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Eur J Cardiothorac Surg 2006;29:760-766
© 2006 Elsevier Science NL

Neutrophil transendothelial migration potential predicts rejection severity in human cardiac transplantation

^a Prof Eoin O’Malley National Centre for Cardiothoracic Surgery, Mater Misericordiae University Hospital, Dublin, Ireland
^b UCD School of Medicine and Medical Science, Mater Misericordiae University Hospital, University College Dublin, Ireland
^c Department of Pathology, Mater Misericordiae University Hospital, Dublin, Ireland
^d Conway Institute of Biomolecular & Biomedical Research, University College Dublin, Ireland

Received 29 September 2005; received in revised form 21 December 2005; accepted 26 January 2006.

^_* Corresponding author. Address: Department of Surgery, Conway Institute of Biomolecular & Biomedical Research, Belfield, University College Dublin, Dublin 4, Ireland. Tel.: +353 1 7166733; fax: +353 1 7166887. (Email: william.watson{at}ucd.ie).

Objective: Transplant rejection remains a clinical problem despite therapies that focus on lymphocyte suppression, with little attention focused on the neutrophil. Neutrophils are however the first leukocyte to infiltrate the allograft, are capable of causing myocardial damage and may facilitate lymphocytes recruitment. We hypothesised that an early allograft neutrophil infiltration influences rejection severity. Methods: Myocardial neutrophil infiltration was assessed using CD15 and myeloperoxidase immunohistochemistry of rejection surveillance endomyocardial biopsy specimens from human cardiac transplant recipients (n = 18). In patients undergoing cardiac transplantation (n = 10), neutrophils were isolated from multiple perioperative blood samples using a ficoll-based density gradient centrifugation method. The expression of the neutrophil adhesion protein CD11b was then assessed using flow cytometry and compared to subsequent endomyocardial biopsy rejection grades. The effects of contemporary immunosuppressive agents on human neutrophil CD11b were also assessed using healthy control volunteers. Results: Myeloperoxidase staining of endomyocardial biopsies from human heart transplant recipients demonstrated a positive correlation between the degree of neutrophil infiltration and rejection severity at the first postoperative biopsy. Rejection severity was unrelated to ischaemic time. Functional assessment of neutrophils obtained from recipients was then performed. Perioperative transplant sampling demonstrated a significant correlation between the preoperative expression of CD11b and rejection grade at the first postoperative biopsy. In addition, dynamic changes in CD11b expression in the first 24 h positively correlated with subsequent rejection severity. In vitro experiments showed that transplant immunosuppression did not alter neutrophil CD11b expression. Conclusion: This study demonstrates a potentially greater role for neutrophils in cardiac transplantation than previously recognised, and suggests that blockade of the early allograft neutrophil infiltration might prevent subsequent lymphocyte recruitment and attenuate rejection.

Abbreviations: CPB = cardiopulmonary bypass • ISHLT = International Society for Heart Lung Transplantation

Key Words: Transplantation • Cardiac • Neutrophil • Rejection • Adhesion molecules • CD11b

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