Characteristics of the included studies are presented in Supplement 1. cells in CLAD pathogenesis is welldocumented, although it is challenging to draw conclusions about their role in tissue processes from predominantly bronchoalveolar lavage data. In restrictive allograft syndrome, a more prominent humoral immune involvement with increased B cells, immunoglobulins and complement deposition is seen. Our evaluation of published studies over the last 20 years summarizes the complex multifactorial immunopathology of CLAD onset and progression. It highlights the phenotype of several key effector immune cells involved in CLAD pathogenesis, as well as the paucity of single cell resolution spatial studies in lung tissue from patients with CLAD. Keywords:adaptive immunity, chemokines, chronic lung allograft dysfunction, cytokines, immune cells, innate immunity, lung transplantation == Abbreviations == antibodymediated rejection bronchoalveolar lavage fluid bronchiolitis obliterans syndrome chronic lung allograft dysfunction immunoglobulins lung transplant recipients matrix metalloproteinases natural killer restrictive allograft syndrome Tregulatory cells == MULTIPLE FACES OF CHRONIC LUNG REJECTION == Lung transplantation is an established treatment option for GZ-793A patients with endstage lung diseases. However, longterm success continues to be challenged by the development of chronic lung rejection, occurring in up to 50% of recipients within five years posttransplant [1]. For a long time, obliterative bronchiolitis, and its clinical surrogate bronchiolitis obliterans syndrome (BOS), was the sole recognized manifestation of chronic lung rejection. Nowadays, the term chronic lung allograft dysfunction (CLAD) is used as an umbrella, which includes two main phenotypes, BOS and restrictive allograft syndrome (RAS), and a mixed phenotype [2,3]. BOS is the best known and most common phenotype, in ~70% of CLAD patients, characterized by progressive airway obliteration leading to airflow obstruction [3]. GZ-793A RAS has more recently been acknowledged as another phenotype of CLAD, occurring in 2030% of CLAD patients. It is characterized by interstitial fibrosis and distortion of lung architecture, a restrictive pulmonary function decline and persistent pleuroparenchymal abnormalities on computed tomography, and is associated with a poor median survival of only 12 years after diagnosis [3,4]. Moreover, patients can switch from one phenotype (often BOS) to another (RAS/mixed) over time or presentde novowith a mixed phenotype, characterized by mixed obstructiverestrictive pulmonary function limitation and persistent parenchymal opacities [4]. The acknowledgement that there are different phenotypes suggests GZ-793A different underlying immunological mechanisms, although BOS and RAS also share commonalities such as the presence of obliterative bronchiolitis lesions in both entities, and areas of alveolar fibrosis in BOS. [5,6,7] == COMPLEXITY OF THE UNDERLYING IMMUNOPATHOLOGY: A CHALLENGE == The exact immunopathological mechanisms leading to CLAD remain unclear, although multiple (immune) mechanisms are thought to contribute. Complex interactions between innate immune responses, alloreactive T, B, natural killer (NK) and dendritic cells, and subsequent adaptive immune mechanisms are considered to GZ-793A be fundamental [8]. Over the last decades, we have gained better understanding of the interactions between innate immunity, adaptive immunity and autoimmunity [9]. A better GPR44 insight into all these processes is of utmost importance because, of all solid organ transplants, lung transplantation has the worst overall median survival of approximately 7 years [1,10,11,12]. A better understanding of the mechanistic differences between CLAD phenotypes and involved pathways in the inflammatory and remodelling processes is crucial. On the one hand, this might help us to identify diseasespecific biomarkers that allow for early diagnosis, differentiation, and ideally predict CLAD development. On the other hand, it could lead to a personalized medicine approach through development of individualized therapies specific to each condition [13]. The primary objective of this systematic review is to comprehensively assess the phenotype of effector immune cells present in GZ-793A allograft tissue or bronchoalveolar lavage fluid (BALF) from lung transplant recipients (LTR) with CLAD. We postulate that most findings will.