Abstract
Transgenic mice were produced containing a 33 kilobase (kb) DNA fragment encompassing the five exons and all the known regulatory regions of the class IIHLA-DRA gene. The transgene displayed regulated expression [constitutive and interferon-γ (IFN)-γ induced] of the human products in most mouse tissues. The tissue distribution of theDRA transgene products more closely resembled that of their mouse homologues, the endogenous H-2 Ea products, than the wider distribution ofDRA products in humans. This was evident in several tissues (endothelia of small vessels, especially those of glomerular capillaries, Kupffer cells, and epithelial cells lining the gastrointestinal tract), known to differentially express class II molecules in the two species. Thus, the wider human specific pattern of expression requires an exact cis/trans complementation which is incompletely reconstituted in transgenic mice, suggesting that human specific cis-acting elements may have arisen during evolution to direct the expression of class II genes to those anatomical regions which usually lack them in the mouse. The only example of aberrant expression of theDRA gene in the present series of transgenic mice was in the dendritic and/or epithelial cells of the thymic cortex, which displayed greately reducedDRA levels in spite of a normal expression of the endogenous Ea molecules.
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References
Adams, T. E., Bodmer, J. G., and Bodmer, W. F.: Production and characterization of monoclonal antibodies recognizing the a-chain subunits of human Ia alloantigens.Immunology 50: 613–624, 1983
Bieberich, C., Yoshioka, T., Tanaka, K., Jay, G., and Scangos, G.: Functional expression of a heterologous major histocompatibility complex class I gene in transgenic mice.Mol Cell Biol 7: 4003–4009, 1987
Bottazzo, G., Pujol Borrel, R., and Hanafusa, T.: Role of aberrant HLA-DRα expression and antigen presentation in induction of endocrine autoimmunity.Lancet 2: 1115–1119, 1983
Bradley, C. M.: Mixed lymphocyte response.In Mishell B. B. and Shiigi S. M. (eds.) Selected methods in Cellular Immunology, pp. 162-164, 1980
Chada, K., Magram, J., and Costantini, F.: An embryonic pattern of expression of a human fetal globin gene in transgenic mice.Nature 319: 685–689, 1986
Chamberlain, J. W., Nolan, J. A., Conrad, P. J., Vasavada, H. A., Vasavada, H. H., Ganguly, S., Janeway, C. A., and Weissman, S. M.: Tissue-specific and cell surface expression of human major histocompatibility complex class I heavy (HLA-B7) and light (β2-microglobulin) chain genes in transgenic mice.Proc Natl Acad Sci USA 85: 7690–7694, 1988
Chirgwin, J. M., Przybyla, A. E., MacDonald, R. J., and Rutter, W. J.: Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease.Biochemistry 18: 5294–5299, 1979
Cowing, C.: Does T cell restriction to Ia limit the need for self tolerance?Immunol Today 6: 72–74, 1985
Dorn, A., Fehling, H. J., Koch, W., le Meur, M., Gerlinger, P., Benoist, C., and Mathis, D.: B-cell control region at the 5′ end of a major histocompatibility complex class II gene: sequences and factors.Mol Cell Biol 8: 3975–3987, 1988
Ehrlich, R., Sharrow, S. O., Maguire, J. E., and Singer, D. S.: Expression of a class I MHC transgene: effects of in vivo α/β interferon treatment.Immunogenetics 30: 18–26, 1989
Gambari, R., Barbieri, R., Piva, R., Tecce, R., Fisher, P. B., Giacomini, P., and Natali, P. G.: Regulation of the expression of class II genes of the human major histocompatibility complex in tumor cells.Ann N Y Acad Sci 511: 292–307, 1987
Gordon, J. W., Chesa, P. G., Nishimura, H., Rettig, W. J., Maccari, J. E., Endo, T., Seravalli, E., Seki, T., and Silver, J.: Regulation of Thy-1 gene expression in transgenic mice.Cell 50: 445–452, 1987
Kollias, G., Wrighton, N., Hurst, J., and Grosveld, F.: Regulated expression of human Aγ-, β-, and hybrid γβ-globin genes in transgenic mice: manipulation of the development expression patterns.Cell 46: 89–94, 1986
Korman, A. J., Boss, J. M., Spies, T., Sorrentino, R., Okada, K., and Strominger, J. L.: Genetic complexity and expression of human class II histocompatibility antigens.Imnumol Rev 85: 45–86, 1985
Larhammar, D., Gustafsson, K., Claesson, L., Bill, P., Wiman, K., Schenning, L., Sundelin, J., Widmark, E., Peterson, P. A., and Rask, L.: Alpha chain of HLA-DRα transplantation antigens is a member of the same protein superfamily as the immunoglobulins.Cell 30: 153–161, 1982
Lawrance, S. K., Karlsson, L., Price, J., Quaranta, V., Ron, Y., Sprent, J., and Peterson, P. A.: Transgenic HLA-DRU faithfully reconstitutes I-E-controlled immune functions and induces crosstolerance to Ea in Eα0 mutant mice.Cell 58: 583–594, 1989
Loken, M. R. and Stall, A.: Flow cytometry as an analytical and preparative tool in immunology.J Immunol Methods 50: R85-R112, 1982
Miller, J., Daitch, L., Rath, S., and Selsing, E.: Tissue specific expression of allogeneic class II MHC molecules induces neither tissue rejection nor clonal inactivation of alloreactive T cells.J Immunol 144: 334–341, 1990
Morahan, G., Allison, J., and Miller, J. F. A. P.: Tolerance of class I histocompatibility antigens expressed extrathymically.Nature 339: 622–624, 1989
Natali, P. G., De Martino, C., Pellegrino, M. A., and Ferrone, S.: Analysis of the expression of I-AK-like antigens in murine fetal and adult tissues with the monoclonal antibody 10–2.16.Scand J Immunol 13: 541–546, 1981
Nishimura, Y., Iwanaga, T., Inamitsu, T., Yanagawa, Y., Yasunami, M., Kimura, A., Hirokawa, K., and Sasazuki, T.: Expression of the human MHC HLA-DQW6 genes alters the immune response in C57BL/6 mice. J Immunol145: 353–360, 1990
Ozato, K., Mayer, N., and Sachs, D. H.: Hybridoma cell lines secreting monoclonal antibodies to mouse H-2 and la antigens.J Immunol 124: 533–540, 1980
Palmiter, R. D. and Brinster, R. L.: Germ-line transformation of mice.Annu Rev Genet 20: 465–499, 1986
Rogers, M. J., Germain, R. N., Hare, J., Long, E., and Singer, D. S.: Comparison of MHC genes among distantly related members of the genus mus.J Immunol 134: 630–636, 1985
Russel, P. S., Chase, C. M., Colvin, R. B., and Plate, J. M. D.: Kidney transplants in mice.J Exp Med 147: 1449–1466, 1978
Skoskiewicz, M. J., Colvin, R. B., Schneeberger, E. E., and Russel, P. S.: Widespread and sellective induction of major histocompatibility complex-determined antigens in vivo by interferon.J Exp Med 162: 1645–1664, 1985
Spies, T., Sorrentino, R., Boss, J. M., Okada, K., and Strominger, J. L.: Structural organization of the DR subregion of the human major histocompatibility complex.Proc Natl Acad Sci 82: 5165–5169, 1985
Sullivan, K. E., Kalman, A. F., Nakanishi, M., Tsang, S. Y., Wang, Y., and Peterlin, B. M.: A model for the transcriptional regulation of MHC class II genes.Immunol Today 8: 289–293, 1987
Sundt, T. M., III and Sachs, D. H.: Applications of molecular biology to transplantation tolerance.Immunol Today 9: 342–344, 1988
Van Ewijk, W., Ron, Y., Monaco, J., Kappler, J., Marrack, P., Le Meur, M., Gerlinger, P., Durand, B., Benoist, C., and Mathis, D.: Compartmentalization of MHC class II gene expression in transgenic mice.Cell 53: 357–370, 1988
Widera, G., Burkly, L. C., Pinkert, C. A., Bottger, E. C., Cowing, C., Palmitter, R. D., Brinster, R. L., and Flavell, R. A.: Transgenic mice selectively lacking MHC class II (I-E) antigen expression on B cells: an in vivo approach to investigate la gene function.Cell 51: 175–187, 1987
Wong, G. H. W., Bartlett, P. F., Clark-Lewis, I., Battye, F., and Schrader, J. W.: Inducible expression of H-2 and la antigens on brain cells.Nature 310: 688–691, 1984
Yamamura, K., Kikutani, H., Folsom, V., Clayton, L. K., Kimoto, M., Akira, S., Kashiwamura, S., Tonegawa, S., and Kishimoto, T.: Functional expression of a microinjected Ead gene in C57BL/6 transgenic mice.Nature 316: 67–69, 1985
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Giacominil, P., Ciucci, A., Nicotra, M.R. et al. Tissue-specific expression of theHLA-DRA gene in transgenic mice. Immunogenetics 34, 385–391 (1991). https://doi.org/10.1007/BF01787489
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DOI: https://doi.org/10.1007/BF01787489