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International Immunology Advance Access originally published online on July 28, 2007
International Immunology 2007 19(9):1083-1093; doi:10.1093/intimm/dxm076
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© The Japanese Society for Immunology. 2007. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Chimeric immune receptors (CIRs) specific to JC virus for immunotherapy in progressive multifocal leukoencephalopathy (PML)

W Yang1, EL Beaudoin1, L Lu1, RA Du Pasquier2, MJ Kuroda2, RA Willemsen3, IJ Koralnik2 and RP Junghans1

1 Division of Surgical Research, Department of Surgery, Boston University School of Medicine, Roger Williams Medical Center, Providence, RI 02908, USA
2 Division of Viral Pathogenesis and Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA
3 Laboratory of Tumor Immunology, Department of Medical Oncology, Erasmus MC-Daniel den Hoed Cancer Center, Groene Hilledijk 301, 3075 EA Rotterdam, The Netherlands

Correspondence to: R. P. Junghans; E-mail: rjunghans{at}rwmc.org

Progressive multifocal leukoencephalopathy (PML) is a deadly brain disease caused by the polyomavirus JC (JCV). The aim of this study is to develop ‘designer T cells’ armed with anti-JCV TCR-based chimeric immune receptors (CIRs) by gene modification for PML immunotherapy. Two T cell lines specific to two dominant CTL epitopes derived from JCV VP1 protein (termed p36 and p100) from an HLA-A0201+ PML survivor were generated for TCR cloning. Two distinct dominant TCR alpha chains (V{alpha}6 and V{alpha}12) and a unique TCR beta chain (Vß5.1) were cloned from the p36-specific cell line, while only one alpha (V{alpha}8.6) and one beta (Vß2) chains were dominant in the p100-specific line. Retroviral constructs encoding CIRs were created with the extracellular domains of TCR {alpha} and ß chains fused to the transmembrane and cytoplasmic portions of CD3{zeta} (V{alpha}C{alpha}CD3{zeta} or VßCßCD3{zeta}). Cellular expression and screening for binding specific peptide-HLA-A0201 tetramer confirmed the reactivity of the p100 TCR{alpha}ß and of one of the two pairs of p36 TCR{alpha}ß (V{alpha}12 and Vß5.1). Functional tests confirmed CIR-expressing T cells secreted cytokines and expressed potent cytotoxicity on contact with A0201+ B-lymphoblastoid line loaded with peptides and/or with HLA-A0201+ cells expressing native JCV VP1 protein. In conclusion, anti-JCV designer T cells were generated.

Keywords: gene transfer, retroviral transduction, T cell, TCR

Transmitting editor: G. Trinchieri

Received 22 December 2006, accepted 14 June 2007.


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