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Lethal graft-versus-host disease in mouse models of T cell receptor gene therapy

Item Type:Article
Title:Lethal graft-versus-host disease in mouse models of T cell receptor gene therapy
Creators Name:Bendle, G.M. and Linnemann, C. and Hooijkaas, A.I. and Bies, L. and de Witte, M.A. and Jorritsma, A. and Kaiser, A.D.M. and Pouw, N. and Debets, R. and Kieback, E. and Uckert, W. and Song, J.Y. and Haanen, J.B.A.G. and Schumacher, T.N.M.
Abstract: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.
Keywords:Gene Therapy, T-Cell Receptor Genes, Graft vs Host Disease, Neoplasms, Antigen, T-Cell Receptors, T-Lymphocytes, Animal Models, Animals, Mice
Source:Nature Medicine
Publisher:Nature Publishing Group
Page Range:565-570, 1p following 570
Date:May 2010
Official Publication:https://doi.org/10.1038/nm.2128
PubMed:View item in PubMed

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