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Updated: Jun 13, 2026
Induction of Graft-versus-host Disease and In Vivo T Cell Monitoring Using an MHC-matched Murine Model
Published on: August 29, 2012
Lethal graft-versus-host disease in mouse models of T cell receptor gene therapy
Gavin M Bendle1, Carsten Linnemann, Anna I Hooijkaas
1Division of Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. g.bendle@nki.nl
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.
Insights
TCR gene therapy shows promise for cancer treatment but can cause autoimmune disease. This study reveals that combining introduced and natural T cell receptor (TCR) chains creates self-reactive TCRs, leading to dangerous pathology in mouse models.
Area of Science:
- Immunology
- Gene Therapy
- Oncology
Background:
- T cell receptor (TCR) gene therapy aims to enhance immune responses against tumors and pathogens by introducing specific TCR genes.
- Clinical trials are underway for cancer patients, highlighting the therapeutic potential of this approach.
Purpose of the Study:
- To investigate the potential for autoimmune pathology in TCR gene therapy models.
- To identify the mechanisms underlying TCR gene therapy-induced autoimmunity.
- To explore strategies for mitigating the risks associated with TCR gene therapy.
Main Methods:
- Utilized mouse models of TCR gene therapy that closely mimic clinical settings.
- Analyzed the formation of T cell receptors (TCRs) resulting from the pairing of introduced and endogenous TCR chains.
- Evaluated the autoimmune consequences of these self-reactive TCRs.
Main Results:
- Demonstrated that TCR gene therapy can induce lethal autoimmune pathology in mouse models.
- Identified the formation of self-reactive TCRs due to the combination of introduced and endogenous TCR chains as the cause of autoimmunity.
- Showcased that modifications in vector design and target cell populations can reduce the risk of autoimmune pathology.
Conclusions:
- TCR gene therapy carries a risk of inducing severe autoimmune side effects.
- Understanding TCR chain pairing is crucial for predicting and preventing TCR gene therapy-induced autoimmunity.
- Optimizing gene therapy vector design and T cell selection can enhance the safety profile of TCR gene therapy for clinical applications.
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