Feline immunodeficiency virus-mediated viral interleukin-10 gene transfer prolongs non-vascularized cardiac allograft survival.
Previous experiments demonstrated plasmid-, retroviral-, or adenoviral-mediated vIL-10 gene transfer could prolong allograft survival, but transgene expression was rapidly extinguished. Feline immunodeficiency virus (FIV) can integrate into genomic DNA of nondividing cells, resulting in indefinite transgene expression. We hypothesized FIV-mediated gene transfer could provide long-term gene expression, and improved allograft survival. FIV-vIL-10 and FIV-beta-gal were produced using the FELIX vector system. With vector transfer to syngeneic cardiac grafts, beta-galactosidase reporter gene expression was noted as early as day 5, was strongly expressed at days 10 and 20, and persisted for 50 days after transplantation. For allografts, FIV-vIL-10 gene transfer more than doubled mean survival from 10 +/- 1.6 to 22.3 +/- 3 days. When combined with other immunosuppressants, such as anti-CD40L mAb, FTY720, or anti-CD3 mAb, the mean survival times were prolonged to 27 +/- 4.6 days, 27.8 +/- 4.6 days, and 45.5 +/- 4.9 days, respectively. Multiple chemokine and chemokine receptor genes were induced by ischemia-reperfusion injury in syngeneic grafts, and in allogeneic grafts more genes were induced and to a greater degree. In allogeneic grafts transduced with FIV-IL-10, a number of the chemokine genes were suppressed. Therefore, FIV virus-mediated vIL-10 gene transfer prolongs allograft survival and, in combination with other agents, produces an additive effect.
Fu
Shuang
S
Carl C. Icahn Institute for Gene Therapy and Molecular Medicine, and Recanati/Miller Transplantation Institute, Mount Sinai School of Medicine, New York, NY 10029, USA.
Chen
Dongmei
D
Mao
Xia
X
Zhang
Nan
N
Ding
Yaozhong
Y
Bromberg
Jonathan S
JS
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017252:CD3 Complex / Q000096:biosynthesis; D018925:Chemokines / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D018014:Gene Transfer Techniques; D017930:Genes, Reporter; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D006082:Graft Enhancement, Immunologic; D006085:Graft Survival; D016027:Heart Transplantation / Q000379:methods*; D016089:Immunodeficiency Virus, Feline / Q000235:genetics*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D016753:Interleukin-10 / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D020411:Oligonucleotide Array Sequence Analysis; D010957:Plasmids / Q000378:metabolism; D019707:Receptors, Chemokine / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D019076:Transgenes; D001616:beta-Galactosidase / Q000378:metabolism
D017252:CD3 Complex; D018925:Chemokines; D018076:DNA, Complementary; D007166:Immunosuppressive Agents; D019707:Receptors, Chemokine; D016753:Interleukin-10; D001616:beta-Galactosidase