Elsevier

Transplant Immunology

Volume 8, Issue 4, February 2001, Pages 229-236
Transplant Immunology

Early lung leukocyte infiltration, HLA and adhesion molecule expression predict chronic rejection

https://doi.org/10.1016/S0966-3274(00)00029-0Get rights and content

Abstract

Obliterative bronchiolitis remains the main cause of graft dysfunction and death after 1 year. Defined by an irreversible airway obstruction, bronchiolitis obliterans syndrome is usually recognized in the advanced stage of the disease, with histological evidence of fibrotic damage. Fibrosis represents the end-stage of an inflammatory process, leading to the postulate that chronic lung graft dysfunction is preceded by cellular and molecular events. This study was performed during the first year following lung transplantation, in the absence of histological or functional criteria of chronic rejection. Transbronchial biopsies from eight lung allografts were examined. Four developed a bronchiolitis obliterans syndrome (Group I), and 4 had good outcomes (Group II) at 2 years. Using immunohistochemistry, the aim of the study was to correlate early immunological events with graft outcomes at 2 years. An up-regulation of HLA class I antigen (P=0.0001), an overexpression of Ki-67 (P=0.006) on bronchial epithelium, and graft infiltration by CD45+, CD25+ cells (P=0.003) were significantly associated with the development of chronic rejection. An overexpression of numerous adhesion molecules was observed. However, only very late antigen-4 had a discriminative value (P=0.04), preceding chronic graft dysfunction. Our results suggest that graft dysfunction is associated with early molecular and cellular events, and raises the possibility that a fibroproliferative disorder is initiated shortly after transplantation. The recognition of such early immunological markers might facilitate improved graft management and prognosis.

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.

References (25)

  • D.S. Milne et al.

    MHC class II and ICAM-1 expression and lymphocyte subsets in transbronchial biopsies from transplant recipients

    Transplantation

    (1994)
  • S.A. Yousem et al.

    A working formulation for the standardization of nomenclature in the diagnosis of heart and lung rejection: lung rejection study group

    J Heart Transplant

    (1990)
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