title: Transfusion of apoptotic beta-cells induces immune tolerance to beta-cell antigens and prevents type 1 diabetes in NOD mice.
abstract: In vivo induction of beta-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 beta-cells to prevent type 1 diabetes, the current study was designed to investigate apoptotic beta-cells induced ex vivo in preventing type 1 diabetes. The NIT-1 cell line serves as a source of beta-cells. Apoptotic NIT-1 cells were prepared by ultraviolet B (UVB) irradiation. Three weekly transfusions of UVB-irradiated NIT-1 cells (1 x 10(5)/mouse) or PBS were used to determine whether transfusions of UVB-irradiated NIT-1 cells induce immune tolerance to beta-cell antigens in vivo and prevent type 1 diabetes. The suppression of anti-beta-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-beta-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 beta-cell antigen-specific T-cell receptor-transgenic T-cells in UVB-irradiated NIT-1-cell treated mice is markedly suppressed. The transfusion of apoptotic beta-cells effectively protects against type 1 diabetes in NOD mice by inducing immune tolerance to beta-cell antigens. This approach has great potential for immune intervention for human type 1 diabetes.
authors.affiliation: Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA. xia@pathology.ufl.edu
authors.forename: Chang-Qing
authors.initials: CQ
authors.lastname: Xia
authors.forename: Ruihua
authors.initials: R
authors.lastname: Peng
authors.forename: Yushi
authors.initials: Y
authors.lastname: Qiu
authors.forename: Mani
authors.initials: M
authors.lastname: Annamalai
authors.forename: David
authors.initials: D
authors.lastname: Gordon
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Clare-Salzler
mesh_terms: D019264:Adoptive Transfer; D017668:Age of Onset; D000818:Animals; D000941:Antigens / Q000276:immunology*; D017209:Apoptosis; D001323:Autoantibodies / Q000276:immunology; D002454:Cell Differentiation; D002460:Cell Line; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control / Q000628:therapy; D007108:Immune Tolerance / Q000276:immunology*; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000276:immunology* / Q000528:radiation effects; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology
chemical_list: D000941:Antigens; D001323:Autoantibodies; D016207:Cytokines