Furthermore, detection of DSA can be missed due to phasic release or absence of the antigen on the screening assay (6). diagnosis, and treatment of AMR continue to exist and future research should focus on these aspects. Keywords:Lung transplantation, graft rejection, allograft tolerance, acute lung injury, complement component, complement C4d, diagnostic techniques and procedures, plasmapheresis, intravenous immunoglobulins (IVIG), rituximab, eculizumab, Galactose 1-phosphate outcome assessment == Introduction == Lung transplantation is the ultimate treatment for selected patients with end-stage lung disease. While advances in surgical technique have improved early survival, long term outcomes remain disappointing, and the median survival after transplantation in the most recent era is 6.5 years (1). Chronic lung allograft dysfunction (CLAD) is the leading cause of death beyond the first year after lung transplantation and has emerged as the main barrier to better long-term outcomes (1). Antibody-mediated rejection (AMR) has been increasingly recognized after lung transplantation and has been consistently identified as a significant cause of morbidity, CLAD, and graft failure (2-7). Here, we present a review of our current understanding of AMR and discuss ongoing research and future directions to further our understanding of AMR and improve the management of this serious complication after lung transplantation. == History == Our understanding of AMR in lung transplantation was historically limited to hyperacute rejection, which occurs when preformed donor-specific antibodies (DSA) bind to mismatched human leukocyte antigens (HLA) (8,9). Patients developed significant and often fatal graft failure intra-operatively or in the immediate post-operative period with hemorrhagic pulmonary edema and diffuse pulmonary infiltrates on imaging studies (8,10,11). Severe graft dysfunction occurred in spite of intensive immunosuppression targeting T-cell proliferation and activity, which suggested a role for humoral immunity in precipitating this response. Typically, these patients were found to have DSA and a positive direct lymphocytotoxicity crossmatch. Further investigation found that allosensitization was associated with worse survival after transplantation unless the reactive HLA were avoided in a prospective donor (8-10,12,13). Case reports of hyperacute rejection suggested the need for standardization of pretransplant crossmatching (6,8). Although hyperacute rejection has become rare in the current era because of improved HLA antibody detection assays, it illustrates that HLA antibodies can cause Galactose 1-phosphate fulminant graft failure and that the capillary endothelium is the focal point of injury. Over time, cases occurring later after transplantation were recognized and our understanding of acute AMR began to evolve. Badesch and colleagues presented a case series of 5 patients with pulmonary capillaritis ranging from 3 weeks to months after transplant (14). In this series, all patients presented with alveolar hemorrhage and graft failure with temporary improvement in graft function with intensification of immunosuppression and plasmapheresis (14). They postulated a humoral immunologic response, though testing for DSA or antibody binding on pathologic specimens was not performed (14). Magro Mouse monoclonal to Plasma kallikrein3 and colleagues described the histologic features of 22 lung transplant recipients who developed pulmonary capillaritis ranging from 1 to 33 months after transplantation (15). They described septal capillary necrosis with staining positive for complement deposition (C1q, C3, and C4d) and immunoglobulin G (IgG) (15). All patients were tested and found to be negative for panel-reactive antibodies (PRA) both before transplantation and at the time of acute rejection; however, the use of older and less sensitive assays limits the significance of this finding (11,15). Treatment with plasmapheresis showed improvement in graft function and a decrease in post-pheresis capillary injury and complement deposition (15). Witt and colleagues detailed a series of 21 patients with acute AMR (3). In this series, all patients had clinical allograft dysfunction, DSA, histology of acute lung injury, and capillary endothelial C4d deposition Galactose 1-phosphate (3). Six patients (29%) died of refractory AMR, while 15 survived to hospital discharge (3). One patient had a diagnosis of bronchiolitis obliterans syndrome (BOS) at AMR diagnosis, and 13 of the remaining 14 survivors developed CLAD during follow up (3). Overall 15/21 (71%) patients died during the study period and median survival after diagnosis of AMR was 593 days.
