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Blood, 15 October 2004, Vol. 104, No. 8, pp. 2397-2402.
Prepublished online as a Blood First Edition Paper on June 24, 2004; DOI 10.1182/blood-2004-01-0324.


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IMMUNOBIOLOGY

Targeted deletion of T-cell clones using alpha-emitting suicide MHC tetramers

Rui Rong Yuan, Phillip Wong, Michael R. McDevitt, Ekaterina Doubrovina, Ingrid Leiner, William Bornmann, Richard O'Reilly, Eric G. Pamer, and David A. Scheinberg

From the Molecular Pharmacology and Chemistry Program and the Departments of Medicine and Pediatrics, Sloan-Kettering Institute and Memorial Sloan-Kettering Cancer Center, New York, NY.

Immunosuppressive agents in current use are nonspecific. The capacity to delete specific CD8 T-cell clones of unique specificity could prove to be a powerful tool for dissecting the precise role of CD8+ T cells in human disease and could form the basis for a safe, highly selective therapy of autoimmune disorders. Major histocompatibility complex (MHC) tetramers (multimeric complexes capable of binding to specific CD8 T-cell clones) were conjugated to 225Ac (an alpha-emitting atomic nanogenerator, capable of single-hit killing from the cell surface) to create an agent for CD8 T-cell clonal deletion. The "suicide" tetramers specifically bound to, killed, and reduced the function of their cognate CD8 T cells (either human anti–Epstein-Barr virus (EBV) or mouse anti-Listeria in 2 model systems) while leaving the nonspecific control CD8 T-cell populations unharmed. Such an approach may allow a pathway to selective ablation of pathogenic T-cell clones ex vivo or in vivo without disturbing general immune function.


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