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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Inducible expression of murine TRAIL on DCs without induction of autocri...
Inducible expression of murine TRAIL on DCs without induction of autocrine suicide. (a) A recombinant AdTRAIL was constructed as described in Methods. DCs from the bone marrow of DBA/1j mice were transfected with 50 pfu/cell of AdTRAIL and then incubated with different concentrations of DOX for 24 hours. The expression of functional TRAIL on the surface of the transfected cells was then evaluated by an ATPlite assay. (b) DCs from the bone marrow of DBA/1j mice were transfected with 50 pfu/cell of AdGFP, and the percentage of GFP+ DCs was quantitated 24 hours later under a fluorescence microscope. (c) TRAIL-sensitive HT1080 fibrosarcoma cells were transfected with 50 pfu/cell of AdTRAIL and then incubated with various concentrations of DOX for 24 hours. The expression of AdTRAIL in the target cells was tested using the ATPlite assay. Results are representative of three experiments.