Skip to main content
NCBI home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1992 Nov 1;89(21):10036–10040. doi: 10.1073/pnas.89.21.10036

Insulitis in transgenic mice expressing tumor necrosis factor beta (lymphotoxin) in the pancreas.

D E Picarella 1, A Kratz 1, C B Li 1, N H Ruddle 1, R A Flavell 1
PMCID: PMC50272  PMID: 1279667

Abstract

Tumor necrosis factor beta (TNF-beta) (lymphotoxin) may play an important role in the immune response and pathologic inflammatory diseases. Insulitis is an important early step in the development of insulin-dependent diabetes mellitus. To understand better the role of TNF-beta in the regulation of inflammation and type 1 diabetes, we produced transgenic mice in which the murine TNF-beta gene was regulated by the rat insulin II promoter. The transgene was expressed in the pancreas, kidney, and skin of transgenic mice. The expression of TNF-beta in the pancreas of transgenic mice resulted in a leukocytic inflammatory infiltrate consisting primarily of B220+ IgM+ B cells and CD4+ and CD8+ T cells. The insulitis is reminiscent of the early stages of diabetes, though the mice did not progress to diabetes.

Full text

PDF
10036

Images in this article

10037Image
on p.10037
10038Image
on p.10038
10039Image
on p.10039
10039Image
on p.10039
10039Image
on p.10039
10039Image
on p.10039
10039Image
on p.10039

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Baxter A. G., Adams M. A., Mandel T. E. Comparison of high- and low-diabetes-incidence NOD mouse strains. Diabetes. 1989 Oct;38(10):1296–1300. doi: 10.2337/diab.38.10.1296. [DOI] [PubMed] [Google Scholar]
  2. Charlton B., Bacelj A., Slattery R. M., Mandel T. E. Cyclophosphamide-induced diabetes in NOD/WEHI mice. Evidence for suppression in spontaneous autoimmune diabetes mellitus. Diabetes. 1989 Apr;38(4):441–447. doi: 10.2337/diab.38.4.441. [DOI] [PubMed] [Google Scholar]
  3. Cornall R. J., Prins J. B., Todd J. A., Pressey A., DeLarato N. H., Wicker L. S., Peterson L. B. Type 1 diabetes in mice is linked to the interleukin-1 receptor and Lsh/Ity/Bcg genes on chromosome 1. Nature. 1991 Sep 19;353(6341):262–265. doi: 10.1038/353262a0. [DOI] [PubMed] [Google Scholar]
  4. De Camilli P., Cameron R., Greengard P. Synapsin I (protein I), a nerve terminal-specific phosphoprotein. I. Its general distribution in synapses of the central and peripheral nervous system demonstrated by immunofluorescence in frozen and plastic sections. J Cell Biol. 1983 May;96(5):1337–1354. doi: 10.1083/jcb.96.5.1337. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Garchon H. J., Bedossa P., Eloy L., Bach J. F. Identification and mapping to chromosome 1 of a susceptibility locus for periinsulitis in non-obese diabetic mice. Nature. 1991 Sep 19;353(6341):260–262. doi: 10.1038/353260a0. [DOI] [PubMed] [Google Scholar]
  6. Gray P. W., Chen E., Li C. B., Tang W. L., Ruddle N. The murine tumor necrosis factor-beta (lymphotoxin) gene sequence. Nucleic Acids Res. 1987 May 11;15(9):3937–3937. doi: 10.1093/nar/15.9.3937. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Lapierre L. A., Fiers W., Pober J. S. Three distinct classes of regulatory cytokines control endothelial cell MHC antigen expression. Interactions with immune gamma interferon differentiate the effects of tumor necrosis factor and lymphotoxin from those of leukocyte alpha and fibroblast beta interferons. J Exp Med. 1988 Mar 1;167(3):794–804. doi: 10.1084/jem.167.3.794. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Li C. B., Gray P. W., Lin P. F., McGrath K. M., Ruddle F. H., Ruddle N. H. Cloning and expression of murine lymphotoxin cDNA. J Immunol. 1987 Jun 15;138(12):4496–4501. [PubMed] [Google Scholar]
  9. Lo D., Burkly L. C., Widera G., Cowing C., Flavell R. A., Palmiter R. D., Brinster R. L. Diabetes and tolerance in transgenic mice expressing class II MHC molecules in pancreatic beta cells. Cell. 1988 Apr 8;53(1):159–168. doi: 10.1016/0092-8674(88)90497-7. [DOI] [PubMed] [Google Scholar]
  10. McInerney M. F., Rath S., Janeway C. A., Jr Exclusive expression of MHC class II proteins on CD45+ cells in pancreatic islets of NOD mice. Diabetes. 1991 May;40(5):648–651. doi: 10.2337/diab.40.5.648. [DOI] [PubMed] [Google Scholar]
  11. Mueller C., Gershenfeld H. K., Lobe C. G., Okada C. Y., Bleackley R. C., Weissman I. L. A high proportion of T lymphocytes that infiltrate H-2-incompatible heart allografts in vivo express genes encoding cytotoxic cell-specific serine proteases, but do not express the MEL-14-defined lymph node homing receptor. J Exp Med. 1988 Mar 1;167(3):1124–1136. doi: 10.1084/jem.167.3.1124. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Mølvig J., Pociot F., Baek L., Worsaae H., Dall Wogensen L., Christensen P., Staub-Nielsen L., Mandrup-Poulsen T., Manogue K., Nerup J. Monocyte function in IDDM patients and healthy individuals. Scand J Immunol. 1990 Sep;32(3):297–311. doi: 10.1111/j.1365-3083.1990.tb02924.x. [DOI] [PubMed] [Google Scholar]
  13. Pober J. S., Gimbrone M. A., Jr, Lapierre L. A., Mendrick D. L., Fiers W., Rothlein R., Springer T. A. Overlapping patterns of activation of human endothelial cells by interleukin 1, tumor necrosis factor, and immune interferon. J Immunol. 1986 Sep 15;137(6):1893–1896. [PubMed] [Google Scholar]
  14. Prochazka M., Serreze D. V., Frankel W. N., Leiter E. H. NOR/Lt mice: MHC-matched diabetes-resistant control strain for NOD mice. Diabetes. 1992 Jan;41(1):98–106. doi: 10.2337/diab.41.1.98. [DOI] [PubMed] [Google Scholar]
  15. Pujol-Borrell R., Todd I., Doshi M., Bottazzo G. F., Sutton R., Gray D., Adolf G. R., Feldmann M. HLA class II induction in human islet cells by interferon-gamma plus tumour necrosis factor or lymphotoxin. Nature. 1987 Mar 19;326(6110):304–306. doi: 10.1038/326304a0. [DOI] [PubMed] [Google Scholar]
  16. Ruddle N. H., Bergman C. M., McGrath K. M., Lingenheld E. G., Grunnet M. L., Padula S. J., Clark R. B. An antibody to lymphotoxin and tumor necrosis factor prevents transfer of experimental allergic encephalomyelitis. J Exp Med. 1990 Oct 1;172(4):1193–1200. doi: 10.1084/jem.172.4.1193. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Sarvetnick N., Liggitt D., Pitts S. L., Hansen S. E., Stewart T. A. Insulin-dependent diabetes mellitus induced in transgenic mice by ectopic expression of class II MHC and interferon-gamma. Cell. 1988 Mar 11;52(5):773–782. doi: 10.1016/0092-8674(88)90414-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Sarvetnick N., Shizuru J., Liggitt D., Martin L., McIntyre B., Gregory A., Parslow T., Stewart T. Loss of pancreatic islet tolerance induced by beta-cell expression of interferon-gamma. Nature. 1990 Aug 30;346(6287):844–847. doi: 10.1038/346844a0. [DOI] [PubMed] [Google Scholar]
  19. Semon D., Kawashima E., Jongeneel C. V., Shakhov A. N., Nedospasov S. A. Nucleotide sequence of the murine TNF locus, including the TNF-alpha (tumor necrosis factor) and TNF-beta (lymphotoxin) genes. Nucleic Acids Res. 1987 Nov 11;15(21):9083–9084. doi: 10.1093/nar/15.21.9083. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Swain S. L., Bradley L. M., Croft M., Tonkonogy S., Atkins G., Weinberg A. D., Duncan D. D., Hedrick S. M., Dutton R. W., Huston G. Helper T-cell subsets: phenotype, function and the role of lymphokines in regulating their development. Immunol Rev. 1991 Oct;123:115–144. doi: 10.1111/j.1600-065x.1991.tb00608.x. [DOI] [PubMed] [Google Scholar]
  21. Todd J. A., Aitman T. J., Cornall R. J., Ghosh S., Hall J. R., Hearne C. M., Knight A. M., Love J. M., McAleer M. A., Prins J. B. Genetic analysis of autoimmune type 1 diabetes mellitus in mice. Nature. 1991 Jun 13;351(6327):542–547. doi: 10.1038/351542a0. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES