Lymphocytes selected in allogeneic thymic epithelium mediate dominant tolerance toward tissue grafts of the thymic epithelium haplotype.

Athymic mice grafted at birth with allogeneic thymic epithelium (TE) from day 10 embryos before hematopoietic cell colonization reconstitute normal numbers of T cells and exhibit full life-long tolerance to skin grafts of the TE haplotype. Intravenous transfers of splenic cells, from these animals to adult syngeneic athymic recipients, reconstitute T-cell compartments and the ability to reject third-party skin grafts. The transfer of specific tolerance to skin grafts of the TE donor strain, however, is not observed in all reconstituted recipients, and the fraction of nontolerant recipients increases with decreasing numbers of cells transferred. Furthermore, transfers of high numbers of total or CD4+ T cells from TE chimeras to T-cell receptor-anti-H-Y antigen transgenic immunocompetent syngeneic hosts specifically hinder the rejection of skin grafts of the TE haplotype that normally occurs in such recipients. These observations demonstrate (i) that mice tolerized by allogeneic TE and bearing healthy skin grafts harbor peripheral immunocompetent T cells capable of rejecting this very same graft; and (ii) that TE selects for regulatory T cells that can inhibit effector activities of graft-reactive cells.

Localization of non-Mhc collagen-induced arthritis susceptibility loci in DBA/1j mice

One approach to understanding common human diseases is to determine the genetic defects responsible for similar diseases in animal models and place those defective genes in their corresponding biochemical pathways. Our laboratory is working with an animal model for human rheumatoid arthritis called collagen-induced arthritis (CIA). We are particularly interested in determining the location of disease-predisposing loci. To that end, we performed experiments to localize susceptibility loci for CIA in an F2 cross between the highly susceptible mouse strain DBA/1j and the highly resistant mouse strain SWR/j. Specifically, a quantitative trait locus analysis was performed to localize regions of the mouse genome responsible for susceptibility/severity to CIA. One susceptibility locus, Cia1 in the major histocompatibility locus, had been identified previously. Two additional loci were detected in our analysis that contribute to CIA severity (Cia2, Cia3) on chromosomes 2 and 6. A third locus was detected that contributes to the age of onset of the disease. This locus (Cia4) was located on chromosome 2 and was linked to the same region as Cia2. Determining the identity of these loci may provide insights into the etiology of human rheumatoid arthritis.