title: Lentivirus-mediated transduction of islet grafts with interleukin 4 results in sustained gene expression and protection from insulitis.
abstract: Autoimmune destruction of islets in the pancreas leads to the development of insulin-dependent diabetes mellitus (IDDM). Replacement of insulin-producing tissue by transplantation of islets provides a cure to disease but requires immunosuppression or a means of controlling anti-graft immune responses. To promote islet survival we have utilized a local approach by expressing immunoregulatory molecules in islet grafts. The results presented here show that the human immunodeficiency virus (HIV)-based lentiviral vector is capable of stably transducing whole islets. Foreign reporter gene expression was observed both in vitro and in vivo 30 days after transplantation. Grafts containing insulin-positive beta-islet cells expressing foreign protein indicate that transduction does not interfere with glucose regulation. The absence of inflammatory infiltrates in grafts suggests that transduction does not activate the immune system. When islets transduced with an HIV vector expressing IL-4 were transplanted into diabetes-prone mice, animals were protected from autoimmune insulitis and islet destruction. As demonstrated by proliferative and cytokine analysis, protection was consistent with a switching of islet-antigen-specific T cell responses toward a Th2 phenotype. These results suggest that HIV-based lentivirus vectors can efficiently transduce islet cells with genes encoding potentially therapeutic molecules, for possibly managing diabetes.
authors.affiliation: Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: W S
authors.initials: WS
authors.lastname: Gallichan
authors.forename: T
authors.initials: T
authors.lastname: Kafri
authors.forename: T
authors.initials: T
authors.lastname: Krahl
authors.forename: I M
authors.initials: IM
authors.lastname: Verma
authors.forename: N
authors.initials: N
authors.lastname: Sarvetnick
mesh_terms: D000818:Animals; D016207:Cytokines / Q000032:analysis; D003922:Diabetes Mellitus, Type 1 / Q000517:prevention & control; D005260:Female; D018014:Gene Transfer Techniques; D017930:Genes, Reporter; D005822:Genetic Vectors; D006085:Graft Survival / Q000235:genetics; D006678:HIV / Q000235:genetics; D007328:Insulin / Q000378:metabolism; D015847:Interleukin-4 / Q000235:genetics* / Q000276:immunology; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D016086:Lentivirus / Q000235:genetics*; D008213:Lymphocyte Activation; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D013154:Spleen / Q000166:cytology; D018418:Th2 Cells / Q000276:immunology; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D016207:Cytokines; D007328:Insulin; D015847:Interleukin-4; D001616:beta-Galactosidase