Efficient delivery of Antennapedia homeodomain fused to CTL epitope with liposomes into dendritic cells results in the activation of CD8+ T cells.
The in vivo induction of a CTL response using Antennapedia homeodomain (AntpHD) fused to a poorly immunogenic CTL epitope requires that the Ag is given in presence of SDS, an unacceptable adjuvant for human use. In the present report, we developed a hybrid CTL epitope delivery system consisting of AntpHD peptide vector formulated in liposomes as an alternative approach to bypass the need for SDS. It is proposed that liposomes will prevent degradation of the Ag in vivo and will deliver AntpHD recombinant peptide to the cytosol of APCs. We show in this work that dendritic cells incubated with AntpHD-fused peptide in liposomes can present MHC class I-restricted peptide and induce CTL response with a minimal amount of Ag. Intracellular processing studies have shown that encapsulated AntpHD recombinant peptide is endocytized before entering the cytosol, where it is processed by the proteasome complex. The processed liposomal peptides are then transported to the endoplasmic reticulum. The increase of the CTL response induced by AntpHD-fused peptide in liposomes correlates with this active transport to the class I-processing pathway. In vivo studies demonstrated that positively charged liposomes increase the immunogenicity of AntpHD-Cw3 when injected s.c. in mice in comparison to SDS. Moreover, addition of CpG oligodeoxynucleotide immunostimulatory sequences further increase the CD8+ T cell response. This strategy combining lipid-based carriers with AntpHD peptide to target poorly immunogenic Ags into the MHC class I processing pathway represents a novel approach for CTL vaccines that may have important applications for development of cancer vaccines.
Chikh
G G
GG
Systemic Therapy Program, Department of Advanced Therapeutics, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada.
Kong
S
S
Bally
M B
MB
Meunier
J C
JC
Schutze-Redelmeier
M P
MP
D000818:Animals; D051943:Antennapedia Homeodomain Protein; D017951:Antigen Presentation / Q000235:genetics; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000235:genetics*; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011992:Endosomes / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D005822:Genetic Vectors / Q000276:immunology; D006056:Golgi Apparatus / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015236:HLA-C Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000276:immunology*; D007424:Intracellular Fluid / Q000276:immunology / Q000378:metabolism; D008081:Liposomes / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D009687:Nuclear Proteins; D010713:Phosphatidylcholines / Q000276:immunology; D021381:Protein Transport / Q000235:genetics / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014157:Transcription Factors; D014407:Tumor Cells, Cultured
D051943:Antennapedia Homeodomain Protein; D018984:Epitopes, T-Lymphocyte; D015236:HLA-C Antigens; C038653:HLA-C*03 antigen; D018398:Homeodomain Proteins; D008081:Liposomes; D009687:Nuclear Proteins; D010713:Phosphatidylcholines; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; C017251:1,2-oleoylphosphatidylcholine