title: Costimulation and autoimmune diabetes in BB rats.
abstract: Costimulatory signals regulate T-cell activation. To investigate the role of costimulation in autoimmunity and transplantation, we studied the BB rat model of type 1 diabetes. Diabetes-prone BB (BBDP) rats spontaneously develop disease when 55-120 days of age. We observed that two anti-CD28 monoclonal antibodies (mAb) with different functional activities completely prevented diabetes in BBDP rats. Anti-CD154 mAb delayed diabetes, whereas treatment with CTLA4-Ig or anti-CD80 mAb accelerated disease. Anti-CD86 or anti-CD134L mAbs had no effect. Diabetes resistant BB (BBDR) rats are disease-free, but >95% of them develop diabetes after treatment with polyinosinic-polycytidylic acid and an mAb that depletes Treg cells. In the induced BBDR model, anti-CD154 mAb delayed onset of diabetes, whereas CTLA4-Ig, anti-CD134L or either of the anti-CD28 mAbs had little or no effect. In contrast, blockade of the CD134-CD134L pathway was highly effective for preventing autoimmune recurrence against syngeneic islet grafts in diabetic BBDR hosts. Blockade of the CD40-CD154 pathway was also effective, but less so. These data suggest that the effectiveness of costimulation blockade in the treatment of type 1 diabetes is dependent on both the costimulatory pathway targeted and the mechanism of induction, stage, intensity and duration of the pathogenic process.
authors.affiliation: Department of Medicine, The University of Massachusetts Medical School, Worcester, and Transplantation Research Center, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: B C
authors.initials: BC
authors.lastname: Beaudette-Zlatanova
authors.forename: B
authors.initials: B
authors.lastname: Whalen
authors.forename: D
authors.initials: D
authors.lastname: Zipris
authors.forename: H
authors.initials: H
authors.lastname: Yagita
authors.forename: J
authors.initials: J
authors.lastname: Rozing
authors.forename: H
authors.initials: H
authors.lastname: Groen
authors.forename: C D
authors.initials: CD
authors.lastname: Benjamin
authors.forename: T
authors.initials: T
authors.lastname: Hunig
authors.forename: H A
authors.initials: HA
authors.lastname: Drexhage
authors.forename: M J
authors.initials: MJ
authors.lastname: Ansari
authors.forename: J
authors.initials: J
authors.lastname: Leif
authors.forename: J P
authors.initials: JP
authors.lastname: Mordes
authors.forename: D L
authors.initials: DL
authors.lastname: Greiner
authors.forename: M H
authors.initials: MH
authors.lastname: Sayegh
authors.forename: A A
authors.initials: AA
authors.lastname: Rossini
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D018106:CD28 Antigens / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000517:prevention & control / Q000601:surgery*; D004195:Disease Models, Animal; D007108:Immune Tolerance; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D051381:Rats; D011913:Rats, Inbred BB; D012008:Recurrence
chemical_list: D000911:Antibodies, Monoclonal; D018106:CD28 Antigens