Virus infection triggers insulin-dependent diabetes mellitus in a transgenic model: role of anti-self (virus) immune response

Oldstone, M B

doi:10.1016/0168-9525(91)90361-s

Cited by 201 publications

(351 citation statements)

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“…In contrast, if these mice are infected with replicating LCMV virus or immunized with DCs expressing LCMV-GP, they mount an LCMV-GPspecific CTL response and develop diabetes. 44,49,50 These experiments illustrate that T cells specific for LCMV-GP are present, but because the antigen is expressed strictly outside secondary lymphoid organs and the antigen does not reach local lymph nodes in a sufficient quantity over a sufficient time period, no specific CTLs are induced and the peripheral antigen is ignored. Alymphoplastic mice (aly /aly ) lack lymph nodes but possess a spleen with functionally normal CTL.…”

Section: Antigen Dose and Localizationmentioning

confidence: 96%

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Principles of tumor immunosurveillance and implications for immunotherapy

Ochsenbein

2002

Cancer Gene Ther

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Although antigen loss variants, major histocompatibility ( MHC ) class I down -regulation, or the expression of inhibitory molecules may explain the failure of immunosurveillance against some tumors, this seems not to apply for many other solid peripheral or lymphohematopoietic tumors. Why then is immunosurveillance so ineffective and can it be improved? This review focuses on one important aspect of tumor immunity, namely the relevance of antigen dose and localization. Immune responses in vivo are induced in organized lymphoid tissues, i.e., in lymph nodes and spleen. The antigen dose that reaches secondary lymphoid organs over time is a crucial parameter that drives antiviral and antitumoral immune responses. Tumors use various strategies to prevent efficient presentation of their antigens in lymphoid organs. A major obstacle to the induction of an endogenous tumor -specific cytotoxic T lymphocyte ( CTL ) response is the inefficient presentation of tumor antigen on MHC class I molecules of professional antigenpresenting cells. Peripheral solid tumors that develop outside lymphoid organs are, therefore, often ignored by the immune system. In other situations, tumors -especially of lymphohematopoietic origin -may tolerize specific CTLs. Understanding tumor immunosurveillance is key to the design of efficient antitumor vaccines. Attempts to improve immunity to tumors include vaccination strategies to ( a ) provide the tumor antigen to secondary lymphoid organs using recombinant viruses or dendritic cells as carriers, ( b ) express costimulatory signals on tumor cells, or ( c ) improve the efficiency of cross -priming.

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Section: Antigen Dose and Localizationmentioning

confidence: 96%

“…Diabetes models with a transgenic antigen expressed on islet cells are very informative for the role of the antigen localization in the induction of CTL. 44,49 RIP-GP transgenic mice express the glycoprotein (GP ) of LCMV under the ratinsulin promoter ( RIP ). These RIP -GP mice do not spontaneously develop diabetes.…”

Section: Antigen Dose and Localizationmentioning

confidence: 99%

Principles of tumor immunosurveillance and implications for immunotherapy

Ochsenbein

2002

Cancer Gene Ther

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“…Significantly, they have shown that vaccination of insulin-dependent HA mice can activate these low avidity CTLs that are able to reject tumor cells expressing high levels of HA, without destruction of pancreatic islet ␤ cells expressing moderate levels of HA. Studies with other transgenic mouse models expressing model proteins as self Ags have shown that T cells with specificity for self proteins can be demonstrated within the peripheral T cell pool (33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43). Often, potentially autoreactive T cells manage to escape deletion by virtue of their lower avidity for self Ag even when the transgene element is present in, or is available to, the thymus (44).…”

Section: Figurementioning

confidence: 99%

Mice with Spontaneous Pancreatic Cancer Naturally Develop MUC-1-Specific CTLs That Eradicate Tumors When Adoptively Transferred

Mukherjee

Ginardi

Madsen

et al. 2000

The Journal of Immunology

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Pancreatic cancer is a highly aggressive, treatment refractory cancer and is the fourth leading cause of death in the United States. In humans, 90% of pancreatic adenocarcinomas overexpress altered forms of a tumor-specific Ag, mucin 1 (MUC1; an epithelial mucin glycoprotein), which is a potential target for immunotherapy. We have established a clinically relevant animal model for pancreatic cancer by developing a double transgenic mouse model (called MET) that expresses human MUC1 as self molecule and develops spontaneous tumors of the pancreas. These mice exhibit acinar cell dysplasia at birth, which progresses to microadenomas and acinar cell carcinomas. The tumors express large amounts of underglycosylated MUC1 similar to humans. Tumor-bearing MET mice develop low affinity MUC1-specific CTLs that have no effect on the spontaneously occurring pancreatic tumors in vivo. However, adoptive transfer of these CTLs was able to completely eradicate MUC1-expressing injectable tumors in MUC1 transgenic mice, and these mice developed long-term immunity. These CTLs were MHC class I restricted and recognized peptide epitopes in the immunodominant tandem repeat region of MUC1. The MET mice appropriately mimic the human condition and are an excellent model with which to elucidate the native immune responses that develop during tumor progression and to develop effective antitumor vaccine strategies.

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“…Despite these elaborate safeguards, T lymphocytes expressing receptors that can recognize self normally persist within the repertoire (10 -12), and under certain circumstances can contribute to autoimmune pathogenesis (13,14). In an effort to understand the origins and immune potential of CD8 ϩ T lymphocytes specific for peripheral self Ag, we have focused on a transgenic model in which the influenza virus hemagglutinin (HA) 3 (3) gene is expressed by ␤ cells within the pancreatic islets (15).…”

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confidence: 99%

Characterization of CD8+ T Lymphocytes That Persist After Peripheral Tolerance to a Self Antigen Expressed in the Pancreas

Nugent

Morgan

Biggs

et al. 2000

The Journal of Immunology

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As a result of expression of the influenza hemagglutinin (HA) in the pancreatic islets, the repertoire of HA-specific CD8+ T lymphocytes in InsHA transgenic mice (D2 mice expressing the HA transgene under control of the rat insulin promoter) is comprised of cells that are less responsive to cognate Ag than are HA-specific CD8+ T lymphocytes from conventional mice. Previous studies of tolerance induction involving TCR transgenic T lymphocytes suggested that a variety of different mechanisms can reduce avidity for Ag, including altered cell surface expression of molecules involved in Ag recognition and a deficiency in signaling through the TCR complex. To determine which, if any, of these mechanisms pertain to CD8+ T lymphocytes within a conventional repertoire, HA-specific CD8+ T lymphocytes from B10.D2 mice and B10.D2 InsHA transgenic mice were compared with respect to expression of cell surface molecules, TCR gene utilization, binding of tetrameric KdHA complexes, lytic mechanisms, and diabetogenic potential. No evidence was found for reduced expression of TCR or CD8 by InsHA-derived CTL, nor was there evidence for a defect in triggering lytic activity. However, avidity differences between CD8+ clones correlated with their ability to bind KdHA tetramers. These results argue that most of the KdHA-specific T lymphocytes in InsHA mice are not intrinsically different from KdHA-specific T lymphocytes isolated from conventional animals. They simply express TCRs that are less avid in their binding to KdHA.

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Virus infection triggers insulin-dependent diabetes mellitus in a transgenic model: role of anti-self (virus) immune response

Cited by 201 publications

References 0 publications

Principles of tumor immunosurveillance and implications for immunotherapy

Principles of tumor immunosurveillance and implications for immunotherapy

Mice with Spontaneous Pancreatic Cancer Naturally Develop MUC-1-Specific CTLs That Eradicate Tumors When Adoptively Transferred

Characterization of CD8+ T Lymphocytes That Persist After Peripheral Tolerance to a Self Antigen Expressed in the Pancreas

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