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Chimeric Receptor1
* Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN, 38105;
Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom; and
University of Tennessee Health Sciences Center, Memphis, TN 38163
Therapies that Ag-specifically target pathologic T lymphocytes responsible for multiple sclerosis (MS) and other autoimmune diseases would be expected to have improved therapeutic indices compared with Ag-nonspecific therapies. We have developed a cellular immunotherapy that uses chimeric receptors to selectively redirect therapeutic T cells against myelin basic protein (MBP)-specific T lymphocytes implicated in MS. We generated two heterodimeric receptors that genetically link the human MBP84–102 epitope to HLA-DR2 and either incorporate or lack a TCR
signaling domain. The Ag-MHC domain serves as a bait, binding the TCR of MBP-specific target cells. The signaling region stimulates the therapeutic cell after cognate T cell engagement. Both receptors were well expressed on primary T cells or T hybridomas using a tricistronic (
, β, green fluorescent protein) retroviral expression system. MBP-DR2--, but not MBP-DR2, modified CTL were specifically stimulated by cognate MBP-specific T cells, proliferating, producing cytokine, and killing the MBP-specific target cells. The receptor-modified therapeutic cells were active in vivo as well, eliminating Ag-specific T cells in a humanized mouse model system. Finally, the chimeric receptor-modified CTL ameliorated or blocked experimental allergic encephalomyelitis (EAE) disease mediated by MBP84–102/DR2-specific T lymphocytes. These results provide support for the further development of redirected therapeutic T cells able to counteract pathologic, self-specific T lymphocytes, and specifically validate humanized MBP-DR2- chimeric receptors as a potential therapeutic in MS.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grant R01 AI056153 (to T.L.G.) and by American Lebanese Syrian Associated Charities/St. Jude Children’s Research Hospital (to I.M., P.N., and T.L.G.).
2 Address correspondence and reprint requests to Dr. Terrence L. Geiger, Department of Pathology, St. Jude Children’s Research Hospital, 332 North Lauderdale Street, D-4047, Memphis, TN 38105. E-mail address: terrence.geiger{at}stjude.org
3 Abbreviations used in this paper: RMTC, receptor-modified T cell; MBP, myelin basic protein; MS, multiple sclerosis; Tg, transgenic; h, human; rh, recombinant human; EAE, experimental allergic encephalomyelitis; TM, transmembrane; Treg, regulatory T lymphocyte; Foxp3, forkhead box protein P3; AUC, area under the curve; NA, not applicable; MSCV, murine stem cell virus.
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  A. Udyavar, R. Alli, P. Nguyen, L. Baker, and T. L. Geiger Subtle Affinity-Enhancing Mutations in a Myelin Oligodendrocyte Glycoprotein-Specific TCR Alter Specificity and Generate New Self-Reactivity J. Immunol., April 1, 2009; 182(7): 4439 - 4447. [Abstract] [Full Text] [PDF]
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R. Alli, P. Nguyen, and T. L. Geiger Retrogenic Modeling of Experimental Allergic Encephalomyelitis Associates T Cell Frequency but Not TCR Functional Affinity with Pathogenicity J. Immunol., July 1, 2008; 181(1): 136 - 145. [Abstract] [Full Text] [PDF]
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