Early lung leukocyte infiltration, HLA and adhesion molecule expression predict chronic rejection
Introduction
Although early outcomes following lung transplantation (LT) have been greatly improved, chronic graft rejection remains the main late complication, responsible for the death of 30–50% of long survivors [1]. Major risk factors for bronchiolitis obliterans syndrome (BOS) are well-described [2], whereas its pathogenesis is still incompletely understood. Because clinical manifestations associated with chronic graft rejection may or may not be correlated to the histological findings, the International Society for Heart–Lung Transplantation (ISHLT) concluded that measurement of lung function was the most appropriate tool for graft surveillance. Accordingly, BOS is defined by a progressive decline on FEV-1 values, reflecting chronic graft dysfunction in the absence of other causes [3], [4]. Diagnosis of BOS is usually delayed, and despite few reports of response to immunosuppression [5], [6], regimens are unsuccessful on irreversible lung lesions.
Expressions of HLA Ags, adhesion molecules and leukocyte phenotypes on lung grafts have been previously described during both acute and chronic rejection [7]. An increase in HLA Ags, adhesion molecule expression and a graft infiltration by T cells were reported within acute rejection lesions. However, little is known about the non-rejecting graft, and in the absence of chronic rejection. We hypothesized that, despite the absence of histological and functional criteria for chronic rejection, an early immune reaction is involved with later development of graft deterioration. The purpose of the study was to determine early patterns of HLA antigen and adhesion molecule expression, and of leukocyte infiltration, predictive of late graft outcomes. Our results suggest that BOS is associated with earlier molecular and cellular modification within lung allografts. Beside diagnosis of acute lung rejection, their early recognition might be of particular interest in immunosuppressive and surveillance strategies.
Section snippets
Study groups
Eight patients who underwent LT have been studied. According to the ISHLT, four patients developed BOS 2 years after LT (Group I), and four remained free of chronic graft dysfunction (Group II). The mean age at transplantation was 43.7 years (range 19–60). Two single LT and six double LT were carried out. The induction immunosuppressive regimens consisted of cyclosporine A, antithymoglobulins (25 mg 15 kg−1 day−1 for 5–7 days), azathioprine and prednisone. Maintenance immunosuppressive drugs
Results
A total of 34 TBB specimens 8 lung transplant recipients (average 4±1.3 TBB patient−1) were obtained during the first 12 months following LT, in the absence of spirometric criteria for BOS. Of these, 18 (53%) TBB were from four patients who developed a chronic graft dysfunction 2 years after LT (Group I), and 13 (72,2%) specimens showed evidence of histological acute rejection (grade 1, n=6; grade 2, n=7). The other four patients were free of BOS (Group II). In this second group, 16 TBB were
Discussion
The expression of HLA class I and II Ags on normal lung has been reported, with ubiquitous distribution of class I Ags on both endothelial and epithelial cells [9]. Conversely, the endothelial and epithelial expression of HLA class II Ags was more heterogeneous, absent, or patchy in more than 2/3 of cases [9]. In the present study, a close pattern of HLA class I and II Ags expression was found in controls.
The allogenic response is associated with an alloreactive T-cell expansion, dependent on
Acknowledgements
The authors greatly appreciate the technical assistance of C. Cherry, C. Claraz, and J. Quentin-Ferran. The authors are indebted to P.Y. Brichon, MD, and D. Blin, MD (Department of Cardiovascular and Thoracic Surgery), and D. Barnoud, MD (Department of Intensive Care Medicine). This work was supported by the French Department of Health, PHRC.
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