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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Figure 5

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CII-pulsed DCs are required for elimination of CII-reactive T cells. (a)...
CII-pulsed DCs are required for elimination of CII-reactive T cells. (a) Spleen T cells were isolated from the mice of various treatment groups shown at the bottom of the figure at the time of sacrifice (19 weeks of age) and were stimulated with γ-irradiated syngeneic spleen cells from DBA/1j mice that were pulsed with CII for 72 hours. The CII-specific T cell–proliferative response was measured using a 3H-thymic uptake assay. The proliferation of the CII-specific T cells was determined after an 18-hour pulse of 3H-thymidine. The counts were determined using a scintillation counter. There was a statistically significant decrease of T cell proliferation in the CII-DC-AdTRAIL+DOX–treatment group, compared with the other treatment groups. **P < 0.01. (b) Decreased secretion of IFN-γ in the CII-DC-AdTRAIL+DOX–treatment group. IFN-γ was determined in the supernatant at 72 hours after culture by an ELISA assay. The results represent the mean plus or minus SEM of duplicate cultures of ten mice per group analyzed separately. There was a statistically significant decrease of IFN-γ production in the CII-DC-AdTRAIL+DOX treatment group compared with the CIA–no treatment group and other treatment groups. **P < 0.01.