Localized immunosuppression in the cardiac allograft induced by a new liposome-mediated IL-10 gene therapy.
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-gamma, and tumor necrosis factor alpha) 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.


CONCLUSIONS
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.
Hong
Yoo Sun
YS
Division of Cardiothoracic Surgery, Department of Surgery, UCLA Medical Center and UCLA School of Medicine, Los Angeles, California 90095, USA.
Laks
Hillel
H
Cui
Guanggen
G
Chong
Terry
T
Sen
Luyi
L
D000818:Animals; D004337:Drug Carriers; D004987:Ethers; D015870:Gene Expression; D018014:Gene Transfer Techniques; D006084:Graft Rejection / Q000235:genetics*; D016027:Heart Transplantation / Q000276:immunology*; D007108:Immune Tolerance / Q000276:immunology*; D007150:Immunohistochemistry; D016753:Interleukin-10 / Q000235:genetics* / Q000378:metabolism; D008081:Liposomes; D000644:Quaternary Ammonium Compounds; D011817:Rabbits; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018417:Th1 Cells / Q000378:metabolism; D014162:Transfection; D023001:Transplantation Tolerance
D004337:Drug Carriers; D004987:Ethers; D008081:Liposomes; C101963:N-(3-aminopropyl)-N,N-dimethyl-2,3-bis(dodecyloxy)-1-propanaminium; D000644:Quaternary Ammonium Compounds; D016753:Interleukin-10