A novel myelin P0–specific T cell receptor transgenic mouse develops a fulminant autoimmune peripheral neuropathy

Diabetes Center and the Department of Medicine, University of California, San Francisco, San Francisco, CA 94143
Journal of Experimental Medicine (Impact Factor: 12.52). 03/2009; 206(3):507-14. DOI: 10.1084/jem.20082113
Source: PubMed


Autoimmune-prone nonobese diabetic mice deficient for B7-2 spontaneously develop an autoimmune peripheral neuropathy mediated by inflammatory CD4(+) T cells that is reminiscent of Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy. To determine the etiology of this disease, CD4(+) T cell hybridomas were generated from inflamed tissue-derived CD4(+) T cells. A majority of T cell hybridomas were specific for myelin protein 0 (P0), which was the principal target of autoantibody responses targeting nerve proteins. To determine whether P0-specific T cell responses were sufficient to mediate disease, we generated a novel myelin P0-specific T cell receptor transgenic (POT) mouse. POT T cells were not tolerized or deleted during thymic development and proliferated in response to P0 in vitro. Importantly, when bred onto a recombination activating gene knockout background, POT mice developed a fulminant form of peripheral neuropathy that affected all mice by weaning age and led to their premature death by 3-5 wk of age. This abrupt disease was associated with the production of interferon gamma by P0-specific T cells and a lack of CD4(+) Foxp3(+) regulatory T cells. Collectively, our data suggest that myelin P0 is a major autoantigen in autoimmune peripheral neuropathy.

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Available from: Cedric Louvet
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    • "Autoimmune peripheral polyneuropathy has also been described in NOD mice after disruption of various pathways involved in immune tolerance such as IL-2, PD-1 or the autoimmune regulator (Aire) and appears to have comparable immunopathogenic properties as the NOD-B7-2KO disease [31e33]. In particular, NOD mice partially deficient in Aire function develop peripheral neuropathy that is mediated by CD4þ T cells targeting myelin P0 and IFN-g is required for disease to develop [33e35], similar to what has been observed in NOD-B7-2KO mice [4] [29] [30]. In contrast, peripheral polyneuropathy does not occur in mice deficient for B7-2, Aire or PD-1 on B6 or mixed B6-129 backgrounds. "
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    • "From the 1B3 hybridoma cDNA, the full-length coding sequences for the TCR- and - chains were cloned by PCR and were subcloned into a CD2 and CD4 expression vector, respectively, allowing expression of the transgenes in both CD4 and CD8 T cells (Wang et al., 2001). Tg mice were generated by microinjection of CD2–TCR- and CD4–TCR- constructs into NOD embryos as described earlier (Louvet et al., 2009). Vectors were provided by N. Killeen (UCSF, San Francisco, CA). "
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