© 2006 American Thoracic Society
Lung Transplantation: Opportunities for Research and Clinical AdvancementTo the Editor:We read with great interest the article by Wilkes and colleagues that summarized the scientific and clinical advancements in lung transplantation (1). We would like to expand on the advancements that have been made in the area of humoral rejection. Wilkes and coworkers describe the association of soluble C4d in bronchoalveolar lavage fluid and the presence of anti-HLA antibodies. In their study, a definitive correlation between C4d levels in the bronchoalveolar lavage fluid and clinical status could not be established, resembling the lack of correlation between clinical status and soluble complement levels in other solid organ settings. In contrast, in situ work on C4d expression in lung tissue has shown that higher levels of C4d expression in lung allograft biopsies are a marker of acute and chronic graft dysfunction, analogous to those described in other solid organ transplant settings (2). While anti-HLA antibodies may be a predictor of acute rejection and bronchiolitis obliterans syndrome (BOS), clinical and pathologic findings compatible with humoral rejection and the development of BOS can be seen in the absence of HLA antibodies (3). Such findings suggest that the implicated antigens, namely, those of endothelial- and/or epithelial-based origin, may not be exclusively HLA related. Wilkes and coworkers indicate that microarrays using rodent models have shown up-regulation of antibody and complement genes in the transplanted lung (1). Morphologic and clinical correlates of this interesting molecular observation have been described in humans. For example, a pauci-inflammatory necrotizing capillary injury phenomenon affecting the septal microvasculature with concomitant immunoreactant microvascular deposition correlates with clinical features of acute rejection (4). In the same vein, additional antigen targets comprising the bronchial epithelium, bronchial wall microvasculature, and chondrocytes by virtue of immunoreactant localization to these aforesaid bronchial wall components have been reported (5). Ultrastructurally, septal microvascular changes virtually identical to those described in the kidney are observed in patients with BOS. Both the kidney and lung changes have fallen under the general rubric of transplant capillaropathy (6). Such vascular changes are attributable to repetitive humorally mediated microvascular injury. High levels of C3d deposition within the septal microvasculature may also be a predictor of chronic graft dysfunction/BOS (7). In conclusion, humoral immunity in the context of lung transplantation may involve a spectrum of antigenic targets that are not always HLA related. Its occurrence is not a rarity but perhaps even common, and finally, its contribution to chronic graft dysfunction may be significant.
The Ohio State University, Columbus, Ohio FOOTNOTES Conflict of Interest Statement: None of the authors have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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