What question did this study set out to answer?

This study aims to investigate how cyclophosphamide-induced diabetes affects islet graft rejection in NOD mice.

June 7, 2026

2421-P: Investigating Cyclophosphamide-Induced Diabetes to Study Autoimmune-Driven Graft Rejection in NOD Mice

Key Points

This study aims to investigate how cyclophosphamide-induced diabetes affects islet graft rejection in NOD mice.
NOD mice were treated with 200mg/kg cyclophosphamide to induce diabetes.
Islets from NOD.Rag were transplanted into NOD and cyclophosphamide-induced diabetic mice.
Blood glucose levels and T-cell profiles were monitored post-transplantation.
Cyclophosphamide induced diabetes in 50% of NOD mice.
Islet transplantation restored normoglycemia but showed accelerated rejection kinetics in CY-ID mice.
Significant differences in CD4+FoxP3+ regulatory T-cells were observed, contributing to graft rejection.

Abstract

Introduction and Objective: Type 1 diabetes (T1D) is caused by beta-cell-specific autoimmune destruction. Spontaneous onset of T1D in NOD mice makes it difficult to synchronize islet transplant studies. Agents that physiologically accelerate diabetes without altering the immune landscape are needed. We used cyclophosphamide (CY), a chemotherapeutic agent, to accelerate T1D in NOD mice to study autoimmune-driven graft rejection. We hypothesize that CY-treatment of NOD mice will induce an immune landscape analogous to spontaneously diabetic mice as a novel model for synchronized islet transplant studies. Methods: Ten-week-old NOD mice were treated intraperitoneally with 200mg/kg CY. NOD.Rag islets were transplanted under the left kidney capsule of spontaneously and CY-induced diabetic (CY-ID) mice. Blood glucose was monitored daily for rejection and immunophenotyping was performed by flow cytometry. Results: CY induced diabetes in 50% of NOD mice. Islet transplantation successfully restored normoglycemia to CY-ID recipients and exhibited accelerated rejection kinetics. CY-ID mice had significant differences in CD4+FoxP3+ regulatory T-cells in the pancreatic lymph node on the day of transplant and in the islet graft 4 days post-transplantation. These differences within FoxP3+ populations likely contribute to accelerated graft rejection in CY-ID recipients. Preliminary results show tetramer positive CD4 and CD8 T-cells in islet grafts from CY-ID recipients, suggesting that graft failure is autoimmune-mediated. Conclusion: From these studies, we determined that islet transplantation can restore normoglycemia to CY-ID mice, islet graft rejection in CY-ID mice is autoimmune-mediated, and graft rejection occurs more quickly in CY-ID than spontaneously diabetic recipients partly due to a decrease in regulatory T-cells. Future work will investigate the ability to manipulate graft survival in CY-ID mice using novel immune-modulatory agents. Disclosure K.S. Burnette: None. S. Tsau: None. O. Peterson: None. R.L. Baker: None. H. Tse: None. Funding NIGMS (F31GM150237); NIDDK (R01-DK126456, R01-DK127497, R01-DK131716, and R01-DK138469); and (SRA-2016-270-S-B, 2-SRA-2019-692-S-B)

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