Liposome-mediated combinatorial cytokine gene therapy induces localized synergistic immunosuppression and promotes long-term survival of cardiac allografts.
Localized gene transfer has the potential to introduce immunosuppressive molecules only into the transplanted allograft, which would limit systemic side effects, and prolong allograft survival. However, an applicable gene transfer strategy is not available, and the feasible therapeutic gene(s) has not yet been determined. We developed an ex vivo liposome-mediated gene therapy strategy that is able to intracoronary deliver the combination of IL-4 and IL-10 cDNA expression vectors to the allograft simultaneously. We examined the efficiency, efficacy, and cardiac adverse effects of this combinatorial gene therapy protocol using a rabbit functional cervical heterotopic heart transplant model. Although the efficiency was moderate, the expression of both transgenes was long lasting and localized only in the target organ. The mean survival of cardiac allograft was prolonged from 7 to >100 days. Synergism of overexpressed IL-4 and IL-10 in the inhibition of T lymphocyte infiltration and cytoxicity, and modulation of Th1/Th2 cytokine production promote long-term survival of cardiac allografts.
Furukawa
Hiroshi
H
Division of Cardiothoracic Surgery, Department of Surgery, University of California, Los Angeles, 90095, USA.
Oshima
Kiyohiro
K
Tung
Thomas
T
Cui
Guanggen
G
Laks
Hillel
H
Sen
Luyi
L
D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D002464:Cell Migration Inhibition; D016207:Cytokines / Q000008:administration & dosage* / Q000096:biosynthesis / Q000235:genetics*; D003602:Cytotoxicity, Immunologic / Q000235:genetics / Q000276:immunology; D004338:Drug Combinations; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods; D005822:Genetic Vectors; D006082:Graft Enhancement, Immunologic / Q000009:adverse effects / Q000379:methods*; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology / Q000517:prevention & control; D006085:Graft Survival / Q000235:genetics / Q000276:immunology*; D016027:Heart Transplantation / Q000009:adverse effects / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects; D016753:Interleukin-10 / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics; D015847:Interleukin-4 / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics; D008081:Liposomes; D011817:Rabbits; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D016042:Transplantation, Heterotopic
D000276:Adjuvants, Immunologic; D016207:Cytokines; D004338:Drug Combinations; D007166:Immunosuppressive Agents; D008081:Liposomes; D016753:Interleukin-10; D015847:Interleukin-4