title: 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-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.
authors.affiliation: Division of Cardiothoracic Surgery, Department of Surgery, UCLA Medical Center and UCLA School of Medicine, Los Angeles, California 90095, USA.
authors.forename: Yoo Sun
authors.initials: YS
authors.lastname: Hong
authors.forename: Hillel
authors.initials: H
authors.lastname: Laks
authors.forename: Guanggen
authors.initials: G
authors.lastname: Cui
authors.forename: Terry
authors.initials: T
authors.lastname: Chong
authors.forename: Luyi
authors.initials: L
authors.lastname: Sen
mesh_terms: 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
chemical_list: 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