Project description
Uncovering hidden human histocompatibility loci
The immune system has the ability to distinguish between self and non-self. Regulation of immune responses are mediated by proteins encoded by highly polymorphic histocompatibility loci located within the major histocompatibility complex (MHC), also known as human leukocyte antigen (HLA) in man. Although matching of HLA molecules reduces complications in bone marrow transplantation and graft rejection, it does not eliminate them. The ERC-funded Histogenomics project aims to identify all unknown histocompatibility loci present in the human genome. Using a pluri-omics approach on kidney transplants and haematopoietic cell transplants, candidate loci will be validated for their ability to elicit immune responses. This unbiased, data-driven method aims to enhance understanding of graft versus host disease and rejection, leading to personalised transplant therapies.
Objective
Allogeneic tissue graft (hematopoietic cell transplantation; HCT) and solid organ transplantation (SOT) (Kidney, Heart, Lung,..) save tens of thousands of lives annually. Yet their success is compounded by a high incidence of the potentially fatal graft-versus-host disease (GvHD) in HCT and chronic rejection (CR) in SOT. This is primarily due to the existence of yet unknown histocompatibility loci which have escaped detection - besides certain immunogenic peptides - since the identification of the Major Histocompatibility Complex (MHC; also called Human Leukocyte antigen HLA in man) in 1940-1950s. The identification of these hitherto unknown histocompatibility loci in man is the major aim of this proposal. Our contribution to MHC genetics includes the identification of the sole, non-HLA, MHC-encoded, class I molecules; the MHC class I chain-related MIC genes (A second lineage of mammalian major histocompatibility complex class I genes. | PNAS), which we recently qualified as a bona fide histocompatibility gene (The MHC class I MICA gene is a histocompatibility antigen in kidney transplantation | Nature Medicine). Here we aim to identify the totality of histocompatibility loci embedded within our genome. We will apply a pluri-omics approach (successfully applied elsewhere Identification of driver genes for critical forms of COVID-19 in a deeply phenotyped young patient cohort (science.org)) on deeply phenotyped cohorts of kidney transplants and HCT. Identified candidate loci will be validated based on their ability to be presented by MHC molecule and to elicit T- and/or B-cell responses. In contrast to the classical, hypothesis-driven approaches, which have collectively failed to identify universally applicable such loci in the past 70 years, our approach is unbiased, data-driven and unprecedented in the field. It shall have direct relevance in our understanding of the primum movens of GvHD and CR and shall lead to a personalized therapy of the transplant patient.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
This project's classification has been human-validated.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
This project's classification has been human-validated.
Keywords
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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HORIZON.1.1 - European Research Council (ERC)
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Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
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Call for proposal
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(opens in new window) ERC-2023-ADG
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67081 Strasbourg
France
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