Kidney transplantationChronic allograft nephropathyHypothesis: Epithelial-to-Mesenchymal Transition is a Common Cause of Chronic Allograft Failure
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
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Cited by (18)
Is the lung a complex organ to rebuild?
2022, 3D Lung Models for Regenerating Lung TissueUrine periostin as a biomarker of renal injury in chronic allograft nephropathy
2014, Transplantation ProceedingsCitation Excerpt :Thus, the data suggest that the de novo expression of periostin during different types of kidney injury and its excretion in kidney tissues are common events during progressive kidney injury. The main pathway of developed CAN is EMT describing the process of phenotypic change that cells of a variety of origins, including mesenchymal cells, resident fibroblasts, and epithelial cells undergo, leading to fibrosis [12]. Currently, periostin is discussed as a major player in tissue fibrosis, but is also a critical component of mechanically challenged biological structures, including kidney tissues.
Novel role for tumor suppressor gene, liver kinase B1, in epithelial–mesenchymal transition leading to chronic lung allograft dysfunction
2022, American Journal of TransplantationFully integrating pathophysiological insights in copd: An updated working disease model to broaden therapeutic vision
2021, European Respiratory ReviewEpithelial–mesenchymal transition, a spectrum of states: Role in lung development, homeostasis, and disease
2018, Developmental Dynamics