Glycolipids and iNKT-cells: a promising marriage in immunity

Matthias Vandekerckhove Anton De Spiegeleer
 Van zeespons tot proefbuis: maken glycolipiden hun beloftevolle toekomst waar?Vooruitgang wordt gekenmerkt door een toenemende complexiteit, een groeiend monster dat niet meer aan de ketting wil. In een gevoel van onbeheersbaarheid slagen weinigen er nog in het overzicht te bewaren. Ook voor de meeste wetenschapsdomeinen is onderzoek complex, kostelijk en onvoorspelbaar geworden, al hoeft een gebrek aan overzichtelijke kennis geen hindernis te vormen voor goede uitvindingen.

Glycolipids and iNKT-cells: a promising marriage in immunity

 

Van zeespons tot proefbuis: maken glycolipiden hun beloftevolle toekomst waar?

Vooruitgang wordt gekenmerkt door een toenemende complexiteit, een groeiend monster dat niet meer aan de ketting wil. In een gevoel van onbeheersbaarheid slagen weinigen er nog in het overzicht te bewaren. Ook voor de meeste wetenschapsdomeinen is onderzoek complex, kostelijk en onvoorspelbaar geworden, al hoeft een gebrek aan overzichtelijke kennis geen hindernis te vormen voor goede uitvindingen. Vaccins zijn hiervan zo’n voorbeeld: in een complexe hoedanigheid als het immuunsysteem kunnen simpele oplossingen verscholen liggen. Vandaag worden er nog steeds pogingen ondernomen om meer vat te krijgen op deze ongrijpbare materie. Als studenten geneeskunde hadden we in onze masterproef het voorrecht om deel uit te maken van dit moeizame proces.

Ons verhaal begint in de jaren negentig. Een Japans farmaceutisch bedrijf –oorspronkelijk een bierbrouwerij (Kirin Brewery)- ontdekte uit extracten van Agelas Mauritianus, een zeespons te vinden nabij de Okinawa-eilanden, een molecule met significante antitumorale kenmerken: op spectaculaire wijze bleek het in staat om uitgezaaide melanomen te bestrijden, bij proefdieren althans. Deze veelbelovende molecule behoorde tot de klasse der glycolipiden en werd naar zijn chemische samenstelling alpha-galactosylceramide (aGC) genoemd.

Het exacte werkingmechanisme van aGC kon toen nog niet verklaard worden: het berustte niet op een klassiek chemotoxisch mechanisme, waarbij naast de kankercellen ook gezonde cellen afsterven, wat de zware bijwerkingen en beperkingen van klassieke chemotherapie verklaart. Het geheim zat verscholen in een tot dan toe onbekende soort immuuncellen: zij kregen de naam “Natural Killer T-cellen”, kortweg NKT-cellen, omdat zij kenmerken vertonen van zowel Natural Killer-cellen als T-cellen, twee reeds gekende immuuncellen. Na activatie door aGC ontpoppen NKT-cellen zich tot handige orkestmeesters die een waaier aan afweermogelijkheden kunnen dirigeren door de productie van signaalstoffen, ‘cytokines’. Hierdoor gaan witte bloedcellen tumorcellen afbreken en opruimen. Dit onderbouwt de recente hypothese dat een falend afweersysteem aan de basis ligt van het onstaan van kanker.

Mochten we deze cellen naar believen kunnen activeren en sturen, zouden we een bijzonder krachtig middel in handen hebben: niet alleen in de strijd tegen kanker, maar ook op alle andere domeinen waar het immuunsysteem bij betrokken is, zoals de ontwikkeling van nieuwe vaccins en de strijd tegen chronische infecties en auto-immuunziekten. Bovendien kon dit ‘immunologisch zakmes’ door relatief simpele en goedkoop te fabriceren glycolipiden gehanteerd worden.

In ons proefwerk hebben we ook de mogelijkheid onderzocht om aGC aan te wenden als hulpstof of ‘adjuvans’ in vaccins, met de bedoeling deze vaccins effectiever te maken. In een reeks experimenten met artritis als proefdiermodel zijn we er niet in geslaagd om aGC als adjuvans te doen werken, al was dit voor ons nog geen reden om pessimistisch te worden. We gingen op zoek naar een andere invalshoek: vele onderzoeksstrategieën zijn erop gericht om via kleine wijzigingen aan de chemische structuur van aGC het immuunsysteem naar de gewenste respons te sturen. Het aantal structuurvariaties van deze aGC-analogen is schier oneindig waardoor het een hele opgave is om de prijsbeesten ervan tussen uit te halen: onderzoek met proefdieren slokt tijd en geld op, zonder ook maar enige garantie op succes. Vandaag de dag varieert de ontwikkelingskost voor een nieuw medicijn tussen 1 à 10 miljard euro, met als startpunt ongeveer 10.000 kandidaat-moleculen, een nog betrekkelijk overzichtelijk getal. Een significante component in het kostenplaatje zijn de middelen die men besteedt aan moleculen die de finish niet halen: deze ‘kost van het falen’ zorgt ervoor dat medicijnen zo ellendig duur kunnen worden. Om het onderzoek naar een theoretisch oneindig aantal moleculen beheersbaar te houden moet men op zoek gaan naar methodes die op een doordachte manier de potentiële kampioenen eruit kunnen screenen.

Vanuit dit opzicht hadden we het plan opgevat een model te ontwikkelen dat in staat is aan de hand van de chemische structuur in te schatten hoe NKT-cellen op nieuwe aGC-analogen zouden reageren. We gebruikten daarvoor een statistische methode van ‘clustering’, wat in dit onderzoeksdomein een volledig nieuwe benadering is. Aan de hand van data uit de literatuur en ons eigen laboratorium bekeken we een 300-tal moleculen die reeds in vivo of in vitro getest waren. Daarvan werden meer dan 3000 chemische eigenschappen gevalideerd en gecorreleerd naar het effect dat ze in vivo vertoonden. In culinaire termen hebben we eigenlijk gezocht naar de smaken waar NKT-cellen op verlekkerd zijn, bijvoorbeeld lange vetstaarten, extra glucose of een snuifje aromaten. De volgende stap –en hier wordt nog aan gewerkt- is om met dit theoretisch model het ideale recept te creëren, d.i. een perfect geoptimaliseerd aGC-analoog dat in staat is via NKT-cellen het immuunsysteem in de gewenste richting te sturen.

Van de zeesponsen van Okinawa tot immunomodulerende therapieën: zulke romantische verhalen verbloemen de tijd, het labeur en de frustraties die inherent deel uit maken van het proces. Vaak is er geen happy end en het kerkhof der gebuisde medicamenten is geen eenzame plek. De schoonheid van fundamenteel onderzoek ligt juist in deze onvoorspelbaarheid: de verrassingen houden onze geesten scherp en onze blik verwonderd. Vanaf een zekere hoogte maakt deze onvoorspelbaarheid kosten-batenanalyses over dergelijke ondernemingen dan ook zinloos: Columbus wist ook niet wat er achter de horizon zat, maar zijn  enthousiaste nieuwsgierigheid en verwondering bleken later het begin van een heel nieuwe wereld... 

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