RNAi-mediated TCR Knockdown Prevents Autoimmunity in Mice Caused by Mixed TCR Dimers Following TCR Gene Transfer

摘要: Genetically modified T cells that express a transduced cell receptor (TCR) α/β heterodimer in addition to their endogenous TCR are used clinical studies treat cancer. These two TCR-α and TCR-β chains do not only compete for CD3 proteins but also form potentially self-reactive mixed dimers, composed of transferred chains. To overcome these deficits, we developed an RNAi-TCR replacement vector simultaneously silences the expresses RNAi-resistant TCR. Transduction virus-specific P14 without RNAi resulted unequal -β chain surface levels, indicating heterodimerization with Such expression was observed following gene optimization. Equal levels introduced were however achieved by silencing Importantly, all mice received native or optimized lethal transfer-induced graft-versus-host-disease (TI-GVHD) due formation dimers. In contrast, TI-GVHD almost completely prevented when using vector. Our data demonstrate RNAi-assisted reduces thereby significantly risk therapy.