ROCHE RESEARCH GRANT 2019

Structural and immunologic organization of the failing human lung in chronic lung allograft rejection following lung transplantation and chronic pulmonary GvHD after allogenic hematopoietic stem cell transplantation: two of a kind?

Lung transplantation (LTx) is a life-saving treatment for patients with end-stage pulmonary disorders, like emphysema, cystic fibrosis, interstitial lung disease or pulmonary arterial hypertension. Long term post-transplant survival is hampered by chronic rejection, which affects almost 50% of patients within 5 years after LTx, often leading to lung allograft failure, respiratory insufficiency and graft loss/death of the transplant recipient (1,2). Chronic lung allograft rejection may clinically present as so-called Chronic Lung Allograft Dysfunction (CLAD) (2), which currently encompasses two distinct phenotypes, being the classical Bronchiolitis Obliterans Syndrome (BOS) - mainly a small airways (bronchiolar) disease without major morphologic changes of the lung parenchyma - on the one hand; and Restrictive Allograft Syndrome (RAS) on the other hand. RAS is typically characterized by gross pleural/septal thickening and parenchymal/interstitial fibrosis, resulting in a restrictive lung function decline, comparable to that of patients with interstitial lung fibrosis. Strikingly, RAS patients have a much worse prognosis (limited to 0.5-1.5 years) compared to BOS patients (3-5years)(3,4).

Allogeneic hematopoietic stem cell transplantation (alloHCT) is a curative treatment for patients suffering from a range of hematologic malignancies. Although long-term survival significantly improved over the last decades, graft versus host disease (GvHD) remains a major concern, as it has significant impact on long-term mortality, morbidity and quality of life (5,6). GvHD basically involves reactivity of donor-derived immune cells against allogeneic recipient tissues, such as the skin, gut, lungs, etc. Despite having a dismal prognosis, the prevalence of pulmonary chronic GvHD (cGvHD) is rather low, with a prevalence of about 5% of all alloHCT, which is most likely due to the fact that patients with pulmonary cGvHD only become symptomatic at an advanced stage late after alloHCT and that serial pulmonary function testing is not part of routine clinical follow-up after alloHCT (7,8). Chronic lung dysfunction in pulmonary cGvHD mostly presents as small airways disease, again referred to as bronchiolitis obliterans syndrome (BOS) (9). However, recent studies also point towards the presence of other, more atypical, presentations, such as cryptogenic organizing pneumonia and progressive interstitial lung disease, with a restrictive pulmonary function defect, as is seen in 12-60% of patients with pulmonary cGvHD, but clear definitions of these entities are still lacking (9-12).

Both chronic lung allograft rejection after LTx and pulmonary chronic GvHD after alloHCT remain incompletely understood and not properly treatable, because the underlying immunological mechanisms leading to these devastating conditions remain largely elusive. Besides allo-reactive T-cell involvement, accumulating data point towards an important role for HLA mismatch, anti-HLA antibodies; and thus allo-reactive B-cell involvement; in both diseases. Indeed, antibody mediated rejection (AMR) (13-16) is thought to be the main factor driving RAS after LTx, which may initially be triggered by local immune activation due to infections or epithelial exposure to noxious agents, particulate matter, gastric aspirate, etc. . HLA mismatch has also been associated with worse outcomes after unrelated (i.e. non HLA-identical or haplo-identical) donor alloHCT (17). However, it is unclear how the involved immunological mechanisms temporarily and locally relate to the observed structural changes in the airways and/or lung parenchyma of the affected lungs. A combined investigational approach assessing co-localization of structural organisation and concurrent immunological findings is therefore pivotal to better understand onset and progression of chronic lung allograft failure in CLAD and cGvHD, as this will allow for better preventive and therapeutic strategies to tackle these devastating conditions in the future, leading to better long-term post-transplant outcomes.