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J Exp Med. Nov 1, 1996; 184(5): 1963–1974.
PMCID: PMC2192884

Local expression of transgene encoded TNF alpha in islets prevents autoimmune diabetes in nonobese diabetic (NOD) mice by preventing the development of auto-reactive islet-specific T cells

Abstract

Lately, TNF alpha has been the focus of studies of autoimmunity; its role in the progression of autoimmune diabetes is, however, still unclear. To analyze the effects of TNF alpha in insulin-dependent diabetes mellitus (IDDM), we have generated nonobese diabetic (NOD) transgenic mice expressing TNF alpha under the control of the rat insulin II promoter (RIP). In transgenic mice, TNF alpha expression on the islets resulted in massive insulitis, composed of CD4+ T cells, CD8+ T cells, and B cells. Despite infiltration of considerable number of lymphoid cells in islets, expression of TNF alpha protected NOD mice from IDDM. To determine the mechanism of TNF alpha action, splenic cells from control NOD and RIP-TNF alpha mice were adoptively transferred to NOD-SCID recipients. In contrast to the induction of diabetes by splenic cells from control NOD mice, splenic cells from RIP- TNF alpha transgenic mice did not induce diabetes in NOD-SCID recipients. Diabetes was induced however, in the RIP-TNF alpha transgenic mice when CD8+ diabetogenic cloned T cells or splenic cells from diabetic NOD mice were adoptively transferred to these mice. Furthermore, expression of TNF alpha in islets also downregulated splenic cell responses to autoantigens. These data establish a mechanism of TNF alpha action and provide evidence that local expression of TNF alpha protects NOD mice from autoimmune diabetes by preventing the development of autoreactive islet-specific T cells.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Castaño L, Eisenbarth GS. Type-I diabetes: a chronic autoimmune disease of human, mouse, and rat. Annu Rev Immunol. 1990;8:647–679. [PubMed]
  • Bosi E, Todd I, Pujol-Borrell R, Bottazzo GF. Mechanisms of autoimmunity: relevance to the pathogenesis of type I (insulin-dependent) diabetes mellitus. Diabetes Metab Rev. 1987 Oct;3(4):893–923. [PubMed]
  • Tarn AC, Thomas JM, Dean BM, Ingram D, Schwarz G, Bottazzo GF, Gale EA. Predicting insulin-dependent diabetes. Lancet. 1988 Apr 16;1(8590):845–850. [PubMed]
  • Pozzilli P, Signore A, Williams AJ, Beales PE. NOD mouse colonies around the world--recent facts and figures. Immunol Today. 1993 May;14(5):193–196. [PubMed]
  • Marliss EB, Nakhooda AF, Poussier P, Sima AA. The diabetic syndrome of the 'BB' Wistar rat: possible relevance to type 1 (insulin-dependent) diabetes in man. Diabetologia. 1982 Apr;22(4):225–232. [PubMed]
  • Rossini AA, Mordes JP, Like AA. Immunology of insulin-dependent diabetes mellitus. Annu Rev Immunol. 1985;3:289–320. [PubMed]
  • Kikutani H, Makino S. The murine autoimmune diabetes model: NOD and related strains. Adv Immunol. 1992;51:285–322. [PubMed]
  • Todd JA, Aitman TJ, Cornall RJ, Ghosh S, Hall JR, Hearne CM, Knight AM, Love JM, McAleer MA, Prins JB, et al. Genetic analysis of autoimmune type 1 diabetes mellitus in mice. Nature. 1991 Jun 13;351(6327):542–547. [PubMed]
  • Prins JB, Todd JA, Rodrigues NR, Ghosh S, Hogarth PM, Wicker LS, Gaffney E, Podolin PL, Fischer PA, Sirotina A, et al. Linkage on chromosome 3 of autoimmune diabetes and defective Fc receptor for IgG in NOD mice. Science. 1993 Apr 30;260(5108):695–698. [PubMed]
  • Hattori M, Buse JB, Jackson RA, Glimcher L, Dorf ME, Minami M, Makino S, Moriwaki K, Kuzuya H, Imura H, et al. The NOD mouse: recessive diabetogenic gene in the major histocompatibility complex. Science. 1986 Feb 14;231(4739):733–735. [PubMed]
  • Wicker LS, Miller BJ, Coker LZ, McNally SE, Scott S, Mullen Y, Appel MC. Genetic control of diabetes and insulitis in the nonobese diabetic (NOD) mouse. J Exp Med. 1987 Jun 1;165(6):1639–1654. [PMC free article] [PubMed]
  • Wicker LS, Miller BJ, Fischer PA, Pressey A, Peterson LB. Genetic control of diabetes and insulitis in the nonobese diabetic mouse. Pedigree analysis of a diabetic H-2nod/b heterozygote. J Immunol. 1989 Feb 1;142(3):781–784. [PubMed]
  • Nepom GT. HLA and type I diabetes. Immunol Today. 1990 Sep;11(9):314–315. [PubMed]
  • Ghosh S, Palmer SM, Rodrigues NR, Cordell HJ, Hearne CM, Cornall RJ, Prins JB, McShane P, Lathrop GM, Peterson LB, et al. Polygenic control of autoimmune diabetes in nonobese diabetic mice. Nat Genet. 1993 Aug;4(4):404–409. [PubMed]
  • Charlton B, Bacelj A, Slattery RM, Mandel TE. Cyclophosphamide-induced diabetes in NOD/WEHI mice. Evidence for suppression in spontaneous autoimmune diabetes mellitus. Diabetes. 1989 Apr;38(4):441–447. [PubMed]
  • Mandrup-Poulsen T, Helqvist S, Wogensen LD, Mølvig J, Pociot F, Johannesen J, Nerup J. Cytokine and free radicals as effector molecules in the destruction of pancreatic beta cells. Curr Top Microbiol Immunol. 1990;164:169–193. [PubMed]
  • Sandler S, Eizirik DL, Svensson C, Strandell E, Welsh M, Welsh N. Biochemical and molecular actions of interleukin-1 on pancreatic beta-cells. Autoimmunity. 1991;10(3):241–253. [PubMed]
  • Corbett JA, McDaniel ML. Does nitric oxide mediate autoimmune destruction of beta-cells? Possible therapeutic interventions in IDDM. Diabetes. 1992 Aug;41(8):897–903. [PubMed]
  • Rabinovitch A. Immunoregulatory and cytokine imbalances in the pathogenesis of IDDM. Therapeutic intervention by immunostimulation? Diabetes. 1994 May;43(5):613–621. [PubMed]
  • Pober JS, Cotran RS. Cytokines and endothelial cell biology. Physiol Rev. 1990 Apr;70(2):427–451. [PubMed]
  • Collins T, Lapierre LA, Fiers W, Strominger JL, Pober JS. Recombinant human tumor necrosis factor increases mRNA levels and surface expression of HLA-A,B antigens in vascular endothelial cells and dermal fibroblasts in vitro. Proc Natl Acad Sci U S A. 1986 Jan;83(2):446–450. [PMC free article] [PubMed]
  • Pujol-Borrell R, Todd I, Doshi M, Bottazzo GF, Sutton R, Gray D, Adolf GR, 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. [PubMed]
  • Keffer J, Probert L, Cazlaris H, Georgopoulos S, Kaslaris E, Kioussis D, Kollias G. Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis. EMBO J. 1991 Dec;10(13):4025–4031. [PMC free article] [PubMed]
  • Higuchi Y, Herrera P, Muniesa P, Huarte J, Belin D, Ohashi P, Aichele P, Orci L, Vassalli JD, Vassalli P. Expression of a tumor necrosis factor alpha transgene in murine pancreatic beta cells results in severe and permanent insulitis without evolution towards diabetes. J Exp Med. 1992 Dec 1;176(6):1719–1731. [PMC free article] [PubMed]
  • Picarella DE, Kratz A, Li CB, Ruddle NH, Flavell RA. Insulitis in transgenic mice expressing tumor necrosis factor beta (lymphotoxin) in the pancreas. Proc Natl Acad Sci U S A. 1992 Nov 1;89(21):10036–10040. [PMC free article] [PubMed]
  • Picarella DE, Kratz A, Li CB, Ruddle NH, Flavell RA. Transgenic tumor necrosis factor (TNF)-alpha production in pancreatic islets leads to insulitis, not diabetes. Distinct patterns of inflammation in TNF-alpha and TNF-beta transgenic mice. J Immunol. 1993 May 1;150(9):4136–4150. [PubMed]
  • Jacob CO, Aiso S, Michie SA, McDevitt HO, Acha-Orbea H. Prevention of diabetes in nonobese diabetic mice by tumor necrosis factor (TNF): similarities between TNF-alpha and interleukin 1. Proc Natl Acad Sci U S A. 1990 Feb;87(3):968–972. [PMC free article] [PubMed]
  • Reichlin S. Neuroendocrine-immune interactions. N Engl J Med. 1993 Oct 21;329(17):1246–1253. [PubMed]
  • Yang XD, Tisch R, Singer SM, Cao ZA, Liblau RS, Schreiber RD, McDevitt HO. Effect of tumor necrosis factor alpha on insulin-dependent diabetes mellitus in NOD mice. I. The early development of autoimmunity and the diabetogenic process. J Exp Med. 1994 Sep 1;180(3):995–1004. [PMC free article] [PubMed]
  • Jacob CO, Aiso S, Schreiber RD, McDevitt HO. Monoclonal anti-tumor necrosis factor antibody renders non-obese diabetic mice hypersensitive to irradiation and enhances insulitis development. Int Immunol. 1992 May;4(5):611–614. [PubMed]
  • Kaufman DL, Clare-Salzler M, Tian J, Forsthuber T, Ting GS, Robinson P, Atkinson MA, Sercarz EE, Tobin AJ, Lehmann PV. Spontaneous loss of T-cell tolerance to glutamic acid decarboxylase in murine insulin-dependent diabetes. Nature. 1993 Nov 4;366(6450):69–72. [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]
  • Satoh J, Seino H, Abo T, Tanaka S, Shintani S, Ohta S, Tamura K, Sawai T, Nobunaga T, Oteki T, et al. Recombinant human tumor necrosis factor alpha suppresses autoimmune diabetes in nonobese diabetic mice. J Clin Invest. 1989 Oct;84(4):1345–1348. [PMC free article] [PubMed]
  • Satoh J, Seino H, Shintani S, Tanaka S, Ohteki T, Masuda T, Nobunaga T, Toyota T. Inhibition of type 1 diabetes in BB rats with recombinant human tumor necrosis factor-alpha. J Immunol. 1990 Sep 1;145(5):1395–1399. [PubMed]
  • Tisch R, Yang XD, Singer SM, Liblau RS, Fugger L, McDevitt HO. Immune response to glutamic acid decarboxylase correlates with insulitis in non-obese diabetic mice. Nature. 1993 Nov 4;366(6450):72–75. [PubMed]
  • DiCosmo BF, Picarella D, Flavell RA. Local production of human IL-6 promotes insulitis but retards the onset of insulin-dependent diabetes mellitus in non-obese diabetic mice. Int Immunol. 1994 Dec;6(12):1829–1837. [PubMed]
  • Liu Y, Janeway CA., Jr Cells that present both specific ligand and costimulatory activity are the most efficient inducers of clonal expansion of normal CD4 T cells. Proc Natl Acad Sci U S A. 1992 May 1;89(9):3845–3849. [PMC free article] [PubMed]

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