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

A murine CTLA4-Fe 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.