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There have been two previous conflicting reports that the development of T-cell-mediated autoimmune diabetes (type 1 diabetes) was respectively unaffected or inhibited in NOD mice genetically deficient in the T-helper (Th) 1 cytokine interferon (IFN)-gamma or the alpha-chain subunit of its receptor. Our goal was to resolve this conundrum by congenically transferring, from a 129 donor strain to the NOD background, a functionally inactivated gene for the beta-chain signaling (located on chromosome 16) rather than the alpha-chain ligand binding domain (located on chromosome 10) of the IFN-gamma receptor. These NOD.IFNgammaRBnull mice were characterized by normal patterns of leukocyte development and T-cells that produced greatly enhanced levels of the putatively type 1 diabetes-protective Th2 cytokine interleukin (IL)-4. However, despite being unable to respond to the primary Thl cytokine IFN-gamma and having T-cells that produce greatly enhanced levels of IL-4, NOD.IFNgammaRBnull mice remained highly susceptible to type 1 diabetes. This result indicated that the previously reported inhibition of type 1 diabetes in NOD mice carrying a functionally inactivated IFN-gamma receptor alpha-chain gene may have been due to a closely linked and previously unidentified diabetes resistance allele. Furthermore, our results indicate that the pathogenicity of diabetogenic T-cells in NOD mice is not dampened by an inability to respond to IFN-gamma and a concurrent shift to greatly enhanced Th2 cytokine production. This finding calls into question whether clinical protocols designed to shift beta-cell autoreactive T-cells from a Thl to Th2 cytokine production profile will truly be safe and efficacious in blocking the development of type 1 diabetes in humans.
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C M Post, and
H D Chapman, and
E A Johnson, and
B Lu, and
P B Rothman
July 2007,
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D V Serreze, and
C M Post, and
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E A Johnson, and
B Lu, and
P B Rothman
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D V Serreze, and
C M Post, and
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E A Johnson, and
B Lu, and
P B Rothman
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D V Serreze, and
C M Post, and
H D Chapman, and
E A Johnson, and
B Lu, and
P B Rothman
June 2019,
Diabetes,
D V Serreze, and
C M Post, and
H D Chapman, and
E A Johnson, and
B Lu, and
P B Rothman
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D V Serreze, and
C M Post, and
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E A Johnson, and
B Lu, and
P B Rothman
November 2002,
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D V Serreze, and
C M Post, and
H D Chapman, and
E A Johnson, and
B Lu, and
P B Rothman
March 2014,
Diabetes,
