Novel histocompatibility loci in man

Descripción del proyecto

Descubrir locus de histocompatibilidad humana ocultos

El sistema inmunitario tiene la capacidad de distinguir entre lo propio y lo ajeno. La regulación de las respuestas inmunitarias está mediada por proteínas codificadas por locus de histocompatibilidad altamente polimórficos situados dentro del complejo principal de histocompatibilidad (MHC), también conocido como antígenos leucocitarios humanos (ALH) en el hombre. Aunque la compatibilidad de las moléculas de ALH reduce las complicaciones del trasplante de médula ósea y el rechazo del injerto, no las elimina. El equipo del proyecto Histogenomics, financiado por el Consejo Europeo de Investigación, pretende identificar todos los locus de histocompatibilidad desconocidos presentes en el genoma humano. Mediante un enfoque pluriómico de los trasplantes de riñón y de células hematopoyéticas, se validarán los locus candidatos para determinar su capacidad de provocar respuestas inmunitarias. Este método imparcial, basado en datos, pretende mejorar la comprensión del injerto contra la enfermedad del hospedador y el rechazo, lo que conducirá a tratamientos de trasplante personalizados.

Objetivo

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.