Establishment and Analysis of Acute Antibody-Mediated Rejection in Murine Cardiac Transplantation.

Abstract

A major contributor to allograft failure in cardiac transplant recipients is antibody-mediated rejection (AMR). The mouse AMR model, therefore, serves as a vital tool for deciphering its underlying mechanisms and fostering the development of innovative treatments. In this study, the recipient mice were divided into three groups: non-sensitized (NS), pre-sensitized (PS), and pre-sensitized with cyclosporine A treatment (PS + CsA). The NS group, which exhibited a mean allograft survival of 6.8 ± 0.7 days, showed no rise in serum DSA levels and negative allograft C4d staining within four days post-cardiac transplantation (CT), suggesting a pathology dominated by acute cellular rejection. This study established an acute AMR model by pre-sensitizing recipients with skin transplantation (ST) one week before CT, thereby pre-activating the immune system. This approach successfully induced a severe AMR phenotype, as evidenced by a short allograft survival of 2.8 ± 0.4 days, a significant rise in DSA-IgG levels post-ST and post-CT, and early pathological hallmarks of vasculitis and extensive C4d deposition within 12 h of CT. Nevertheless, the extreme severity of this model constrains its broader application. To minimize the concurrent T cell activation induced by ST and establish a more specific acute AMR model, this study administered cyclosporine A. Consequently, the PS + CsA group exhibited an allograft survival time of 5.2 ± 0.4 days. Serum DSA-IgG levels were significantly elevated by day 7 post-ST and remained high within five days post-CT. Pathological assessment on day 2 post-CT confirmed significant vasculitis and C4d deposition, findings which collectively meet the diagnostic criteria for moderately severe acute AMR. In conclusion, this study established a highly practical and translatable mouse model of acute AMR following CT, defined by robust DSA production, characteristic pathological changes, and moderate allograft survival.