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

Research output: Contribution to journalArticlepeer-review

Authors

  • Carsten Linnemann
  • Anna I Hooijkaas
  • Laura Bies
  • Moniek A de Witte
  • Annelies Jorritsma
  • Andrew D M Kaiser
  • Nadine Pouw
  • Reno Debets
  • Elisa Kieback
  • Wolfgang Uckert
  • Ji-Ying Song
  • John B A G Haanen
  • Ton N M Schumacher

Colleges, School and Institutes

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.

Details

Original languageEnglish
Pages (from-to)565-70, 1p following 570
JournalNature Medicine
Volume16
Issue number5
Publication statusPublished - May 2010