Nucleosome-specific regulatory T cells engineered by triple gene transfer suppress a systemic autoimmune disease.
The mechanisms of systemic autoimmune disease are poorly understood and available therapies often lead to immunosuppressive conditions. We describe here a new model of autoantigen-specific immunotherapy based on the sites of autoantigen presentation in systemic autoimmune disease. Nucleosomes are one of the well-characterized autoantigens. We found relative splenic localization of the stimulative capacity for nucleosome-specific T cells in (NZB x NZW)F(1) (NZB/W F(1)) lupus-prone mice. Splenic dendritic cells (DCs) from NZB/W F(1) mice spontaneously stimulate nucleosome-specific T cells to a much greater degree than both DCs from normal mice and DCs from the lymph nodes of NZB/W F(1) mice. This leads to a strategy for the local delivery of therapeutic molecules using autoantigen-specific T cells. Nucleosome-specific regulatory T cells engineered by triple gene transfer (TCR-alpha, TCR-beta, and CTLA4Ig) accumulated in the spleen and suppressed the related pathogenic autoantibody production. Nephritis was drastically suppressed without impairing the T cell-dependent humoral immune responses. Thus, autoantigen-specific regulatory T cells engineered by multiple gene transfer is a promising strategy for treating autoimmune diseases.
Fujio
Keishi
K
Department of Allergy and Rheumatology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
Okamoto
Akiko
A
Tahara
Hiroyuki
H
Abe
Masaaki
M
Jiang
Yi
Y
Kitamura
Toshio
T
Hirose
Sachiko
S
Yamamoto
Kazuhiko
K
D000069594:Abatacept; D000818:Animals; D017951:Antigen Presentation; D001324:Autoantigens / Q000276:immunology*; D001327:Autoimmune Diseases / Q000276:immunology / Q000628:therapy*; D003433:Crosses, Genetic; D003713:Dendritic Cells / Q000276:immunology; D004195:Disease Models, Animal; D019673:Genes, T-Cell Receptor alpha; D019674:Genes, T-Cell Receptor beta; D015316:Genetic Therapy; D018796:Immunoconjugates / Q000235:genetics*; D008180:Lupus Erythematosus, Systemic / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008814:Mice, Inbred NZB; D009707:Nucleosomes / Q000276:immunology*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000276:immunology; D013154:Spleen / Q000276:immunology / Q000473:pathology; D037182:T-Cell Antigen Receptor Specificity; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000637:transplantation; D014161:Transduction, Genetic
D001324:Autoantigens; D018796:Immunoconjugates; D009707:Nucleosomes; D016693:Receptors, Antigen, T-Cell, alpha-beta; D000069594:Abatacept