EVEROLIMUS FAVOURABLY ALTERS LUNG ALLOGRAFT IMMUNE RESPONSES: RESULTS OF A PROSPECTIVE RANDOMISED TRIAL.

Abstract

O482 Aims: While current immunosuppressives (IS) have been effective in controlling acute rejection (AR) following lung transplantation (LTx), chronic rejection (bronchiolitis obliterans-BOS) remains a major cause of morbidity and mortality. Everolimus (RAD-Novartis Pharmaceuticals), a novel IS agent with anti-proliferative and anti-fibrotic properties, has the potential to ameliorate processes associated with BOS. The aim of this study was to determine if RAD, compared to Azathioprine (AZA) alters the cellular and cytokine milleau of the lung allograft, and correlate any significant results with clinical outcomes. Methods: 23 stable LTx recipients were randomized in a double-blind study to receive RAD (n=13) or AZA (n=10) plus standard cyclosorine and prednisolone (a subset of a larger clinical trial). Bronchoalveolar lavage (BAL) and endobronchial biopsies (EBB) were performed at baseline (study entry- T0) and on 2 further occasions, 3-6months (T1) and 9-12 months (T2) later, to evaluate extensive cellular and cytokine profiles via immunocytochemistry, immunohistology and ELISA techniques. Clinical data including rejection and infection episodes was collected prospectively. Results: Analysis showed no group differences for demographics, clinical or rejection (AR, BOS) events through-out the study, nor were there any differences in cellular and cytokine markers at baseline (T0). BAL lymphocyte cell count fell in AZA group by T2 (p<0.05). BAL & EBB CD4 measures were significantly lower by T2 in the RAD group (p<0.05). EBB neutrophils rose in AZA group and declined in RAD group resulting in a significant difference at T2 (p=0.01). BAL TGFβ and IL8 levels were not significantly different between groups. Conclusions: This study, representing the only blinded, prospective, longitudinal study of the effect of RAD on human tissue, shows that RAD is associated with lower CD4 and neutrophil counts in BAL and EBB. These results are consistent with the known actions of RAD; prevention of cytokine transcription as well as inhibition of neutrophil migration. We conclude that RAD may produce an allograft profile at less risk of subsequent BOS development, and longer follow-up with correlation of these cellular/ cytokine differences and the incidence of BOS will be of great interest.