Evidence That Humoral Allograft Rejection in Lung Transplant Patients Is Not Histocompatibility Antigen-Related

Abstract

We have recently recognized humoral rejection (HR) in lung allograft recipients and its association with acute and chronic graft dysfunction. We have shown that C4d, a stable marker of classic complement activation, is deposited in lung allografts, correlating with clinical rejection and parenchymal injury. The antigenic target may be endothelium in the setting of recurrent acute rejection while varying components of the bronchial wall may be important in chronic graft dysfunction. We sought to establish whether there is a role for antibodies with histocompatibility antigen specificity in the lung humoral allograft phenomenon. Flow cytometric and ELISA assays to assess donor-specific antigens were conducted on sera from 25 lung transplant recipients who had experienced one or more episodes of clinical rejection; in addition, the serum samples were tested for evidence of antiendothelial cell antibody activity. Morphologically, each case had biopsies showing septal capillary injury with significant deposits of immunoreactants with microvascular localization and positive indirect immunofluorescent antiendothelial cell antibody assay. Panel-reactive antibody testing showed absence of MHC Class I/II alloantibodies; ELISA based crossmatch detecting donor-specific MHC Class I/II specific antibodies was negative. HR can occur in the absence of antibodies with HLA specificity; antigenic targets may be of endothelial cell origin.

Pathology of pulmonary antibody-mediated rejection: 2012 update from the Pathology Council of the ISHLT

“…[30][31][32][33][34][35][36][37][38][39][40][41][42] In 2002, Magro and colleagues 30 introduced the term ''septal capillary injury syndrome'' to describe alterations in the alveolar spaces and interstitium, usually alveolar septal necrosis, observed in patients with decline in pulmonary function. Complement (C1q, C3, C4d and/or C5b-9) and immunoglobulin deposition of variable intensity were seen in the majority of biopsies.…”

Humoral Rejection of Organ Allografts

“…In chronic rejection with bronchiolitis obliterans syndrome (BOS), deposits of C4d were detected in the bronchial wall as opposed to the rarity of this finding in non-BOS patients. Although no association with antidonor HLA Class I/II alloantibodies was demonstrated in a complementary study of the same group, these data likewise suggest that C4d analysis in transbronchial biopsies may have some diagnostic value after lung transplantation (57). In an experimental study, anti-HLA antibodies were demonstrated to induce proliferation of airway epithelial cell proliferation and thus to play a potential role in BOS (58).…”

Plasma Exchange and Immunoadsorption of Patients with Thoracic Organ Transplantation

“…Antigenic target of non-HLA-ab described so far include various minor MHC, vascular receptors, adhesion molecules, and intermediate filaments. Non-HLA-ab may function as complement-and non-complement-fixing antibodies, and they may induce a wide variety of allograft injuries [7,8]. Pretransplant-detected non-HLA-ab often resulted in accelerated rejection of the allograft.…”