Expression of a tumor necrosis factor alpha transgene in murine pancreatic beta cells results in severe and permanent insulitis without evolution towards diabetes - PubMed (original) (raw)

Comparative Study

Expression of a tumor necrosis factor alpha transgene in murine pancreatic beta cells results in severe and permanent insulitis without evolution towards diabetes

Y Higuchi et al. J Exp Med. 1992.

Abstract

Mice bearing a tumor necrosis factor (TNF) alpha transgene controlled by an insulin promoter developed an increasingly severe lymphocytic insulitis, apparently resulting from the induction of endothelial changes with features similar to those observed in other places of intense lymphocytic traffic. This was accompanied by dissociation of the endocrine tissue (without marked decrease in its total mass), islet fibrosis, and the development of intraislet ductules containing, by places, beta cells in their walls, suggesting a regenerative capacity. Islet disorganization and fibrosis did not result from lymphocytic infiltration, since they were also observed in SCID mice bearing the transgene. Diabetes never developed, even though a number of potentially inducing conditions were used, including the prolonged perfusion of interferon gamma and the permanent expression of a nontolerogenic viral protein on beta cells (obtained by using mice bearing two transgenes). It is concluded that (a) a slow process of TNF release in pancreatic islets induces insulitis, and may be instrumental in the insulitis resulting from local cell-mediated immune reactions, but (b) that insulitis per se is not diabetogenic, lymphocyte stimulation by cells other than beta cells being necessary to trigger extensive beta cell damage. This provides an explanation for the discrepancy between the occurrence of insulitis and that of clinical disease in autoimmune diabetes.

PubMed Disclaimer

Cited by

Fas/Fas-Ligand Interaction As a Mechanism of Immune Homeostasis and β-Cell Cytotoxicity: Enforcement Rather Than Neutralization for Treatment of Type 1 Diabetes.
Yolcu ES, Shirwan H, Askenasy N. Yolcu ES, et al. Front Immunol. 2017 Mar 27;8:342. doi: 10.3389/fimmu.2017.00342. eCollection 2017. Front Immunol. 2017. PMID: 28396667 Free PMC article. No abstract available.
Stem Cells in the Treatment of Insulin-Dependent Diabetes Mellitus.
Borisov MA, Petrakova OS, Gvazava IG, Kalistratova EN, Vasiliev AV. Borisov MA, et al. Acta Naturae. 2016 Jul-Sep;8(3):31-43. Acta Naturae. 2016. PMID: 27795842 Free PMC article.
Neutralization Versus Reinforcement of Proinflammatory Cytokines to Arrest Autoimmunity in Type 1 Diabetes.
Kaminitz A, Ash S, Askenasy N. Kaminitz A, et al. Clin Rev Allergy Immunol. 2017 Jun;52(3):460-472. doi: 10.1007/s12016-016-8587-y. Clin Rev Allergy Immunol. 2017. PMID: 27677500 Review.
Improved Treatment of Pancreatic Cancer With Drug Delivery Nanoparticles Loaded With a Novel AKT/PDK1 Inhibitor.
Kobes JE, Daryaei I, Howison CM, Bontrager JG, Sirianni RW, Meuillet EJ, Pagel MD. Kobes JE, et al. Pancreas. 2016 Sep;45(8):1158-66. doi: 10.1097/MPA.0000000000000607. Pancreas. 2016. PMID: 26918875 Free PMC article.
Transgenic rescue of adipocyte glucose-dependent insulinotropic polypeptide receptor expression restores high fat diet-induced body weight gain.
Ugleholdt R, Pedersen J, Bassi MR, Füchtbauer EM, Jørgensen SM, Kissow HL, Nytofte N, Poulsen SS, Rosenkilde MM, Seino Y, Thams P, Holst PJ, Holst JJ. Ugleholdt R, et al. J Biol Chem. 2011 Dec 30;286(52):44632-45. doi: 10.1074/jbc.M111.311779. Epub 2011 Oct 25. J Biol Chem. 2011. PMID: 22027838 Free PMC article.

References

1. J Immunol. 1988 Oct 1;141(7):2325-9 - PubMed
1. Proc Natl Acad Sci U S A. 1989 Jun;86(11):4282-6 - PubMed
1. J Immunol. 1987 Dec 15;139(12):4077-82 - PubMed
1. Nature. 1988 Feb 18;331(6157):624-7 - PubMed
1. Diabetes. 1987 May;36(5):641-7 - PubMed

Expression of a tumor necrosis factor alpha transgene in murine pancreatic beta cells results in severe and permanent insulitis without evolution towards diabetes - PubMed (original) (raw)