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

被引：335

作者：

Bendle, Gavin M. ^{[1
]}

Linnemann, Carsten ^{[1
]}

Hooijkaas, Anna I. ^{[1
]}

Bies, Laura ^{[1
]}

de Witte, Moniek A. ^{[1
]}

Jorritsma, Annelies ^{[1
]}

Kaiser, Andrew D. M. ^{[1
]}

Pouw, Nadine ^{[2
]}

Debets, Reno ^{[2
]}

Kieback, Elisa ^{[3
]}

Uckert, Wolfgang ^{[3
]}

Song, Ji-Ying ^{[4
]}

Haanen, John B. A. G. ^{[1
,5
]}

Schumacher, Ton N. M. ^{[1
]}

机构：

[1] Netherlands Canc Inst, Div Immunol, NL-1066 CX Amsterdam, Netherlands

[2] Erasmus MC Daniel den Hoed Canc Ctr, Lab Expt Tumor Immunol, Dept Med Oncol, Rotterdam, Netherlands

[3] Max Delbruck Ctr Mol Med, Berlin, Germany

[4] Netherlands Canc Inst, Div Expt Anim Pathol, NL-1066 CX Amsterdam, Netherlands

[5] Netherlands Canc Inst, Div Med Oncol, NL-1066 CX Amsterdam, Netherlands

来源：

NATURE MEDICINE | 2010年 / 16卷 / 05期

关键词：

ENHANCED ANTITUMOR-ACTIVITY; BONE-MARROW FAILURE; CANCER REGRESSION; TUMOR-REGRESSION; TCR-ALPHA; LYMPHOCYTES; IMMUNOTHERAPY; BETA; MELANOMA; ANTIGEN;

D O I：

10.1038/nm.2128

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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.

引用

页码：565 / U98

页数：7

共 41 条

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