Acute Humoral Rejection of Human Lung Allografts and Elevation of C4d in Bronchoalveolar Lavage Fluid

Abstract

Antibody-mediated rejection is well established for renal allografts but remains controversial for lung allografts. Cardinal features of antibody-mediated rejection in renal allografts include antibodies to donor human leukocyte antigen (HLA) and evidence for antibody action, such as complement activation demonstrated by C4d deposition. We report a lung allograft recipient with circulating antibodies to donor HLA who failed treatment for acute cellular rejection but responded to therapy for humoral rejection. To address the second criteria for antibody-mediated rejection, we determined whether complement activation could be detected by measuring C4d in bronchoalveolar lavage fluid (BALF) by ELISA. Airway allergen challenge of asthmatics activates the complement pathway; therefore, we used BALF from asthmatics pre-and postallergen challenge to measure C4d. These controls demonstrated that ELISA could detect increases in C4d after allergen challenge. BALF from the index patient had elevated C4d concomitant with graft dysfunction and anti-donor HLA in the absence of infection. Analysis of BALF from 25 additional lung allograft recipients showed that C4d concentrations > >100 ng/mL were correlated with anti-HLA antibodies (p = = 0.006), but were also observed with infection and in asyptomatic patients. The findings support the occurrence of anti-HLA-mediated lung allograft rejection and suggest that C4d measurement in BALF may be useful in diagnosis.

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.…”

Donor-specific antibodies are associated with antibody-mediated rejection, acute cellular rejection, bronchiolitis obliterans syndrome, and cystic fibrosis after lung transplantation

“…8 When positive, tissue histopathology for C4d may constitute an important confirmatory signal. 6,12,18,19 In this single-center retrospective study, we identified additional risks of DSAs and AMR, including a CF diagnosis, HLA class II DSAs with anti-DQ specificity, BOS, and possibly, ACR.…”

Acute Antibody-mediated Rejection After Lung Transplantation

“…In addition, subsequent surveillance biopsies lacked C4d positivity, suggesting pathologic resolution of his prior antibody-mediated rejection, which has not been documented previously in cases suggestive of antibody-mediated rejection. 14 The absence of cellular rejection on the second biopsy (POD 33) without any intervening treatment was somewhat unexpected. It is possible that this was due to sampling error, but the biopsies included 6 pieces of alveolated parenchyma that were sufficient for the diagnosis of antibody-mediated rejection.…”