Localized immunosuppression in the cardiac allograft induced by a new liposome-mediated IL-10 gene therapy

Abstract

Background Overexpression of interleukin 10 (IL-10) in the donor heart prolongs allograft survival in animals. Interleukin-10 has many immunosuppressive effects; however, the mechanism(s) of its protective effect on allograft rejection remains unknown. Methods Recently, we optimized an ex vivo, intracoronary infusion of the GAP:DLRIE, liposome-mediated, IL-10 gene method using a rabbit, cervical, heterotopic heart transplant model. Results The efficiency of this new-generation, liposome-mediated, IL-10 gene transfer to the donor hearts was 15% in hypothermic conditions, which represents a 30% increase from the efficiency of other liposomes, such as DOSPA/DOPE, DOGS/DOPE, and DMRIE/DOPE. Cardiac allograft survival was prolonged from 6.0 ± 0.7 days to 14.3 ± 1.8 days. Infiltrating lymphocyte sub-populations CD3 +, CD4 +, and CD8 + decreased significantly in the gene therapy group compared with the control group. Local IL-10 overexpression correlated significantly with decreased CD4 + and CD8 + responsiveness and Type-1 helper (Th1) cytokine gene (IL-2, interferon-γ, and tumor necrosis factor α) expression level and correlated inversely with the allograft rejection grade. In the gene therapy group, the cytotoxic activity of infiltrating T cells in the allograft decreased greatly, but the time course of this decrease did not parallel the rejection process. Conclusion We conclude that GAP:DLRIE is the best cationic liposome for ex vivo gene transfection in hypothermic conditions. The effects of IL-10 gene therapy on antigen-specific T-lymphocyte proliferation and Th1-cytokine expression may play an important role in localized immunosuppression and tolerance induction.