Lentivectors encoding immunosuppressive proteins genetically engineer pancreatic β-cells to correct diabetes in allogeneic mice
| Autor: | Teresa P. DiLorenzo, Tsoline Kojaoghlanian, Aviva Joseph, Harris Goldstein, Antonia Follenzi, Margarita Leiser, Jian Hua Zheng, Norman Fleischer, Marshall S. Horwitz |
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| Rok vydání: | 2008 |
| Předmět: |
Graft Rejection
Genetic enhancement Genetic Vectors Islets of Langerhans Transplantation Mice Inbred Strains Gene delivery Biology Major histocompatibility complex Article Diabetes Mellitus Experimental Immune tolerance Mice Downregulation and upregulation Transduction Genetic Insulin-Secreting Cells Adenovirus E3 Proteins Immune Tolerance Genetics medicine Animals Molecular Biology Mice Inbred C3H Reverse Transcriptase Polymerase Chain Reaction Adenovirus Early Proteins Lentivirus Transplantation Disease Models Animal Diabetes Mellitus Type 1 medicine.anatomical_structure Cell culture Immunology biology.protein Molecular Medicine Female Genetic Engineering Pancreas |
| Zdroj: | Gene Therapy. 16:340-348 |
| ISSN: | 1476-5462 0969-7128 |
| DOI: | 10.1038/gt.2008.172 |
| Popis: | 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 beta-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 beta-cells from an alloimmune attack. The insulin-producing beta-cell line beta TC-tet (C3HeB/FeJ-derived) was transduced with lentiviruses encoding the AdE3 proteins gp19K and RID alpha/beta. The efficiency of lentiviral transduction of beta TC-tet cells exceeded 85%. Lentivector expression of gp19K decreased surface class I major histocompatibility complex expression by over 90%, whereas RID alpha/beta expression inhibited cytokine-induced Fas upregulation by over 75%. beta TC-tet cells transduced with gp19K and RID alpha/beta 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 beta-cells using gp19K- and RID alpha/beta-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. |
| Databáze: | OpenAIRE |
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