Lethal graft-versus-host disease in mouse models of T cell receptor gene therapy.
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.
Bendle
Gavin M
GM
Division of Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. g.bendle@nki.nl
Linnemann
Carsten
C
Hooijkaas
Anna I
AI
Bies
Laura
L
de Witte
Moniek A
MA
Jorritsma
Annelies
A
Kaiser
Andrew D M
AD
Pouw
Nadine
N
Debets
Reno
R
Kieback
Elisa
E
Uckert
Wolfgang
W
Song
Ji-Ying
JY
Haanen
John B A G
JB
Schumacher
Ton N M
TN
D000818:Animals; D019672:Genes, T-Cell Receptor; D015316:Genetic Therapy / Q000379:methods*; D006086:Graft vs Host Disease / Q000276:immunology / Q000473:pathology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009369:Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics* / Q000276:immunology; D013601:T-Lymphocytes / Q000378:metabolism
D011948:Receptors, Antigen, T-Cell
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