CD8+ T-cell tolerance can be broken by an adenoviral vaccine while CD4+ T-cell tolerance is broken by additional co-administration of a Toll-like receptor ligand.
T-cell tolerance to tumor antigens is a considerable challenge to cancer immunotherapy. The existence of a murine model transgenic for human carcinoembryonic antigen (CEA) allows CEA vaccination efficacy to be studied in a physiologically tolerant context. Immunization of CEA-transgenic mice with an adenoviral vector coding for CEA induced a significant CD8+ T-cell response specific to CEA but failed to induce CEA-specific CD4+ T cells and antibodies. To overcome CD4+ T-cell tolerance, we explored the effect of adjuvants inducing in vivo dendritic cell maturation. Two different Toll-like receptor ligands, monophosphoryl lipid A (MPL) and CpG motif-containing oligodeoxynucleotides (CpG-ODN), were tested. CD4+-mediated IFN-gamma production was induced in the CEA-transgenic mice only when the genetic immunization was performed in the presence of these adjuvants. Moreover, CpG-ODN had a greater effect than MPL in inducing CD4+ T-cell response and enabling anti-CEA antibody production.
Salucci
V
V
Istituto di Ricerca di Biologia Molecolare, Pomezia, Italy.
Mennuni
C
C
Calvaruso
F
F
Cerino
R
R
Neuner
P
P
Ciliberto
G
G
La Monica
N
N
Scarselli
E
E
D000256:Adenoviridae / Q000276:immunology*; D000276:Adjuvants, Immunologic; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002272:Carcinoembryonic Antigen / Q000235:genetics / Q000276:immunology; D018899:CpG Islands; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D008024:Ligands; D008050:Lipid A / Q000008:administration & dosage / Q000031:analogs & derivatives*; D051379:Mice; D008822:Mice, Transgenic; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage; D018417:Th1 Cells / Q000276:immunology; D051193:Toll-Like Receptors / Q000276:immunology*; D014611:Vaccination; D014765:Viral Vaccines / Q000276:immunology*
D000276:Adjuvants, Immunologic; C408982:CPG-oligonucleotide; D002272:Carcinoembryonic Antigen; D008024:Ligands; D008050:Lipid A; D009838:Oligodeoxyribonucleotides; D051193:Toll-Like Receptors; D014765:Viral Vaccines; C048436:monophosphoryl lipid A