Acute Cellular and Antibody-Mediated Allograft Rejection

Abstract

Survival post-lung transplantation remains limited to ∼ 50% at 5 years, far below survival after other solid organ transplants. Allograft rejection is a major cause of this limited survival. At least a third of lung transplant recipients experience acute rejection within 1 year posttransplantation. Acute rejection, though rarely a direct cause of death, represents the principal risk factor for chronic rejection, which is the greatest obstacle to long-term post-lung transplant survival. This article reviews in detail the two major subtypes of acute rejection: acute cellular rejection (ACR) and antibody-mediated rejection (AMR). ACR is diagnosed primarily by bronchoscopic transbronchial biopsies and is defined as perivascular or peribronchiolar lymphocytic infiltrates in the absence of infection. AMR remains poorly defined but is thought to involve anti-donor antibodies, allograft dysfunction, and pathological evidence of lung tissue injury or deposition of complement. Pathophysiological mechanisms, clinical presentation, clinical significance, known risk factors, and treatment strategies are discussed. Additionally, the limitations of current diagnostic modalities for both ACR and AMR are explained. Emerging data on the importance of donor-specific and non-donor-specific anti-human leukocyte antigen (anti-HLA) antibodies as well as non-HLA antibodies are presented. Larger cohorts have improved statistical analyses in recent years, leading to a clearer understanding of important topics related to ACR and AMR. Further collaborative studies and multicenter trials will be key in further advancing lung transplantation knowledge and improving outcomes in years to come.

Early donor-specific antibodies in lung transplantation: Risk factors and impact on survival

“…These can then function as antigen-presenting cells through the direct pathway, stimulating recruitment of recipient adaptive immune cells, including CD4 þ T-helper cells and B-cells, which play important roles in both cellular and humoral immune responses. [6][7][8]16 Alloantigen priming of CD4 þ T-and B-cells may then occur in the presence of both a proinflammatory environment and donor antigen, leading to early development of donor-specific cellular immunity and DSA. 23 Finally, we found a relationship between the number of intra-operative packed red blood cell (PRBC) units and DSA development in univariate but not multivariate analysis (Table 5).…”

Lung transplantation: Chronic allograft dysfunction and establishing immune tolerance

“…Following transplant, T cell dependent donor specific B cells develop resulting in anti-donor antibody production by plasma cells. Antibodies bind their donor antigenic target, as well as complement factor C1q, resulting in activation of the complement cascade [10]. The involvement of antibody mediated rejection in OB has been suggested by findings that donor specific antibodies precede the onset of BOS and are strongly associated with its development [11].…”

Donor-Reactive Regulatory T Cell Frequency Increases During Acute Cellular Rejection of Lung Allografts

“…Chronic rejection is considered to be the major barrier to long-term survival following transplantation. Acute cellular rejection, in addition to causing morbidity directly, can contribute to development of chronic rejection pathology 2 . To identify sub-clinical acute cellular rejection, some transplantation centers, including ours, have allograft surveillance protocols that include bronchoscopy with transbronchial biopsies 3 .…”