Humoral Immunity and the Development of Obliterative Bronchiolitis after Lung Transplantation

Abstract

Lung transplantation is considered the definitive treatment for many end-stage lung diseases. However, the lung is rejected more commonly than other solid organ allografts. Obliterative bronchiolitis (OB) is the leading cause of chronic allograft dysfunction, and the key reason why the 5-year survival of lung transplant recipients is only 50%. The pathophysiology of OB is incompletely understood. Although a clear role for the immune response to donor antigens has been observed (also known as anti-human leukocyte antigens), evidence is emerging about the role of autoimmunity to self-antigens. This review highlights the current understanding of humoral immunity in the development of OB after lung transplantation.Keywords: antibodies; lung transplant; obliterative bronchiolitis; rejection Lung transplantation remains the only treatment option for many end-stage lung diseases. However, the survival of lung allografts is limited by chronic allograft rejection, a pathological condition referred to as obliterative bronchiolitis (OB), with an incidence of 50% within 3 years after transplantation. In fact, the lung is rejected more commonly than any other solid allografts, and the 5-year survival of lung transplant recipients is approximately 50% (1).OB is a pathological entity presenting in two forms. In most cases, it is characterized by extensive peribronchiolar connective tissue deposition, the loss of bronchiolar epithelium, and progressive scarring that ultimately obliterates the small airways. Although some debate remains, proliferative forms of bronchiolitis obliterans have also been considered part of the spectrum in chronic allograft dysfunction. These lesions differ from classic OB in that their histopathology may reveal proliferating fibrous plugs of granulation tissue that protrude into and may ultimately obliterate small airways (2, 3). Because certain lung pathologies may reflect varied pathogenic mechanisms, it remains unclear whether differential immune pathways, either cellular (T cellmediated) or humoral (antibody-mediated), account for these two forms of OB.The diagnosis of OB via transbronchial biopsy is difficult because of its patchy nature in the transplanted lung. Therefore, its clinical correlate, bronchiolitis obliterans syndrome (BOS), defined by a sustained decline of 20 to 50% in forced expiratory volume in 1 second (FEV 1 ) relative to the maximum posttransplant, has become the standard clinical marker of OB/BOS (4).The pathophysiology of OB is incompletely understood. Several risk factors have been associated with the development of OB, including acute rejection, human leukocyte antigen (HLA) mismatches, HLA antibodies, lymphocytic bronchiolitis, viral infection, gastroesophageal reflux, and primary graft dysfunction (PGD) (5). Although a clear role exists for immune responses in the form of anti-donor antigen (anti-HLA) antibody formation, referred to as alloimmunity, a role has also emerged for immune responses to self-antigens (autoimmunity) in the development of OB (6-8). We will revie...

Models of Lung Transplant Research: a consensus statement from the National Heart, Lung, and Blood Institute workshop

“…Human lung transplant recipients develop antibodies against col(V), a protein mainly located in the lung interstitium and not ordinarily exposed to the immune system. In the rat lung transplant model, allografts in minor histocompatibility complex-mismatched recipients induce col(V)-specific T and B immunity after transplantation and appear to be an important source of autoantigen that autoantibodies ligate (74). Better understanding of the exact roles of allo-and autoantibodies in AR, like chronic rejection, will clearly benefit from improved modeling and biomarkers that delineate disease phenotypes and also incorporate orthotopic lung transplant mouse models.…”

Insight on immune cells in rejection and infection postlung transplant

“…The use of immunosuppressive drugs in clinical practice has significantly reduced the morbidity of hyperacute and acute rejection in lung transplant recipients. However, the long‐term survival of these patients is often impacted by chronic rejection, which is primarily manifested as BO and affects approximately 50% of recipients within the first 3 years posttransplantation 63 . While immunosuppressants can effectively treat rejection, they may also lead to immunodeficiency and increase the risk of infection.…”

“…However, the long‐term survival of these patients is often impacted by chronic rejection, which is primarily manifested as BO and affects approximately 50% of recipients within the first 3 years posttransplantation. 63 While immunosuppressants can effectively treat rejection, they may also lead to immunodeficiency and increase the risk of infection. Thus, achieving a balance between immune defense and immune tolerance is crucial for long‐term survival.…”

Bronchiolitis obliterans syndrome after lung or haematopoietic stem cell transplantation: current management and future directions

“…Trigger events likely include T-cell-mediated ACR, CARV infections with lower respiratory tract tropism (such as respiratory syncytial virus), certain coronavirus infections, bacterial infections (such as P. aeruginosa, mycoplasma, and chlamydia) and inflammation from aspiration of gastric contents [112]. The possibility of autoimmunity to cryptic self-antigens liberated by these triggers is supported by the presence of self-antigens in microvesicles and the development of autoantibodies against Type V collagen and K-α1 tubulin [113,114]. Novel therapies will need to embrace these concepts to successfully prevent tissue damage and modify aberrant repair.…”