Cellular immune response to cryptic epitopes during therapeutic gene transfer
作者： C. Li , K. Goudy , M. Hirsch , A. Asokan , Y. Fan
关键词:
摘要: The immune response has been implicated as a critical factor in determining the success or failure of clinical gene therapy trials. Generally, such is elicited by desired transgene product or, some cases, delivery system. In current study, we report previously uncharacterized finding that therapeutic cassette currently being used for human investigation displays alternative reading frames (ARFs) generate unwanted protein products to induce cytotoxic T lymphocyte (CTL) response. particular, tested hypothesis antigenic epitopes derived from an ARF coagulation IX (F9) cDNA can CTL reactivity, subsequently killing F9-expressing hepatocytes. One peptide (p18) 3 candidates F9 induced CD8+ cell reactivity mice expressing MHC class I molecule B0702. Subsequently, upon systemic administration adeno-associated virus (AAV) serotype 2 vectors packaged with (AAV2/F9), robust was against p18. Of particular importance epitope-specific CTLs eliminated AAV2/F9-transduced hepatocytes but not AAV2/F9 codon-optimized (AAV2/F9-opt)-transduced liver cells which p18 epitope deleted. These results demonstrate undiscovered mechanism responses be cryptic generated and have significant implications all modalities. Such unforeseen generation warrants careful analysis sequences ARFs reduce potential adverse events arising during protocols.
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sci-hub.se 参考文章(22)
Jian Chen, Qi Wu, PingAr Yang, Hui-Chen Hsu, John D. Mountz, Determination of Specific CD4 and CD8 T Cell Epitopes after AAV2- and AAV8-hF.IX Gene Therapy Molecular Therapy. ,vol. 13, pp. 260- 269 ,(2006) , 10.1016/J.YMTHE.2005.10.006
Federico Mingozzi, Marcela V Maus, Daniel J Hui, Denise E Sabatino, Samuel L Murphy, John E J Rasko, Margaret V Ragni, Catherine S Manno, Jurg Sommer, Haiyan Jiang, Glenn F Pierce, Hildegund C J Ertl, Katherine A High, CD8(+) T-cell responses to adeno-associated virus capsid in humans. Nature Medicine. ,vol. 13, pp. 419- 422 ,(2007) , 10.1038/NM1549
S. R. Schwab, Constitutive display of cryptic translation products by MHC class I molecules. Science. ,vol. 301, pp. 1367- 1371 ,(2003) , 10.1126/SCIENCE.1085650
Hua Li, Samuel L Murphy, Wynetta Giles-Davis, Shyrie Edmonson, Zhiquan Xiang, Yan Li, Marcio O Lasaro, Katherine A High, Hildegund CJ Ertl, Pre-existing AAV Capsid-specific CD8+ T Cells are Unable to Eliminate AAV-transduced Hepatocytes Molecular Therapy. ,vol. 15, pp. 792- 800 ,(2007) , 10.1038/SJ.MT.6300090
Zhijian Wu, Aravind Asokan, R. Jude Samulski, Adeno-associated virus serotypes: vector toolkit for human gene therapy. Molecular Therapy. ,vol. 14, pp. 316- 327 ,(2006) , 10.1016/J.YMTHE.2006.05.009
J. Karttunen, S. Sanderson, N. Shastri, Detection of rare antigen-presenting cells by the lacZ T-cell activation assay suggests an expression cloning strategy for T-cell antigens Proceedings of the National Academy of Sciences of the United States of America. ,vol. 89, pp. 6020- 6024 ,(1992) , 10.1073/PNAS.89.13.6020
Jeff Alexander, Carla Oseroff, John Sidney, Alessandro Sette, Derivation of HLA-B*0702 transgenic mice: functional CTL repertoire and recognition of human B*0702-restricted CTL epitopes Human Immunology. ,vol. 64, pp. 211- 223 ,(2003) , 10.1016/S0198-8859(02)00786-3
Denise E. Sabatino, Federico Mingozzi, Daniel J. Hui, Haifeng Chen, Peter Colosi, Hildegund C.J. Ertl, Katherine A. High, Identification of mouse AAV capsid-specific CD8+ T cell epitopes Molecular Therapy. ,vol. 12, pp. 1023- 1033 ,(2005) , 10.1016/J.YMTHE.2005.09.009
On Ho, William R. Green, Alternative Translational Products and Cryptic T Cell Epitopes: Expecting the Unexpected Journal of Immunology. ,vol. 177, pp. 8283- 8289 ,(2006) , 10.4049/JIMMUNOL.177.12.8283
Rebecca P. Haberman, Thomas J. McCown, Richard Jude Samulski, Novel Transcriptional Regulatory Signals in the Adeno-Associated Virus Terminal Repeat A/D Junction Element Journal of Virology. ,vol. 74, pp. 8732- 8739 ,(2000) , 10.1128/JVI.74.18.8732-8739.2000