X-LINKED MINOR HISTOCOMPATIBILITY BARRIERS IN MICE

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DESCRIPTION (Applicant's Abstract): This proposal is focused on the whole-animal and molecular characterization of X-linked minor histocompatibility (H) barriers in mice. One such allogenic locus on the X, dubbed H-Xby Bailey and more recently renamed Hxa, has been described previously for 4 different inbred mouse strain combinations, but has not been characterized in any detail. Here we propose to reopen investigation of X-linked minor histocompatibility barriers in mice, with the principle aim of integrating this classical whole-animal immunogenetic phenotype (allograft rejection) with the recently established molecular genetic framework of the murine X chromosome. In general, we aim to further characterize the X-linked minor H barriers we identify between various inbred strain combinations by mapping each antigenic locus to one or more discrete locations on the mouse X chromosome. This approach will also allow us to test two current hypotheses in immunogenetics. First, fine structure mapping of the gene(s) responsible for X-linked histoincompatibility will allow us to test the two-gene model for minor histocompatibility-locus structure recently proposed by Roopenian and coworkers. X-linked histoincompatibility will provide a unique test of this model, as the proposed components of this classical H locus could be widely spread apart on the X chromosome, rather than tightly linked as has been found for all the autosomal H-loci studied. Second, by taking this mapping approach independently with several different inbred strain combinations we will be able to test the hypothesis that the various examples of X-linked histoincompatibility in mice identify different alleles of a single Hxa locus. Instead, it could be that each different X-mediated interstrain histoincompatibility could identify distinct sets of antigen-encoding loci of importance in transplantation biology. Whatever the outcome in terms of Hxa structure and allelism, the approach we describe will set the stage for the eventual positional cloning of any X-linked histocompatibility locus we identify.