{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T18:10:20Z","timestamp":1791137420017,"version":"4.1.0"},"reference-count":43,"publisher":"Rockefeller University Press","issue":"8","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[1998,10,19]]},"abstract":"<jats:p>Activation of autoreactive T cells can lead to autoimmune diseases such as insulin-dependent diabetes mellitus (IDDM). The initiation and maintenance of IDDM by dendritic cells (DC), the most potent professional antigen-presenting cells, were investigated in transgenic mice expressing the lymphocytic choriomeningitis virus glycoprotein (LCMV-GP) under the control of the rat insulin promoter (RIP-GP mice). We show that after adoptive transfer of DC constitutively expressing the immunodominant cytotoxic T lymphocyte (CTL) epitope of the LCMV-GP, RIP-GP mice developed autoimmune diabetes. Kinetic and functional studies of DC-activated CTL revealed that development of IDDM was dependent on dose and timing of antigenic stimulation. Strikingly, repeated CTL activation by DC led to severe destructive mononuclear infiltration of the pancreatic islets but also to de novo formation of islet-associated organized lymphoid structures in the pancreatic parenchyma. In addition, repetitive DC immunization induced IDDM with lymphoid neogenesis also in perforin-deficient RIP-GP mice, illustrating that CD8+ T cell\u2013dependent inflammatory mechanisms independent of perforin could induce IDDM. Thus, DC presenting self-antigens not only are potent inducers of autoreactive T cells, but also help to maintain a peripheral immune response locally; therefore, the induction of autoimmunity against previously ignored autoantigens represents a potential hazard, particularly in DC-based antitumor therapies.<\/jats:p>","DOI":"10.1084\/jem.188.8.1493","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T16:49:30Z","timestamp":1027702170000},"page":"1493-1501","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":239,"title":["Dendritic Cells Induce Autoimmune Diabetes and Maintain Disease via De Novo Formation of Local Lymphoid Tissue"],"prefix":"10.1084","volume":"188","author":[{"given":"Burkhard","family":"Ludewig","sequence":"first","affiliation":[{"name":"From the Institute of Experimental Immunology, University of Z\u00fcrich, CH-8091, Z\u00fcrich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernhard","family":"Odermatt","sequence":"additional","affiliation":[{"name":"From the Institute of Experimental Immunology, University of Z\u00fcrich, CH-8091, Z\u00fcrich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salome","family":"Landmann","sequence":"additional","affiliation":[{"name":"From the Institute of Experimental Immunology, University of Z\u00fcrich, CH-8091, Z\u00fcrich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans","family":"Hengartner","sequence":"additional","affiliation":[{"name":"From the Institute of Experimental Immunology, University of Z\u00fcrich, CH-8091, Z\u00fcrich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rolf M.","family":"Zinkernagel","sequence":"additional","affiliation":[{"name":"From the Institute of Experimental Immunology, University of Z\u00fcrich, CH-8091, Z\u00fcrich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[1998,10,19]]},"reference":[{"key":"2023072508245979100_B1","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.1002\/eji.1830250430","article-title":"Epitope specificity, cytokine production profile and diabetogenic activity of insulin-specific T cell clones isolated from NOD mice","volume":"25","author":"Daniel","year":"1995","journal-title":"Eur J Immunol"},{"key":"2023072508245979100_B2","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1038\/366072a0","article-title":"Immune response to glutamic acid decarboxylase correlates with insulitis in non-obese diabetic mice","volume":"366","author":"Tisch","year":"1993","journal-title":"Nature"},{"key":"2023072508245979100_B3","doi-asserted-by":"crossref","first-page":"2435","DOI":"10.1073\/pnas.84.8.2435","article-title":"The first external domain of the nonobese diabetic mouse class II I-A beta chain is unique","volume":"84","author":"Acha-Orbea","year":"1987","journal-title":"Proc Natl Acad Sci USA"},{"key":"2023072508245979100_B4","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1038\/329599a0","article-title":"HLA-DQ beta gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus","volume":"329","author":"Todd","year":"1987","journal-title":"Nature"},{"key":"2023072508245979100_B5","doi-asserted-by":"crossref","first-page":"1371","DOI":"10.1007\/BF00401772","article-title":"Indications that maternal coxsackie B virus infection during pregnancy is a risk factor for childhood-onset IDDM","volume":"38","author":"Dahlquist","year":"1995","journal-title":"Diabetologia"},{"key":"2023072508245979100_B6","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1038\/371351a0","article-title":"Evidence for superantigen involvement in insulin-dependent diabetes mellitus aetiology","volume":"371","author":"Conrad","year":"1994","journal-title":"Nature"},{"key":"2023072508245979100_B7","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1126\/science.271.5246.173","article-title":"Immunology taught by viruses","volume":"271","author":"Zinkernagel","year":"1996","journal-title":"Science"},{"key":"2023072508245979100_B8","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1146\/annurev.iy.09.040191.001415","article-title":"The dendritic cell system and its role in immunogenicity","volume":"9","author":"Steinman","year":"1991","journal-title":"Annu Rev Immunol"},{"key":"2023072508245979100_B9","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1084\/jem.183.4.1287","article-title":"New insights into the mobilization and phagocytic activity of dendritic cells","volume":"183","author":"Austyn","year":"1996","journal-title":"J Exp Med"},{"key":"2023072508245979100_B10","doi-asserted-by":"crossref","first-page":"6032","DOI":"10.1073\/pnas.80.19.6032","article-title":"Induction of immune responses in vivo with small numbers of veiled (dendritic) cells","volume":"80","author":"Knight","year":"1983","journal-title":"Proc Natl Acad Sci USA"},{"key":"2023072508245979100_B11","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1038\/318059a0","article-title":"Abolition of specific immune response defect by immunization with dendritic cells","volume":"318","author":"Boog","year":"1985","journal-title":"Nature"},{"key":"2023072508245979100_B12","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/0090-1229(90)90065-X","article-title":"Dendritic cells and class II MHC expression on thyrocytes during the autoimmune thyroid disease of the BB rat","volume":"55","author":"Voorby","year":"1990","journal-title":"Clin Immunol Immunopathol"},{"key":"2023072508245979100_B13","doi-asserted-by":"crossref","first-page":"59","DOI":"10.3109\/08916939409014659","article-title":"Adherence of RFD-1 positive dendritic cells to the basal surface of thyroid follicular cells in Graves' disease","volume":"17","author":"Molne","year":"1994","journal-title":"Autoimmunity"},{"key":"2023072508245979100_B14","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/0090-1229(88)90021-9","article-title":"Induction of autoimmunity with dendritic cells: studies on thyroiditis in mice","volume":"48","author":"Knight","year":"1988","journal-title":"Clin Immunol Immunopathol"},{"key":"2023072508245979100_B15","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.1084\/jem.186.8.1183","article-title":"Dendritic cells as adjuvants for immune-mediated resistance to tumors","volume":"186","author":"Schuler","year":"1997","journal-title":"J Exp Med"},{"key":"2023072508245979100_B16","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1084\/jem.183.1.7","article-title":"Dendritic cells as adjuvants for class I major histocompatibility complex\u2013restricted antitumor immunity","volume":"183","author":"Young","year":"1996","journal-title":"J Exp Med"},{"key":"2023072508245979100_B17","doi-asserted-by":"crossref","first-page":"173","DOI":"10.3109\/08830189709116851","article-title":"Immunobiology of human melanoma antigens MART-1 and gp100 and their use for immuno-gene therapy","volume":"14","author":"Kawakami","year":"1997","journal-title":"Int Rev Immunol"},{"key":"2023072508245979100_B18","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/0092-8674(91)90164-T","article-title":"Ablation of \u201ctolerance\u201d and induction of diabetes by virus infection in viral antigen transgenic mice","volume":"65","author":"Ohashi","year":"1991","journal-title":"Cell"},{"key":"2023072508245979100_B19","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/0092-8674(91)90165-U","article-title":"Virus infection triggers insulin-dependent diabetes mellitus in a transgenic model: role of anti-self (virus) immune response","volume":"65","author":"Oldstone","year":"1991","journal-title":"Cell"},{"key":"2023072508245979100_B20","doi-asserted-by":"crossref","first-page":"5185","DOI":"10.4049\/jimmunol.150.11.5185","article-title":"Induction of diabetes is influenced by the infectious virus and local expression of MHC class I and tumor necrosis factor-\u03b1","volume":"150","author":"Ohashi","year":"1993","journal-title":"J Immunol"},{"key":"2023072508245979100_B21","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/1074-7613(94)90101-5","article-title":"How virus induces a rapid or slow onset insulin-dependent diabetes mellitus in a transgenic model","volume":"1","author":"von Herrath","year":"1994","journal-title":"Immunity"},{"key":"2023072508245979100_B22","doi-asserted-by":"crossref","first-page":"2143","DOI":"10.1084\/jem.183.5.2143","article-title":"Development of insulitis without diabetes in transgenic mice lacking perforin-dependent cytotoxicity","volume":"183","author":"Kagi","year":"1996","journal-title":"J Exp Med"},{"key":"2023072508245979100_B23","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1084\/jem.185.3.531","article-title":"Interferon-\u03b3 is essential for destruction of \u03b2 cells and development of insulin-dependent diabetes mellitus","volume":"185","author":"von Herrath","year":"1997","journal-title":"J Exp Med"},{"key":"2023072508245979100_B24","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1038\/342559a0","article-title":"Tolerance induction in double specific T-cell receptor transgenic mice varies with antigen","volume":"342","author":"Pircher","year":"1989","journal-title":"Nature"},{"key":"2023072508245979100_B25","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1084\/jem.187.5.763","article-title":"Viral and bacterial infections interfere with peripheral tolerance induction and activate CD8+T cells to cause immunopathology","volume":"187","author":"Ehl","year":"1998","journal-title":"J Exp Med"},{"key":"2023072508245979100_B26","doi-asserted-by":"crossref","first-page":"3812","DOI":"10.1128\/JVI.72.5.3812-3818.1998","article-title":"Dendritic cells efficiently induce protective antiviral immunity","volume":"72","author":"Ludewig","year":"1998","journal-title":"J Virol"},{"key":"2023072508245979100_B27","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1002\/eji.1830170707","article-title":"The immune response of the mouse to lymphocytic choriomeningitis virus. V. High numbers of cytolytic T lymphocytes are generated in the spleen during acute infection","volume":"17","author":"Moskophidis","year":"1987","journal-title":"Eur J Immunol"},{"key":"2023072508245979100_B28","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1038\/312548a0","article-title":"Therapy with monoclonal antibodies by elimination of T-cell subsets in vivo","volume":"312","author":"Cobbold","year":"1984","journal-title":"Nature"},{"key":"2023072508245979100_B29","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1093\/intimm\/3.2.141","article-title":"Novel pathways of antigen presentation for the maintenance of memory","volume":"3","author":"Gray","year":"1991","journal-title":"Int Immunol"},{"key":"2023072508245979100_B30","doi-asserted-by":"crossref","first-page":"1753","DOI":"10.1084\/jem.171.5.1753","article-title":"The distinct leukocyte integrins of mouse spleen dendritic cells as identified with new hamster monoclonal antibodies","volume":"171","author":"Metlay","year":"1990","journal-title":"J Exp Med"},{"key":"2023072508245979100_B31","doi-asserted-by":"crossref","first-page":"1461","DOI":"10.1084\/jem.183.4.1461","article-title":"Chronic inflammation caused by lymphotoxin is lymphoid neogenesis","volume":"183","author":"Kratz","year":"1996","journal-title":"J Exp Med"},{"key":"2023072508245979100_B32","doi-asserted-by":"crossref","first-page":"10036","DOI":"10.1073\/pnas.89.21.10036","article-title":"Insulitis in transgenic mice expressing tumor necrosis factor beta (lymphotoxin) in the pancreas","volume":"89","author":"Picarella","year":"1992","journal-title":"Proc Natl Acad Sci USA"},{"key":"2023072508245979100_B33","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1056\/NEJM198508083130604","article-title":"In situ characterization of autoimmune phenomena and expression of HLA molecules in the pancreas in diabetic insulitis","volume":"313","author":"Bottazzo","year":"1985","journal-title":"N Engl J Med"},{"key":"2023072508245979100_B34","first-page":"132","article-title":"Recurrent diabetes mellitus in the pancreas iso- and allograft. A light and electron microscopic and immunohistochemical analysis of four cases","volume":"53","author":"Sibley","year":"1985","journal-title":"Lab Invest"},{"key":"2023072508245979100_B35","doi-asserted-by":"crossref","first-page":"31","DOI":"10.3109\/08916939309004836","article-title":"An immunohistochemical study on organized lymphoid cell infiltrates in fetal and neonatal pancreases. A comparison with similar infiltrates found in the pancreas of a diabetic infant","volume":"15","author":"Jansen","year":"1993","journal-title":"Autoimmunity"},{"key":"2023072508245979100_B36","doi-asserted-by":"crossref","first-page":"1693","DOI":"10.1002\/eji.1830230744","article-title":"Antigen-presenting cells in adoptively transferred and spontaneous autoimmune diabetes","volume":"23","author":"Lo","year":"1993","journal-title":"Eur J Immunol"},{"key":"2023072508245979100_B37","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1084\/jem.183.1.87","article-title":"Therapy of murine tumors with tumor peptide\u2013pulsed dendritic cells: dependence on T cells, B7 costimulation, and T helper cell 1\u2013associated cytokines","volume":"183","author":"Zitvogel","year":"1996","journal-title":"J Exp Med"},{"key":"2023072508245979100_B38","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1002\/eji.1830240317","article-title":"Murine dendritic cells pulsed in vitro with tumor antigen induce tumor resistance in vivo","volume":"24","author":"Flamand","year":"1994","journal-title":"Eur J Immunol"},{"key":"2023072508245979100_B39","doi-asserted-by":"crossref","first-page":"1177","DOI":"10.1084\/jem.186.7.1177","article-title":"Bone marrow\u2013generated dendritic cells pulsed with tumor extracts or tumor RNA induce antitumor immunity against central nervous system tumors","volume":"186","author":"Ashley","year":"1997","journal-title":"J Exp Med"},{"key":"2023072508245979100_B40","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1084\/jem.184.2.465","article-title":"Dendritic cells pulsed with RNA are potent antigen-presenting cells in vitro and in vivo","volume":"184","author":"Boczkowski","year":"1996","journal-title":"J Exp Med"},{"key":"2023072508245979100_B41","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.1084\/jem.186.8.1247","article-title":"Dendritic cells genetically modified with an adenovirus vector encoding the cDNA for a model antigen induce protective and therapeutic antitumor immunity","volume":"186","author":"Song","year":"1997","journal-title":"J Exp Med"},{"key":"2023072508245979100_B42","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1084\/jem.186.8.1213","article-title":"Dendritic cells retrovirally transduced with a model antigen gene are therapeutically effective against established pulmonary metastases","volume":"186","author":"Specht","year":"1997","journal-title":"J Exp Med"},{"key":"2023072508245979100_B43","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1038\/nm0597-558","article-title":"Induction of antitumor activity by immunization with fusions of dendritic and carcinoma cells","volume":"3","author":"Gong","year":"1997","journal-title":"Nat Med"}],"container-title":["The Journal of Experimental Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/188\/8\/1493\/1691646\/98-0814.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/188\/8\/1493\/1691646\/98-0814.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,25]],"date-time":"2023-07-25T09:35:18Z","timestamp":1690277718000},"score":1,"resource":{"primary":{"URL":"https:\/\/rupress.org\/jem\/article\/188\/8\/1493\/7759\/Dendritic-Cells-Induce-Autoimmune-Diabetes-and"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1998,10,19]]},"references-count":43,"journal-issue":{"issue":"8","published-print":{"date-parts":[[1998,10,19]]}},"URL":"https:\/\/doi.org\/10.1084\/jem.188.8.1493","relation":{},"ISSN":["0022-1007","1540-9538"],"issn-type":[{"value":"0022-1007","type":"print"},{"value":"1540-9538","type":"electronic"}],"subject":[],"published":{"date-parts":[[1998,10,19]]}}}