CII-DC-AdTRAIL cell gene therapy inhibits infiltration of CII-reactive T cells and CII-induced arthritis
Zhongyu Liu, … , Huang-Ge Zhang, John D. Mountz
Zhongyu Liu, … , Huang-Ge Zhang, John D. Mountz
Published November 1, 2003
Citation Information: J Clin Invest. 2003;112(9):1332-1341. https://doi.org/10.1172/JCI19209.
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Article Genetics

CII-DC-AdTRAIL cell gene therapy inhibits infiltration of CII-reactive T cells and CII-induced arthritis

Abstract

Previously, we described an APC-adenovirus (APC-Ad) FasL cell gene therapy method which could be used to deplete autoreactive T cells in vivo. FasL was toxic, however, and controlled regulation of FasL was not achieved. Here we describe an improved approach to delivering TNF-related apoptosis-inducing ligand (TRAIL) in vivo in which collagen II–induced (CII-induced) arthritis–susceptible (CIA-susceptible) DBA/1j mice were treated with CII-pulsed DCs that had been transfected with a novel Ad system. The Ad was engineered to exhibit inducible TRAIL under the control of the doxycycline-inducible (DOX-inducible) tetracycline response element (TRE). Four groups of mice were treated with CII-DC-AdTRAIL+DOX, CII-DC-AdTRAIL (no DOX), CII-DC-AdGFP+DOX, or DC-AdTRAIL+DOX (no CII), beginning 2 weeks after priming with CII in CFA. The incidence of arthritis and infiltration of T cells in the joint was significantly decreased in CII-DC-AdTRAIL+DOX–treated mice. The in vitro splenic T cell proliferative response and induction of IFN-γ to bovine CII stimulation were also significantly reduced in mice treated with CII-DC-AdTRAIL+DOX. AdTRAIL+DOX was not toxic to DCs or mice but could induce activated T cells to undergo apoptosis in the spleen. Our results suggest that CII-DC-AdTRAIL+DOX cell gene therapy is a safe and effective method for inhibiting the development of CIA.

Authors

Zhongyu Liu, Xin Xu, Hui-Chen Hsu, Albert Tousson, Ping-Ar Yang, Qi Wu, Cunren Liu, Shaohua Yu, Huang-Ge Zhang, John D. Mountz

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CII-DC-AdTRAIL+DOX treatment effectively prevents CII arthritis. (a) Dia...
CII-DC-AdTRAIL+DOX treatment effectively prevents CII arthritis. (a) Diagram of treatment protocol as described in Methods. (b) CIA incidence in mice. Arthritis incidence in the different treatment groups was recorded every week until the mice were sacrificed. Shown are the statistically significant differences of the instances of mice that develop arthritis, comparing the CIA–no treatment group with each of the four treatment groups, as determined by the Mann-Whitney U test. (c) DBA1j mice were challenged with CII and treated with CII-DC-AdTRAIL+DOX, CII-DC-AdTRAIL, CII-DC-AdGFP+DOX, or DC-AdTRAIL+DOX. The mice were sacrificed at 19 weeks of age. Tissue sections were stained with H&E. C, cartilage; BM, bone marrow cavity; SLC, synovial lining cells; SH, synovial hyperplasia. Original magnification, ×20. (d) The joint severity score was quantitated using a double-blinded method. The severity score was divided into four levels using the scoring system described in Methods. Each bar represents the mean severity score from ten mice in each treatment group. The asterisk above the bar indicates treatment groups of mice that were significantly different from the CIA–no treatment group of mice. *P < 0.05; **P < 0.01.