Development of Novel Murine Antibody Mediated Rejection Model after Orthotopic Lung Transplant

Abstract

Purpose Antibody mediated rejection (AMR) has been playing an important role in organ transplantation inducing acute or chronic graft failure, which directly influence the survival of graft. There is little knowledge about AMR in lung transplant compared with other organ. Animal disease model is warranted to elucidate mechanism and development of novel drug for AMR, hence our purpose of this study is to establish murine AMR model of lung transplant. Methods 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. Study groups were divided into two groups, including pre-sensitized by skin transplant (PS) group (n=10) and non-sensitized (NS) group (n=10). Skin transplant was performed 14days before lung transplant only in PS group, and orthotopic left lung transplant were performed in both groups. They were sacrificed at 2day or 7day post lung transplant, and evaluated for histopathology including acute rejection score, C4d immunostaining, and donor specific antibody (DSA) in serum. Isograft model (IS) using C57/BL6 murine was used for control. Results NS group showed only localized rejection features on their graft and rejection score (0.36±0.13, p=0.13; Fig a, b) at day 2 after lung transplant, on the other hand, PS group showed clinical features of AMR, including high rejection score (2.19±0.27, p=0.003), C4d deposition on vascular endothelium, and DSA in serum at day 2 after lung transplant. On day 7 after lung transplant, the both groups showed extensive destruction of alveolar wall in graft, high acute rejection score (NS 3.25±0.18, p Conclusion The murine orthotopic allograft lung transplant model satisfied criteria of AMR. The allograft model pre-sensitized by skin transplant showed enhanced AMR at early period post lung transplant; therefore this model could be useful to examine pathogenesis of AMR and development of new therapy for AMR.