Enhanced CD4+ T-cell response in DR4-transgenic mice to a hybrid peptide linking the Ii-Key segment of the invariant chain to the melanoma gp100(48-58) MHC class II epitope.
Linking the Ii-Key functional group LRMK, through a simple polymethylene linker, to the melanoma gp100(48-58) MHC class II epitope significantly enhances the vaccine response to that epitope in DR4-IE transgenic mice. A homologous series of Ii-Key/gp100(46-58) hybrids was synthesized to test the influence of spacer length (between Ii-Key and the gp100(48-58) epitope) on in vivo enhancement of gp100(48-58)-specific CD4+ T-lymphocyte responses. As measured by IFN-gamma and IL-4 ELISPOT cytokine assays, the most effective vaccine hybrid was the one with a shorter linker between Ii-Key and the epitope. Mechanistic reasons for this observation are considered. This structure-activity relationship was seen with bulk and CD4+ purified T cells, and both primary and secondary in vitro restimulation assays. CFA augmented the IFN-gamma response and to a lesser extent the IL-4 response. CpG enhanced a strong IFN-gamma response, with a negligible IL-4 response. The 3- to 5-times enhancement of the total ELISPOT responses (number of spots x mean spot area) observed after vaccination with peptides consisting of an MHC class II epitope engineered into an Ii-Key hybrid indicates a potent vaccine effect. Such constructs can be applied to many diagnostic and therapeutic uses.
Antigen Express, Inc., Worcester, Massachusetts 01606-2478, USA.
Nikoletta L
NL
Kallinteris
Shuzhen
S
Wu
Xueqing
X
Lu
Robert E
RE
Humphreys
Eric
E
von Hofe
Minzhen
M
Xu
D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D004247:DNA / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D006684:HLA-DR Antigens / Q000235:genetics; D059805:HLA-DR alpha-Chains; D015804:HLA-DR4 Antigen / Q000235:genetics*; D059811:HLA-DRB1 Chains; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000276:immunology*; D009838:Oligodeoxyribonucleotides; D010446:Peptide Fragments / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000235:genetics; D013154:Spleen / Q000166:cytology / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology; D014611:Vaccination; D058951:gp100 Melanoma Antigen
D000944:Antigens, Differentiation, B-Lymphocyte; C423449:CpG ODN 1826; D018984:Epitopes, T-Lymphocyte; D006684:HLA-DR Antigens; D059805:HLA-DR alpha-Chains; D015804:HLA-DR4 Antigen; D059811:HLA-DRB1 Chains; D000949:Histocompatibility Antigens Class II; C024138:I-E-antigen; D007376:Interleukin-2; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D009838:Oligodeoxyribonucleotides; C548637:PMEL protein, human; D010446:Peptide Fragments; C548642:Pmel protein, mouse; D011993:Recombinant Fusion Proteins; D058951:gp100 Melanoma Antigen; C045084:invariant chain; D015847:Interleukin-4; D007371:Interferon-gamma; D004247:DNA