Ontwikkeling van humane T cellen met gemodificeerde T-celreceptor en karakterisering van hun antitumoractiviteit

Gils Roex
Persbericht

Er was eens… de geherprogrammeerde T-cel

Er was eens… het leven! Begin jaren 2000 keken vele kinderen gefascineerd naar de televisiereeks op Ketnet waarin de werking van het lichaam werd uitgelegd. Uiteraard was het afweersysteem hier ook een onderdeel van. De witte bloedcellen patrouilleren door ons lichaam om ons niet alleen vrij te houden van infecties, maar ook om erop toe te zien dat elke cel zijn normale functie blijft vervullen. Maar niets is perfect. Kwaadaardige cellen kunnen ontstaan door verstoringen in hun genetische code. Eens de patrouilles omzeild, kunnen ze uitgroeien tot kankercellen.

Een grote variatie aan tumoren wordt vaak onder de overkoepelende term ‘kanker’ geplaatst. Ze kunnen nog verder opgedeeld worden op basis van weefsel of orgaan tot het type cel. Bij elke nieuwe ontdekking weten de verschillende soorten kanker zich verder van elkaar te onderscheiden, wat zowel de ziekte als de behandeling alleen maar complexer maakt. Leukemie is een zeldzame bloedkanker die ontstaat uit voorlopercellen in het beenmerg. Het zijn deze cellen die zich continu delen tot verschillende gespecialiseerde bloedcellen. Bij leukemie is de specialisatie onvolledig en voeren de bloedcellen hun taak niet naar behoren uit. In sommige gevallen kunnen tumorcellen van gezonde cellen onderscheiden worden door de productie van eiwitten in abnormale hoeveelheid of vorm. Zo produceren leukemiecellen in vergelijking met gezonde cellen een immense hoeveelheid van het Wilms’ tumor 1-eiwit of kortweg WT1. Zoals alle eiwitten, wordt WT1 in kleine stukjes geknipt, peptiden genaamd, en op het oppervlak van de cel tentoongesteld.

De soldaten van het afweersysteem die instaan voor het uitschakelen van kwaadaardige indringers, zijn de T-cellen. Tijdens hun training ontwikkelen ze twee delen van een T-celreceptor die samen zorgen voor de herkenning van een specifiek peptide op het oppervlak van een cel. T-cellen die met hun receptor lichaamseigen peptiden herkennen en hiertegen reageren, worden ontslagen uit hun functie. Het nadeel hiervan is dat tumorcellen die te herkennen zijn aan een hoge productie van een lichaamseigen eiwit op deze manier vaak ontsnappen aan de screening van de T-cellen. Bovendien is er ook een hulpreceptor nodig om een verbinding te garanderen die de T-cel zal alarmeren. De aanwezigheid van één van twee hulpreceptoren, CD4 en CD8 genaamd, maakt het onderscheid tussen de twee grote groepen CD4 T-cellen en CD8 T-cellen. T-cellen met CD8 worden aanzien als de echte killers, terwijl deze met CD4 gekend zijn een ondersteunende rol te spelen voor de CD8 T-cellen. Onderzoek heeft echter aangetoond dat CD4 T-cellen ook over de capaciteit beschikken om cellen af te doden. De combinatie van killer- en helperkwaliteiten maakt de CD4 T-cel een interessante kandidaat om te bewapenen tegen leukemie via een genetische herprogrammering met een specifieke T-celreceptor dat het WT1-eiwit kan herkennen.

Doorgaans worden T-cellen geherprogrammeerd met behulp van virussen die de bouwplannen voor een T-celreceptor tegen een eiwit, zoals WT1, bevatten. De virussen infecteren de T-cellen en nestelen zich in de genetische code van hun gastheer waardoor de nieuwe T-celreceptor permanent geproduceerd wordt. Het werken met virussen brengt echter veiligheidsrisico’s met zich mee. Daarom ontwikkelden wij de techniek van elektroporatie om cellen te herprogrammeren, waarbij de celwand tijdelijk gaatjes krijgt door middel van een elektrische schok. Langs deze gaatjes kan vervolgens genetisch materiaal naar binnen stromen met bijna hetzelfde resultaat als bij de virussen: de aanmaak van de nieuwe T-celreceptor, maar dan tijdelijk. Tegelijkertijd wordt ook het bouwplan binnengebracht voor de CD8 hulpreceptor, die ontbreekt in CD4 T-cellen, maar die wel nodig is om de nieuwe T-celreceptor naar behoren te laten werken. Via een tweede elektrische schok wordt ook een stuk genetische code in de T-cel gebracht om de bouwplannen van de reeds aanwezig T-celreceptor te verstoppen. Dit is belangrijk voor de veiligheid, want een combinatie van bouwplannen voor twee T-celreceptoren zou kunnen zorgen voor een receptor met een onbekend doelwit, wat heel wat schade zou kunnen toebrengen in het lichaam.

Na de herprogrammering door middel van twee elektroporaties worden er gekleurde vlaggetjes aan de nieuwe T-celreceptor en CD8 hulpreceptor gehangen. Met een lasertoestel worden dan de hoeveelheid vlaggetjes op de T-cellen gemeten. CD4 T-cellen staan bekend als moeilijk te herprogrammeren cellen. Het aantonen van grote hoeveelheden van beide receptoren bewijst dat onze elektroporatiemethode toch een uitstekende manier is om dit type van T-cellen te herprogrammeren. De aanwezigheid van beide receptoren alleen is echter geen bewijs dat de CD4 T-cellen ook werkzaam zijn. Om dit te bevestigen, brengen we de geherprogrammeerde T-cellen samen in een proefbuis met leukemiecellen waarvan het oppervlak vol staat met stukjes WT1-eiwit waarvoor de T-cellen gevoelig zijn. Bij herkenning van de peptiden kunnen we aanmaak van het celdodende molecule granzyme B door de CD4 T-cellen meten. Hiermee tonen we aan dat onze CD4 T-cellen over de capaciteit beschikken om leukemiecellen schade toe te brengen. Een volgende reeks experimenten moet bevestigen of de leukemiecellen daadwerkelijk ten onder gaan na de CD4 T-celaanval.

Het ultieme doel is om deze geherprogrammeerde T-cellen als behandeling te gebruiken voor leukemie en hopelijk ook voor andere kankers. De T-cellen van een patiënt worden uit het bloed gehaald, alvorens een kuur van chemotherapie te starten. Terwijl de chemotherapie het grootste deel van de leukemiecellen afdoodt, worden de T-cellen in het labo geherprogrammeerd. Vervolgens worden ze terug geïnjecteerd teruggegeven aan dezelfde patiënt om de achtergebleven tumorcellen, die de chemotherapie overleven, op te sporen en te doden. De bevindingen van deze scriptie vormen de basis voor een meer uitgebreid onderzoek naar de ontwikkeling van deze nieuwe T-celtherapie die aanvullend gebruikt kan worden om de effectiviteit van de huidige therapieën te vergroten. Het klinkt misschien wat stroef, maar wie weet krijgen we ooit een aflevering van Er was eens… de geherprogrammeerde T-cel te zien.

Overzichtsfiguur van het volledige proces van herprogammering van de T-cellen.

 

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Universiteit of Hogeschool
Bio-ingenieurswetenschappen: cel- en gentechnologie
Publicatiejaar
2018
Promotor(en)
Prof. Viggo Van Tendeloo, Prof. Jan Paeshuyse
Kernwoorden
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