Ectopic expression of neural autoantigen in mouse liver suppresses experimental autoimmune neuroinflammation by inducing antigen-specific Tregs
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Ectopic expression of neural autoantigen in mouse liver suppresses experimental autoimmune neuroinflammation by inducing antigen-specific Tregs. / Lüth, Stefan; Huber, Samuel; Schramm, Christoph; Buch, Thorsten; Zander, Stefan; Stadelmann, Christine; Brück, Wolfgang; Wraith, David C; Herkel, Johannes; Lohse, Ansgar W.
In: J CLIN INVEST, Vol. 118, No. 10, 10, 10.2008, p. 3403-3410.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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T1 - Ectopic expression of neural autoantigen in mouse liver suppresses experimental autoimmune neuroinflammation by inducing antigen-specific Tregs
AU - Lüth, Stefan
AU - Huber, Samuel
AU - Schramm, Christoph
AU - Buch, Thorsten
AU - Zander, Stefan
AU - Stadelmann, Christine
AU - Brück, Wolfgang
AU - Wraith, David C
AU - Herkel, Johannes
AU - Lohse, Ansgar W
PY - 2008/10
Y1 - 2008/10
N2 - Tregs are important mediators of immune tolerance to self antigens, and it has been suggested that Treg inactivation may cause autoimmune disease. Therefore, immunotherapy approaches that aim to restore or expand autoantigen-specific Treg activity might be beneficial for the treatment of autoimmune disease. Here we report that Treg-mediated suppression of autoimmune disease can be achieved in vivo by taking advantage of the ability of the liver to promote immune tolerance. Expression of the neural autoantigen myelin basic protein (MBP) in the liver was accomplished stably in liver-specific MBP transgenic mice and transiently using gene transfer to liver cells in vivo. Such ectopic MBP expression induced protection from autoimmune neuroinflammation in a mouse model of multiple sclerosis. Protection from autoimmunity was mediated by MBP-specific CD4+CD25+Foxp3+ Tregs, as demonstrated by the ability of these cells to prevent disease when adoptively transferred into nontransgenic mice and to suppress conventional CD4+CD25- T cell proliferation after antigen-specific stimulation with MBP in vitro. The generation of MBP-specific CD4+CD25+Foxp3+ Tregs in vivo depended on expression of MBP in the liver, but not in skin, and occurred by TGF-beta-dependent peripheral conversion from conventional non-Tregs. Our findings indicate that autoantigen expression in the liver may generate autoantigen-specific Tregs. Thus, targeting of autoantigens to hepatocytes may be a novel approach to prevention or treatment of autoimmune diseases.
AB - Tregs are important mediators of immune tolerance to self antigens, and it has been suggested that Treg inactivation may cause autoimmune disease. Therefore, immunotherapy approaches that aim to restore or expand autoantigen-specific Treg activity might be beneficial for the treatment of autoimmune disease. Here we report that Treg-mediated suppression of autoimmune disease can be achieved in vivo by taking advantage of the ability of the liver to promote immune tolerance. Expression of the neural autoantigen myelin basic protein (MBP) in the liver was accomplished stably in liver-specific MBP transgenic mice and transiently using gene transfer to liver cells in vivo. Such ectopic MBP expression induced protection from autoimmune neuroinflammation in a mouse model of multiple sclerosis. Protection from autoimmunity was mediated by MBP-specific CD4+CD25+Foxp3+ Tregs, as demonstrated by the ability of these cells to prevent disease when adoptively transferred into nontransgenic mice and to suppress conventional CD4+CD25- T cell proliferation after antigen-specific stimulation with MBP in vitro. The generation of MBP-specific CD4+CD25+Foxp3+ Tregs in vivo depended on expression of MBP in the liver, but not in skin, and occurred by TGF-beta-dependent peripheral conversion from conventional non-Tregs. Our findings indicate that autoantigen expression in the liver may generate autoantigen-specific Tregs. Thus, targeting of autoantigens to hepatocytes may be a novel approach to prevention or treatment of autoimmune diseases.
KW - Animals
KW - Autoantigens
KW - Brain
KW - CD4-Positive T-Lymphocytes
KW - Encephalomyelitis, Autoimmune, Experimental
KW - Female
KW - Gene Expression Regulation
KW - Liver
KW - Male
KW - Mice
KW - Mice, Transgenic
KW - Myelin Basic Protein
KW - Neurons
KW - T-Lymphocytes, Regulatory
KW - Thymus Gland
KW - Time Factors
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1172/JCI32132
DO - 10.1172/JCI32132
M3 - SCORING: Journal article
C2 - 18802476
VL - 118
SP - 3403
EP - 3410
JO - J CLIN INVEST
JF - J CLIN INVEST
SN - 0021-9738
IS - 10
M1 - 10
ER -