Novel histocompatibility loci in man

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.