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Transfusion of Apoptotic ß-Cells Induces Immune Tolerance to ß-Cell Antigens and Prevents Type 1 Diabetes in NOD Mice

From the Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, Florida

Address correspondence and reprint requests to Dr. Chang-Qing Xia, Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL 32610. E-mail: xia{at}pathology.ufl.edu

Abbreviations: APC, allophycocyanin; CFSE, carboxyfluorescein diacetate succinimidyl ester; IFN, interferon; IL, interleukin; MFI, mean fluorescence intensity; PLN, pancreatic draining lymph node; TCR, T-cell receptor; Th, T-helper; Tr1, T-regulatory type 1; UVB, ultraviolet B

In vivo induction of ß-cell apoptosis has been demonstrated to be effective in preventing type 1 diabetes in NOD mice. Based on the notion that steady-state cell apoptosis is associated with self-tolerance and the need for developing a more practical approach using apoptotic ß-cells to prevent type 1 diabetes, the current study was designed to investigate apoptotic ß-cells induced ex vivo in preventing type 1 diabetes. The NIT-1 cell line serves as a source of ß-cells. Apoptotic NIT-1 cells were prepared by ultraviolet B (UVB) irradiation. Three weekly transfusions of UVB-irradiated NIT-1 cells (1 x 10⁵/mouse) or PBS were used to determine whether transfusions of UVB-irradiated NIT-1 cells induce immune tolerance to ß-cell antigens in vivo and prevent type 1 diabetes. The suppression of anti–ß-cell antibodies, polarization of T-helper (Th) cells, and induction of regulatory T-cells by UVB-irradiated NIT-1 cell treatment were investigated. The transfusions of apoptotic NIT-1 cells suppress anti–ß-cell antibody development and induce Th2 responses and interleukin-10–producing regulatory type 1 cells. Importantly, this treatment significantly delays and prevents the onset of diabetes when 10-week-old NOD mice are treated. Adoptive transfer of splenocytes from UVB-irradiated NIT-1 cell–treated mice prevents diabetes caused by simultaneously injected diabetogenic splenocytes in NOD-Rag^–/– mice. Moreover, the proliferation of adoptively transferred carboxyfluorescein diacetate succinimidyl ester–labeled ß-cell antigen–specific T-cell receptor–transgenic T-cells in UVB-irradiated NIT-1–cell treated mice is markedly suppressed. The transfusion of apoptotic ß-cells effectively protects against type 1 diabetes in NOD mice by inducing immune tolerance to ß-cell antigens. This approach has great potential for immune intervention for human type 1 diabetes.

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