Lentivectors encoding immunosuppressive proteins genetically engineer pancreatic β-cells to correct diabetes in allogeneic mice

• Published in: Gene therapy Vol. 16; no. 3; pp. 340 - 348
• Main Authors: Kojaoghlanian, T, Joseph, A, Follenzi, A, Zheng, J H, Leiser, M, Fleischer, N, Horwitz, M S, DiLorenzo, T P, Goldstein, H
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.03.2009; Nature Publishing Group
• Subjects: Adenovirus E3 Proteins - genetics; Adenovirus E3 Proteins - immunology; Adenovirus Early Proteins - genetics; Adenovirus Early Proteins - immunology; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Applied cell therapy and gene therapy; Beta cells; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Biotechnology; Care and treatment; Cell Biology; Cytokines; Diabetes; Diabetes mellitus (insulin dependent); Diabetes Mellitus, Experimental - immunology; Diabetes Mellitus, Experimental - therapy; Diabetes Mellitus, Type 1 - immunology; Diabetes Mellitus, Type 1 - therapy; Disease Models, Animal; Early region; Effector cells; Female; Fundamental and applied biological sciences. Psychology; Gene Expression; Gene Therapy; Genetic aspects; Genetic engineering; Genetic Engineering - methods; Genetic Vectors; Genomes; Graft rejection; Graft Rejection - immunology; Graft Rejection - prevention & control; Health aspects; Health. Pharmaceutical industry; Human Genetics; Hyperglycemia; Immune Tolerance; Immunodeficiency; Immunosuppressive agents; Industrial applications and implications. Economical aspects; Insulin; Insulin-Secreting Cells - immunology; Islets of Langerhans Transplantation - methods; Lentivirus; Lentivirus - genetics; Major histocompatibility complex; Medical sciences; Mice; Mice, Inbred C3H; Mice, Inbred Strains; Nanotechnology; original-article; Proteins; Reverse Transcriptase Polymerase Chain Reaction - methods; Transduction, Genetic; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; Transplantation; United States; lentiviral vectors; diabetes; genetic engineering; transplantation; Endocrinopathy; Diabetes mellitus; Rodentia; Retroviridae; Transplantation; Lentivirus; Protein; Virus; Vertebrata; Mammalia; Mouse; Genetic engineering; β Cell; Pancreas; Gene therapy; Vector
• ISSN: 0969-7128; 1476-5462
• DOI: 10.1038/gt.2008.172

The effectiveness of genetic engineering with lentivectors to protect transplanted cells from allogeneic rejection was examined using, as a model, type 1 diabetes treatment with β-cell transplantation, whose widespread use has been limited by the requirement for sustained immunosuppressive treatment to prevent graft rejection. We examined whether lentivectors expressing select immunosuppressive proteins encoded by the adenoviral genome early region 3 (AdE3) would protect transplanted β-cells from an alloimmune attack. The insulin-producing β-cell line βTC-tet (C3HeB/FeJ-derived) was transduced with lentiviruses encoding the AdE3 proteins gp19K and RIDα/β. The efficiency of lentiviral transduction of βTC-tet cells exceeded 85%. Lentivector expression of gp19K decreased surface class I major histocompatibility complex expression by over 90%, whereas RIDα/β expression inhibited cytokine-induced Fas upregulation by over 75%. βTC-tet cells transduced with gp19K and RIDα/β lentivectors, but not with a control lentivector, provided prolonged correction of hyperglycemia after transplantation into diabetic BALB/c severe combined immunodeficient mice reconstituted with allogeneic immune effector cells or into diabetic allogeneic BALB/c mice. Thus, genetic engineering of β-cells using gp19K- and RIDα/β-expressing lentiviral vectors may provide an alternative that has the potential to eliminate or reduce treatment with the potent immunosuppressive agents necessary at present for prolonged engraftment with transplanted islets.