title: Lupus-Prone Mice Resist Immune Regulation and Transplant Tolerance Induction.
abstract: The strongly immunogenic environment in autoimmune diseases such as lupus may pose a stringent barrier to transplantation. Despite available murine models of lupus, transplant tolerance in this setting has yet to be fully investigated in highly penetrant genetic models of disease. Such studies are of clear clinical importance because lupus is a transplant indication in which transplanted kidneys have a substantially increased risk of rejection including a role for recurrent nephritis. In the fully penetrant B6.SLE123 mouse, we determined that CD4 T follicular helper and germinal center B cells were significantly expanded compared with healthy controls. We traced this expansion to resistance of effector CD4 T and B cells in B6.SLE123 mice to regulation by either CD4 T regulatory cells (CD4Tregs) or CD8 T regulatory cells (CD8Tregs), despite demonstrating normal function by Tregs in this strain. Finally, we determined that B6.SLE123 mice resist anti-CD45RB-mediated tolerance induction to foreign islet allografts, even in the absence of islet autoimmunity. Overall, B6.SLE123 lupus-prone mice are highly resistant to transplant tolerance induction, which provides a new model of failed tolerance in autoimmunity that may elucidate barriers to clinical transplantation in lupus through further cellular and genetic dissection.
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN.
authors.forename: B T
authors.initials: BT
authors.lastname: Stocks
authors.affiliation: Department of Medicine, Division of Cardiovascular Medicine, Vanderbilt University, Nashville, TN.
authors.forename: A J
authors.initials: AJ
authors.lastname: Wilhelm
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN.
authors.forename: C S
authors.initials: CS
authors.lastname: Wilson
authors.affiliation: Department of Pediatrics, Ian Burr Division of Endocrinology and Diabetes, Vanderbilt University, Nashville, TN.
authors.forename: A F
authors.initials: AF
authors.lastname: Marshall
authors.forename: N E
authors.initials: NE
authors.lastname: Putnam
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN.|Department of Medicine, Division of Cardiovascular Medicine, Vanderbilt University, Nashville, TN.
authors.forename: A S
authors.initials: AS
authors.lastname: Major
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN.|Department of Pediatrics, Ian Burr Division of Endocrinology and Diabetes, Vanderbilt University, Nashville, TN.
authors.forename: D J
authors.initials: DJ
authors.lastname: Moore
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000097:blood / Q000276:immunology*; D015551:Autoimmunity / Q000276:immunology*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology; D006084:Graft Rejection / Q000276:immunology*; D006085:Graft Survival / Q000276:immunology; D016381:Islets of Langerhans Transplantation / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000150:complications / Q000276:immunology*; D008181:Lupus Nephritis / Q000209:etiology* / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D016688:Mice, Inbred NOD; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D023001:Transplantation Tolerance / Q000276:immunology*
chemical_list: D001323:Autoantibodies
keywords: T cell biology; alloantibody; autoimmunity; basic (laboratory) research / science; immune regulation; immunobiology; islet transplantation; tolerance: mechanisms