Kidney transplantation
Chronic allograft nephropathy
Hypothesis: Epithelial-to-Mesenchymal Transition is a Common Cause of Chronic Allograft Failure

https://doi.org/10.1016/j.transproceed.2004.12.203Get rights and content

Abstract

Renal, hepatic, and lung allografts are compromised by aggressively deteriorating function. This chronic process is produced by an overall burden of organ damage, but the pathophysiology remains poorly understood. Rates of chronic rejection in the lung, for example, have not substantially improved over the last decade, despite new immunosuppressive drugs and improvements in surgical procedure. We present a hypothesis that epithelial-to-mesenchymal transition is a common cause of chronic allograft failure. Research in this area may provide insights into chronic rejection of kidney, liver, and lung allografts that impact on future therapeutic strategies.

Section snippets

The problem

Transplantation is often the only available therapy for patients with end-stage, solid organ failure. However, renal, hepatic, and lung allografts are compromised by aggressively deteriorating function. This chronic process is produced by an overall burden of organ damage, some of which is immunological, resulting in graft fibrosis (Fig 1). This is irreversible and leads to high-dependency patient care, retransplantation, or death.

A final common terminal effector of chronic rejection

A striking common denominator of chronic allograft failure is remodeling and fibrosis of epithelialized functional units, with epithelial loss, basement membrane damage, and interstitial fibrosis.1, 2, 3, 4, 5 Tubular atrophy and loss of nephrons occur in kidneys.5 In livers, bile ducts are characteristic targets,5 while lungs show scarring, remodeling, and the loss of small airways.5 These pathological changes underlie physiological deterioration and eventual graft failure. Episodes of acute

Stage 1: Inflammation, alloreactive CD8 T cells target the epithelia

Pathologically, acute allograft rejection is recognized by patterns of inflammation. Acute lung allograft rejection is defined by a mononuclear cell infiltrate and linked to the development of airway inflammation (lymphocytic bronchiolitis4). Pathological definition of chronic lung rejection in turn describes a lymphohistiocytic cytotoxicity, characteristically directed at the respiratory epithelium.3 In kidneys, the Banff protocol for rejection pathology uses tubulitis and epithelial

Stage 2: The intraepithelial microenvironment supports αeβ7 integrin-positive, long-lived CD8 T cells that adhere to epithelial E-cadherin

On infiltrating epithelia, CD8 cells are exposed to a specific microenvironment. IL-15 and IL-21 activate and promote clonal expansion and suppress apoptotic deletion.8 We and others have shown increased levels of TGF-β in BAL even in clinically stable lung transplant recipients, with immunoreactivity present in the bronchial epithelium,14 and, in vitro, TGF-β causes over 60% of proliferating CD8 cells to express the αEβ7 integrin, CD103.8 The αEβ7 integrin binding to epithelial E-cadherin

Stage 3: TGF-β links intraepithelial CD8 cells and chronic fibrosis of allografts

Epithelial cells are pluripotent and exhibit phenotypic plasticity in vivo and in vitro,16, 17 but while axiomatic in developmental biology and the oncology literatures, this has not been a traditional avenue of transplant research. Chronically activated, intraepithelial CD103/CD8 T cells elicit ongoing production of TGF-β, which is stereotypically expressed in various forms of tissue fibrosis and implicated by a divergent literature in epithelial transition.18 TGF-β causes loss of

If a common effector mechanism is involved why do lung allografts fare badly?

Our hypothesis can explain variable rates of chronic rejection within and between organs allograft types at two levels. Different organs have variable tolerances to damage, and the liver, which is relatively resistant to chronic rejection, has substantial reserve function and good regenerative capacity.5 Furthermore, the liver has a capacity to induce apoptotic deletion of activated T cells.22 In contrast, the predisposition of the lung to chronic allograft dysfunction may be a reflection of

The therapeutic significance of epithelial to mesenchymal transition

Epithelial-to-mesenchymal transition might represent a logical therapeutic target in allografts. Systemic administration of a 35-kDa homodimeric protein and member of the TGF-β superfamily (bone morphogenic protein-7; BMP-7) reverses TGF-β-induced epithelial-to-mesenchymal transition, accompanied by reinduction of E-cadherin, repair of severely damaged tubular epithelial cells, and reversal of chronic injury in a murine model of chronic kidney disease,18 BMP-7 is a licensed therapy in human

Testing the hypothesis

Our hypothesis should be tested in human allografts, with the relevance of animal models to human chronic rejection unknown. Studies are particularly practicable in lung allografts since clinical surveillance bronchoscopy and biopsy are routine and complemented by contemporaneous lung function assessments. Crucially, this strategy allows longitudinal, in vivo pathophysiological studies. Human clinical protocol biopsy material, coupled with functional organ assessment, is also available from

References (26)

  • W.C. Parks et al.

    Matrix metalloproteinases in lung biology

    Respir Res

    (2001)
  • C.E. Brinckerhoff et al.

    Matrix metalloproteinases: a tail of a frog that became a prince

    Nat Rev Mol Cell Biol

    (2002)
  • W.C. Forrest I et al.

    Thorax

    (2002)
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