Determination of specific CD4 and CD8 T cell epitopes after AAV2- and AAV8-hF.IX gene therapy.
The application of AAV2 or AAV8 vectors for delivery of human coagulation factor IX (hF.IX) is a promising gene therapy for hemophilia B. One major limitation of this therapy is the development of antibodies and a cytotoxic T lymphocyte (CTL) response against both the vector capsid and the transgene. We determined the class I and class II MHC peptide epitopes for AAV2, AAV8, and hF.IX after administration of AAV-2-hF.IX or AAV8-hF.IX in H2(b) (C57BL/6), H2(d) (BALB/c), or H2(k) (C3H) strains of mice. The results indicate that the AAV2 capsid peptide AA(373-381), the AAV8 capsid peptide AA(50-58), and the hF.IX transgene peptide AA(311-319) can elicit a CTL response as indicated by an IFN-gamma ELISPOT assay and an in vivo CTL assay. Furthermore, a strong H2(k) MHC II-restricted Th1 response can be elicited in C3H mice by the AAV8 capsid peptide AA(126-140) and the hF.IX peptide AA(108-122), whereas a strong Th2 response can be elicited by the AAV2 peptide AA(475-489). These results show that specific CTL responses are generated to both AAV capsid epitopes and hF.IX epitopes after injection of AAV-hF.IX, and MHC class II epitopes derived from AAV-hF.IX promote development of either Th1 or Th2 cells.
Chen
Jian
J
Department of Medicine, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, 35294, USA.
Wu
Qi
Q
Yang
Pingar
P
Hsu
Hui-Chen
HC
Mountz
John D
JD
D000595:Amino Acid Sequence; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D036022:Capsid Proteins / Q000235:genetics / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000378:metabolism*; D005164:Factor IX / Q000378:metabolism; D005260:Female; D015316:Genetic Therapy / Q000379:methods; D006183:H-2 Antigens / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D011485:Protein Binding / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism / Q000821:virology
D036022:Capsid Proteins; D018984:Epitopes, T-Lymphocyte; D006183:H-2 Antigens; C068318:H-2E(k) antigen; C032876:H-2Kb protein, mouse; D000949:Histocompatibility Antigens Class II; C024138:I-E-antigen; C108503:antigen H-2A(k); D005164:Factor IX