Descripción del proyecto
Descodificación de las interacciones entre receptores inmunitarios y antígenos
Las células presentadoras de antígenos, como los macrófagos y las células dendríticas, expresan en su superficie el receptor de manosa, que participa en el reconocimiento y la captación de antígenos glicosilados. El receptor de manosa desempeña un papel vital en la capacidad del sistema inmunitario para reconocer y responder a los agentes patógenos, así como para prevenir las respuestas autoinmunes. Sin embargo, su mecanismo de acción sigue siendo desconocido. El proyecto Crosstag, financiado por el Consejo Europeo de Investigación, tiene como objetivo investigar los parámetros estructurales de los antígenos glicoproteicos que potencian la presentación del antígeno mediante su unión al receptor de manosa. En última instancia, el objetivo del proyecto es mejorar las terapias inmunitarias contra el cáncer potenciando la presentación cruzada.
Objetivo
Immune therapies are therefore currently being pursued to reinvigorate the immune reaction against tumours. This is not trivial, as the right type of immune cells must be activated against a tumour-specific antigen. One method to achieve this is by targeting tumour antigens to certain cross-presentation-promoting receptors on antigen presenting cells. The most intriguing of these is the mannose receptor (MR) as the method by which it does this is unknown.
This glycoprotein-binding receptor appears to have two functions on APCs: general uptake-enhancement and, in certain isolated cases, cross-presentation-enhancment. What ligand parameters are important in causing cross-presentation enhancement is not known. Current tools, such as anti-MR antibodies and randomly glycosylated ligands fail to selectively enhance cross-presentation. The main aim of this proposal is to determine what structural parameters of the glycoprotein antigen result in enhanced cross-presentation upon MR-ligation.
I will synthesise a library of biologically traceable single glycoform ligands - with controlled variation in glycan nature, stoichiometry and positioning - for the MR and study differences in uptake, routing and antigen presentation.
A 2nd aim is to uncover what happens to the antigen after uptake by the MR. I.e. whether changes in antigen routing and proteolysis are responsible for enhanced cross presentation of different glycoforms. A 3rd aim is to develop a new method to study the kinetics of surface appearance of epitopes without T-cell reagents to quantify differences between glycoforms.
With this approach I aim to gain new insight into methods for enhancing cross-presentation resulting in improved immune therapies against cancer. My background in carbohydrate and protein modification chemistry will provide the toolkit to synthesise the relevant reagents and my background in immunology will ensure the successful immunological validation of the synthetic single glycoforms.
Ámbito científico
- natural sciencesphysical sciencesopticsmicroscopysuper resolution microscopy
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- medical and health sciencesbasic medicinepharmacology and pharmacypharmaceutical drugsvaccines
- medical and health sciencesclinical medicineoncology
- medical and health sciencesbasic medicineimmunologyimmunotherapy
Programa(s)
Régimen de financiación
ERC-STG - Starting GrantInstitución de acogida
2311 EZ Leiden
Países Bajos