24-
`well flat-bottomed microtitre plates. After 2 days, the
`medium was removed, and HUT 78 T cells (105/mL)
`were placed in an insert well (Millipore, 0·45 ␮m pore
`size) 2 mm above the top of the keratinocytes with a
`
`final volume of 2 mL of RPMI þ 10% FCS. After 24 h,
`half the medium was removed. FAEs (DMF, Ca-MEF, Mg-
`MEF or Zn-MEF) were added to the cultures at final
`concentrations of 5 and 30 ␮mol/L (Fumapharm, Swit-
`zerland) over 24 h, and the culture supernatants were
`collected. HUT 78 T cells were washed out from the
`insert well with phosphate-buffered saline (PBS), and
`keratinocytes were trypsinized with 0·5% trypsin and
`0·05% EDTA. The cell numbers were determined in a
`Neugebauer counting chamber, and the viability of the
`cells was analysed by Trypan blue exclusion.
`
`Monocultures
`
`Corresponding to these cocultures, monocultures and
`experiments with FAEs were performed over the same
`time period, and the cytokine contents were measured
`in culture supernatants. Additionally, HUT 78 T cells
`(105/mL; n ¼ 5) were monocultivated with another
`stimulus, in this case with the mitogen phytohaemag-
`glutinin (PHA; 5 ␮g/mL), and IL-10 and IFN-␥ concen-
`trations were determined after 2, 4, 8 and 12 h in the
`culture supernatants. At this time point, total RNA was
`isolated from the HUT 78 T cells (n ¼ 4), and Northern
`blot analysis for IL-10 and IFN-␥ was done as follows.
`Similarly, to confirm the inhibition of TGF-␣ secretion in
`psoriatic cocultures by DMF, keratinocytes from psoria-
`tic patients and from control subjects (n ¼ 5) were
`activated with epidermal growth factor (EGF; 5 ng/
`mL), and the effect of DMF on TGF-␣ mRNA expression
`was analysed by Northern blotting.
`
`Cytokine detection in culture supernatants
`
`The culture supernatants were collected, and the cyto-
`kine concentrations of IL-6, IL-8, IL-10, IFN-␥ and TGF-␣
`were measured using standard enzyme-linked immuno-
`sorbent assay (ELISA) techniques. ELISA kits for IL-8 and
`IL-10 were obtained from Medgenix (Ratingen, Ger-
`many), for IL-6 and TGF-␣ from Immunotech (Staufen-
`berg, Germany) and for IFN-␥ from Laboserv (Hamburg,
`Germany). The cytokine concentration was standardized
`to 2 · 105 lymphocytes or keratinocytes in the mono-
`culture and to 4 · 105 cells in the coculture system after
`the density and viability of keratinocytes and HUT 78 T
`cells had been analysed. The sensitivity of the ELISAs as
`well as the necessary cell numbers for the detection of
`cytokines in these systems were tested during the estab-
`lishment of the mono- and coculture system. Statistical
`significance was determined using the Wilcoxon–Mann–
`Witney test.
`
`䉷 1998 British Association of Dermatologists, British Journal of Dermatology, 139, 390–395
`
`Sawai (IPR2019-00789), Ex. 1021, p. 002
`
`

`

`392
`
`H.M.OCKENFELS et al.
`
`Northern blot analysis
`
`In order to correlate the results of the protein level
`assays, Northern blot analysis of IL-10, IFN-␥ and TGF-
`␣ mRNA levels in keratinocytes and/or in HUT 78 T
`cells was performed. Total RNA was isolated both from
`monocultured keratinocytes (with/without stimulation
`by EGF, 5 ng/mL) and from HUT 78 T cells according to
`established procedures. For Northern blotting, dena-
`tured total cellular RNA was separated by gel electro-
`phoresis using 1% agarose gels containing 6·3%
`formaldehyde and 1 · MOPS. Gels were run at 85 V for
`2 h and subsequently transferred to a nylon filter by
`capillary blotting. Filters were baked at 80 ⬚C for 2 h.
`After prehybridization according to standard protocols,
`hybridization was conducted using deoxyadenosin-50-
`[32P]triphosphate-labelled cDNA probes encoding speci-
`fically for TGF-␣, IL-10 and IFN-␥ (ATCC). cDNA probes
`were labelled by random priming. After two washes,
`hybridized membranes were exposed on Kodak X-OMAT
`AR films at – 80 ⬚C. For purposes of comparison, the
`background was subtracted from the cytokine signals
`and the glyceraldehyde-3-phosphate dehydrogenase sig-
`nals (serving as a control for RNA loading), and the
`ratio of their intensities was calculated using Scan
`Analysis software.
`
`Results
`As expected,1–3,7,8 we measured higher cytokine levels
`of IL-6 and TGF-␣ in the psoriatic mono- and cocultures
`(P < 0·05) than in the cultures with control keratino-
`cytes (Table 1). The cocultivation of HUT 78 T cells with
`keratinocytes did not alter the cytokine concentrations
`compared with monocultures, with the exception that
`the IFN-␥ secretion of HUT 78 T cells was raised above
`50% under coculture conditions. No IFN-␥ and no IL-10
`could be measured by ELISAs in the monocultures of
`keratinocytes; moreover, no TGF-␣ was measured in the
`HUT 78 T cell monocultures.
`The IL-8 concentration was not significantly altered
`by FAEs (data not shown). By comparison with the salts
`of MEF, only the addition of DMF exclusively altered the
`cytokine levels in the cell cultures. The addition of DMF,
`even at a concentration of 5 ␮mol/L, diminished TGF-␣
`and IL-6 concentrations only in the psoriatic cocultures
`(P < 0·005). We also detected a reduction in the cyto-
`kine concentration in the psoriatic monocultures but
`not in the monocultures of control subjects. However,
`this effect was not significant (P < 0·1). These data are
`presented in Table 1. In Table 1, Mg-MEF represents the
`
`Wilcoxon–Mann–Witneytest.
`*Cytokinelevelswereelevatedinpsoriaticcultures(P<0·05).**DMFsignificantlyalteredthecytokinesecretioncomparedwithDMF-untreatedcultures(P<0·05);P-valuesbasedon
`
`䉷 1998 British Association of Dermatologists, British Journal of Dermatology, 139, 390–395
`
`345⫾28·5**289⫾19·9
`260⫾30·8340⫾28·9**273⫾23·2
`66⫾11·2208⫾19·5272⫾25·3**203⫾10·2
`
`90⫾14·1**137⫾9·1
`
`139⫾11
`83⫾9·142·3⫾5**
`
`133⫾26·5113⫾21·3155⫾19·396·1⫾10·2**140⫾10·4276⫾31
`
`<5
`<5
`
`<5
`<5
`
`<5
`<5
`
`–
`
`–
`
`–
`
`–
`
`–
`
`127⫾29·8132⫾19
`174⫾35·4197⫾42·3–
`
`310⫾44·3*164·9⫾21·2**341⫾26
`
`–
`
`–
`
`142⫾17·8135⫾18·3106⫾23·5
`146⫾24**293⫾24
`38⫾5·1
`143⫾29·8147⫾31·997⫾22·1
`195⫾41·5208⫾59·7*
`202⫾49
`
`32⫾7·8–
`
`KCConþT125⫾19·1
`KCPsoþT277⫾52*
`34⫾4·6
`HUT78
`126⫾37·9
`KCCon
`241⫾65*
`KcPso
`
`þMg-MEF
`
`þDMF
`
`Without
`
`þMg-MEF
`
`þDMF
`
`Without
`
`þMg-MEF
`
`þDMF
`
`Without
`
`þMg-MEF
`
`þDMF
`
`Without
`
`IL-10
`
`IFN-␥
`
`TGF-␣
`
`II-6
`
`HUT78Tcells.DMForMg-MEFwereaddedat5␮mol/L.Mean⫾SEM.
`Psoriatic(KCPso)andcontrol(KCCon)keratinocytesandHUT78Tcells(HUT78)weremonocultured.Psoriatic(KCPsoþT)orcontrol(KCConþT)keratinocyteswerecocultivatedwith
`Table1.Cytokineconcentrationsinmono-andcoculturesofkeratinocytesfrompsoriaticpatientsandcontrolsubjectsandHUT78Tcellswith/withouttheadditionoffumaratesover24h.
`
`Sawai (IPR2019-00789), Ex. 1021, p. 003
`
`

`

`DIMETHYLFUMARATE, CYTOKINES AND PSORIASIS
`
`393
`
`Figure 1. Effect of dimethylfumarate (DMF)
`on cytokine secretion of
`phytohaemagglutinin-stimulated HUT 78 T
`cells over 2, 4, 8 and 12 h. Values are given
`in pg/mL/105 cells. n ¼ 5; DMF ¼ 5 ␮mol/L
`final concentration. Differences in
`interleukin-10 secretion after 2 and 4 h
`(P < 0·002; P < 0·05) and interferon-␥
`secretion after 2 and 12 h (P < 0·05;
`P < 0·002) are significant.
`
`data of the salts of MEF. Mg-MEF also distinctly reduced
`the cytokine concentration of IL-6 and TGF-␣ in the
`monocultures of psoriatic keratinocytes (P < 0·1), but
`this effect was not observed in the psoriatic cocultures
`(in contrast to DMF). All other variations in the cyto-
`kine values obtained without the addition of MEFs are
`not significant. Using Northern blot analysis, we found
`that DMF, but not the salts of MEF, impressively sup-
`presses EGF-induced TGF-␣ mRNA expression in psor-
`iatic keratinocytes. This effect was not observed in
`control or in unstimulated keratinocytes (data not
`shown).
`In contrast to the DMF-induced specific downregula-
`tion of IL-6 and TGF-␣ concentration in psoriatic cocul-
`tures, DMF influenced the INF-␥ and IL-10 content in
`both psoriatic and control cocultures. DMF reduced the
`IFN-␥ content in all HUT 78 T cells containing cultures,
`including unstimulated HUT 78 monocultures (Table
`1). Additionally, the IFN-␥ concentration in PHA-sti-
`mulated HUT 78 T cells was inhibited even by 5 ␮mol/L
`DMF (Fig. 1). In contrast to this inhibitory effect of DMF
`on the TH1 cytokine IFN-␥, the concentration of the
`TH2 cytokine IL-10 was increased in HUT 78 T cells
`containing cocultures after 24 h (Table 1). This could be
`based on a very early stimulatory effect of DMF on IL-10
`secretion, because we found a maximum of DMF-
`induced IL-10 triggering in PHA-stimulated HUT 78 T
`cells after 2 h (Fig. 1). This immunomodulatory effect of
`
`DMF on the T-cell cytokine secretion was confirmed by
`Northern blot analysis, as shown in Fig. 2(a,b).
`
`Discussion
`In this study, we found that the antipsoriatic agent DMF
`suppresses cytokines of the psoriatic cytokine network
`(IL-6 and TGF-␣) and immunomodulates secretion of
`the T-cell cytokines IFN-␥ and IL-10 in vitro. The so-
`called ‘fumaric acid therapy’ of psoriasis is a complex
`dynamic treatment and consists of the oral administra-
`tion of DMF starting at a dosage of 30 mg once daily
`and increasing first to 120 mg daily after 3 weeks and
`then to 240–720 mg/day in the next weeks. The treat-
`ment includes the fixed combination of DMF (120 mg
`tablet) with the above-mentioned salts of MEF (95 mg
`tablet). Our
`investigations confirm the conclusion
`reached by other investigations, namely that DMF,
`which is metabolized to monomethylfumarate (MMF),
`is apparently the most potent antipsoriatic substance
`in this mixture.12,13 DMF offers antiproliferative acti-
`vity on human keratinocytes even at concentrations
`(> 4 ␮mol/L) three times lower than MEF.13
`At the concentration used, DMF and the salts of MEF
`did not influence the viability of keratinocytes and T
`cells. This is not surprising, because the toxic effects of
`fumarates on cell viability have been described for
`> 12 ␮mol/L DMF and for > 35 ␮mol/L Mg-MEF.13–15
`
`䉷 1998 British Association of Dermatologists, British Journal of Dermatology, 139, 390–395
`
`Sawai (IPR2019-00789), Ex. 1021, p. 004
`
`

`

`394
`
`H.M.OCKENFELS et al.
`
`Figure 2. Cytokine mRNA expression in dimethylfumarate (DMF)-
`treated HUT 78 T cells. (a) Induction of interleukin (IL)-10 mRNA after
`2 h in DMF-treated (5 ␮mol/L; lane 1), phytohaemagglutinin (PHA)-
`activated (lane 2) HUT 78 T cells. Lane 3 represents the IL-10 mRNA
`level in HUT 78 T cells without the addition of PHA and DMF. (b)
`Suppression of interferon (IFN)-␥ mRNA by DMF (5 ␮mol/L; lane 1)
`after 4 h in PHA-activated HUT 78 T cells (lane 4). Lane 5 represents
`the IFN-␥ mRNA level in unactivated HUT 78 T cells. No inhibitory
`effect of Ca-monethylfumarate (MEF) (lane 2) or of Mg-MEF (lane 3) on
`the IFN-␥ mRNA induction even at 30 ␮mol/L could be detected.
`
`For fibroblasts, IC50 values were characterized between
`10 and 30 ␮mol/L DMF.15 In contrast to these data, de
`Jong et al.16 did not observe an inhibitory effect of the
`proliferative response of < 200 ␮mol/L MMF on T cells.
`Moreover, DMF monotherapy has been shown in a
`clinical study to be more effective than the mixtures of
`MEFs.17 However, despite the in vitro data obtained so
`far and the side-effects observed in the clinical treatment
`
`of patients with FAEs (e.g. gastrointestinal complaints,
`nephrotoxicity, eosinophilia and lymphopenia) little was
`known about this drug.6,18
`To investigate putative FAE-induced interactions
`between keratinocytes and T cells via their secretion of
`different cytokines, the in vivo situation was modulated
`by cocultivating keratinocytes with the stimulatory
`neighbourhood of HUT 78 T cells. Indeed, HUT 78 T
`cells are not representative of the TH1 T cells that are
`found in the psoriatic skin lesions, because they are able
`to produce both TH1 as well as TH2 cytokines.8–11 If an
`imbalance of TH1–TH2 cytokines is created by genetic
`determination and trigger factors, a suppression of TH1
`cytokines, as performed by drugs such as cyclosporin A,
`as well as an augmentation of TH2 cytokines could be
`desirable therapeutic mechanisms in the treatment of
`this disease.2 Analysing the FAE-induced cytokine secre-
`tion in a coculture model, we chose the HUT 78 T cells
`with their various cytokine profiles as the favoured cell
`line for another time.7,8
`In this sensitive model, we detected a reduced cyto-
`kine secretion of IL-6 and of TGF-␣ only in the cocul-
`tures with psoriatic keratinocytes but not with control
`keratinocytes or in unstimulated monocultures.
`TGF-␣ is strongly secreted by lesional psoriatic kera-
`tinocytes and is thought to be one of the most important
`cytokines provoking the hyperproliferation of psoriatic
`keratinocytes via an autocrine stimulation.2,4 There-
`fore, we focused on this cytokine and confirmed the
`coculture data by finding a suppressive effect of DMF on
`EGF-induced TGF-␣ mRNA induction in psoriatic kera-
`tinocytes. So, the described antiproliferative effect of
`DMF on highly proliferative keratinocytes12,13 could
`be focused on a downregulation of TGF-␣ cytokine
`secretion in psoriatic keratinocytes to values similar to
`those measured in healthy control subjects (Table 1). In
`contrast to TGF-␣, the cytokine IL-6 can be secreted by
`keratinocytes as well as by HUT 78 T cells.7,8,19 Because
`DMF induced only a diminished IL-6 level in psoriatic
`cocultures, we speculated that DMF inhibits this cyto-
`kine secretion in psoriatic keratinocytes or inhibits
`other cytokine secretions of these interactive cells and
`influences IL-6 secretion via paracrine effects between
`psoriatic keratinocytes and HUT 78 T cells.
`Furthermore, and these are the most surprising data,
`DMF immunomodulates cytokine secretion away from
`the TH1 cytokine IFN-␥ to the secretion of the TH2
`cytokine IL-10. First, we detected this effect in our
`coculture model and then demonstrated a time-depen-
`dent influence of IL-10 and IFN-␥ mRNA expression in
`PHA-stimulated HUT 78 T cells by DMF. Recently, a
`
`䉷 1998 British Association of Dermatologists, British Journal of Dermatology, 139, 390–395
`
`Sawai (IPR2019-00789), Ex. 1021, p. 005
`
`

`

`DIMETHYLFUMARATE, CYTOKINES AND PSORIASIS
`
`395
`
`stimulatory effect of DMF on the TH2 cytokine secretion
`of peripheral blood mononulear cells and human T cells
`has been reported by two other groups.16,20 de Jong
`et al.16 reported a great stimulatory effect of MMF on the
`TH2 cytokines IL-4 and IL-5 but did not detect an
`inhibition of the TH1 cytokines. However, this group
`used other culture conditions and different stimuli for
`their cells, e.g. antibodies, and analysed cytokine secre-
`tion in long-term cultures after 3 days. Knowing these
`data and analysing our (co)culture conditions in the
`first 2–24 h together with the mRNA data presented in
`this paper, these results invite the speculation that DMF
`offers an inhibitory effect on TH1 cytokine secretion,
`particularly over a short rather than over a longer time.
`Over a long time, the TH2 stimulatory effect could be
`the most impressive result of the use of fumarates. This
`speculation may be emphasized by the increased
`number of eosinophils seen in patients treated with
`FAEs. This is a known side-effect of systemic treatment
`with FAEs,6 which also suggests the clinical relevance of
`this immunomodulation from TH1 to TH2 cytokine
`production in vivo.
`In vivo, treatment with FAEs reduces the number of
`CD4-positive T cells,21 but serum cytokine concentra-
`tions were never investigated. The administration of one
`to two tablets of Fumaderm (120 mg of DMF, 95 mg of
`MEF) once or twice a day led to a serum concentration
`of the metabolite MMF of about 18·5 ␮mol/l (Dr Strebel,
`Fumapharm AG, personal communication). Therefore,
`the concentration we used correlated with the putative
`therapeutic levels and is more than toxic in vitro con-
`centrations.
`The TH2 cytokines such as IL-4, IL-5 and IL-10 are
`known to play an antagonistic role with respect to TH1-
`mediated diseases and to inhibit the secretion of the
`cytokines IL-2, IL-12 and IFN-␥.22 Psoriasis is known to
`be a TH1-mediated disease, and cytokines of the TH1
`type are the predominant T-cell cytokines in the psor-
`iatic skin lesion.22 If DMF also offers (i) an immunomo-
`dulatory effect in vivo by suppressing TH1 and inducing
`TH2 cytokines, and (ii) specifically inhibiting the cyto-
`kine secretion of TGF-␣ and IL-6 in the psoriatic skin
`lesions, this could explain the beneficial effect of fuma-
`rates seen in psoriasis. The immunomodulatory poten-
`tial of DMF has encouraged us to gain experience with
`this drug in other TH1-mediated diseases.
`
`References
`1 Baker BS, Fry L. The immunology of psoriasis. Br J Dermatol 1993;
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`
`2 Christophers E. The immunopathology of psoriasis. Int Arch
`Allergy Immunol 1996; 110: 199–206.
`3 Uyemura K, Yamamura M, Fivenson DF et al. The cytokine
`network in lesional and lesion-free psoriatic skin is characterized
`by a T-helper type 1 cell-mediated response. J Invest Dermatol
`1993; 101: 701–5.
`4 Elder JT, Fisher GJ, Linquist P et al. Overexpression of transforming
`growth factor-␣ in psoriatic skin. Science 1998; 243: 811–14.
`5 Schweckendiek W. Heilung von Psoriasis vulgaris. Med Monatsschr
`1959; 13: 103–4.
`6 Altmeyer PJ, Matthes U, Pawlak F et al. Anti-psoriatic effect of
`fumaric acid derivatives: results of a multicentre double blind
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`Sawai (IPR2019-00789), Ex. 1021, p. 006
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