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J Exp Med. 1996 April 1; 183(4): 1657–1662.
PMCID: PMC2192523

Breaking self-tolerance in nonobese diabetic mice


Unresponsiveness to self is maintained through two mechanisms of immune regulation: thymic-negative selection and peripheral tolerance. Although thymic-negative selection is a major mechanism to eliminate self-reactive T cells, normal mice have readily detectable populations of T cells reactive to self-proteins but do not exhibit autoimmune responses. It has been postulated that autoimmune disease results from breakdown or loss of peripheral tolerance. We present data that demonstrate that peripheral tolerance or unresponsiveness to self can be broken in nonobese diabetic (NOD) mice. Immunization of NOD mice (but not of conventional mice) with self-peptides caused an immune response to self-peptide with resultant autoproliferation of peripheral lymphocytes. Autoproliferation of self-reactive T cells in NOD mice resulted from the recognition and proliferation of the activated T cells to endogenously processed and presented self-antigens. This loss of self-tolerance demonstrated in vitro may well be the basis of NOD autoimmune disease in vivo.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Lorenz RG, Allen PM. Direct evidence for functional self-protein/Ia-molecule complexes in vivo. Proc Natl Acad Sci U S A. 1988 Jul;85(14):5220–5223. [PubMed]
  • Lorenz RG, Allen PM. Thymic cortical epithelial cells can present self-antigens in vivo. Nature. 1989 Feb 9;337(6207):560–562. [PubMed]
  • Agrawal B, Manickasundari M, Fraga E, Singh B. T cells that recognize peptide sequences of self MHC class II molecules exist in syngeneic mice. J Immunol. 1991 Jul 15;147(2):383–390. [PubMed]
  • Ohashi PS, Oehen S, Buerki K, Pircher H, Ohashi CT, Odermatt B, Malissen B, Zinkernagel RM, Hengartner H. Ablation of "tolerance" and induction of diabetes by virus infection in viral antigen transgenic mice. Cell. 1991 Apr 19;65(2):305–317. [PubMed]
  • Humphreys-Beher MG, Hu Y, Nakagawa Y, Wang PL, Purushotham KR. Utilization of the non-obese diabetic (NOD) mouse as an animal model for the study of secondary Sjögren's syndrome. Adv Exp Med Biol. 1994;350:631–636. [PubMed]
  • Matsuoka N, Bernard N, Concepcion ES, Graves PN, Ben-Nun A, Davies TF. T-cell receptor V region beta-chain gene expression in the autoimmune thyroiditis of non-obese diabetic mice. J Immunol. 1993 Aug 1;151(3):1691–1701. [PubMed]
  • Krug J, Williams AJ, Beales PE, Doniach I, Gale EA, Pozzilli P. Parathyroiditis in the non-obese diabetic mouse--a new finding. J Endocrinol. 1991 Nov;131(2):193–196. [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]
  • 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]
  • Ruberti G, Gaur A, Fathman CG, Livingstone AM. The T cell receptor repertoire influences V beta element usage in response to myoglobin. J Exp Med. 1991 Jul 1;174(1):83–92. [PMC free article] [PubMed]
  • Livingstone AM, Fathman CG. The structure of T-cell epitopes. Annu Rev Immunol. 1987;5:477–501. [PubMed]
  • Sakaguchi S, Sakaguchi N. Organ-specific autoimmune disease induced in mice by elimination of T cell subsets. V. Neonatal administration of cyclosporin A causes autoimmune disease. J Immunol. 1989 Jan 15;142(2):471–480. [PubMed]
  • Saï P, Senecat O, Martignat L, Gouin E. Neonatal injections of cyclosporin enhance autoimmune diabetes in non-obese diabetic mice. Clin Exp Immunol. 1994 Jul;97(1):138–145. [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]
  • Boitard C, Yasunami R, Dardenne M, Bach JF. T cell-mediated inhibition of the transfer of autoimmune diabetes in NOD mice. J Exp Med. 1989 May 1;169(5):1669–1680. [PMC free article] [PubMed]
  • Rohane PW, Shimada A, Kim DT, Edwards CT, Charlton B, Shultz LD, Fathman CG. Islet-infiltrating lymphocytes from prediabetic NOD mice rapidly transfer diabetes to NOD-scid/scid mice. Diabetes. 1995 May;44(5):550–554. [PubMed]
  • Gaur A, Ruberti G, Haspel R, Mayer JP, Fathman CG. Requirement for CD8+ cells in T cell receptor peptide-induced clonal unresponsiveness. Science. 1993 Jan 1;259(5091):91–94. [PubMed]
  • Lehmann PV, Forsthuber T, Miller A, Sercarz EE. Spreading of T-cell autoimmunity to cryptic determinants of an autoantigen. Nature. 1992 Jul 9;358(6382):155–157. [PubMed]
  • Carrasco-Marin E, Shimizu J, Kanagawa O, Unanue ER. The class II MHC I-Ag7 molecules from non-obese diabetic mice are poor peptide binders. J Immunol. 1996 Jan 15;156(2):450–458. [PubMed]

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