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Unexpected acceleration of type 1 diabetes by transgenic expression of B7-H1 in NOD mouse peri-islet glia.


ABSTRACT:

Objective

Autoimmune target tissues in type 1 diabetes include pancreatic ?-cells and peri-islet Schwann cells (pSC)--the latter active participants or passive bystanders in pre-diabetic autoimmune progression. To distinguish between these alternatives, we sought to suppress pSC autoimmunity by transgenic expression of the negative costimulatory molecule B7-H1 in NOD pSC.

Research design and methods

A B7-H1 transgene was placed under control of the glial fibrillary acidic protein (GFAP) promoter. Transgenic and wild-type NOD mice were compared for transgene PD-1 affinities, diabetes development, insulitis, and pSC survival. Mechanistic studies included adoptive type 1 diabetes transfer, B7-H1 blockade, and T-cell autoreactivity and sublineage distribution.

Results

Transgenic and endogenous B7-H1 bound PD-1 with equal affinities. Unexpectedly, the transgene generated islet-selective CD8(+) bias with accelerated rather than suppressed diabetes progression. T-cells of diabetic transgenics transferred type 1 diabetes faster. There were no earlier pSC losses due to conceivable transgene toxicity, but transgenic pSC loss was enhanced by 8 weeks, preceded by elevated GFAP autoreactivity, with high-affinity T-cells targeting the major NOD K(d)-GFAP epitope, p253-261. FoxP3(+) regulatory T- and CD11c(+) dendritic cell pools were unaffected.

Conclusions

In contrast with transgenic B7-H1 in NOD mouse ?-cells, transgenic B7-H1 in pSC promotes rather than protects from type 1 diabetes. Here, ectopic B7-H1 enhanced the pathogenicity of effector T-cells, demonstrating that pSC can actively impact diabetes progression-likely through modification of intraislet T-cell selection. Although pSC cells emerge as a new candidate for therapeutic targets, caution is warranted with regard to the B7-H1-PD1 axis, where B7-H1 overexpression can lead to accelerated autoimmune disease.

SUBMITTER: Yantha J 

PROVIDER: S-EPMC3279538 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Publications

Unexpected acceleration of type 1 diabetes by transgenic expression of B7-H1 in NOD mouse peri-islet glia.

Yantha Jason J   Tsui Hubert H   Winer Shawn S   Song Aihua A   Wu Ping P   Paltser Geoff G   Ellis James J   Dosch H-Michael HM  

Diabetes 20100603 10


<h4>Objective</h4>Autoimmune target tissues in type 1 diabetes include pancreatic β-cells and peri-islet Schwann cells (pSC)--the latter active participants or passive bystanders in pre-diabetic autoimmune progression. To distinguish between these alternatives, we sought to suppress pSC autoimmunity by transgenic expression of the negative costimulatory molecule B7-H1 in NOD pSC.<h4>Research design and methods</h4>A B7-H1 transgene was placed under control of the glial fibrillary acidic protein  ...[more]

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