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Changes in function of antigen‐specific lymphocytes correlating with progression towards diabetes in a transgenic model
Author(s) -
Sarukhan Adelaida,
Lanoue Astrid,
Franzke Anke,
Brousse Nicole,
Buer Jan,
von Boehmer Harald
Publication year - 1998
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/17.1.71
Subject(s) - biology , transgene , function (biology) , genetically modified mouse , antigen , diabetes mellitus , immunology , microbiology and biotechnology , computational biology , genetics , gene , endocrinology
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‐γ 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‐γ 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‐α, compared with diabetic mice. This scenario is consistent with the view that β cell destruction depends upon the increased production of certain pro‐inflammatory cytokines by infiltrating T cells. Our inability to detect Fas expression on β cells, but not on lymphoid cells, in diabetic and non‐diabetic mice, puts some constraints on the role of Fas in β cell destruction.