Immune processes in the pathogenesis of chronic lung allograft dysfunction: identifying the missing pieces of the puzzle

Abstract

Lung transplantation is the optimal treatment for selected patients with end-stage chronic lung diseases. However, chronic lung allograft dysfunction remains the leading obstacle to improved long-term outcomes. Traditionally, lung allograft rejection has been considered primarily as a manifestation of cellular immune responses. However, in reality, an array of complex, interacting and multifactorial mechanisms contribute to its emergence. Alloimmune-dependent mechanisms, including T-cell-mediated rejection and antibody-mediated rejection, as well as non-alloimmune injuries, have been implicated. Moreover, a role has emerged for autoimmune responses to lung self-antigens in the development of chronic graft injury. The aim of this review is to summarise the immune processes involved in the pathogenesis of chronic lung allograft dysfunction, with advanced insights into the role of innate immune pathways and crosstalk between innate and adaptive immunity, and to identify gaps in current knowledge.

Collagen Type IV Alpha 5 Chain in Bronchiolitis Obliterans Syndrome After Lung Transplant: The First Evidence

“…Matrix metalloproteinase breaks down different fragments of collagen. While patients chronic rejection showed small-airway inflammation known as “obliterative bronchiolitis” that leads to epithelial damage, airway fibrosis and remodelling of the ECM affect the lung interstitial matrix and basement membrane [ 29 ]. Some studies showed that besides their role in tissue remodelling, serum concentrations of different MMPs (especially MMP-9) were correlated with BAL neutrophilia in patients with BOS [ 30 , 31 ].…”

Lymphocyte Depleting and Modulating Therapies for Chronic Lung Allograft Dysfunction

“…We can speculate that these agents might have a beneficial effect when given in combination with other therapies, as antibodies and various subsets of B cells are involved in CLAD pathogenesis. (Bos et al, 2022c) However, combination therapy may increase the complexity of treatment and risk of side effects.…”

“…(Verleden et al, 2019) It is postulated that CLAD occurs as a result of the host's adaptive and innate immune responses directed to the lung allograft, in which a complex array of immune cells and mechanisms is involved. (Bos et al, 2022b;Bos et al, 2022c) Next to medical noncompliance with immunosuppressive treatment, various risk factors for CLAD have been identified, both alloimmune and non-alloimmune factors, including ischaemia-reperfusion injury, acute cellular rejection, antibody-mediated rejection, respiratory infections, gastroesophageal reflux, and air pollution. (Verleden et al, 2019) The type of standard immunosuppressive maintenance treatment after lung transplantation varies between centres, but usually consists of triple therapy with a calcineurin inhibitor (tacrolimus/cyclosporine), a cell cycle inhibitor (mycophenolate mofetil/azathioprine) and corticosteroids.…”

The Immunopathology of Pulmonary Rejection after Murine Lung Transplantation

“…Long-term outcomes after lung transplantation remain the worst among all solid organ transplants, with a median survival of only six years [3,4]. These low survival rates can be attributed mainly to chronic lung graft dysfunction, which is assumed to be the result 2 of 13 of repeated or chronic graft injury that ultimately leads to progressive and pathological fibrosis and eventual graft failure [5]. This clinical phenomenon has long been referred to as 'chronic rejection'.…”