β-Cell-targeted blockage of PD1 and CTLA4 pathways prevents development of autoimmune diabetes and acute allogeneic islets rejection

Gene Therapy
M M El KhatibY Ikeda

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 stu...Continue Reading

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Citations

Mar 1, 2016·Acta Diabetologica·Silvia PellegriniLorenzo Piemonti
May 28, 2011·Seminars in Immunology·Nina PilatThomas Wekerle
Jan 26, 2020·Cells·Bushra Memon, Essam M Abdelalim
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Dec 21, 2017·Frontiers in Endocrinology·Adam L BurrackBrian T Fife
Jul 10, 2020·Stem Cell Research & Therapy·Shuai ChenChunlin Zou
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Mar 16, 2021·Frontiers in Endocrinology·Eleonora de Klerk, Matthias Hebrok
May 7, 2021·Current Diabetes Reports·Christopher G TuckerTijana Martinov
May 10, 2021·Molecular Aspects of Medicine·David J Hill
Jul 2, 2021·Pharmacological Reviews·Leslie S SatinEmily M Walker

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