Project

Discipline

Cancer; CD80; Atherosclerosis; Positron Emission Tomography; Plaque vulnerability; Imaging; Transplant rejection; Inflammation

Lead
Das Immunsystem kann zur Heilung einer Krankheit beitragen oder aber destruktiv wirken. Viele Therapien modulieren die Immunantwort, oft sind jedoch weder das ideale noch das erreichte Ausmass der Modulation bekannt. Das Projekt hat zum Ziel, mittels eines bildgebenden Verfahrens Immunaktivierung zu quantifizieren.
Lay summary
Krebszellen können nur überleben, wenn sie vom Immunsystem nicht als „fremd“ erkannt werden, das heisst, wenn sie Immuntoleranz bewirken. Moderne Therapieansätze versuchen, diese Immuntoleranz rückgängig zu machen. Bei Erkrankungen wie Arteriosklerose, Multipler Sklerose oder Transplantations-Abstossung versucht man in der Therapie die Immunogenität zu reduzieren, da sie hier zerstörerisch wirkt. Das Gleichgewicht zwischen Immuntoleranz und Immunogenität zu finden ist eine grosse Herausforderung. Um Immunogenität im Gewebe zu quantifizieren, entwickeln wir „Tracer“, die an gewisse Proteine binden, die bei Immunogenität hochreguliert sind. Ein solches Protein ist CD80. Der Tracer enthält ein radioaktives Isotop, das erlaubt, seine Anreicherung im Gewebe mittels Positron-Emissions-Tomographie (PET) zu lokalisieren und quantifizieren. In Mausmodellen überprüfen wir, ob und wie unser Ansatz die Diagnostik sowie die Planung und Steuerung der Therapie unterstützen kann. Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts Das Projekt soll in der Grundlagenforschung dazu beitragen, die Zusammenhänge zwischen Immunreaktion, Krankheit und Therapie besser zu verstehen. In der Klinik soll das bildgebende Verfahren die Wahl und Dosierung der Therapie unterstützen. Dies soll Patienten helfen und Kosten für ineffektive Therapien einsparen.

Direct link to Lay Summary

Last update: 16.12.2014

Active participation

Number	Title	Start	Funding scheme

The co-stimulatory molecule CD80 (B7-1) and its receptors CTLA-4 and CD28 have key functions in several pathological conditions with involvement of the immune system including cancer, atherosclerosis and transplant rejection. The high affinity interaction between CD80 and CTLA-4 promotes immune tolerance, while at higher CD80 levels, the weak-affinity interaction between CD80 and CD28 is involved in immunogenicity. CD80 has thus two diametrically opposed functions and it depends on the underlying disease and the level of CD80 whether an increase (or decrease) has beneficial or detrimental consequences. CD80 and its receptors are targeted by novel therapies for various indications. Following its dual functionality, finding the right balance in CD80 modulation is not trivial. For these reasons, diagnosis, disease staging and therapy planning would highly profit from a non-invasive method to detect and quantify immunogenic CD80 in tissue.The goal of this project is to develop a tracer for the non-invasive imaging and quantification of immunogenic CD80 by positron emission tomography (PET) and to follow the levels of immunogenic CD80 in mouse models of disease and therapy with proven or suspected involvement of CD80 for proof of concept.We developed a 11C-labeled low molecular weight probe ([11C]AM7) with high affinity (IC50 ca 2 nM) to human CD80. The tracer accumulates strongly in sections of human lymphoma xenografts, human vulnerable athero-sclerotic plaques, moderately in mouse lymphatic tissues and only weakly in tissue with negligible CD80. Small animal PET with a modified 18F-labeled tracer showed high radioactivity accumulation in a draining lymph node close to a human lymphoma xenograft. With both tracers, no accumulation was observed in the poorly vascularized xenografts, in agreement with the predicted and experimentally confirmed unfavorable physico-chemical and pharmacokinetic properties of [11C]AM7, namely high plasma protein binding at low lipophilicity and extensive biliary excretion. As concluded from the binding affinities between CD80 and its receptors and from our own data, our tracers bind to free and CD28-interacting CD80 but not to CD80 bound to CTLA-4. CD80 PET will thus recognize immunogenic CD80 but not CD80 that promotes immune tolerance.In this project, we will develop one or more tracers with optimized in vivo properties allowing quantification of immunogenic CD80 by PET. Tracers will not only be optimized for small animal PET in mouse, we will in addition take into account metabolism by human plasma and microsomal enzymes and transport by human hepatic and renal transporters. With an optimized tracer, we will follow CD80 levels in preclinical models of cancer treated with confirmed and suspected CD80-modulating agents. Furthermore, we will scan mice with allogenic and syngenic skin transplantations to evaluate whether CD80 PET could recognize transplant rejection at an early stage. In all models, levels of co-stimulatory molecules and their receptors will in addition be characterized by molecular biology methods. We are currently establishing a mouse model with vulnerable and stable atherosclerotic plaques. These animals will first be characterized by molecular biology methods for CD80 levels in the atherosclerotic lesions and if enhanced CD80 is confirmed, they will be scanned with our CD80 PET probe for proof of concept towards clinical CD80 PET with patients at risk for vulnerable plaques. Imaging of immunogenic CD80 by PET has the potential to recognize, localize and monitor immunogenic hot spots in disease and under therapy. The planning of therapies targeting CD80 or its receptor interactions could highly profit from CD80 imaging by PET.