Efficacy of CTLA4-Ig in Preventing Acute Rejection of Fully Allogeneic Heart Allografts in Sensitized Recipients.

Abstract

Belatacept, a high-affinity variant of CTLA4-Ig, is a recently approved immunosuppressive agent for the prevention of acute rejection. It functions as a potent antagonist of the CD28-B7 interactions, thereby inhibiting T cell co-stimulation and activation. Experimental data involving the transient use of CTLA4-Ig to induce allograft tolerance have shaped the current paradigm that CTLA-4Ig is ineffective at inhibiting memory T cell responses, and by extension T-dependent alloantibody responses. This resistance is explained by the acquisition of additional activation-induced costimulatory molecules by memory T cells. We noted that the efficacy of CTLA4-Ig as a continuously administered drug for controlling rejection in sensitized recipients has not been investigated. Here we report on the efficacy of CTLA4-Ig in preventing acute rejection in sensitized C57BL/6 recipients that had received BALB/c spleen cell transfusion 3-6 months previously. We set up four experimental groups. Group 1 (N=5): sensitized mice with HTX and CTLA4-Ig treated (Day -2, Day 0, Day2, then weekly (1 mg/dose) Group 2 (N=3): sensitized mice with HTX and no CTLA4-Ig, Group 3: (N=10) naive mice with HTX and CTLA4-Ig treated, Group 4 (N=10): naive mice with HTX and no CTLA4-Ig. In the untreated Groups 2 & 4, allografts were rejected within 7 days post-transplantation, whereas in Group 3 of naive mice receiving CTLA4-Ig, all the grafts survived long-term (>90 days). In Group 1 of sensitized recipients receiving CTLA4-Ig, the allografts survived for 42, 42, 49, >90, >90 days. The pre-transplant donor-specific antibody (DSA) titers in the recipients that went on to reject their graft was significantly higher compared to those that accepted their grafts. Furthermore, DSA titers increased post-transplantation in the recipients that went on to reject their allografts, whereas DSA titers decreased in those that accepted their grafts. In conclusion, these observations illustrate the efficacy of CTLA-4Ig treatment at controlling rejection in sensitized recipients, and underscore the barrier pre-transplantation DSA poses to long-term graft acceptance. This experimental model also provides a unique opportunity for testing if DSA promotes antibody-mediated rejection or alloreactive memory T cell priming and T cell-mediated rejection in CTLA4-Ig treated recipients, and for identifying therapies that promote long-term graft survival in sensitized recipients.