Logo of jexpmedHomeThe Rockefeller University PressEditorsContactInstructions for AuthorsThis issue
J Exp Med. 1994 Sep 1; 180(3): 995–1004.
PMCID: PMC2191653

Effect of tumor necrosis factor alpha on insulin-dependent diabetes mellitus in NOD mice. I. The early development of autoimmunity and the diabetogenic process


Tumor necrosis factor (TNF) alpha is a cytokine that has potent immune regulatory functions. To assess the potential role of this cytokine in the early development of autoimmunity, we investigated the effect of TNF on the development of insulin-dependent diabetes mellitus (IDDM) in nonobese diabetic (NOD) mice, a spontaneous murine model for autoimmune, insulin-dependent type I diabetes. Treatment of newborn female NOD mice with TNF every other day for 3 wk, led to an earlier onset of disease (10 versus 15 wk of age in control mice) and 100% incidence before 20 wk of age (compared to 45% at 20 wk of age in control phosphate-buffered saline treated female mice). In contrast, administration of an anti-TNF monoclonal antibody, TN3.19.12, resulted in complete prevention of IDDM. In vitro proliferation assays demonstrated that mice treated with TNF developed an increased T cell response to a panel of beta cell autoantigens, whereas anti-TNF treatment resulted in unresponsiveness to the autoantigens. In addition, autoantibody responses to the panel of beta cell antigens paralleled the T cell responses. The effects mediated by TNF appear to be highly age dependent. Treatment of animals either from birth or from 2 wk of age had a similar effect. However, if treatment was initiated at 4 wk of age, TNF delayed disease onset. These data suggest that TNF has a critical role in the early development of autoimmunity towards beta-islet cells.

Full Text

The Full Text of this article is available as a PDF (955K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Beutler B, Cerami A. The biology of cachectin/TNF--a primary mediator of the host response. Annu Rev Immunol. 1989;7:625–655. [PubMed]
  • Vassalli P. The pathophysiology of tumor necrosis factors. Annu Rev Immunol. 1992;10:411–452. [PubMed]
  • Powrie F, Coffman RL. Cytokine regulation of T-cell function: potential for therapeutic intervention. Immunol Today. 1993 Jun;14(6):270–274. [PubMed]
  • Tartaglia LA, Goeddel DV. Two TNF receptors. Immunol Today. 1992 May;13(5):151–153. [PubMed]
  • Held W, MacDonald HR, Weissman IL, Hess MW, Mueller C. Genes encoding tumor necrosis factor alpha and granzyme A are expressed during development of autoimmune diabetes. Proc Natl Acad Sci U S A. 1990 Mar;87(6):2239–2243. [PMC free article] [PubMed]
  • Pukel C, Baquerizo H, Rabinovitch A. Destruction of rat islet cell monolayers by cytokines. Synergistic interactions of interferon-gamma, tumor necrosis factor, lymphotoxin, and interleukin 1. Diabetes. 1988 Jan;37(1):133–136. [PubMed]
  • Eizirik DL. Interleukin-1 induced impairment in pancreatic islet oxidative metabolism of glucose is potentiated by tumor necrosis factor. Acta Endocrinol (Copenh) 1988 Nov;119(3):321–325. [PubMed]
  • Rabinovitch A, Baquerizo H, Pukel C, Sumoski W. Effects of cytokines on rat pancreatic islet cell monolayer cultures: distinction between functional and cytotoxic effects on islet beta-cells. Reg Immunol. 1989 Mar-Apr;2(2):77–82. [PubMed]
  • Campbell IL, Iscaro A, Harrison LC. IFN-gamma and tumor necrosis factor-alpha. Cytotoxicity to murine islets of Langerhans. J Immunol. 1988 Oct 1;141(7):2325–2329. [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. 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]
  • Jacob CO, McDevitt HO. Tumour necrosis factor-alpha in murine autoimmune 'lupus' nephritis. Nature. 1988 Jan 28;331(6154):356–358. [PubMed]
  • Lapchak PH, Guilbert LJ, Rabinovitch A. Tumor necrosis factor production is deficient in diabetes-prone BB rats and can be corrected by complete Freund's adjuvant: a possible immunoregulatory role of tumor necrosis factor in the prevention of diabetes. Clin Immunol Immunopathol. 1992 Nov;65(2):129–134. [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]
  • Gordon C, Ranges GE, Greenspan JS, Wofsy D. Chronic therapy with recombinant tumor necrosis factor-alpha in autoimmune NZB/NZW F1 mice. Clin Immunol Immunopathol. 1989 Sep;52(3):421–434. [PubMed]
  • Giroir BP, Brown T, Beutler B. Constitutive synthesis of tumor necrosis factor in the thymus. Proc Natl Acad Sci U S A. 1992 Jun 1;89(11):4864–4868. [PMC free article] [PubMed]
  • de Kossodo S, Grau GE, Daneva T, Pointaire P, Fossati L, Ody C, Zapf J, Piguet PF, Gaillard RC, Vassalli P. Tumor necrosis factor alpha is involved in mouse growth and lymphoid tissue development. J Exp Med. 1992 Nov 1;176(5):1259–1264. [PMC free article] [PubMed]
  • Sheehan KC, Ruddle NH, Schreiber RD. Generation and characterization of hamster monoclonal antibodies that neutralize murine tumor necrosis factors. J Immunol. 1989 Jun 1;142(11):3884–3893. [PubMed]
  • van der Meide PH, Dubbeld M, Vijverberg K, Kos T, Schellekens H. The purification and characterization of rat gamma interferon by use of two monoclonal antibodies. J Gen Virol. 1986 Jun;67(Pt 6):1059–1071. [PubMed]
  • Wicker LS, Miller BJ, Mullen Y. Transfer of autoimmune diabetes mellitus with splenocytes from nonobese diabetic (NOD) mice. Diabetes. 1986 Aug;35(8):855–860. [PubMed]
  • Boitard C, Bendelac A, Richard MF, Carnaud C, Bach JF. Prevention of diabetes in nonobese diabetic mice by anti-I-A monoclonal antibodies: transfer of protection by splenic T cells. Proc Natl Acad Sci U S A. 1988 Dec;85(24):9719–9723. [PMC free article] [PubMed]
  • Hänninen A, Taylor C, Streeter PR, Stark LS, Sarte JM, Shizuru JA, Simell O, Michie SA. Vascular addressins are induced on islet vessels during insulitis in nonobese diabetic mice and are involved in lymphoid cell binding to islet endothelium. J Clin Invest. 1993 Nov;92(5):2509–2515. [PMC free article] [PubMed]
  • Dardenne M, Lepault F, Bendelac A, Bach JF. Acceleration of the onset of diabetes in NOD mice by thymectomy at weaning. Eur J Immunol. 1989 May;19(5):889–895. [PubMed]
  • Bach JF, Boitard C, Yasunami R, Dardenne M. Control of diabetes in NOD mice by suppressor cells. J Autoimmun. 1990 Apr;3 (Suppl 1):97–100. [PubMed]
  • Leiter EH, Serreze DV. Antigen presenting cells and the immunogenetics of autoimmune diabetes in NOD mice. Reg Immunol. 1992 Sep-Oct;4(5):263–273. [PubMed]
  • Katz JD, Wang B, Haskins K, Benoist C, Mathis D. Following a diabetogenic T cell from genesis through pathogenesis. Cell. 1993 Sep 24;74(6):1089–1100. [PubMed]
  • Ranges GE, Zlotnik A, Espevik T, Dinarello CA, Cerami A, Palladino MA., Jr Tumor necrosis factor alpha/cachectin is a growth factor for thymocytes. Synergistic interactions with other cytokines. J Exp Med. 1988 Apr 1;167(4):1472–1478. [PMC free article] [PubMed]
  • Suda T, Murray R, Fischer M, Yokota T, Zlotnik A. Tumor necrosis factor-alpha and P40 induce day 15 murine fetal thymocyte proliferation in combination with IL-2. J Immunol. 1990 Mar 1;144(5):1783–1787. [PubMed]
  • Defresne MP, Humblet C, Rongy AM, Greimers R, Boniver J. Effect of interferon-gamma and tumor necrosis factor-alpha on lymphoepithelial interactions within thymic nurse cells. Eur J Immunol. 1990 Feb;20(2):429–432. [PubMed]
  • De Togni P, Goellner J, Ruddle NH, Streeter PR, Fick A, Mariathasan S, Smith SC, Carlson R, Shornick LP, Strauss-Schoenberger J, et al. Abnormal development of peripheral lymphoid organs in mice deficient in lymphotoxin. Science. 1994 Apr 29;264(5159):703–707. [PubMed]
  • Pfeffer K, Matsuyama T, Kündig TM, Wakeham A, Kishihara K, Shahinian A, Wiegmann K, Ohashi PS, Krönke M, Mak TW. Mice deficient for the 55 kd tumor necrosis factor receptor are resistant to endotoxic shock, yet succumb to L. monocytogenes infection. Cell. 1993 May 7;73(3):457–467. [PubMed]
  • Lee KU, Amano K, Yoon JW. Evidence for initial involvement of macrophage in development of insulitis in NOD mice. Diabetes. 1988 Jul;37(7):989–991. [PubMed]
  • Hutchings P, Rosen H, O'Reilly L, Simpson E, Gordon S, Cooke A. Transfer of diabetes in mice prevented by blockade of adhesion-promoting receptor on macrophages. Nature. 1990 Dec 13;348(6302):639–642. [PubMed]
  • Harrison LC, Campbell IL, Allison J, Miller JF. MHC molecules and beta-cell destruction. Immune and nonimmune mechanisms. Diabetes. 1989 Jul;38(7):815–818. [PubMed]
  • Charlton B, Mandel TE. Progression from insulitis to beta-cell destruction in NOD mouse requires L3T4+ T-lymphocytes. Diabetes. 1988 Aug;37(8):1108–1112. [PubMed]
  • Trinchieri G. Interleukin-12 and its role in the generation of TH1 cells. Immunol Today. 1993 Jul;14(7):335–338. [PubMed]
  • Scott B, Liblau R, Degermann S, Marconi LA, Ogata L, Caton AJ, McDevitt HO, Lo D. A role for non-MHC genetic polymorphism in susceptibility to spontaneous autoimmunity. Immunity. 1994 Apr;1(1):73–83. [PubMed]
  • Doukas J, Pober JS. IFN-gamma enhances endothelial activation induced by tumor necrosis factor but not IL-1. J Immunol. 1990 Sep 15;145(6):1727–1733. [PubMed]
  • Osborn L. Leukocyte adhesion to endothelium in inflammation. Cell. 1990 Jul 13;62(1):3–6. [PubMed]
  • Yang XD, Karin N, Tisch R, Steinman L, McDevitt HO. Inhibition of insulitis and prevention of diabetes in nonobese diabetic mice by blocking L-selectin and very late antigen 4 adhesion receptors. Proc Natl Acad Sci U S A. 1993 Nov 15;90(22):10494–10498. [PMC free article] [PubMed]
  • Ruddle NH, Bergman CM, McGrath KM, Lingenheld EG, Grunnet ML, Padula SJ, Clark RB. An antibody to lymphotoxin and tumor necrosis factor prevents transfer of experimental allergic encephalomyelitis. J Exp Med. 1990 Oct 1;172(4):1193–1200. [PMC free article] [PubMed]
  • Williams RO, Feldmann M, Maini RN. Anti-tumor necrosis factor ameliorates joint disease in murine collagen-induced arthritis. Proc Natl Acad Sci U S A. 1992 Oct 15;89(20):9784–9788. [PMC free article] [PubMed]
  • Feldmann M, Brennan FM, Williams RO, Cope AP, Gibbons DL, Katsikis PD, Maini RN. Evaluation of the role of cytokines in autoimmune disease: the importance of TNF alpha in rheumatoid arthritis. Prog Growth Factor Res. 1992;4(3):247–255. [PubMed]
  • Patton JS, Peters PM, McCabe J, Crase D, Hansen S, Chen AB, Liggitt D. Development of partial tolerance to the gastrointestinal effects of high doses of recombinant tumor necrosis factor-alpha in rodents. J Clin Invest. 1987 Dec;80(6):1587–1596. [PMC free article] [PubMed]
  • Fraker DL, Stovroff MC, Merino MJ, Norton JA. Tolerance to tumor necrosis factor in rats and the relationship to endotoxin tolerance and toxicity. J Exp Med. 1988 Jul 1;168(1):95–105. [PMC free article] [PubMed]
  • Bendtzen K, Svenson M, Jønsson V, Hippe E. Autoantibodies to cytokines--friends or foes? Immunol Today. 1990 May;11(5):167–169. [PubMed]
  • Hansen MB, Svenson M, Diamant M, Bendtzen K. High-affinity IgG autoantibodies to IL-6 in sera of normal individuals are competitive inhibitors of IL-6 in vitro. Cytokine. 1993 Jan;5(1):72–80. [PubMed]
  • Suzuki H, Kamimura J, Ayabe T, Kashiwagi H. Demonstration of neutralizing autoantibodies against IL-1 alpha in sera from patients with rheumatoid arthritis. J Immunol. 1990 Oct 1;145(7):2140–2146. [PubMed]
  • Bemelmans MH, Gouma DJ, Buurman WA. LPS-induced sTNF-receptor release in vivo in a murine model. Investigation of the role of tumor necrosis factor, IL-1, leukemia inhibiting factor, and IFN-gamma. J Immunol. 1993 Nov 15;151(10):5554–5562. [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]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press


Save items

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • Gene
    Gene records that cite the current articles. Citations in Gene are added manually by NCBI or imported from outside public resources.
  • GEO Profiles
    GEO Profiles
    Gene Expression Omnibus (GEO) Profiles of molecular abundance data. The current articles are references on the Gene record associated with the GEO profile.
  • HomoloGene
    HomoloGene clusters of homologous genes and sequences that cite the current articles. These are references on the Gene and sequence records in the HomoloGene entry.
  • MedGen
    Related information in MedGen
  • PubMed
    PubMed citations for these articles
  • Substance
    PubChem chemical substance records that cite the current articles. These references are taken from those provided on submitted PubChem chemical substance records.

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...