Inducible and reversible beta-cell autoimmunity and hyperplasia in transgenic mice expressing a conditional oncogene.
Expression of the SV40 T antigen (Tag) in pancreatic beta-cells in transgenic mice has been shown to induce beta-cell tumorigenesis. We generated transgenic mice in which Tag expression is inducible and reversible by the tet-on gene regulation system. These mice develop beta-cell tumors only when treated with the inducer doxycycline (dox). Tag expression in vivo is reversible upon dox withdrawal. As a result, beta-cell proliferation is greatly reduced, indicating that genetic changes, which may occur in the transformed cells, do not allow Tag-independent proliferation. Induction of Tag expression after immune recognition of self-antigens has been established triggers an autoimmune response against beta-cells, as evidenced by insulitis. Shut-off of Tag expression results in elimination of insulitis, suggesting that this process depends on continuous expression of the target antigen. In addition, the reversibility of autoimmunity suggests that beta-cell damage caused by the anti-Tag immune response does not elicit secondary responses to other newly exposed beta-cell antigens, which would have persisted after Tag elimination. beta-Cell proliferation in this model is accompanied by cell apoptosis. Apoptosis persisted for several weeks in the islets after dox removal. In close to 40% of the mice analyzed, this process reduced the islet size back to normal, suggesting the existence of a homeostatic mechanism that maintains beta-cell mass within the normal range.
Berkovich
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Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
Efrat
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D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000032:analysis; D017209:Apoptosis; D015551:Autoimmunity; D002455:Cell Division; D004318:Doxycycline / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006965:Hyperplasia; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D007515:Islets of Langerhans / Q000276:immunology* / Q000473:pathology* / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics; D009857:Oncogenes / Q000502:physiology*
D000952:Antigens, Polyomavirus Transforming; D004318:Doxycycline