title: β-Cell-targeted blockage of PD1 and CTLA4 pathways prevents development of autoimmune diabetes and acute allogeneic islets rejection.
abstract: Protection of β cells from autoimmune destruction potentially cures type 1 diabetes mellitus (T1D). During antigen presentation, interactions between cytotoxic T-lymphocyte antigen-4 (CTLA4) and B7 molecules, or programmed death 1 (PD1) and its ligand PDL1, negatively regulate immune responses in a non-redundant manner. Here we employed β-cell-targeted adeno-associated virus serotype 8 (AAV8)-based vectors to overexpress an artificial PDL1-CTLA4Ig polyprotein or interleukin 10 (IL10). β-Cell-targeted expression of PDL1-CTLA4Ig or IL10 preserved β-cell mass and protected NOD mice from T1D development. When NOD mice were treated with vectors at early onset of hyperglycemia, PDL1-CTLA4Ig or IL10 alone failed to normalize the early onset of hyperglycemia. When drug-induced diabetic mice received major histocompatibility complex (MHC)-matched allo-islets, with or without pretreatment of the PDL1-CTLA4Ig-expressing vector, PDL1-CTLA4Ig-expressing islets were protected from rejection for at least 120 days. Similarly, transplantation of PDL1-CTLA4Ig-expressing MHC-matched islets into mice with established T1D resulted in protection of allo-islets from acute rejection, although islet grafts were eventually rejected. Thus the present study demonstrates the potent immuno-suppressive effects of β-cell-targeted PDL1-CTLA4Ig overexpression against T1D development and allo-islet rejection. The gene-based simultaneous inhibition of PD1 and CTLA4 pathways provides a unique strategy for immunosuppression-free tissue/organ transplantation, especially in the setting of no established autoimmunity.
authors: Department of Molecular Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors: M M
authors: MM
authors: El Khatib
authors: Department of Molecular Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors: T
authors: T
authors: Sakuma
authors: Department of Molecular Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors: J M
authors: JM
authors: Tonne
authors: Department of Molecular Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors: M S
authors: MS
authors: Mohamed
authors: Department of Molecular Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors: S J
authors: SJ
authors: Holditch
authors: Department of Molecular Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors: B
authors: B
authors: Lu
authors: Division of Endocrinology, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors: Y C
authors: YC
authors: Kudva
authors: Department of Molecular Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors: Y
authors: 0000000298747537
authors: Y
authors: Ikeda
mesh_terms: D000818:Animals; D015551:Autoimmunity; D060890:B7-H1 Antigen / Q000276:immunology*; D060908:CTLA-4 Antigen / Q000276:immunology*; D003921:Diabetes Mellitus, Experimental / Q000276:immunology* / Q000628:therapy; D006084:Graft Rejection; D057809:HEK293 Cells; D006801:Humans; D007165:Immunosuppression Therapy; D050417:Insulin-Secreting Cells / Q000276:immunology* / Q000637:transplantation; D051379:Mice; D008807:Mice, Inbred BALB C; D008813:Mice, Inbred ICR; D016688:Mice, Inbred NOD; D014184:Transplantation, Homologous
chemical_list: D060890:B7-H1 Antigen; D060908:CTLA-4 Antigen