title: Costimulation blockade of both inducible costimulator and CD40 ligand induces dominant tolerance to islet allografts and prevents spontaneous autoimmune diabetes in the NOD mouse.
abstract: Costimulation blockade is a promising strategy for preventing allograft rejection and inducing tolerance. Using a fully allogeneic mouse model, we tested the effectiveness of the combined blockade of the CD40 ligand and the inducible costimulator (ICOS) on islet allograft survival and in the prevention of autoimmune diabetes in the NOD mouse. Recipients treated with blocking monoclonal antibodies (mAbs) to ICOS and the CD40 ligand had significant prolongation of graft survival, with 26 of 28 functioning for >200 days. Long-term engrafted mice maintained antidonor proliferative and cytotoxic responses, but donor-specific immunization did not induce graft rejection, and challenge with second, same donor but not third-party grafts resulted in long-term acceptance. The immunohistology of tolerant grafts demonstrated the presence of CD4(+)CD25(+) T-cells expressing Foxp3, and islet/kidney composite grafts from tolerant mice, but not from mice lacking lymphocytes, were accepted indefinitely when transplanted into naïve B6 mice, suggesting that recipient T-cells were necessary to generate dominant tolerance. Combined anti-ICOS and anti-CD40 ligand mAb therapy also prevented diabetes in NOD mice, with only 11% of treated recipients developing diabetes compared with 75% of controls. These data demonstrate that the blockade of CD40 ligand and ICOS signaling induces islet allograft tolerance involving a dominant mechanism associated with intragraft regulatory cells and prevents autoimmune diabetes in NOD mice.
authors.affiliation: Roberts Centre, 2000 College Plaza, University of Alberta, 2000 College Plaza, 8215 112 St., Edmonton, Alberta, Canada T6G 2C8.
authors.forename: Sulaiman A
authors.initials: SA
authors.lastname: Nanji
authors.forename: Wayne W
authors.initials: WW
authors.lastname: Hancock
authors.forename: Bin
authors.initials: B
authors.lastname: Luo
authors.forename: Colleen D
authors.initials: CD
authors.lastname: Schur
authors.forename: Rena L
authors.initials: RL
authors.lastname: Pawlick
authors.forename: Lin Fu
authors.initials: LF
authors.lastname: Zhu
authors.forename: Colin C
authors.initials: CC
authors.lastname: Anderson
authors.forename: A M James
authors.initials: AM
authors.lastname: Shapiro
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology*; D023201:CD40 Ligand / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000517:prevention & control*; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control; D006085:Graft Survival / Q000276:immunology*; D007108:Immune Tolerance / Q000276:immunology*; D060889:Inducible T-Cell Co-Stimulator Protein; D007515:Islets of Langerhans / Q000166:cytology; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D016688:Mice, Inbred NOD
chemical_list: D000911:Antibodies, Monoclonal; D000945:Antigens, Differentiation, T-Lymphocyte; C556694:Icos protein, mouse; D060889:Inducible T-Cell Co-Stimulator Protein; D023201:CD40 Ligand