Gene transfection and expression of transforming growth factor-beta1 in nonobese diabetic mouse islets protects beta-cells in syngeneic islet grafts from autoimmune destruction.
Nonobese diabetic (NOD) mice develop diabetes and destroy syngeneic islet grafts through an autoimmune response. Because transforming growth factor (TGF)-beta1 downregulates immune responses, we tested whether overexpression of TGF-beta1 by gene transfection of NOD mouse islets could protect beta-cells in islet grafts from autoimmune destruction. NOD mouse islet cells were transfected with an adenoviral DNA expression vector encoding porcine latent TGF-beta1 (Ad TGF-beta1) or the adenoviral vector alone (control Ad vector). The frequency of total islet cells expressing TGF-beta1 protein was increased from 12 +/- 1% in control Ad vector-transfected cells to 89 +/- 4% in Ad TGF-beta1-transfected islet cells, and the frequency of beta-cells that expressed TGF-beta1 was increased from 12 +/- 1% to 60 +/- 7%. Also, secretion of TGF-beta1 was significantly increased in islets that overexpressed TGF-beta1. Ad TGF-beta1-transfected NOD mouse islets that overexpressed TGF-beta1 prevented diabetes recurrence after transplantation into diabetic NOD mice for a median of 22 days compared with only 7 days for control Ad vector-transfected islets (p = 0.001). Immunohistochemical examination of the islet grafts revealed significantly more TGF-beta1+ cells and insulin+ cells and significantly fewer CD45+ leukocytes in Ad TGF-beta1-transfected islet grafts. Also, islet beta-cell apoptosis was significantly decreased whereas apoptosis of graft-infiltrating leukocytes was significantly increased in Ad TGF-beta1-transfected islet grafts. These observations demonstrate that overexpression of TGF-beta1, by gene transfection of NOD mouse islets, protects islet beta-cells from apoptosis and autoimmune destruction and delays diabetes recurrence after islet transplantation.
Suarez-Pinzon
Wilma L
WL
Department of Medicine, University of Alberta, Edmonton, Canada.
Marcoux
Yvonne
Y
Ghahary
Aziz
A
Rabinovitch
Alex
A
D000818:Animals; D002478:Cells, Cultured; D005260:Female; D005786:Gene Expression Regulation; D015316:Genetic Therapy; D005822:Genetic Vectors; D006084:Graft Rejection / Q000517:prevention & control; D007150:Immunohistochemistry; D007515:Islets of Langerhans / Q000166:cytology / Q000276:immunology*; D016381:Islets of Langerhans Transplantation / Q000276:immunology* / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000378:metabolism; D013552:Swine; D014162:Transfection / Q000379:methods; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D014185:Transplantation, Isogeneic
D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta