Chamberlain, C. S.; Kapadia, D.; Abad Santos, E.; Huang, L.; Holm, A.; Leavens, C.; Palwasha Khan, A.; Gorski, K. M.; Steck, C. C.; Mikat, A. S.; Tremmel, D. M.; Chlebeck, P.; Talerico, K.; Estrada, E.; McIntosh, B.; Brown, M. E.; Sackett, S. D.; Odorico, J. S.

Using toxin receptor-mediated cell ablation, a diabetes mouse model was generated that supports engraftment of human hematopoietic stem/progenitor cells (HSPCs) without the need for irradiation. The NBSGW immunodeficient strain was crossed with the NSG RIP-DTR which carries the diphtheria toxin receptor (hDTR) under the control of the rat insulin promoter to generate the NBSGW RIP-DTR mouse. This model enables controlled {beta}-cell ablation, robust human immune system reconstitution without myeloablative conditioning, and evaluation of human immune-mediated graft rejection within a single platform. NBSGW RIP-DTR mice exhibited reproducible and titratable diabetes induction, supported durable human islet engraftment and glycemic correction, and retained efficient human hematopoietic reconstitution comparable to the parental NBSGW strain. In humanized mice, diphtheria toxin-mediated diabetes induction was well tolerated and enabled assessment of human immune responses to allogeneic islet grafts. Collectively, these findings establish the NBSGW RIP-DTR mouse as an integrated and clinically relevant platform for studying {beta}-cell replacement therapies and human immune-mediated graft rejection.