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-DCAdTRAIL+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-DCAdTRAIL+DOX cell gene therapy is a safe and effective method for inhibiting the development of CIA.

Gene therapy works in animal models of rheumatoid arthritis so what!

“…An effective approach in the treatment of collageninduced arthritis (CIA) is the eradication of antigenspecific T cells by transfer of antigen-pulsed DCs that overexpress TRAIL or FasL [11,12]. Since DCs do not migrate to the joint, they probably exert their effect in the spleen and lymph nodes.…”

The TRAIL to arthritis

“…In this issue of the JCI, Liu et al (9) report suppression of collagen-induced arthritis using DCs pulsed with collagen and transfected with an adenovirus-based vector expressing the TRAIL gene under the control of the doxycycline-inducible (DOX-inducible) tetracycline response element. The system offered two novel features: DCs were primed to recognize collagen-spe-cific T cells and to express TRAIL only when the expression vector was activated with DOX ( Figure 1a).…”

“…Primary synovial cells from patients with rheumatoid arthritis succumb to TRAIL-mediated apoptosis if infected with a TRAILexpressing vector (5). The study by Liu et al (9) does not address the localization of the infused modified DCs, although there is no doubt that these cells trafficked though the lymphoid organs and the inflamed tissues. Also, it is not known how long these DCs survived, and it is logical to assume that their half-life should be limited.…”

“…How should the results reported by Liu et al (9) be translated to patients with rheumatoid arthritis? Will a trial using Ig-TRAIL be informative?…”

“…Despite recent advances in the treatment of rheumatoid arthritis, significant challenges remain that call for the development of more efficient treatments that lack side effects. The data presented by Liu et al (9) offer new possibilities for cell-based treatment of patients with rheumatoid arthritis, provided we use the culprit autoantigens to provide specificity and solve problems inherent in gene transfer.…”