CII-DC-AdTRAIL cell gene therapy inhibits infiltration of CII-reactive T cells and CII-induced arthritis.
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-gamma 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.
Department of Medicine, Division of Clinical Immunology and Rheumatology, The University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
Zhongyu
Z
Liu
Xin
X
Xu
Hui-Chen
HC
Hsu
Albert
A
Tousson
Ping-Ar
PA
Yang
Qi
Q
Wu
Cunren
C
Liu
Shaohua
S
Yu
Huang-Ge
HG
Zhang
John D
JD
Mountz
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000906:Antibodies / Q000276:immunology; D000917:Antibody Formation; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D001172:Arthritis, Rheumatoid / Q000628:therapy*; D002465:Cell Movement; D064987:Cell- and Tissue-Based Therapy; D024043:Collagen Type II / Q000276:immunology*; D003713:Dendritic Cells / Q000502:physiology*; D004317:Doxorubicin / Q000494:pharmacology; D005260:Female; D015316:Genetic Therapy; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000502:physiology; D051379:Mice; D008811:Mice, Inbred DBA; D013154:Spleen / Q000473:pathology; D013601:T-Lymphocytes / Q000502:physiology*; D053221:TNF-Related Apoptosis-Inducing Ligand; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000502:physiology
D000906:Antibodies; D051017:Apoptosis Regulatory Proteins; D024043:Collagen Type II; D008562:Membrane Glycoproteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D004317:Doxorubicin