Immunological risk stratification of the bronchiolitis obliterans syndrome after lung transplantation

Abstract

The development of chronic allograft rejection after lung transplantation (LTx) is the most common cause of poor long-term survival in lung transplant recipients. This rejection leads to obliteration of the bronchioli. Since this obliteration has a patchy distribution and normal lung tissue obtained by a transbronchial biopsy does not exclude rejection, a surrogate marker based on lung function decline is currently the gold standard: the presence of bronchiolitis obliterans syndrome (BOS). The exact mechanism of BOS is unknown but repetitive damage of (sub) epithelial cells seems important and may lead to a response from the immune system and eventually inflammation. Due to this response markers may be elevated or decreased. This thesis describes the identification of patients who are at risk for developing BOS using blood samples obtained during regular follow up visits. CD30 is expressed on Th2 cells and a soluble form (sCD30) is shed into the blood if Th2 cells are activated. In contrast to values prior to LTx, we demonstrated that sCD30 values after lung transplantation did not discriminate patients developing BOS. However, we demonstrated that high sCD30 values before LTx were suppressed after transplantation. We hypothesized that immunosuppressive drugs suppressed sCD30 values and demonstrated in atopic dermatitis (AD) patients, a mainly Th2 associated disease, that the immunosuppressive drug enteric coated mycophenolate sodium (EC-MPS) but not cyclosporine (CsA) indeed do suppress sCD30 values. The chemokine TARC binds to CCR4 expressed on Th2 cells. We demonstrated that TARC levels in patients developing BOS were lower compared to non-BOS patients. If TARC values were below the 325 pg/ml at the first month after LTx there is an increased risk of developing BOS. In our cohort of AD patients we demonstrated a correlation between TARC levels and parameters to evaluate disease activity not only during EC-MPS treatment but also during CsA. The mannose binding lectin (MBL) is an important player in innate immunity and plays a role in the elimination of viruses and bacteria. We demonstrated a correlation between low MBL values before and CMV reactivation after LTx. There was a trend between low MBL levels before transplantation and a superior survival rate after transplantation. No association was found between MBL values and the development of BOS. Natural Killer (NK) cells are one of the main cellular components of the innate immunity and play a role in the lysis of viral infected cells. The action of NK cells is controlled by activating and inhitory Killer Immunoglobulin-like receptors (KIRs). We demonstrated that KIR gene content of recipients, escpecially activating KIRs, is associated with BOS but not with the reactivation of CMV. In conclusion we found that MBL values, KIR genotype and TARC values are associated with the development of BOS and that the type of immune suppressive regimen applied after LTx may influence the applicability of possible biomarkers.