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.

TRAIL and immunity: more than a license to kill tumor cells

“…12 Accordingly, gene transfer of TRAIL-encoding adenoviruses was able to significantly ameliorate clinical signs of arthritis. 30 This beneficial effect of TRAIL gene therapy was most likely due to the induction of apoptosis in activated T cells and synoviocytes. Thus, these different studies illustrate that TRAIL has an important immunoregulatory role in the pathogenesis of rheumatoid arthritis, and also demonstrates the potential of TRAIL-based therapies.…”

Modulation of tumor necrosis factor related apoptosis-inducing ligand (TRAIL) receptors in a human osteoclast model in vitro

“…In another arthritis study, mice receiving collagen-treated TRAIL-expressing DCs had diminished joint inflammation compared with controls. These mice exhibited a lowered T-cell proliferation and IFN-y production, suppressing the arthritis (Liu et al, 2003). When TRAIL induces apoptosis in Thl cells, there is a correlated reduction of IFN-y, which in turn regulated chemokine production.…”

Cytotoxic T Lymphocytes Elicited by Dendritic Cell-Targeted Delivery of Human Papillomavirus Type-16 E6/E7 Fusion Gene Exert Lethal Effects on CaSki Cells

“…From their original application to the cancer, DC have been used in the more areas at present, for example, infectious diseases, immunoregulatory diseases, allergic diseases and allograft rejection. Genetic modification of DC with genes encoding immunoregulatory molecules provides a potential approach for Ag-specific regulation of T cell-mediated immunity by selectively targeting antigen-specific T cells (Matsue et al, 1999;Lu et al, 1999;Morita et al, 2001;Liu et al, 2003;Watanabe et al, 2003).…”