title: Induction of robust diabetes resistance and prevention of recurrent type 1 diabetes following islet transplantation by gene therapy.
abstract: We have previously shown that the development of type 1 diabetes (T1D) can be prevented in nonobese diabetic (NOD) mice by reconstitution with autologous hemopoietic stem cells retrovirally transduced with viruses encoding MHC class II I-A beta-chain molecules associated with protection from the disease. In this study we examined whether a blockade of the programmed death-1 (PD-1)-programmed death ligand-1 (PD-L1) pathway, a major pathway known to control diabetes occurrence, could precipitate T1D in young NOD mice following reconstitution with autologous bone marrow retrovirally transduced with viruses encoding protective MHC class II I-A beta-chain molecules. In addition, we examined whether the expression of protective MHC class II alleles in hemopoietic cells could be used to prevent the recurrence of diabetes in mice with pre-existing disease following islet transplantation. Protection from the occurrence of T1D diabetes in young NOD mice by the expression of protective MHC class II I-A beta-chain molecules in bone marrow-derived hemopoietic cells was resistant to induction by PD-1-PD-L1 blockade. Moreover, reconstitution of NOD mice with pre-existing T1D autologous hemopoietic stem cells transduced with viruses encoding protective MHC class II I-A beta-chains allowed for the successful transplantation of syngeneic islets, resulting in the long-term reversal of T1D. Reversal of diabetes was resistant to induction by PD-1-PDL-1 blockade and depletion of CD25(+) T cells. These data suggest that expression of protective MHC class II alleles in bone marrow-derived cells establishes robust self-tolerance to islet autoantigens and is sufficient to prevent the recurrence of autoimmune diabetes following islet transplantation.
authors.affiliation: Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Chaorui
authors.initials: C
authors.lastname: Tian
authors.forename: Mohammed Javeed I
authors.initials: MJ
authors.lastname: Ansari
authors.forename: Jesus
authors.initials: J
authors.lastname: Paez-Cortez
authors.forename: Jessamyn
authors.initials: J
authors.lastname: Bagley
authors.forename: Jonathan
authors.initials: J
authors.lastname: Godwin
authors.forename: Michela
authors.initials: M
authors.lastname: Donnarumma
authors.forename: Mohamed H
authors.initials: MH
authors.lastname: Sayegh
authors.forename: John
authors.initials: J
authors.lastname: Iacomini
mesh_terms: D000483:Alleles; D000818:Animals; D000943:Antigens, Differentiation / Q000276:immunology; D018122:B7-1 Antigen / Q000276:immunology; D060890:B7-H1 Antigen; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control*; D015870:Gene Expression; D015316:Genetic Therapy; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D007515:Islets of Langerhans / Q000276:immunology*; D016381:Islets of Langerhans Transplantation; D008562:Membrane Glycoproteins / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010455:Peptides / Q000276:immunology; D061026:Programmed Cell Death 1 Receptor; D012190:Retroviridae; D013601:T-Lymphocytes / Q000276:immunology; D014161:Transduction, Genetic; D014181:Transplantation Immunology; D023001:Transplantation Tolerance / Q000235:genetics; D014182:Transplantation, Autologous; D014185:Transplantation, Isogeneic
chemical_list: D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D000949:Histocompatibility Antigens Class II; C474482:I-A(b) antigen, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D008562:Membrane Glycoproteins; C491383:Pdcd1 protein, mouse; D010455:Peptides; D061026:Programmed Cell Death 1 Receptor