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Liposome-Mediated Combinatorial Cytokine Gene Therapy Induces Localized Synergistic Immunosuppression and Promotes Long-Term Survival of Cardiac Allografts¹

Hiroshi Furukawa^*, Kiyohiro Oshima^*, Thomas Tung^*, Guanggen Cui^*,, Hillel Laks^* and Luyi Sen^2,*,

^* Division of Cardiothoracic Surgery, Department of Surgery, and Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095

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.

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				K. Oshima, G. Cui, T. Tung, O. Okotie, H. Laks, and L. Sen Exogenous IL-10 overexpression reduces perforin production by activated allogenic CD8+ cells and prolongs cardiac allograft survival Am J Physiol Heart Circ Physiol, January 1, 2007; 292(1): H277 - H284. [Abstract] [Full Text] [PDF]