Abstract
Mice that express influenza hemagglutinin under control of the rat insulin promoter (INS-HA) as well as a class II major histocompatibility complex (MHC)-restricted HA-specific transgenic TCR (TCR-HA), develop early insulitis with huge infiltrates, but progress late and irregularly to diabetes. Initially, in these mice, INS-HA modulates the reactivity of antigen-specific lymphocytes, such that outside the pancreas they do not cause lethal shock like their naive counterparts in single transgenic TCR-HA mice, when stimulated with high doses of antigen. Inside the pancreas, the antigen-specific cells do not initially attack the islet cells, and produce some IFN-gamma as well as IL-10 and IL-4. Spontaneous progression to diabetes, which can be accelerated by cyclophosphamide injection, is accompanied by a 10-fold increase in IFN-gamma and a 3-fold decrease in IL-10 and IL-4 production by the locally residing antigen-specific T cells. Also, total islets from non-diabetic mice contain more TNF-alpha, compared with diabetic mice. This scenario is consistent with the view that beta cell destruction depends upon the increased production of certain pro-inflammatory cytokines by infiltrating T cells. Our inability to detect Fas expression on beta cells, but not on lymphoid cells, in diabetic and non-diabetic mice, puts some constraints on the role of Fas in beta cell destruction.
Full Text
The Full Text of this article is available as a PDF (665.9 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- André I., Gonzalez A., Wang B., Katz J., Benoist C., Mathis D. Checkpoints in the progression of autoimmune disease: lessons from diabetes models. Proc Natl Acad Sci U S A. 1996 Mar 19;93(6):2260–2263. doi: 10.1073/pnas.93.6.2260. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Benoist C., Mathis D. Cell death mediators in autoimmune diabetes--no shortage of suspects. Cell. 1997 Apr 4;89(1):1–3. doi: 10.1016/s0092-8674(00)80174-9. [DOI] [PubMed] [Google Scholar]
- Campbell I. L., Kay T. W., Oxbrow L., Harrison L. C. 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. doi: 10.1172/JCI115055. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chervonsky A. V., Wang Y., Wong F. S., Visintin I., Flavell R. A., Janeway C. A., Jr, Matis L. A. The role of Fas in autoimmune diabetes. Cell. 1997 Apr 4;89(1):17–24. doi: 10.1016/s0092-8674(00)80178-6. [DOI] [PubMed] [Google Scholar]
- Debray-Sachs M., Carnaud C., Boitard C., Cohen H., Gresser I., Bedossa P., Bach J. F. Prevention of diabetes in NOD mice treated with antibody to murine IFN gamma. J Autoimmun. 1991 Apr;4(2):237–248. doi: 10.1016/0896-8411(91)90021-4. [DOI] [PubMed] [Google Scholar]
- Degermann S., Reilly C., Scott B., Ogata L., von Boehmer H., Lo D. On the various manifestations of spontaneous autoimmune diabetes in rodent models. Eur J Immunol. 1994 Dec;24(12):3155–3160. doi: 10.1002/eji.1830241236. [DOI] [PubMed] [Google Scholar]
- Faveeuw C., Gagnerault M. C., Lepault F. Isolation of leukocytes infiltrating the islets of Langerhans of diabetes-prone mice for flow cytometric analysis. J Immunol Methods. 1995 Nov 16;187(1):163–169. doi: 10.1016/0022-1759(95)00180-i. [DOI] [PubMed] [Google Scholar]
- Förster I., Hirose R., Arbeit J. M., Clausen B. E., Hanahan D. Limited capacity for tolerization of CD4+ T cells specific for a pancreatic beta cell neo-antigen. Immunity. 1995 Jun;2(6):573–585. doi: 10.1016/1074-7613(95)90002-0. [DOI] [PubMed] [Google Scholar]
- Grewal I. S., Grewal K. D., Wong F. S., Picarella D. E., Janeway C. A., Jr, Flavell R. A. 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. J Exp Med. 1996 Nov 1;184(5):1963–1974. doi: 10.1084/jem.184.5.1963. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Harada M., Makino S. Promotion of spontaneous diabetes in non-obese diabetes-prone mice by cyclophosphamide. Diabetologia. 1984 Dec;27(6):604–606. doi: 10.1007/BF00276978. [DOI] [PubMed] [Google Scholar]
- Heath W. R., Allison J., Hoffmann M. W., Schönrich G., Hämmerling G., Arnold B., Miller J. F. Autoimmune diabetes as a consequence of locally produced interleukin-2. Nature. 1992 Oct 8;359(6395):547–549. doi: 10.1038/359547a0. [DOI] [PubMed] [Google Scholar]
- Higuchi Y., Herrera P., Muniesa P., Huarte J., Belin D., Ohashi P., Aichele P., Orci L., Vassalli J. D., 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. doi: 10.1084/jem.176.6.1719. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hotamisligil G. S., Murray D. L., Choy L. N., Spiegelman B. M. Tumor necrosis factor alpha inhibits signaling from the insulin receptor. Proc Natl Acad Sci U S A. 1994 May 24;91(11):4854–4858. doi: 10.1073/pnas.91.11.4854. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hultgren B., Huang X., Dybdal N., Stewart T. A. Genetic absence of gamma-interferon delays but does not prevent diabetes in NOD mice. Diabetes. 1996 Jun;45(6):812–817. doi: 10.2337/diab.45.6.812. [DOI] [PubMed] [Google Scholar]
- Itoh N., Imagawa A., Hanafusa T., Waguri M., Yamamoto K., Iwahashi H., Moriwaki M., Nakajima H., Miyagawa J., Namba M. Requirement of Fas for the development of autoimmune diabetes in nonobese diabetic mice. J Exp Med. 1997 Aug 18;186(4):613–618. doi: 10.1084/jem.186.4.613. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jacob C. O., Aiso S., Michie S. A., McDevitt H. O., 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. doi: 10.1073/pnas.87.3.968. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Katz J. D., Benoist C., Mathis D. T helper cell subsets in insulin-dependent diabetes. Science. 1995 May 26;268(5214):1185–1188. doi: 10.1126/science.7761837. [DOI] [PubMed] [Google Scholar]
- Katz J. D., 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. doi: 10.1016/0092-8674(93)90730-e. [DOI] [PubMed] [Google Scholar]
- Kirberg J., Baron A., Jakob S., Rolink A., Karjalainen K., von Boehmer H. Thymic selection of CD8+ single positive cells with a class II major histocompatibility complex-restricted receptor. J Exp Med. 1994 Jul 1;180(1):25–34. doi: 10.1084/jem.180.1.25. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lanoue A., Bona C., von Boehmer H., Sarukhan A. Conditions that induce tolerance in mature CD4+ T cells. J Exp Med. 1997 Feb 3;185(3):405–414. doi: 10.1084/jem.185.3.405. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lo D., Freedman J., Hesse S., Palmiter R. D., Brinster R. L., Sherman L. A. Peripheral tolerance to an islet cell-specific hemagglutinin transgene affects both CD4+ and CD8+ T cells. Eur J Immunol. 1992 Apr;22(4):1013–1022. doi: 10.1002/eji.1830220421. [DOI] [PubMed] [Google Scholar]
- Miethke T., Wahl C., Heeg K., Echtenacher B., Krammer P. H., Wagner H. T cell-mediated lethal shock triggered in mice by the superantigen staphylococcal enterotoxin B: critical role of tumor necrosis factor. J Exp Med. 1992 Jan 1;175(1):91–98. doi: 10.1084/jem.175.1.91. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ohashi P. S., Oehen S., Buerki K., Pircher H., Ohashi C. T., Odermatt B., Malissen B., Zinkernagel R. M., 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. doi: 10.1016/0092-8674(91)90164-t. [DOI] [PubMed] [Google Scholar]
- Reiner S. L., Zheng S., Corry D. B., Locksley R. M. Constructing polycompetitor cDNAs for quantitative PCR. J Immunol Methods. 1993 Sep 27;165(1):37–46. doi: 10.1016/0022-1759(93)90104-f. [DOI] [PubMed] [Google Scholar]
- Scott B., Liblau R., Degermann S., Marconi L. A., Ogata L., Caton A. J., McDevitt H. O., Lo D. A role for non-MHC genetic polymorphism in susceptibility to spontaneous autoimmunity. Immunity. 1994 Apr;1(1):73–83. doi: 10.1016/1074-7613(94)90011-6. [DOI] [PubMed] [Google Scholar]
- Yasunami R., Bach J. F. Anti-suppressor effect of cyclophosphamide on the development of spontaneous diabetes in NOD mice. Eur J Immunol. 1988 Mar;18(3):481–484. doi: 10.1002/eji.1830180325. [DOI] [PubMed] [Google Scholar]
- Zaghouani H., Steinman R., Nonacs R., Shah H., Gerhard W., Bona C. Presentation of a viral T cell epitope expressed in the CDR3 region of a self immunoglobulin molecule. Science. 1993 Jan 8;259(5092):224–227. doi: 10.1126/science.7678469. [DOI] [PubMed] [Google Scholar]