Journal
NATURE MEDICINE
Volume 16, Issue 5, Pages 565-U98Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.2128
Keywords
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Funding
- Leukaemia and Lymphoma Research Travel Fellowship [06037]
- Netherlands Organization for Scientific Research [431-00-005]
- Dutch Cancer Society [NKI 2009-4282, 2003-2860]
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The transfer of T cell receptor (TCR) genes can be used to induce immune reactivity toward defined antigens to which endogenous T cells are insufficiently reactive. This approach, which is called TCR gene therapy, is being developed to target tumors and pathogens, and its clinical testing has commenced in patients with cancer. In this study we show that lethal cytokine-driven autoimmune pathology can occur in mouse models of TCR gene therapy under conditions that closely mimic the clinical setting. We show that the pairing of introduced and endogenous TCR chains in TCR gene-modified T cells leads to the formation of self-reactive TCRs that are responsible for the observed autoimmunity. Furthermore, we demonstrate that adjustments in the design of gene therapy vectors and target T cell populations can be used to reduce the risk of TCR gene therapy-induced autoimmune pathology.
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