title: Genetic disassociation of autoimmunity and resistance to costimulation blockade-induced transplantation tolerance in nonobese diabetic mice.
abstract: Curing type 1 diabetes by islet transplantation requires overcoming both allorejection and recurrent autoimmunity. This has been achieved with systemic immunosuppression, but tolerance induction would be preferable. Most islet allotransplant tolerance induction protocols have been tested in nonobese diabetic (NOD) mice, and most have failed. Failure has been attributed to the underlying autoimmunity, assuming that autoimmunity and resistance to transplantation tolerance have a common basis. Out of concern that NOD biology could be misleading in this regard, we tested the hypothesis that autoimmunity and resistance to transplantation tolerance in NOD mice are distinct phenotypes. Unexpectedly, we observed that (NOD x C57BL/6)F(1) mice, which have no diabetes, nonetheless resist prolongation of skin allografts by costimulation blockade. Further analyses revealed that the F(1) mice shared the dendritic cell maturation defects and abnormal CD4(+) T cell responses of the NOD but had lost its defects in macrophage maturation and NK cell activity. We conclude that resistance to allograft tolerance induction in the NOD mouse is not a direct consequence of overt autoimmunity and that autoimmunity and resistance to costimulation blockade-induced transplantation tolerance phenotypes in NOD mice can be dissociated genetically. The outcomes of tolerance induction protocols tested in NOD mice may not accurately predict outcomes in human subjects.
authors.affiliation: Program in Immunology and Virology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Todd
authors.initials: T
authors.lastname: Pearson
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Markees
authors.forename: David V
authors.initials: DV
authors.lastname: Serreze
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Pierce
authors.forename: Michele P
authors.initials: MP
authors.lastname: Marron
authors.forename: Linda S
authors.initials: LS
authors.lastname: Wicker
authors.forename: Laurence B
authors.initials: LB
authors.lastname: Peterson
authors.forename: Leonard D
authors.initials: LD
authors.lastname: Shultz
authors.forename: John P
authors.initials: JP
authors.lastname: Mordes
authors.forename: Aldo A
authors.initials: AA
authors.lastname: Rossini
authors.forename: Dale L
authors.initials: DL
authors.lastname: Greiner
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D015703:Antigens, CD / Q000096:biosynthesis; D001327:Autoimmune Diseases / Q000235:genetics* / Q000473:pathology; D051940:B7-2 Antigen; D001854:Bone Marrow Cells / Q000276:immunology / Q000473:pathology; D016516:CD4-CD8 Ratio; D019013:CD40 Antigens / Q000276:immunology; D023201:CD40 Ligand / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D002448:Cell Adhesion / Q000235:genetics / Q000276:immunology; D002452:Cell Count; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D003433:Crosses, Genetic; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D005260:Female; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D006085:Graft Survival / Q000235:genetics / Q000276:immunology; D006720:Homozygote; D007113:Immunity, Innate / Q000235:genetics; D007275:Injections, Intravenous; D007694:Killer Cells, Natural / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology*; D017710:Lymphocyte Transfusion; D008231:Lymphopenia / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000166:cytology / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D016038:Skin Transplantation / Q000276:immunology; D023001:Transplantation Tolerance / Q000235:genetics*
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D051940:B7-2 Antigen; D019013:CD40 Antigens; C497965:Cd86 protein, mouse; D005819:Genetic Markers; D008562:Membrane Glycoproteins; D015375:Receptors, Interleukin-2; D023201:CD40 Ligand