Impact of the severity of acute rejection in the early phase after rat lung transplantation on the effectiveness of mycophenolate mofetil to treat chronic allograft rejection

Prevention and treatment of bronchiolitis obliterans (BO) after lung transplantation (LTX) remains disappointing. The high prevalence and the critical detection of early mild acute lung rejection aggravated optimum immunosuppressive therapy. In this study, two hypotheses were investigated: (i) mycophenolate mofetil (MMF) prevented the development of BO after rat LTX. (ii) The effectiveness of MMF depended on the degree of acute rejection (AR) at the time of drug initiation. A rat model of left lung allo-transplantation (Fisher 344 to Wistar Kyoto) was used to evaluate the basic effect of MMF (30 mg/kg body weight per day) on the development BO. MMF therapy began on Days 0, 7 and 14 after transplantation characterizing different degree of AR of the allograft at the time of drug initiation and ended on Day 60 after transplantation. Non-treated animals were used as controls. Histopathological alterations were analysed according to the International Society for Heart and Lung Transplantation (ISHLT). MMF treatment of allografts with high-grade AR (ISHLT-A3-4/B2R; from Day 14 to 60) failed. All animals developed vascular fibrosis and BO. Promising long-term outcome was shown after treatment of mild to moderate acute rejecting of allografts (MMF from Day 7 to 60). The proportion of animals with high grade acute airway inflammation was significantly reduced (33%; P < 0.05). All animals were free of BO and chronic vascular alterations (90%). MMF (Day 0-60) significantly reduced the proportion of animals with severe acute vascular rejection and high grade airway inflammation (17 and 0%, respectively; P < 0.05, each). None of the animals treated with MMF from Day 0 to 60 developed chronic rejection (CR). MMF significantly reduced AR and CR after rat LTX. However, only allografts with no or mild AR at the time of drug initiation benefited from MMF treatment. In addition, the appearance of early signs of fibroproliferative alterations in the airway structures might prevent a successful long-term outcome.