NO324557B1 - Use of fatty acid analogues to prevent and / or treat inflammatory and / or autoimmune disorders. - Google Patents
Use of fatty acid analogues to prevent and / or treat inflammatory and / or autoimmune disorders. Download PDFInfo
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- NO324557B1 NO324557B1 NO20032054A NO20032054A NO324557B1 NO 324557 B1 NO324557 B1 NO 324557B1 NO 20032054 A NO20032054 A NO 20032054A NO 20032054 A NO20032054 A NO 20032054A NO 324557 B1 NO324557 B1 NO 324557B1
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Description
Den foreliggende oppfinnelse vedrører fettsyreanaloger som kan anvendes for hindre og/eller behandle inflammatoriske og/eller autoimmune forstyrrelser. The present invention relates to fatty acid analogues which can be used to prevent and/or treat inflammatory and/or autoimmune disorders.
Bakgrunn og teknikkens stilling Background and state of the art
Interleukiner, interferoner, kolonistimulerende faktorer og TNFa er eksempler på en gruppe forskjellige multifunksjonelle proteiner benevnt cytokiner. Cytokiner er en klasse av utskilte løselige proteiner som normalt foreligger i svært lave konsentrasjoner i en rekke celler. Lymfoider, inflammatorisk hemopoietiske celler og andre celler så som bindevevsceller (f.eks. fibroblaster, osteoblaster) utskiller en rekke cytokiner som regulerer immune, inflammatoriske, repara-sjons og akuttfase responser ved å regulere celleproliferasjon, differensiering og effektorfunksjoner. Effektene av cytokinene medieres gjennom binding til høyaffinitetsreseptorer på spesifikke celletyper. Interleukins, interferons, colony-stimulating factors and TNFα are examples of a group of different multifunctional proteins called cytokines. Cytokines are a class of secreted soluble proteins that are normally present in very low concentrations in a variety of cells. Lymphoids, inflammatory haemopoietic cells and other cells such as connective tissue cells (e.g. fibroblasts, osteoblasts) secrete a number of cytokines which regulate immune, inflammatory, repair and acute phase responses by regulating cell proliferation, differentiation and effector functions. The effects of the cytokines are mediated through binding to high-affinity receptors on specific cell types.
Et viktig cytokin er IL-10, et 35-40 kDa peptid produsert av hjelper T-celler, B-celler, monocytter, makrofager og andre celletyper. In vitro har IL-10 vist seg å ha immunundertrykkende egenskaper som det er fremkommet ved dets evne til å undertrykke cytokinproduksjon inkluderende IL-1 og TNFa. IL-10 inhiberer også aktivering av andre inflammatoriske cytokiner, og har derfor potent anti-inflammatorisk aktivitet. An important cytokine is IL-10, a 35-40 kDa peptide produced by helper T cells, B cells, monocytes, macrophages and other cell types. In vitro, IL-10 has been shown to have immunosuppressive properties as demonstrated by its ability to suppress cytokine production including IL-1 and TNFα. IL-10 also inhibits the activation of other inflammatory cytokines, and therefore has potent anti-inflammatory activity.
Det har vært av interesse å administrere IL-10 i behandlingen av visse tilstander karakterisert ved overskudd av IL-1 og TNFa-produksjon. Slike sykdommer eller tilstander inkluderer tap av prostetiske leddimplantater, inflammasjon, diabetes, kreft, graft versus vert sykdom, virale, fungale og bakterielle infeksjoner, lipopolysakkaridendotoksinsjokk, sykdommer av undertrykt benmargsfunksjon, trombocytopeni, osteoporose, spondyloartropati, Pagets sykdom, inflammatorisk magesykdom, artritt, osteoartritt, autoimmune sykdommer så som reumatoid artritt, systemisk lupus erytematosus, og bindevevssykdommer. It has been of interest to administer IL-10 in the treatment of certain conditions characterized by excess IL-1 and TNFα production. Such diseases or conditions include loss of prosthetic joint implants, inflammation, diabetes, cancer, graft versus host disease, viral, fungal and bacterial infections, lipopolysaccharide endotoxin shock, diseases of suppressed bone marrow function, thrombocytopenia, osteoporosis, spondyloarthropathy, Paget's disease, inflammatory bowel disease, arthritis, osteoarthritis , autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and connective tissue diseases.
F.eks. har renset IL-10 vist seg in vitro å undertrykke visse typer av virale infeksjoner. US-Patent Nr 5,665,345 beskriver en fremgangsmåte for å inhibere replikasjon av det human immunsviktvirus, retrovirus, og Kaposis sarkom i humane celler ved administrering av IL-10. IL-10 er også blitt foreslått for anvendelse i behandling av visse typer kreft. US-Patent Nr 5.570.190 beskriver administrering av eksogent IL-10 for å behandle pattedyr som lider av akutt myelogen leukemi og akutt lymfocyttisk leukemi. IL-10 administreres enten i den rensede eller rekombinante form og antas å inhibere proliferasjon av akutte leukemiblastceller. E.g. purified IL-10 has been shown in vitro to suppress certain types of viral infections. US Patent No. 5,665,345 describes a method for inhibiting replication of the human immunodeficiency virus, retrovirus, and Kaposi's sarcoma in human cells by administration of IL-10. IL-10 has also been proposed for use in the treatment of certain types of cancer. US Patent No. 5,570,190 describes the administration of exogenous IL-10 to treat mammals suffering from acute myelogenous leukemia and acute lymphocytic leukemia. IL-10 is administered in either the purified or recombinant form and is believed to inhibit proliferation of acute leukemia blast cells.
Tilsvarende har IL-10 vist seg å inhibere benmargsmetastaser i alvorlig kombinerte immunsviktsmus. Similarly, IL-10 has been shown to inhibit bone marrow metastases in severe combined immunodeficiency mice.
Den ovenfor konvensjonelle løsninger for å behandle tilstander karakterisert ved overskudd av produksjon av IL-1 og TNFa har vært begrenset til administrering av eksogent renset eller rekombinant IL-10 intravenøst. Siden IL-10 er et protein er det vanskelig å infusere intravenøst inn i pattedyret pga. at proteiner ofte lekker ut av løsning og binder til plasten eller glasset som anvendes ved det intravenøse administrasjonssett. Videre er også proteinene ofte inkompatible og presipiterer idet de blandes med fysiologiske løsninger så som dekstrose eller saltløsning. I tillegg er orale og topikale ruter ikke til-gjengelige for IL-10-administrering. Den orale rute er ikke tilgjengelig fordi protein degraderes i den gastrointestinale trakt. The above conventional solutions for treating conditions characterized by excess production of IL-1 and TNFα have been limited to the administration of exogenous purified or recombinant IL-10 intravenously. Since IL-10 is a protein, it is difficult to infuse intravenously into the mammal because that proteins often leak out of solution and bind to the plastic or glass used in the intravenous administration set. Furthermore, the proteins are also often incompatible and precipitate when they are mixed with physiological solutions such as dextrose or saline. In addition, oral and topical routes are not available for IL-10 administration. The oral route is not available because protein is degraded in the gastrointestinal tract.
Ingen av de fremgangsmåter som antydes ovenfor foreslår å styrke endogen produksjon av IL-10 i pattedyr for profylakse og behandling av sykdommer eller tilstander. None of the methods suggested above suggest enhancing endogenous production of IL-10 in mammals for the prophylaxis and treatment of diseases or conditions.
Videre er det kjent at IL-10 er en nyttig deaktivator av makrofager og T-celler, og inadekvat produksjon er blitt implisert i en rekke autoimmune og inflammatoriske forstyrrelser. Furthermore, IL-10 is known to be a useful deactivator of macrophages and T cells, and inadequate production has been implicated in a number of autoimmune and inflammatory disorders.
Det foreliggende forsøk viser at TTA både forbedrer LPS- og PHA-stimulert IL-10, og undertrykker PHA-stimulert IL-2-produksjon i PBMC fra friske bloddonorer. Dette kan ha en rekke implikasjoner. For det første antyder disse funn en markant anti-inflammatorisk nettoeffekt av TTA både ved å forsterke fri-gjøring av det anti-inflammatoriske IL-10 og ved å undertrykke frigjøring av det inflammatoriske cytokin IL-2. For det andre viser våre funn at TTA både kan modulere monocytt (dvs. LPS-stimulering) og lymfocyttaktivering (dvs. PHA-stimulering). Til slutt kan in vitro effekten av TTA på aktiverte PBMC fra friske bloddonorer reflektere situasjonen i en rekke pasientpopulasjoner karakterisert ved forhøyet inflammatorisk aktivering in vivo. Faktisk kan eks-vivo aktiverte PBMC fra friske kontroller representere de relevante målceller for terapeutisk intervensjon in vivo i forskjellige inflammatoriske forstyrrelser. The present experiment shows that TTA both enhances LPS- and PHA-stimulated IL-10, and suppresses PHA-stimulated IL-2 production in PBMC from healthy blood donors. This can have a number of implications. First, these findings suggest a marked anti-inflammatory net effect of TTA both by enhancing release of the anti-inflammatory IL-10 and by suppressing release of the inflammatory cytokine IL-2. Second, our findings show that TTA can modulate both monocyte (ie LPS stimulation) and lymphocyte activation (ie PHA stimulation). Finally, the in vitro effect of TTA on activated PBMCs from healthy blood donors may reflect the situation in a number of patient populations characterized by elevated inflammatory activation in vivo. Indeed, ex-vivo activated PBMCs from healthy controls may represent the relevant target cells for therapeutic intervention in vivo in various inflammatory disorders.
Detaljert beskrivelse av oppfinnelsen Detailed description of the invention
Den foreliggende patentsøknad beskriver at en foretrukket forbindelse ifølge oppfinnelsen, dvs. den svovelsubstituerte fettsyre tetradecyltioeddiksyre (TTA) modulerer frigivelse av inflammatoriske (dvs. IL-2, IL-1 p og TNFa) og anti-inflammatoriske (dvs. IL-10) cytokiner i den dyrkede cellelinje PBMC. The present patent application describes that a preferred compound according to the invention, i.e. the sulphur-substituted fatty acid tetradecylthioacetic acid (TTA) modulates the release of inflammatory (i.e. IL-2, IL-1β and TNFα) and anti-inflammatory (i.e. IL-10) cytokines in the cultured cell line PBMC.
Nærmere bestemt beskriver foreliggende oppfinnelse at TTA markant undertrykker den PHA-stimulerte frigivelsen av IL-2, og også forsterker den PHA-stimulerte frigivelsen av IL-10. More specifically, the present invention describes that TTA markedly suppresses the PHA-stimulated release of IL-2, and also enhances the PHA-stimulated release of IL-10.
Disse to effekter adderes opp til en utstrakt antiinflammatorisk effekt, og det antas således at forbindelsen ifølge foreliggende oppfinnelse er lovende og interessante forbindelser for behandling og/eller forhindring av forstyrrelser relatert til inflammasjon. These two effects add up to an extensive anti-inflammatory effect, and it is thus assumed that the compound according to the present invention are promising and interesting compounds for the treatment and/or prevention of disorders related to inflammation.
Den foreliggende oppfinnelse vedrører således anvendelse av fettsyreanaloger med den generelle (I): - hvori Ri er; The present invention thus relates to the use of fatty acid analogues with the general formula (I): - in which Ri is;
- en C2-C24 alken, og/eller - a C2-C24 alkene, and/or
- en C2-C24 alkyn, og/eller - a C2-C24 alkyne, and/or
- en C1-C24 alkyl, eller C1-C24 alkyl substituert i én eller flere posisjoner med én eller flere forbindelser valgt fra gruppen som omfatter fluorid, klorid, hydroksy, C1-C4 alkoksy, C1-C4 alkyltio, C2-C5-acyloksy eller C1-C4 alkyl, og - a C1-C24 alkyl, or C1-C24 alkyl substituted in one or more positions with one or more compounds selected from the group comprising fluoride, chloride, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, C2-C5 acyloxy or C1-C4 alkyl, and
- hvor R2 representerer hydrogen eller C1-C4 alkyl, og - where R2 represents hydrogen or C1-C4 alkyl, and
- hvor n er et heltall fra 1 til 12, og - where n is an integer from 1 to 12, and
- hvor /' er et oddetall som indikerer posisjon i forhold til COOR2, og - where /' is an odd number indicating position in relation to COOR2, and
- hvor X, uavhengig av hverandre er valgt fra gruppen som omfatter O, S, SO, S02, Se og CH2, og - where X, independently of each other, is selected from the group comprising O, S, SO, SO2, Se and CH2, and
- med den forutsetning at minst én av X, ikke er CH2, - with the proviso that at least one of X, is not CH2,
- med den forutsetning at dersom R1 er alkyn, da er en av karbon-karbon trippelbindingene posisjonert mellom (co-1) karbon og (w-2) karbon, eller mellom (co-2) karbon og (u)-3) karbon, eller mellom (u)-3) karbon og (co-4) karbon, og - med den forutsetning at dersom R1 er alken, da er en av karbon-karbon dobbeltbindingene posisjonert mellom (io-1) karbon og (to-2) karbon, eller mellom (to-2) karbon og (io-3) karbon. - with the proviso that if R1 is alkyne, then one of the carbon-carbon triple bonds is positioned between (co-1) carbon and (w-2) carbon, or between (co-2) carbon and (u)-3) carbon , or between (u)-3) carbon and (co-4) carbon, and - with the proviso that if R1 is alkene, then one of the carbon-carbon double bonds is positioned between (io-1) carbon and (to-2 ) carbon, or between (to-2) carbon and (io-3) carbon.
eller et salt, prodrug eller kompleks derav, for fremstilling av et farmasøytisk materiale å hindre og/eller behandle inflammatoriske og/eller autoimmune forstyrrelser. or a salt, prodrug or complex thereof, for the manufacture of a pharmaceutical material to prevent and/or treat inflammatory and/or autoimmune disorders.
Ytterligere foretrukne utførelser av oppfinnelsen er angitt i underkravene 2-6. Further preferred embodiments of the invention are stated in sub-claims 2-6.
FIGURER FIGURES
Fig. 1 viser effekten av forskjellige konsentrasjoner av TTA på proliferasjon av Fig. 1 shows the effect of different concentrations of TTA on proliferation of
PBMC. PBMC.
Fig. 2 viser effekten av forskjellige konsentrasjoner av TTA på frigivelsen av IL-10 (A), IL-2 (B), TNFa (C) og IL-1 p (D) i PBMC-supernatanter. Fig. 3 viser effekten av TNFa (10 ng/ml) alene eller i kombinasjon med forskjellige konsentrasjoner av TTA på frigivelse av IL-10 (A) og IL-1 p (B) i PBMC supematanter. Fig. 4. Effekten av IL-2 (10 ng/ml) og anti-IL-10 (5 ug/ml) på den TTA-medierte inhibering av PHA-stimulert PBMC-proliferasjon. Fig. 2 shows the effect of different concentrations of TTA on the release of IL-10 (A), IL-2 (B), TNFα (C) and IL-1β (D) in PBMC supernatants. Fig. 3 shows the effect of TNFα (10 ng/ml) alone or in combination with different concentrations of TTA on the release of IL-10 (A) and IL-1β (B) in PBMC supernatants. Fig. 4. The effect of IL-2 (10 ng/ml) and anti-IL-10 (5 µg/ml) on the TTA-mediated inhibition of PHA-stimulated PBMC proliferation.
ADMINISTRERING AV FORBINDELSENE IFØLGE FORELIGGENDE OPPFINNELSE ADMINISTRATION OF THE COMPOUNDS ACCORDING TO THE PRESENT INVENTION
Som et farmasøytisk medikament kan forbindelsene ifølge foreliggende oppfinnelse administreres direkte til pattedyret med enhver egnet teknikk, inkluderende parenteralt, intranasalt, oralt, eller ved absorpsjon gjennom huden. De kan administreres lokalt eller systemisk. Den spesifikke rute for administrering av hvert middel vil avhenge f.eks. av den medisinske historie til pattedyret. As a pharmaceutical drug, the compounds of the present invention may be administered directly to the mammal by any suitable technique, including parenterally, intranasally, orally, or by absorption through the skin. They can be administered locally or systemically. The specific route of administration of each agent will depend on e.g. of the medical history of the mammal.
I tillegg kan forbindelsen ifølge foreliggende oppfinnelse hensiktsmessig administreres i kombinasjon med andre behandlinger for å behandle eller å hindre inflammasjon og autoimmune forstyrrelser. In addition, the compound according to the present invention can be appropriately administered in combination with other treatments to treat or prevent inflammation and autoimmune disorders.
Den foreliggende oppfinnelse vil fremgå tydeligere med henvisning til de påfølgende eksempler. Disse skal imidlertid ikke anses som begrensende for oppfinnelsens ramme. The present invention will appear more clearly with reference to the following examples. However, these should not be considered as limiting the scope of the invention.
EKSPERIMENTELL DEL EXPERIMENTAL PART
Eksempel 1. Fremstilling og karakterisering av forbindelsene Example 1. Preparation and characterization of the compounds
Syntese av 3- substituerte fettsvreanaloger Synthesis of 3-substituted fatty acid analogues
Forbindelsene anvendt i samsvar med foreliggende oppfinnelse hvor substituenten Xj=3 er et svovelatom eller selenatom, kan fremstilles i samsvar med den følgende generelle prosedyre: The compounds used in accordance with the present invention where the substituent Xj=3 is a sulfur atom or selenium atom, can be prepared in accordance with the following general procedure:
X er et svovelatom X is a sulfur atom
Den tio-substituerte forbindelse anvendt i samsvar med foreliggende oppfinnelse kan fremstilles med den generelle prosedyren angitt nedenfor: The thio-substituted compound used in accordance with the present invention may be prepared by the general procedure set forth below:
Svovelforbindelsen, nemlig tetradecyltioeddiksyre (TTA), (CH3-(CH2)i3-S-CH2-COOH ble fremstilt som vist i EP Nr 345.038. The sulfur compound, namely tetradecylthioacetic acid (TTA), (CH 3 -(CH 2 )i 3 -S-CH 2 -COOH) was prepared as shown in EP No 345,038.
X er et selenatom X is a selenium atom
Den selensubstituerte forbindelse anvendt i samsvar med foreliggende oppfinnelse fremstilles med den følgende generelle prosedyre: The selenium-substituted compound used in accordance with the present invention is prepared by the following general procedure:
Denne forbindelse ble renset med forsiktig krystallisering fra etanol eller metanol. This compound was purified by careful crystallization from ethanol or methanol.
Den endelige forbindelse, f.eks. idet alkyl er tetradecyl, (CH3-(CH3)i3-Se-CH2-COOH (tetradecylseleneddiksyre (TSA) kan renses ved krystallisering fra dietyleter og heksan. The final connection, e.g. where alkyl is tetradecyl, (CH3-(CH3)i3-Se-CH2-COOH (tetradecylselenoacetic acid (TSA) can be purified by crystallization from diethyl ether and hexane.
Andre forbindelser i samsvar med foreliggende oppfinnelse kan syntetiseres som angitt i søkers patentsøknader PCT/NO99/00135 og NO 20001123. Other compounds in accordance with the present invention can be synthesized as indicated in the applicant's patent applications PCT/NO99/00135 and NO 20001123.
Eksempel 2 Example 2
Lymfocvttproliferasion Lymphocyte proliferation
Bloddonor (n=5) perifere blod mononukleære celler (PBMC) ble hentet fra heparinisert blod med Isopaque-Ficoll (Lymphoprep, Nycomed Pharma AS, Oslo, Norway)-gradientsentrifugering innen 1 t etter blodtaking. PBMC ble re-suspendert i RPMI 1640 med 2 mM L-glutamin og 25 mM HEPES-buffer (Gibco BRL, Paisley, UK) tilsatt med 10% varmeinaktivert samlet humant AB<+->serum (dyrkningsmedium). Endotoksinnivået i dyrkningsmedium, reagenser og stimulerende midler var <10 pg/ml (kvantitativ kromogenisk limulus amebocytt-lysattest, BioWhittaker, Inc., Walkerswille, MD). Blood donor (n=5) peripheral blood mononuclear cells (PBMC) were obtained from heparinized blood by Isopaque-Ficoll (Lymphoprep, Nycomed Pharma AS, Oslo, Norway) gradient centrifugation within 1 h of blood collection. PBMC were re-suspended in RPMI 1640 with 2 mM L-glutamine and 25 mM HEPES buffer (Gibco BRL, Paisley, UK) supplemented with 10% heat-inactivated pooled human AB<+->serum (culture medium). The endotoxin level in culture medium, reagents, and stimulants was <10 pg/ml (quantitative chromogenic limulus amebocyte light test, BioWhittaker, Inc., Walkerswille, MD).
PMNC (10<6->celler/ml) ble inkubert i flatbunnede, 96brønns-mikrotiterbrett (200 ul/brønn); Costar, Cambridge, MA) i medium alene, eller med fytohemaglutinin (PHA; Murex Diagnostics Ltd., Dartford, UK; final konsentrasjon 1:100), enten alene eller med forskjellige konsentrasjoner av TTA. Bovint serum albumin (BSA, Calbiochem, La Jolla, CA) ble anvendt som en negativ kontroll for TTA (vehikkel). I noen eksperimenter ble nøytraliserende monoklonalt anti-humant interleukin (IL)-10 (final konsentrasjon 5 ug/ml; Endogen, Cambridge, MA) eller rekombinant humant IL-2 (final konsentrasjon 10 ng/ml; R&D Systems, Minneapolis, MN) også tilsatt til cellekulturer før stimulering. Etter 481 ble cellene pulset med 1 uCi <3>H-thymidin (Amersham International pla, Little Chalfont, UK) og 16 t senere ble kulturene høstet for glassfilterstrimler, ved anvendelse av en automatisert multiprøvehøster (Skatron, Lier, Norge). <3>H-thymidininkorporering ble bestemt ved væskescintillasjonstelling som tellinger pr. min. (cpm). PMNC (10<6>cells/ml) were incubated in flat-bottomed, 96-well microtiter plates (200 µl/well); Costar, Cambridge, MA) in medium alone, or with phytohemagglutinin (PHA; Murex Diagnostics Ltd., Dartford, UK; final concentration 1:100), either alone or with different concentrations of TTA. Bovine serum albumin (BSA, Calbiochem, La Jolla, CA) was used as a negative control for TTA (vehicle). In some experiments, neutralizing monoclonal anti-human interleukin (IL)-10 (final concentration 5 ug/ml; Endogen, Cambridge, MA) or recombinant human IL-2 (final concentration 10 ng/ml; R&D Systems, Minneapolis, MN) also added to cell cultures before stimulation. After 481, the cells were pulsed with 1 uCi <3>H-thymidine (Amersham International pla, Little Chalfont, UK) and 16 h later the cultures were harvested for glass filter strips, using an automated multisample harvester (Skatron, Lier, Norway). <3>H-thymidine incorporation was determined by liquid scintillation counting as counts per my. (cpm).
Resultater Results
Idet TTA ikke har noen effekt på lymfocyttproliferasjon idet den ble gitt alene, undertrykte TTA vesentlig PHA-stimulert proliferasjon av PBMC på en doseavhengig måte (~60 reduksjon; Fig. 1). En slik undertrykkende effekt ses i alle 5 bloddonorer. I motsetning ble det ikke sett noen effekt på PHA-stimulert PBMC-proliferasjon når vehikkelen (BSA) ble gitt alene (Fig. 1). Whereas TTA has no effect on lymphocyte proliferation when given alone, TTA significantly suppressed PHA-stimulated proliferation of PBMC in a dose-dependent manner (∼60 reduction; Fig. 1 ). Such a suppressive effect is seen in all 5 blood donors. In contrast, no effect on PHA-stimulated PBMC proliferation was seen when the vehicle (BSA) was given alone (Fig. 1).
Eksempel 3 Example 3
Frigivelse av cytokiner i PBMC supernatanter Release of cytokines in PBMC supernatants
PBMC (10<6->celler/ml) ble inkubert i flatbunnet, 96-brønns mikrotiterplater (200 ul/brønn, Costar) i medium alene (se ovenfor) eller med PHA (final konsentrasjon 1:100), lipopolysakkarid (LPS) fra E. coli 026:B6 (finalkonsentrasjon 10 ng/ml; Sigma, St.Louis, MO) eller tumor-nekrosefaktor (TNF) (final konsentrasjon 10 ng/ml; R&D Systems) med, eller uten forskjellige konsentrasjoner av TTA. BSA ble anvendt som en negativ kontroll for TTA (vehikkel). Cellefrie supernatanter ble høstet etter 201 og lagret ved -8°C. PBMC (10<6> cells/ml) were incubated in flat-bottomed, 96-well microtiter plates (200 µl/well, Costar) in medium alone (see above) or with PHA (final concentration 1:100), lipopolysaccharide (LPS) from E. coli 026:B6 (final concentration 10 ng/ml; Sigma, St.Louis, MO) or tumor necrosis factor (TNF) (final concentration 10 ng/ml; R&D Systems) with or without different concentrations of TTA. BSA was used as a negative control for TTA (vehicle). Cell-free supernatants were harvested after 201 and stored at -8°C.
Enzym immunanalvse ( EIA' er) Enzyme immunoassays (EIAs)
Konsentrasjon av cytokiner i PBMC supernatanter ble analysert ved hjelp av EIA'er i samsvar med produsentens beskrivelse (IL-1p og IL-10: CLB, Amsterdam, Nederland; IL-2: R&D Systems). Concentration of cytokines in PBMC supernatants was analyzed using EIAs according to the manufacturer's description (IL-1p and IL-10: CLB, Amsterdam, The Netherlands; IL-2: R&D Systems).
Statistisk analyse Statistical analysis
For evaluering av effekten av TTA (eller BSA) på forskjellige parametere ble paret prøve T-test anvendt. P-verdier (to-sidet) vurderes som signifikant idet P<0,05. For evaluation of the effect of TTA (or BSA) on different parameters, the paired sample T-test was used. P-values (two-sided) are considered significant when P<0.05.
Resultater Results
Effekten av TTA på c<y>tokinnivåer i PBMC supernatanter The effect of TTA on c<y>tokine levels in PBMC supernatants
Som vist i Fig. 2 hadde TTA alene ingen effekt på produksjon av noen av cytokinene IL-2, IL-1 (3, IL-10 og TNFa. As shown in Fig. 2, TTA alone had no effect on the production of any of the cytokines IL-2, IL-1 (3, IL-10 and TNFa.
Imidlertid fremkom betydelig signifikante funn idet TTA ble tilsatt til celle-kulturene i kombinasjon med PHA eller LPS. However, significantly significant findings emerged when TTA was added to the cell cultures in combination with PHA or LPS.
For det første undertrykte TTA i markant grad PHA-stimulert frigivelse av IL-2 på en doseavhengig måte (ca. 75% reduksjon) (Fig. 2). First, TTA markedly suppressed PHA-stimulated release of IL-2 in a dose-dependent manner (approximately 75% reduction) (Fig. 2).
For det andre, i kontrast til denne undertrykkende effekt, induserte TTA på en doseavhengig måte en forbedret LPS-stimulert (3 gangers økning), og spesielt PHA-stimulert (11 gangers økning) av frigivelse av det anti-inflammatoriske cytokin IL-10 (Fig. 2). Second, in contrast to this suppressive effect, TTA induced in a dose-dependent manner an enhanced LPS-stimulated (3-fold increase), and especially PHA-stimulated (11-fold increase) release of the anti-inflammatory cytokine IL-10 ( Fig. 2).
For det tredje, i kontrast til disse uttalte effekter på IL-2- og IL-10-nivåer, hadde TTA ingen eller kun en svak effekt på LPS-stimulert frigivelse av TNFa og IL-1 (3 (Fig. 2). Det var ingen effekter på vehikkelen (BSA) verken på PHA eller LPS-stimulert frigivelse av cytokiner (Fig. 2). Third, in contrast to these pronounced effects on IL-2 and IL-10 levels, TTA had no or only a weak effect on LPS-stimulated release of TNFα and IL-1 (3 (Fig. 2). It were no effects of the vehicle (BSA) on either PHA or LPS-stimulated release of cytokines (Fig. 2).
I konklusjon har TTA flere effekter på LPS og spesielt på PHA-stimulert frigivelse av cytokiner i PBMC, noe som gir anti-inflammatoriske nettoeffekter. In conclusion, TTA has multiple effects on LPS and especially on PHA-stimulated release of cytokines in PBMC, providing anti-inflammatory net effects.
Effekten av TTA på TNFa- stimulert frigivelse av cytokiner i PBMC supernatanter The effect of TTA on TNFα-stimulated release of cytokines in PBMC supernatants
Fettsyrer er rapportert å modulere forskjellige TNFamedierte effekter. TNFa kan indusere produksjonen av andre cytokiner så som IL-10 og IL-1 (3 (11,12), og vi har derfor undersøkt om TTA kan modulere den TNFa-induserte frigivelse av disse cytokiner fra PBMC i 5 friske bloddonorer. Det skal bemerkes at idet TTA ikke hadde noen effekt på LPS-stimulert frigivelse av TNFa (Fig. 2), forsterket TTA betydelig den TNFa-stimulerte frigivelse både av IL-113 (5 gangers økning) og spesielt IL-10 (11 gangers økning) (Fig. 3). Disse funn antyder at TTA i betydelig grad kan forsterke TNFa-stimulert frigivelse av cytokiner fra PBMC med spesielt forsterkende effekt på frigivelse av IL-10. Fatty acids have been reported to modulate various TNF-mediated effects. TNFα can induce the production of other cytokines such as IL-10 and IL-1 (3 (11,12), and we have therefore investigated whether TTA can modulate the TNFα-induced release of these cytokines from PBMC in 5 healthy blood donors. of note, whereas TTA had no effect on LPS-stimulated release of TNFα (Fig. 2), TTA significantly enhanced the TNFα-stimulated release of both IL-113 (5-fold increase) and especially IL-10 (11-fold increase) ( Fig. 3).These findings suggest that TTA can significantly enhance TNFα-stimulated release of cytokines from PBMC with a particularly enhancing effect on the release of IL-10.
Eksempel 4 Example 4
Effekt av IL- 2 og anti- IL- 10 på TTA- mediert inhibering av lymfocvttproliferasion IL-2 og IL-10 er kjent for å forsterke og inhibere lymfocyttproliferasjon, respek-tivt. Vi undersøkte derfor om den anti-proliferative effekt av TTA på PHA-stimulert PBMC-proliferasjon var relatert til TTA-mediert effekt på disse cytokiner (se ovenfor). Imidlertid hadde tilsetningen av anti-IL-10 til cellekulturer ingen effekt og IL-2 kun en svak motvirkende effekt på TTA-mediert inhibering av lymfocyttproliferasjon (Fig. 4). Det synes således som om den anti-proliferative- og anti-inflammatoriske effekt av TTA i det minste delvis representerer forskjellige biologiske mekanismer. Effect of IL-2 and anti-IL-10 on TTA-mediated inhibition of lymphocyte proliferation IL-2 and IL-10 are known to enhance and inhibit lymphocyte proliferation, respectively. We therefore investigated whether the anti-proliferative effect of TTA on PHA-stimulated PBMC proliferation was related to TTA-mediated effect on these cytokines (see above). However, the addition of anti-IL-10 to cell cultures had no effect and IL-2 only a weak counteracting effect on TTA-mediated inhibition of lymphocyte proliferation (Fig. 4). It thus seems that the anti-proliferative and anti-inflammatory effects of TTA at least partially represent different biological mechanisms.
Konklusjoner Conclusions
Som vist i den eksperimentelle seksjonen har TTA flere effekter for frigivelse av cytokiner fra aktivert PBMC med en markant økning i IL-10 ledsaget av en reduksjon i IL-2nivåer. Dette favoriserer anti-inflammatoriske nettoeffekter, og det antas således at forbindelsene ifølge foreliggende oppfinnelse kan anvendes for å regulere inflammatoriske prosesser, og kan således anvendes som medikamenter for behandlingen og/eller hindring av inflammatoriske forstyrrelser. As shown in the experimental section, TTA has several effects on the release of cytokines from activated PBMC with a marked increase in IL-10 accompanied by a decrease in IL-2 levels. This favors anti-inflammatory net effects, and it is thus assumed that the compounds according to the present invention can be used to regulate inflammatory processes, and can thus be used as drugs for the treatment and/or prevention of inflammatory disorders.
Vi har videre vist at TTA potensierer cytokin-stimulerende effekter av TNFa på disse celler med en spesielt forsterkende effekt på IL-10-nivåene. We have further shown that TTA potentiates the cytokine-stimulating effects of TNFα on these cells with a particularly enhancing effect on IL-10 levels.
Til slutt undertrukket TTA signifikant PBMC-proliferasjon, og denne anti-proliferative effekt involverer ikke en forsterket apoptose og synes i det minste delvis å være forskjellig fra de anti-inflammatoriske effekter på TTA. Finally, TTA significantly suppressed PBMC proliferation, and this anti-proliferative effect does not involve an enhanced apoptosis and seems to be at least partially different from the anti-inflammatory effects of TTA.
Våre funn antyder potente anti-inflammatoriske og anti-proliferative effekter på TTA i aktivert PBMC i mennesker. Our findings suggest potent anti-inflammatory and anti-proliferative effects of TTA in activated human PBMC.
Det er flere forstyrrelser hvor forsterkede IL-10 og reduserte IL-2-nivåer kan være av terapeutisk viktighet. Disse inkluderer en rekke immun-medierte forstyrrelser, så som reumatoid artritt, systemisk vaskulitt, systemisk lupos erytematosus, systemisk sklerose, dermatomyositt, polymyositt, forskjellige autoimmune endokrine forstyrrelser (f. eks. thyroiditis og adrenalitis), forskjellige immunmedierte neurologiske forstyrrelser (f.eks. multippel sklerose og myastenia gravis), forskjellige kardiovaskulære forstyrrelser (f.eks. myokarditt, kongestiv hjertesvikt, arteriosklerose og stabil- og ustabil angina, og Wegeners granulomatose), inflammatorisk tarmsykdom og Crohns kolitt, nefritt, forskjellige inflammatoriske hudforstyrrelser (f.eks. psoriasis, atopisk dermatitt og matallergi) og akutt- og kronisk allograft-transplantat-avvisning etter transplantasjoner. There are several disorders where enhanced IL-10 and reduced IL-2 levels may be of therapeutic importance. These include a variety of immune-mediated disorders, such as rheumatoid arthritis, systemic vasculitis, systemic lupus erythematosus, systemic sclerosis, dermatomyositis, polymyositis, various autoimmune endocrine disorders (eg thyroiditis and adrenalitis), various immune-mediated neurological disorders (eg . multiple sclerosis and myasthenia gravis), various cardiovascular disorders (e.g. myocarditis, congestive heart failure, arteriosclerosis and stable and unstable angina, and Wegener's granulomatosis), inflammatory bowel disease and Crohn's colitis, nephritis, various inflammatory skin disorders (e.g. psoriasis, atopic dermatitis and food allergy) and acute and chronic allograft rejection after transplants.
Det er kjent at IL-10 er en kraftig deaktivator av makrofager og T-celler, og inadekvat produksjon av IL-10 er blitt implisert i forskjellige autoimmune og inflammatoriske forstyrrelser. Det antas således at forbindelsen ifølge foreliggende oppfinnelse kan anvendes for å hindre og/eller behandle autoimmune og inflammatoriske forstyrrelser. IL-10 is known to be a potent deactivator of macrophages and T cells, and inadequate production of IL-10 has been implicated in various autoimmune and inflammatory disorders. It is thus assumed that the compound according to the present invention can be used to prevent and/or treat autoimmune and inflammatory disorders.
Autoimmune modeller for reumatoid artritt, thyroiditis, kollagenindusert artritt og eksperimentell allergenisk encefalimyelitt tyder alle på en negativ regulatorisk rolle for IL-10 med å begrense inflammasjon og immunpatologi. Videre utvikler mus med en målrettet ødeleggelse i IL-10-genet spontant en generalisert enterokolitt. I mennesker kan Crohns kolitt og psoriasis også være utsatt for behandling med systemisk administrert IL-10. Til slutt er IL-10 også nylig funnet å ha beskyttende effekter på utvikling av arteriosklerose og viral myokarditt i mus. Således kan behandlingsmodaliteter som forsterker IL-10-nivåer være av stor interesse i behandling av de ovenfor angitte og andre antoimmune og anti-inflammatoriske forstyrrelser, og det antas at forbindelsene ifølge foreliggende oppfinnelse kan ha slike egenskaper. Autoimmune models of rheumatoid arthritis, thyroiditis, collagen-induced arthritis and experimental allergic encephalmyelitis all suggest a negative regulatory role for IL-10 in limiting inflammation and immune pathology. Furthermore, mice with a targeted deletion in the IL-10 gene spontaneously develop a generalized enterocolitis. In humans, Crohn's colitis and psoriasis may also be susceptible to treatment with systemically administered IL-10. Finally, IL-10 has also recently been found to have protective effects on the development of arteriosclerosis and viral myocarditis in mice. Thus, treatment modalities that enhance IL-10 levels may be of great interest in the treatment of the above and other anti-immune and anti-inflammatory disorders, and it is believed that the compounds according to the present invention may have such properties.
Videre har vi vist at TTA markant øker det TNFot-induserte IL-10-nivået, og slike anti-inflammatoriske egenskaper dersom de utnyttes terapeutisk kan potensielt representere en beskyttelse mot skadelige effekter av TNFa. Furthermore, we have shown that TTA markedly increases the TNFot-induced IL-10 level, and such anti-inflammatory properties, if exploited therapeutically, could potentially represent a protection against the harmful effects of TNFa.
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