Costimulation blockade of both inducible costimulator and CD40 ligand induces dominant tolerance to islet allografts and prevents spontaneous autoimmune diabetes in the NOD mouse.

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.

Robust tolerance to fully allogeneic islet transplants achieved by chimerism with minimal conditioning.

Background: Whether mixed chimeras induced by nonmyeloablative conditioning are tolerant to challenge with donor allogeneic islet grafts is unknown. Here we investigate whether our nonmyeloablative, costimulation blockade-free and sirolimus (SRL)-based protocol could facilitate mixed chimerism via bone marrow transplantation (BMT) and induce islet allograft tolerance.

Methods: After low dose (1-3 Gy) total body irradiation (TBI, day -1), with or without prior lymphocyte depletion, C57BL/6 mice were transfused with 40 x 10(6) BALB/c bone marrow cells (day 0) and received SRL (3 mg/kg/day) for 4 weeks.

Multiple combination therapies involving blockade of ICOS/B7RP-1 costimulation facilitate long-term islet allograft survival.

In recent years a series of novel costimulatory molecules have been identified, including inducible costimulator (ICOS). In a fully major histocompatibility complex (MHC)-mismatched mouse model of islet transplantation, we demonstrate that while monotherapy with CTLA4-Ig, CD40 ligand monoclonal antibody (CD40L mAb) or rapamycin each improves islet allograft survival, graft rejection eventually develops. Immunohistologic analysis of rejected grafts revealed increased ICOS expression, suggesting a role for this costimulatory molecule as an alternate pathway for T-cell activation.