Short‐term suppression of the xeno‐immune response with mCTLA4‐Fc treatment

A murine CTLA4‐Fc chimeric fusion protein was used to determine if inhibition of the CD28‐B7 pathway for T‐cell activation could result in prolonged or indefinite survival of pancreatic islet xenografts in mice. B6AF1 recipients of Wistar rat pancreatic islet xenografts that received short‐term mCTLA4‐Fc treatment had prolonged graft survival (28 days vs. 9 days) but all animals rejected their grafts. This survival advantage was similar to that achieved with short‐term depletion of CD3+ or CD4+ T cells with 145.2C11 (median graft survival 21 days) or GK1.5 mAb (median graft survival 33 days), respectively. Combined GK1.5, 145.2C11, and mCTLA4‐Fc treatment for the first 2 weeks post‐transplant and maintenance therapy with GK1.5 and mCTLA4‐Fc for the next 4 weeks produced the best results (median survival 63 days). However, islet xenografts were rapidly rejected upon cessation of treatment. Unlike in allografts, short‐term inhibition of the CD28‐B7 pathway with mCTLA4‐Fc did not result in long‐term rat xenograft survival. This suggests that the conditions necessary for quenching xenograft rejection and inducing tolerance differ significantly from those found in allotransplantation and acquired xenograft tolerance may be difficult to achieve.