Division of Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Nat Med. 2010 May;16(5):565-70, 1p following 570. doi: 10.1038/nm.2128. Epub 2010 Apr 18.
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.
T 细胞受体 (TCR) 基因的转移可用于诱导针对内源性 T 细胞反应不足的特定抗原的免疫反应。这种方法称为 TCR 基因治疗，正被开发用于针对肿瘤和病原体，并且已经在癌症患者中开始了临床试验。在这项研究中，我们表明，在非常类似于临床环境的条件下，TCR 基因治疗的小鼠模型中会发生致命的细胞因子驱动的自身免疫病理。我们表明，在 TCR 基因修饰的 T 细胞中引入的和内源性 TCR 链的配对导致形成负责观察到的自身免疫的自身反应性 TCR。此外，我们证明可以调整基因治疗载体和靶 T 细胞群体的设计，以降低 TCR 基因治疗引起的自身免疫病理的风险。
