DonoR-specific antilbodiES in cryo-bioPsIes and bRonchoAlveolar lavage fluid during rejecTIOn after luNg transplantation [Acronym: RESPIRATION]

Lung transplantation (LTx) is a life-saving treatment for patients with end-stage lung disease. Survival after LTx is limited due to development of chronic rejection of the transplant lungs, also termed chronic lung allograft dysfunction (CLAD), affecting 50% of patients within 5 years. Differences in human leukocyte antigens (HLA) between the donor and recipient (‘alloantigens’) are recognized by the recipient’s immune system, which subsequently becomes activated and induces rejection via cellular and/or antibody-mediated cytotoxicity, leading to injury and failure of the transplanted organ. The prevalence of cellular and antibody-mediated rejection after LTx is high (30-90%), despite current immunosuppressive management. The diagnosis of rejection after LTx is routinely based on histologic evaluation of lung biopsies (tissue obtained by bronchoscopic sampling of the small airways) and assessment of antibodies directed against alloantigens (donor-specific anti-HLA antibodies, DSA) in the blood, while bronchoalveolar lavage fluid (BALF) is evaluated to rule out infection. Most centers therefore perform serial surveillance bronchoscopy (BALF and biopsies) and serum DSA (sDSA) measurements to monitor the health of the transplanted lungs after LTx. However, discrepancies between serological and histopathological findings are common, due to a “sponge effect” of the transplanted organ, whereby endothelial binding and fixation of circulating sDSA inside the vascular bed of the lungs (‘graft’ DSA/gDSA) may obscure the detection of (unbound) sDSA in the blood. In the current project, we therefore aim to assess the presence of DSA within lung tissue and BALF samples, in order to evaluate their potential role as biomarkers for (subclinical) graft rejection and regarding long-term outcome after LTx. For this purpose, prospectively collected biobanked biopsies (obtained by transbronchial cryo-biopsy), BALF and blood samples from the Leuven and Prague Lung Transplant Programs will be analyzed. We expect this study will result in better detection of truly pathogenic DSA, i.e. tissue-bound (gDSA) or unbound DSA in BALF, which may improve current diagnostic management after LTx and may help to optimize current therapeutic strategies for rejection after LTx, resulting in better post-transplant outcomes.

Keywords:lung transplantation, acute rejection, donor-specific antibodies, chronic rejection, chronic lung allograft dysfunction

Disciplines:Transplantation immunology