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Mol Med. 1998 August; 4(8): 495–501.
PMCID: PMC2230405

Beta-cell apoptosis in an accelerated model of autoimmune diabetes.

Abstract

BACKGROUND: The non-obese diabetic (NOD) mouse is a model of human type 1 diabetes in which autoreactive T cells mediate destruction of pancreatic islet beta cells. Although known to be triggered by cytotoxic T cells, apoptosis has not been unequivocally localized to beta cells in spontaneously diabetic NOD mice. We created a model of accelerated beta-cell destruction mediated by T cells from spontaneously diabetic NOD mice to facilitate the direct detection of apoptosis in beta cells. MATERIALS AND METHODS: NOD.scid (severe combined immunodeficiency) mice were crossed with bm1 mice transgenically expressing the costimulatory molecule B7-1 (CD80) in their beta cells, to generate B7-1 NOD.scid mice. Apoptosis in islet cells was measured as DNA strand breakage by the TdT-mediated-dUTP-nick end labeling (TUNEL) technique. RESULTS: Adoptive transfer of splenocytes from spontaneously diabetic NOD mice into B7-1 NOD.scid mice caused diabetes in recipients within 12-16 days. Mononuclear cell infiltration and apoptosis were significantly greater in the islets of B7-1 NOD.scid mice than in nontransgenic NOD.scid mice. Dual immunolabeling for TUNEL and either B-7 or insulin, or the T cell markers CD4 and CD8, and colocalization by confocal microscopy clearly demonstrated apoptosis in beta cells as well in a relatively larger number of infiltrating T cells. The clearance time of apoptotic beta cells was estimated to be less than 6 min. CONCLUSIONS: B7-1 transgenic beta cells undergo apoptosis during their accelerated destruction in response to NOD mouse effector T cells. Rapid clearance implies that beta cells undergoing apoptosis would be detected only rarely during more protracted disease in spontaneously diabetic NOD mice.

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Selected References

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  • Kay TW, Parker JL, Stephens LA, Thomas HE, Allison J. RIP-beta 2-microglobulin transgene expression restores insulitis, but not diabetes, in beta 2-microglobulin null nonobese diabetic mice. J Immunol. 1996 Oct 15;157(8):3688–3693. [PubMed]
  • Wong FS, Visintin I, Wen L, Flavell RA, Janeway CA., Jr CD8 T cell clones from young nonobese diabetic (NOD) islets can transfer rapid onset of diabetes in NOD mice in the absence of CD4 cells. J Exp Med. 1996 Jan 1;183(1):67–76. [PMC free article] [PubMed]
  • Kägi D, Odermatt B, Seiler P, Zinkernagel RM, Mak TW, Hengartner H. Reduced incidence and delayed onset of diabetes in perforin-deficient nonobese diabetic mice. J Exp Med. 1997 Oct 6;186(7):989–997. [PMC free article] [PubMed]
  • Chervonsky AV, Wang Y, Wong FS, Visintin I, Flavell RA, Janeway CA, Jr, Matis LA. The role of Fas in autoimmune diabetes. Cell. 1997 Apr 4;89(1):17–24. [PubMed]
  • Stassi G, De Maria R, Trucco G, Rudert W, Testi R, Galluzzo A, Giordano C, Trucco M. Nitric oxide primes pancreatic beta cells for Fas-mediated destruction in insulin-dependent diabetes mellitus. J Exp Med. 1997 Oct 20;186(8):1193–1200. [PMC free article] [PubMed]
  • Itoh N, Imagawa A, Hanafusa T, Waguri M, Yamamoto K, Iwahashi H, Moriwaki M, Nakajima H, Miyagawa J, Namba M, et al. Requirement of Fas for the development of autoimmune diabetes in nonobese diabetic mice. J Exp Med. 1997 Aug 18;186(4):613–618. [PMC free article] [PubMed]
  • Campbell IL, Kay TW, Oxbrow L, Harrison LC. Essential role for interferon-gamma and interleukin-6 in autoimmune insulin-dependent diabetes in NOD/Wehi mice. J Clin Invest. 1991 Feb;87(2):739–742. [PMC free article] [PubMed]
  • Nicholson DW, Thornberry NA. Caspases: killer proteases. Trends Biochem Sci. 1997 Aug;22(8):299–306. [PubMed]
  • O'Brien BA, Harmon BV, Cameron DP, Allan DJ. Apoptosis is the mode of beta-cell death responsible for the development of IDDM in the nonobese diabetic (NOD) mouse. Diabetes. 1997 May;46(5):750–757. [PubMed]
  • Kurrer MO, Pakala SV, Hanson HL, Katz JD. Beta cell apoptosis in T cell-mediated autoimmune diabetes. Proc Natl Acad Sci U S A. 1997 Jan 7;94(1):213–218. [PubMed]
  • Columbano A. Cell death: current difficulties in discriminating apoptosis from necrosis in the context of pathological processes in vivo. J Cell Biochem. 1995 Jun;58(2):181–190. [PubMed]
  • Gavrieli Y, Sherman Y, Ben-Sasson SA. Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol. 1992 Nov;119(3):493–501. [PMC free article] [PubMed]
  • Shimizu S, Eguchi Y, Kamiike W, Waguri S, Uchiyama Y, Matsuda H, Tsujimoto Y. Retardation of chemical hypoxia-induced necrotic cell death by Bcl-2 and ICE inhibitors: possible involvement of common mediators in apoptotic and necrotic signal transductions. Oncogene. 1996 May 16;12(10):2045–2050. [PubMed]
  • Coles HS, Burne JF, Raff MC. Large-scale normal cell death in the developing rat kidney and its reduction by epidermal growth factor. Development. 1993 Jul;118(3):777–784. [PubMed]
  • Allison J, Stephens LA, Kay TW, Kurts C, Heath WR, Miller JF, Krummel MF. The threshold for autoimmune T cell killing is influenced by B7-1. Eur J Immunol. 1998 Mar;28(3):949–960. [PubMed]
  • Coulombe M, Yang H, Guerder S, Flavell RA, Lafferty KJ, Gill RG. Tissue immunogenicity: the role of MHC antigen and the lymphocyte costimulator B7-1. J Immunol. 1996 Dec 1;157(11):4790–4795. [PubMed]
  • Herrera PL, Harlan DM, Fossati L, Izui S, Huarte J, Orci L, Vassalli JD, Vassalli P. A CD8+ T-lymphocyte-mediated and CD4+ T-lymphocyte-independent autoimmune diabetes of early onset in transgenic mice. Diabetologia. 1994 Dec;37(12):1277–1279. [PubMed]
  • Wong S, Guerder S, Visintin I, Reich EP, Swenson KE, Flavell RA, Janeway CA., Jr Expression of the co-stimulator molecule B7-1 in pancreatic beta-cells accelerates diabetes in the NOD mouse. Diabetes. 1995 Mar;44(3):326–329. [PubMed]
  • Razi-Wolf Z, Freeman GJ, Galvin F, Benacerraf B, Nadler L, Reiser H. Expression and function of the murine B7 antigen, the major costimulatory molecule expressed by peritoneal exudate cells. Proc Natl Acad Sci U S A. 1992 May 1;89(9):4210–4214. [PubMed]

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