Abstract
Despite advances in management of immunosuppression, graft rejection remains a significant clinical problem in solid organ transplantation. Non-invasive biomarkers of graft rejection can facilitate earlier diagnosis and treatment of acute rejection. The purpose of this study was to investigate the potential role of heparan sulfate as a novel biomarker for acute cellular rejection. Heparan sulfate is released from the extracellular matrix during T-cell infiltration of graft tissue via the action of the enzyme heparanase. In a murine heart transplant model, serum heparan sulfate is significantly elevated during rejection of cardiac allografts. Moreover, expression of the enzyme heparanase is significantly increased in activated T-cells. In human studies, plasma heparan sulfate is significantly elevated in kidney transplant recipients with biopsy-proven acute cellular rejection compared to healthy controls, recipients with stable graft function, and recipients without acute cellular rejection on biopsy. Taken together, these findings support further investigation of heparan sulfate as a novel biomarker of acute cellular rejection in solid organ transplantation.
Highlights
Organ transplantation is the definitive treatment for end-stage organ disease
The purpose of the current study is to investigate the biology of HS and Hpase in allograft rejection, using both a murine cardiac transplant model and investigation of human samples from kidney transplant recipients
While both syngeneic and allogeneic grafts demonstrate Hpase in the endothelium, an increased number of Hpase-expressing graft-infiltrating leukocytes (GILs) was present in rejecting allografts compared to syngeneic grafts (Fig 2)
Summary
Despite advances in our understanding of immune mechanisms and immunosuppression therapy, graft rejection remains a primary driver of long-term graft failure, with 25–50% grafts lost within 5 years [1, 2]. In the context of ongoing organ shortages, there is a critical need for improved methods for the detection and prevention of graft rejection. The “gold standard” for diagnosing transplant rejection is the detection of immune injury (e.g. lymphocyte infiltration) on graft biopsy. Biopsies are typically performed when serum creatinine (sCr) levels become significantly elevated over baseline. SCr is an imperfect indicator of allograft rejection for multiple reasons: it rises late in the process of immune injury, the magnitude of change above baseline can be minimal, and it is not specific for rejection. Protocol biopsies performed at designated intervals can detect
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