Ectopic expression of neural autoantigen in mouse liver suppresses experimental autoimmune neuroinflammation by inducing antigen-specific Tregs. Export

@article{citeulike:3346879, abstract = {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.}, address = {Department of Medicine I, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Department of Pathology, University Hospital Zurich, Zurich, Switzerland. Department of Neuropathology, Georg-August-University, G\"{o}ttingen, Germany. Department of Pathology and Microbiology, University of Bristol, Bristol, United Kingdom.}, author = {L\"{u}th, Stefan and Huber, Samuel and Schramm, Christoph and Buch, Thorsten and Zander, Stefan and Stadelmann, Christine and Br\"{u}ck, Wolfgang and Wraith, David C C. and Herkel, Johannes and Lohse, Ansgar W W.}, citeulike-article-id = {3346879}, citeulike-linkout-0 = {http://dx.doi.org/10.1172/JCI32132}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/18802476}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=18802476}, day = {18}, doi = {10.1172/JCI32132}, issn = {0021-9738}, journal = {The Journal of clinical investigation}, keywords = {for\_print, liver, neuroinflamatory\_dis, treg}, month = {September}, posted-at = {2008-09-28 13:49:19}, priority = {5}, title = {Ectopic expression of neural autoantigen in mouse liver suppresses experimental autoimmune neuroinflammation by inducing antigen-specific Tregs.}, url = {http://dx.doi.org/10.1172/JCI32132}, year = {2008} }

TY - JOUR ID - citeulike:3346879 L3 - citeulike-article-id:3346879 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. JF - The Journal of clinical investigation SN - 0021-9738 AD - Department of Medicine I, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Department of Pathology, University Hospital Zurich, Zurich, Switzerland. Department of Neuropathology, Georg-August-University, Göttingen, Germany. Department of Pathology and Microbiology, University of Bristol, Bristol, United Kingdom. TI - Ectopic expression of neural autoantigen in mouse liver suppresses experimental autoimmune neuroinflammation by inducing antigen-specific Tregs. KW - for_print KW - liver KW - neuroinflamatory_dis KW - treg 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 - 2008/09/18/ UR - http://dx.doi.org/10.1172/JCI32132 ER -