Genomics-based immunological risk stratification in kidney transplantation (GenTX)
A project of the Medical University of Vienna supported by the Wiener Wissenschafts-, Forschungs und Technologiefonds (LS20-081)
Description
In our previous WWTF funded research (Polimorph) we showed that non-HLA genetic mismatch in kidney transplant donor and recipient pairs have a major impact on graft survival (Reindl-Schwaighofer et al. Lancet 2019). This data extended the concept of HLA epitope mismatch to genome-wide incompatibilities. The applied genotyping approach allowed for the simultaneous evaluation of over 50,000 genetic variants that result in amino acid mismatches and reflected genetic variation on the population level. Not all identified variants were immunogenic and resulted in antibody formation. Following up on this data we propose a refined risk prediction tool based on: a) whole exome sequencing in 350 transplant pairs from our prospective transplant biobank to cover individual level genetic variation that can not be identified using genotyping and b) a refined bioinformatics pipeline to identify immunogenic variants by integrating antibody accessibility (protein structure) and indirect allorecognition by recipient T-cells (MHC-restriction). As a proof of principle, the detection of antigen-specific indirectly alloreactive T-cells will be tested by using HLA class II / allopeptide tetramers to provide novel insight into the immunogenicity of HLA and non-HLA incompatibilities on a mechanistic level. Overall this research will increase our understanding of immunological non-self and ultimately make immunological risk stratification clinically feasible and thus allow for a personalized medicine approach.
GenTx is a multi-year research project funded by the Vienna Science and Technology Fund (WWTF - LS20-081). It has started in 2021.
Beschreibung
In unserem letzten WWTF-geförderten Projekt konnten wir zeigen, dass genetische Unterschiede zwischen Spendern und Empfängern bei Nierentransplantation einen großen Einfluss auf das Überleben der Organe haben (Reindl-Schwaighofer et al. Lancet 2019). Diese Ergebnisse erweiterten das Konzept des immunologischen "selbst" bei Organtransplantation, welches nun Varianten, die über das gesamte Genom verteilt sind, umfasst. In einem nächsten Schritt sollen im aktuellen Projekt auch seltene genetische Varianten, die nur bei einzelnen Individuen vorkommen, durch Sequenzierung des Erbguts erkannt werden. Nicht alle Varianten führen aber zu einem gleich großen Effekt auf das Immunsystem, weshalb zusätzlich eine verbesserte Charakterisierung der Inkompatibilitäten erfolgen muss: Hier werden wir speziell darauf eingehen ob einzelne Varianten durch Antikörper erreicht bzw. durch das Immunsystem des Empfängers überhaupt erkannt werden können. Darüber hinaus soll eine Immunantwort gegen diese Varianten nachgewiesen werden, wobei wir sowohl Antikörpern als auch Immunzellen untersuchen werden. Insgesamt erlauben die durch diese Studie gewonnen Daten eine individualisierte Risikoabschätzung vor einer Nierentransplantation und wird eine individualisierte Therapie ermöglichen.
Investigators
Principal Investigator: Rainer Oberbauer Medical University of Vienna
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Rainer Oberbauer is a senior scientist in the field of transplantation and was the principal investigator of the previous WWTF funded research project (Polimorph). He has a long-standing track record in biomarker development using OMICS data as well as genetics in transplantation. He will coordinate and supervise the research efforts of this follow-up project.
Co-principal Investigator: Roman Reindl-Schwaighofer
Roman Reindl-Schwaighofer was the leading scientist in the previous research efforts on genome-wide incompatibility in transplantation (Polimorph) and has conceptualized the current proposal together with Rainer Oberbauer. He is in charge of the prospective Vienna transplant cohort and biobanking efforts and responsible for the implementation of the bioinformatics workflow in the POLiMORPH project. He will oversee and coordinate the WES and the implementation of the enhanced bioinformatics workflow for improved risk prediction based on donor recipient genetic mismatch.
Co-principal Investigator: Nikolina Papac-Milicevic
Nikolina Papac-Milicevic is a young scientist and was also involved in the Polimorph project as core member of Christoph Binder ́s research group. She has a great experience in immunology and will oversee the wet-lab experiments including antibody testing and tetramer-staining.
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