Complement Inhibition as Potential Novel Therapy for Antibody-Mediated Rejection after Lung Transplantation in Murine Antibody-Mediated Rejection Model

Abstract

Antibody-mediated rejection (AMR) can induce acute or chronic graft failure in organ transplantations. There are few reports regarding AMR in lung transplant, and no reports of effective therapy for AMR after lung transplant. This study aimed to verify the efficacy of anti-complement 5(anti-C5), which is reported to prevent AMR in kidney transplant, in an AMR-enhanced mouse model after lung transplant. As allograft model, BALB/c (Major histocompatibility complex; MHC H2b) and C57BL/6 (MHC H2b) were used for donor and recipient in order to detect and enhance AMR. Skin transplants were performed to pre-sensitize, and subsequently, orthotopic left lung transplants were performed 14 days after skin transplant. The mice were treated with anti-C5 (40mg/kg/day) (n=5), or cyclosporine (CyA, 10mg/kg/day) /methylprednisolone (mPSL, 1.6mg/kg/day) (n=5), or anti-C5/CyA/mPSL (n=5), or with isotype-matched irrelevant control mAb (n=5) subcutaneously until sacrifice. The mice were sacrificed 2 days after lung transplant and evaluated for histopathology, including acute rejection score, C4d immunostaining, and donor-specific antibody (DSA) in serum. The mice with anti-C5 showed significantly lower C5 in serum compared with the mice with isotype control (1472.50±110.44 vs. 2081.87±75.17 pg/ml, p=0.002). The mice treated with anti-C5 and anti-C5/CyA/mPSL showed significantly lower rejection A score (0.63±0.23; p=0.002, 0.59±0.22; p=0.001) compared with the mice with isotype control (2.58±0.35). All groups showed C4d deposition on vascular endothelium and DSA in serum. Anti-C5 effectively prevented AMR against transplanted allogeneic lung in the pre-sensitized murine model, in which AMR was strongly augmented.