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Major Histocompatibility Complex Class II Genes Control Susceptibility to Hypersensitivity Pneumonitis in the Mouse
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human surfactant protein SP-C gene confers bronchiolar-alveolar cell specificity in transgenic mice. Am J Physiol 1991; 261: 1..349-56 Paul SR, Bennett F, Calvetti JA, et al. Molecular cloning of a eDNA encoding IL-11, astromal cell-derived lymphopoietic cytokine. Proc Nat! Acad Sci USA 1990; 87:7512-16 Turner KJ, Clark SC. Interleukin-11: biological and clinical perspectives. In: Mertelsmann R, Herrmann F, eds. Hematopoietic growth factors in clinical applications. New York: Marcel Dekker, 1995; 315-36 Patterson PH, Nawa H. Neuronal differentiation factors/cytokines and synaptic plasticity. Cell1993; 72(suppl):123-37 Elias JA, Zheng T, Whiting NL, et al. Interleukin-1 and transfanning growth factor (3 regulation of fibroblast-derived interleukin-11. J lmmunol1994; 152:2421-29 Zheng T, Nathanson M, Elias JA. Histamine augments cytokinestimulated IL-11 production by human lung fibroblasts . J Immunol1994; 153:4742-52 Elias JA, Zheng T, Einarsson 0, et al. Epithelial interleukin-11: regulation by cytokines, respiratory syncytial virus and retinoic acid. J Bioi Chern 1994; 269:22261-68 Gossen M, Bonin AL, Bujard H. Control of gene activity in higher eukaryotic cells by prokaryotic regulatory elements. TIBS 1993; 18:471-75 Gossen M, Bujard H. Tight control of gene expression in mammalian cells by tetracycline responsive promoters. Proc Nat! Acad Sci USA 1992; 89:5547-51 Efrat S, Fusco-DeMane D, Lemberg H, et a!. Conditional transformation of a pancreatic (3-cellline derived from transgenic mice expressing a tetracycline-regulated oncogene. Proc Nat! Acad Sci USA 1995; 92:3576-80
Major Histocompatibility Complex Class II Genes Control Susceptibility to Hypersensitivity Pneumonitis in the Mouse* Kevin B. Donnelly, DVM; Bradford 0. Brooks, PhD; Enderson S. Cruz, BS; and Donald L. Wassom, PhD
,l irbome exposure to organic and inorganic dusts, or to ~ certain microbial antigens is !mown to cause hypersen*From the Department of Pathology, Colorado State University, Fort Collins (Drs. Donnelly, Cruz, and Wassom); and the Center for Process and Product Toxicology, IBM Corporation, Boulder, Colo (Dr. Brooks).
sitivity pneumonitis (HP) in animals and humans, but not all exposed individuals develop signs of disease. We initiated studies of inbred mice, sensitized with antigens of Themwactinomyces vulgaris, to identifY the genes that influence susceptibility to HP in this experimental model. Our long range goal was to characterize the specific responses regulated by the relevant genes. To investigate the influence of major histocompatibility complex (MHC) and non-MHC genes in determining levels of susceptibility to disease, we tested inbred and congenic mouse strains, representing four different MHC haplotypes expressed on each of several different genetic backgrounds. Lung lesions consistent with HP differed in severity among the mouse strains tested; mice expressing the k and b MHC haplotypes developed severe lesions when compared to mice expressing d or q haplotypes, even when the MHC genes were expressed on a common genetic background. Mice sharing common MHC genes on different backgrounds presented with a similar response phenotype. Thus, MHC genes played a significant role in determining levels of susceptibility to the induction of HP. To confirm this observation, we determined levels of susceptibility to HP in MHC class I and class II lmockout mice, and lmockout mice transfected with specific MHC genes. Mice deficient in MHC class I expression (132-microglobulin lmockouts) developed disease comparable to that of class I sufficient control mice. In contrast, MHC class II lmockout mice that did not express the products of class II genes failed to develop severe lesions as did normal control mice that expressed H2A molecules. Moreover, susceftibility to disease could be restored by transfecting the Ea gene _into the class II lmockout mice. Transgenic mice that expressed the products of both the H2A and H2E genes developed lesions that were more severe than those occurring in mice that expressed one but not both of the class II gene products. Serum antibodies from sensitized mice recognized antigens from T vulgaris on immunoblot analysis, and the patterns of antigen recognition differed according to MHC haplotype. These data confirm an important role for MHC class II genes in regulating levels of susceptibility to HP induced by T vulgaris and provide an experimental model wherein the responses regulated by these genes can be thoroughly characterized.
CHEST I 109 I 3 I MARCH, 1996 I Supplement
73S
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human surfactant protein SP-C gene confers bronchiolar-alveolar cell specificity in transgenic mice. Am J Physiol 1991; 261: 1..349-56 Paul SR, Bennett F, Calvetti JA, et al. Molecular cloning of a eDNA encoding IL-11, astromal cell-derived lymphopoietic cytokine. Proc Nat! Acad Sci USA 1990; 87:7512-16 Turner KJ, Clark SC. Interleukin-11: biological and clinical perspectives. In: Mertelsmann R, Herrmann F, eds. Hematopoietic growth factors in clinical applications. New York: Marcel Dekker, 1995; 315-36 Patterson PH, Nawa H. Neuronal differentiation factors/cytokines and synaptic plasticity. Cell1993; 72(suppl):123-37 Elias JA, Zheng T, Whiting NL, et al. Interleukin-1 and transfanning growth factor (3 regulation of fibroblast-derived interleukin-11. J lmmunol1994; 152:2421-29 Zheng T, Nathanson M, Elias JA. Histamine augments cytokinestimulated IL-11 production by human lung fibroblasts . J Immunol1994; 153:4742-52 Elias JA, Zheng T, Einarsson 0, et al. Epithelial interleukin-11: regulation by cytokines, respiratory syncytial virus and retinoic acid. J Bioi Chern 1994; 269:22261-68 Gossen M, Bonin AL, Bujard H. Control of gene activity in higher eukaryotic cells by prokaryotic regulatory elements. TIBS 1993; 18:471-75 Gossen M, Bujard H. Tight control of gene expression in mammalian cells by tetracycline responsive promoters. Proc Nat! Acad Sci USA 1992; 89:5547-51 Efrat S, Fusco-DeMane D, Lemberg H, et a!. Conditional transformation of a pancreatic (3-cellline derived from transgenic mice expressing a tetracycline-regulated oncogene. Proc Nat! Acad Sci USA 1995; 92:3576-80
Major Histocompatibility Complex Class II Genes Control Susceptibility to Hypersensitivity Pneumonitis in the Mouse* Kevin B. Donnelly, DVM; Bradford 0. Brooks, PhD; Enderson S. Cruz, BS; and Donald L. Wassom, PhD
,l irbome exposure to organic and inorganic dusts, or to ~ certain microbial antigens is !mown to cause hypersen*From the Department of Pathology, Colorado State University, Fort Collins (Drs. Donnelly, Cruz, and Wassom); and the Center for Process and Product Toxicology, IBM Corporation, Boulder, Colo (Dr. Brooks).
sitivity pneumonitis (HP) in animals and humans, but not all exposed individuals develop signs of disease. We initiated studies of inbred mice, sensitized with antigens of Themwactinomyces vulgaris, to identifY the genes that influence susceptibility to HP in this experimental model. Our long range goal was to characterize the specific responses regulated by the relevant genes. To investigate the influence of major histocompatibility complex (MHC) and non-MHC genes in determining levels of susceptibility to disease, we tested inbred and congenic mouse strains, representing four different MHC haplotypes expressed on each of several different genetic backgrounds. Lung lesions consistent with HP differed in severity among the mouse strains tested; mice expressing the k and b MHC haplotypes developed severe lesions when compared to mice expressing d or q haplotypes, even when the MHC genes were expressed on a common genetic background. Mice sharing common MHC genes on different backgrounds presented with a similar response phenotype. Thus, MHC genes played a significant role in determining levels of susceptibility to the induction of HP. To confirm this observation, we determined levels of susceptibility to HP in MHC class I and class II lmockout mice, and lmockout mice transfected with specific MHC genes. Mice deficient in MHC class I expression (132-microglobulin lmockouts) developed disease comparable to that of class I sufficient control mice. In contrast, MHC class II lmockout mice that did not express the products of class II genes failed to develop severe lesions as did normal control mice that expressed H2A molecules. Moreover, susceftibility to disease could be restored by transfecting the Ea gene _into the class II lmockout mice. Transgenic mice that expressed the products of both the H2A and H2E genes developed lesions that were more severe than those occurring in mice that expressed one but not both of the class II gene products. Serum antibodies from sensitized mice recognized antigens from T vulgaris on immunoblot analysis, and the patterns of antigen recognition differed according to MHC haplotype. These data confirm an important role for MHC class II genes in regulating levels of susceptibility to HP induced by T vulgaris and provide an experimental model wherein the responses regulated by these genes can be thoroughly characterized.
CHEST I 109 I 3 I MARCH, 1996 I Supplement
73S