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Lung Transplantation: Opportunities for Research and Clinical Advancement

Posted on: Friday, 24 February 2006, 06:00 CST

By Magro, Cynthia M; Pope-Harman, Amy L; Abbas, Abbas E; Ross, Patrick Jr; Wilkes, David S

To 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 Immorally 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.

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.

CYNTHIA M. MACRO

AMY L. POPE-HARMAN

ABBAS E. ABBAS

PATRICK ROSS, JR.

The Ohio State University

Columbus, Ohio

References

1. Wilkes DS, Egan TM, Reynolds HY. Lung transplantation: opportunities for research and clinical advancement. Am J Respir Crit Care Med 2005;172:944-955.

2. Magro CM, Pope-Harman A, Klinger D, Orosz C, Adams P, Waldman J, Knight D, Kelsey M, Ross P Jr. Use of C4d as a diagnostic adjunct in lung allograft biopsies. Am J Transplant 2003;3:1143-1154.

3. Magro CM, Klinger DM, Adams PW, Orosz CG, Pope-Harman AL, Waldman WJ, Knight D, Ross P Jr. Evidence that humoral allograft rejection in lung transplant patients is not histocompatibility antigen-related. Am J Transplant 2003;3:1264-1272.

4. Magro CM, Deng A, Pope-Harman A, Waldman WJ, Bernard Collins A, Adams PW, Kelsey M, Ross P. Humorally mediated posttransplantation septal capillary injury syndrome as a common form of pulmonary allograft rejection: a hypothesis. Transplantation 2002;74:1273-1280. [Published erratum in Transplantation 2003;76:1009.]

5. Magro CM, Ross P Jr, Kelsey M, Waldman WJ, Pope-Harman A. Association of humoral immunity and bronchiolitis obliterans syndrome. Am J Transplant 2003;3:1155-1166.

6. Magro CM, Calomeni EP, Nadasdy T, Shusterman BD, Pope-Harman AL, Ross P Jr. Ultrastructure as a diagnostic adjunct in the evaluation of lung allograft biopsies. Ultrastruct Pathol 2005;29:95- 106.

7. Magro CM, Abbas A, Seilstad KH, Harman AL, Nadasdy T, Ross P Jr. C3d as a marker of chronic lung allograft dysfunction. Hum Immunol (In press)

From the Authors:

We would like to thank Dr. Magro and colleagues for their letter regarding the Summary Statement from the National Institutes of Health-sponsored meeting regarding the scientific and clinical advancements in lung transplantation (1). The authors fully agree with your suggestion that humoral immunity has a role in the pathogenesis of lung transplant rejection. Moreover, the antibodies are not always related to HLA antigens as suggested by Magro and coworkers and confirmed in their prior studies. Indeed, the role of non-HLA antibodies, including autoantibodies, in the pathogenesis of the rejection response is an area of transplantation medicine in need of more investigation such that specific targets may be identified for therapeutic intervention.

Conflict of Interest Statement: D.S.W. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

DAVID S. WILKES

Indiana University School of Medicine

Indianapolis, Indiana

References

1. Wilkes DS, Egan TM, Reynolds HY. Lung transplantation: opportunities for research and clinical advancement. Am J Respir Crit Care Med 2005;172:944-955.

Copyright American Thoracic Society Feb 15, 2006

Source: American Journal of Respiratory and Critical Care Medicine

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