C4d deposition in lung allografts is associated with circulating anti-HLA alloantibody☆
Introduction
Acute cellular rejection (ACR) is considered the most important independent risk factor for the development of chronic rejection and graft loss in lung transplantation (LTX) [1], [2], [3]. The “gold standard” for diagnosis of ACR is perivascular lymphocytic infiltration, while the pathogenic role of antibody-mediated rejection (AMR) alone or in conjunction with cellular rejection is less well documented [4].
We have previously reported that the development of anti-HLA alloantibody (HLA-Ab) was associated with high-grade and refractory ACR, lymphocytic bronchiolitis, and increased use of cytolytics and/or immunosuppressive therapy [5], [6]. Furthermore, we and others described significant associations between HLA-Ab and bronchiolitis obliterans syndrome (BOS) [6], [7], [8], [9], [10], [11], [12]. However, a statistical association does not imply a cause–effect relationship.
Section snippets
Objective
C4d is a tissue marker for antibody-mediated rejection in kidney allografts, but its association with HLA-Ab has not been documented in LTX [13], [14], [15]. We have previously found increased soluble C4d in the bronchial lavage of LTX patients with HLA-Ab [16].
In the current study, we investigate C4d deposition in lung allograft biopsies from patients with or without circulating IgG HLA-Ab.
Materials and methods
Thirty-two patients who received lung transplantation between 1999 and 2002 and had at least 2 years of follow-up were included in the study. The Institutional Review Board of the University of Pittsburgh approved the protocol and informed consent was obtained from all patients.
Antibody detection
After the analysis of 415 serum samples for the presence of HLA-Ab in 32 lung allograft recipients, 16 patients exhibited multiple positive results, while 16 patients remained ELISA-negative. In 65% of cases, the first detection of HLA-Ab was in the first 6 months after transplantation, while one third appeared between 6 months and 2 years post-LTX. The donor specificity of HLA-Ab was proved in 8 out of 16 patients (50%).
Acute and chronic rejection in patients with or without HLA-Ab
No differences were seen between the histological features of ACR in
Discussion
In this study, we describe the specific C4d staining pattern in lung allografts, the sensitivity and specificity of C4d immunohistochemical stain in paraffin-embedded tissue, and its association with circulating HLA-Ab.
The specific C4d deposition in kidney allografts is considered as continuous, linear subendothelial staining of peritubular capillaries and is incorporated into the Banff classification [15], [21]. Similarly, in lung allografts, we considered specific the continuous, linear,
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2016, Journal of Heart and Lung TransplantationReproducibility of Complement 4d deposition by immunofluorescence and immunohistochemistry in lung allograft biopsies
2014, Journal of Heart and Lung TransplantationPathology of Lung Transplantation
2014, Pathobiology of Human Disease: A Dynamic Encyclopedia of Disease Mechanisms
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This work was partially supported by NIH grant HL-65189.
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Have equal contribution in the preparation of this manuscript.