T-cells from NOD-PerIg mice transfer aggressive peripheral neuritis to NOD. scid recipients

Abstract Recently, we created NOD mice transgenically expressing a peripherin reactive B cell receptor (BCR) inducing rapid onset T1D (NOD-PerIg). We unexpectedly discovered that in addition to T1D, NOD.scid recipients receiving transferred NOD-PerIg T-cells or whole splenocytes developed a visible hind leg weakness caused by aggressive limb neuritis. Neurobehavior phenotyping failed to uncover any measurable clinical metric that could predict onset of visible hind leg symptoms. Nerve conduction velocities were measured on hind limbs in mice that made it to the critical 15-weeks post transfer window, and revealed that most mice with clinical symptoms of neuritis had little to no discernible nerve conduction, while those without clinical symptoms of neuritis had near normal NOD.scid-like levels of nerve conduction. A longitudinal flow cytometry analysis of sciatic nerves at onset of diabetes, onset of visible hind leg symptoms, or at the end of incidence revealed that mice with clinical symptoms of neuritis had increased CD45+ cells amongst live cells compared to controls, and increased T-cells amongst CD45+ cells compared to both controls and mice without clinical symptoms. Depletion of either CD4 or CD8 T-cells after transfer of whole NOD-PerIg splenocytes led to the complete prevention of diabetes development. Interestingly, CD4 but not CD8 T-cell depletion led to the absence of any clinical manifestation of neuritis by 20 weeks post transfer. Finally, we have observed lymphocyte infiltration in both primary NOD-PerIg and NOD mice, likely explaining the occasional NOD mouse that has developed neuritis in The Jackson Laboratory’s extensive NOD collection.