H-2 class I knockout, HLA-A2.1-transgenic mice: a versatile animal model for preclinical evaluation of antitumor immunotherapeutic strategies.
H-2 class I-negative, HLA-A2.1-transgenic HHD mice were used for a comparative evaluation of the immunogenicity of HLA-A2.1-restricted human tumor-associated cytotoxic T lymphocyte (CTL) epitopes. A hierarchy was established among these peptides injected into mice in incomplete Freund's adjuvant which correlates globally with their capacity to bind and stabilize HLA-A2.1 molecules. Co-injection of a helper peptide enhanced most CTL responses. In contrast, classical HLA class I-transgenic mice which still express their own class I molecules did not, in most cases, develop HLA-A2.1-restricted CTL responses under the same experimental conditions. Different monoepitope immunization strategies of acceptable clinical usage were compared in HHD mice. Recombinant Ty-virus-like particles, or DNA encoding epitopes fused to the hepatitis B virus middle envelope protein gave the best results. Using this latter approach and a melanoma-based polyepitope construct, CTL responses against five distinct epitopes could be elicited simultaneously in a single animal. Thus, HHD mice provide a versatile animal model for preclinical evaluation of peptide-based cancer immunotherapy.
Firat
H
H
Unité d'Immunité Cellulaire Antivirale, Département SIDA-Rétrovirus, Institut Pasteur, Paris, France. hfirat@pasteur.fr
Garcia-Pons
F
F
Tourdot
S
S
Pascolo
S
S
Scardino
A
A
Garcia
Z
Z
Michel
M L
ML
Jack
R W
RW
Jung
G
G
Kosmatopoulos
K
K
Mateo
L
L
Suhrbier
A
A
Lemonnier
F A
FA
Langlade-Demoyen
P
P
D000595:Amino Acid Sequence; D000818:Animals; D016827:CD8 Antigens / Q000276:immunology / Q000627:therapeutic use; D019496:Cancer Vaccines / Q000235:genetics* / Q000276:immunology*; D004195:Disease Models, Animal; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D006183:H-2 Antigens / Q000235:genetics* / Q000276:immunology; D015789:HLA-A2 Antigen / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D006512:Hepatitis B Core Antigens / Q000276:immunology; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology / Q000627:therapeutic use; D016233:Immunotherapy, Active / Q000379:methods*; D008545:Melanoma / Q000276:immunology; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology* / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010455:Peptides / Q000276:immunology / Q000627:therapeutic use
D016827:CD8 Antigens; D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D006183:H-2 Antigens; D015789:HLA-A2 Antigen; D006512:Hepatitis B Core Antigens; D016056:Immunodominant Epitopes; D010455:Peptides