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

Gavin M Bendle, et al. 2010. Nature Medicine 16, 565-570

Speaker: Shih-Ying Wu (吳思瑩)                         Time: 13:10~14:10, Dec. 15, 2010

Commentator: Dr. Yee-Shin Lin (林以行老師)   Place: Room 601

Abstract:

T cell receptor gene therapy can induce a strong specific immune response toward the target antigen, and has been considered as a treatment of cancer and other disease, such as human immunodeficient virus infection, which has already been on phase 1 clinical trial. However, some studies pointed out that the T cell receptor gene therapy may be dangerous because it may cause graft-versus-host disease (GVHD). To address this question, the authors used an animal model which mimicked the clinical settings of GVHD. The mice were received a small amount of TCR-transduced CD8⁺ T cells and given a high-dose of IL-2 after the transfer. They found that the mice exhibited lethal autoimmune pathology and the formation of mixed TCR dimer, and that the doses of IL-2 were related to the TCR gene transfer-induced graft versus-host disease (TI-GVHD). In addition, monocyte chemoattractant protein-1, tumor necrosis factor, and IFN-gamma positively mediated the development of TI-GVHD. In contrast, TGF- beta played a opposite role by inhibiting the T cell proliferation. Notably, multiple TCRs could cause TI-GVHD including the melanocytedifferentiation antigen gp100-specific pmel-1 TCR, the SV40 lager T oncogenes-specific SV40_IV TCR, the influenza A nucleoprotein-specific F5 TCR, the melanocyte differentiation antigen tyrosinase-ralated protein-2(TRP2)-specific TRP2 TCR, and the OT-1 TCR. Finally, the authors tried to resolve the TI-GVHD following TCR gene therapy by preventing mixed TCR dimer formation using F5 TCR tg OT-I TCR Td or OT-I Cys-TCR-P2A Td . In summary, the authors proved that TI-GVHD might occur following TCR gene therapy in mouse model, and that they proposed some strategies to resolve this problem.

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