Synthetic lipopeptides incorporated in liposomes: in vitro stimulation of the proliferation of murine splenocytes and in vivo induction of an immune response against a peptide antigen.
Amphiphilic lipopeptides, such as Pam3CysAlaGly and Pam3CysSerSer, were synthesized and incorporated into liposomes, and their ability to induce the proliferation of BALB/c mouse splenocyte was tested in vitro. When compared to monophosphoryl lipid A (MPL) the following potency order was found: liposomal lipopeptides > liposomal MPL > free (emulsified) lipopeptides. These results strongly depend on the size of the vesicles used: a mitogenic effect was observed only with lipopeptides incorporated within vesicles of diameter < or = 100 nm while lipopeptides in larger vesicles (diameter approximately 300 nm) gave no response. This may be related to the necessity for the liposome-associated lipopeptides to be endocytosed to reach putative intracellular targets. As immunoadjuvanticity seems to be linked to B-lymphocyte activation, the lipopeptides represent attractive alternatives to MPL for the realization of completely synthetic liposome-based peptide vaccine formulations. This was borne out by showing that Pam3CysAlaGly and Pam3CysSerSer, when incorporated in small unilamellar vesicles carrying a covalently conjugated synthetic peptide of sequence IRGERA, corresponding to an epitope of the C-terminal region of histone H3, were able to induce a potent and long-lasting immune response.
Fernandes
I
I
Laboratoire de Chimie Bioorganique (URA CNRS 1386), Université Louis Pasteur, Illkirch, France.
Frisch
B
B
Muller
S
S
Schuber
F
F
D000276:Adjuvants, Immunologic / Q000138:chemical synthesis / Q000378:metabolism; D000818:Animals; D000917:Antibody Formation; D002455:Cell Division / Q000187:drug effects; D004151:Dipeptides / Q000138:chemical synthesis / Q000276:immunology*; D004705:Endocytosis; D005260:Female; D008050:Lipid A / Q000031:analogs & derivatives / Q000276:immunology; D008074:Lipoproteins / Q000138:chemical synthesis / Q000276:immunology*; D008081:Liposomes; D051379:Mice; D008807:Mice, Inbred BALB C; D008938:Mitosis / Q000187:drug effects; D010446:Peptide Fragments / Q000276:immunology; D013154:Spleen / Q000166:cytology*
D000276:Adjuvants, Immunologic; D004151:Dipeptides; D008050:Lipid A; D008074:Lipoproteins; D008081:Liposomes; D010446:Peptide Fragments; C061110:N-palmitoyl-5,6-dipalmitoylcysteinyl-alanyl-glycine; C047210:2,3-bis-(palmitoyloxy)-2-propyl-N-palmitoyl-cysteinylserine; C048436:monophosphoryl lipid A