Gene therapy of arthritis with TCR isolated from the inflamed paw.
In recent years, the treatment of autoimmune diseases has been significantly advanced by the use of biological agents. However, some biologics are accompanied with severe side effects, including tuberculosis and other types of infection. There is thus a critical need for nonsystemic and lesion-specific methods of delivering these therapeutic agents. We attempted to treat a mouse model of arthritis by using T cells that expressed a regulatory molecule and were specifically directed to the inflamed paw. To this end, we first identified the TCR alphabeta genes accumulating in the inflamed paw of mice with collagen-induced arthritis (CIA) by a combination of single-strand chain polymorphism analysis of TCR and single-cell sorting. We identified an expanded clone B47 which is autoreactive but is not specific to type II collagen. In vivo, TCR genes from B47-transduced T cells accumulated in the inflamed paw. Injection of cells cotransduced with the B47 and soluble TNFRIg genes resulted in a significant suppression of CIA. The suppression was correlated with the amount of TNFRIg transcripts in the hind paw, not with the serum concentrations of TNFRIg. Moreover, T cells cotransduced with the B47 and intracellular Foxp3 genes significantly suppressed CIA with reductions in TNF-alpha, IL-17A, and IL-1beta expression and bone destruction. T cells cotransduced with B47 and Foxp3 genes also suppressed the progression of established CIA. Therefore, immunosuppressive therapy with autoreactive TCR is a promising therapeutic strategy for arthritis whether the TCRs are used to deliver either soluble or intracellular suppressive molecules.
Fujio
Keishi
K
Department of Allergy and Rheumatology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. kfujio-tky@umin.ac.jp
Okamoto
Akiko
A
Araki
Yasuto
Y
Shoda
Hirofumi
H
Tahara
Hiroyuki
H
Tsuno
Nelson H
NH
Takahashi
Koki
K
Kitamura
Toshio
T
Yamamoto
Kazuhiko
K
D019264:Adoptive Transfer; D000595:Amino Acid Sequence; D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000517:prevention & control*; D001323:Autoantibodies / Q000276:immunology; D001324:Autoantigens / Q000276:immunology; D049109:Cell Proliferation; D005434:Flow Cytometry; D005552:Forelimb / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000276:immunology; D015316:Genetic Therapy / Q000379:methods*; D006614:Hindlimb / Q000276:immunology; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology; D051379:Mice; D008811:Mice, Inbred DBA; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D011948:Receptors, Antigen, T-Cell / Q000235:genetics* / Q000276:immunology*; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology; D014161:Transduction, Genetic / Q000379:methods*
D001323:Autoantibodies; D001324:Autoantigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D011948:Receptors, Antigen, T-Cell; D018124:Receptors, Tumor Necrosis Factor