Histocompatibility antigens on melanoblasts and hair follicle cells. Cell-localized homograft rejection in allophenic skin grafts.
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Biomedical subjects
Publications and source records attributed to B Mintz.
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Erythropoietic cells of two unrelated strains, C3H (or C3Hf) and C57BL/6, can coexist throughout hematopoiesis in allophenic mice experimentally produced from aggregated, undifferentiated blastomeres of separate genotypes. The presence of two red cell genotypes in these circumstances signifies that the erythroid population must normally be multiclonal, i.e., derived mitotically from at least two genetically determined cells. The two strains were detected by hemagglutination and absorption tests of erythrocytes for the specific histocompatibility antigens dictated by the H-2(k) and H-2(b) alleles. Of 34 C3H(f) <--> C57BL/6 allophenics tested, 16 had both red cell types; the remaining 18 showed only C3H or C57 red cells and included 12 mice with both cell strains present in some other tissues. All animals with evidence of two H-2 phenotypes among circulating erythrocytes were permanently immunologically tolerant of both antigenic types and remained free of runt disease. They lived a full lifespan, up to 2 yr 7(1/2) months of age. The data suggest a possible specific selective advantage of C57BL/6 over C3H erythropoietic tissue. There is considerable individual variability, not only in proportions of antigenically distinct erythrocytes, but also in strain composition of other tissues in the same animals. A broad spectrum of distinctive situations is found, in which parameters are varied within or outside of the circulatory system. Allophenic mice can therefore serve as investigative tools for entirely new kinds of experimental studies of gene control mechanisms and blood physiology in normal hematopoiesis and in a number of hereditary blood diseases.
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Mice experimentally derived from pairs of conjoined, undifferentiated, cleavage-stage embryos of different histocompatibility genotypes can retain cells of each strain, which still produce their characteristic antigenic products. The animals are permanently tolerant of cells of both original types, remain free of runt disease, and display a normal and specific immune response to introduction of a foreign antigen. Absence of autoimmunity in development of ordinary animals is explainable by the "intrinsic" kind of tolerance found here.
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Mouse malignant teratocarcinoma cells, upon injection into early embryos at the blastocyst stage, become integrated into the developing embryo and stably normalized. In the mosaic mice that are formed, tumor-derived cells can give rise to the full range of normal, functional somatic tissues, and also to germ cells from which progeny are obtained. Totipotent mouse teratocarcinoma cells thus provide a new and essentially parasexual means of generating entire animals. The advantages of in vitro and in vivo technologies can now therefore be combined to synthesize mice with experimentally useful mutations. After mutagenization of the teratocarcinoma cells in culture, and selection or screening for the desired mutant phenotype, cells of mutant clones are microinjected into genetically marked blastocysts for further differentiation and full gene expression within the framework of the organism. An example is the isolation, by 6-thioguanine resistance, of cells deficient in hypoxanthine-guanine phosphoribosyl transferase -- the same deficiency that characterizes human patients with the X-linked Lesch-Nyhan disease. In work in progress, these cells have been cycled into genetically marked blastocysts, where the tumor lineage has successfully given rise to fully differentiated tissue contributions in which the enzyme defect persists. Such experiments present numerous possibilities for introducing specific mutations into mice, toward the ends of studying gene mechanisms responsible for differentiation and of producing animal models of human genetic diseases. Teratocarcinoma cells may also serve as vehicles for introducing foreign genetic material into mice in order to facilitate analyses of gene control mechanisms in development and disease.