Differential outcomes in prediabetic vs. overtly diabetic NOD mice nonmyeloablatively conditioned with costimulatory...

Autoimmune diabetes can be reversed with mixed chimerism. However, the myelotoxic agents currently required to establish chimerism have prevented the translation of this approach to the clinic. Here, we investigated whether multimodal costimulatory blockade would enhance chimerism and promote islet allograft tolerance in spontaneously diabetic nonobese diabetic (NOD) mice.

Prediabetic and spontaneously diabetic NOD mice were preconditioned with anti-CD8 monoclonal antibody before conditioning with 500 cGy total body irradiation and transplantation with 30 × 10(6) B10.BR bone marrow cells. Overtly diabetic animals were conditioned similarly and transplanted with 300 to 400 B10.BR islets. After irradiation, both groups of recipients were treated with anti-CD154, anti-OX40L, and anti-inducible T-cell costimulatory monoclonal antibodies. Urine, blood glucose levels, and chimerism were monitored.

Conditioning of NOD mice with costimulatory blockade significantly enhanced engraftment, with 61% of mice engrafting at 1 month. Eleven of 12 chimeric animals with engraftment at 1 month remained diabetes-free over a 12-month follow-up, whereas nonchimeric animals progressed to diabetes. In contrast, similar conditioning prolonged islet allograft survival in only 2 of 11 overtly diabetic NOD recipients. Chimerism levels in the 9 islet rejector animals were 0%.

Although nonmyeloablative conditioning reversed the autoimmune process in prediabetic NOD mice, the same regimen was significantly less effective in establishing chimerism and reversing autoimmune diabetes in spontaneously diabetic NOD mice.