CAN IMMUNE ACCOMMODATION BE PREDICTED USING “-OMICS” TOOLS?
Bruce McManus, Professor, Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
1. To convey the overall discovery rationale and strategies in the Biomarkers in Transplantation initiative within the PROOF Centre of Excellence.
2. To share current data and early insights regarding the ability to predict rejection or its absence in kidney and heart allograft recipients.
3. To foster discussion and collaboration in regards to prediction and the use of “-Omic” tools.
Introduction: Organ transplantation remains the main treatment for end-stage heart and kidney failure. The Biomarkers in Transplantation (BiT) team and the PROOF Centre of Excellence have undertaken an unbiased discovery strategy to identify and ultimately validate biomarker panels diagnostic and predictive of immune rejection in prospectively enrolled heart and kidney failure patients receiving transplanted allografts. Utilizing high-performance genomics, proteomics and metabolomics platforms, the BiT team has internally validated peripheral blood-derived diagnostic biomarker panels of acute and chronic rejection. These panels are currently undergoing external validation and qualification in a Canada-wide trial.
Predictive Biomarkers: The challenges of precision, accuracy, timeliness and invasiveness of current patient monitoring approaches post-transplant provide significant impetus to a search for “-Omics” markers for prediction of those at risk of immune rejection. Indeed, a significant goal in transplant immunology remains the prediction and prevention of organ rejection as opposed to the diagnosis and treatment. The realization that humans are immunologically distinct, dating back to discoveries of ABO blood groups and MHC antigens, has led to extensive research directed towards predicting and preventing organ rejection. The application of “-Omics” technologies to the task of predicting immune accommodation, tolerance or rejection is a natural extension of these efforts.
Kidney Transplantation: Biomarkers of early graft accommodation would offer an important option for post-transplant monitoring and permit timely and effective therapeutic intervention. The BiT team investigated longitudinal PAXgene-based gene expression patterns in peripheral blood of quiescent kidney transplant recipients to better understand early phases of accommodation. We have generated a comprehensive signature of immediate gene expression changes in whole blood after renal transplantation reflecting a variety of immune and inflammatory processes, as well as regenerative processes occurring after the transplantation procedure. Monitoring longitudinal changes in biological processes as reflected in peripheral gene expression may provide insights into the mechanisms of immunological accommodation, and thus facilitate personalization of immunosuppressive regimens.
Heart Transplantation: End-stage heart failure is characterized by a peripheral blood molecular signature reflective of the homogeneity of the final common pathways of failure. Reversion of the levels of these markers post-transplant to baseline may be reflective of “normalized” graft performance and could impact patient outcomes. The BiT team analyzed gene expression profiles of a subset of patients, demonstrating that approximately one third of end-stage genomic markers revert to normal levels post-transplant. These molecular signatures may give insight into both the pathogenesis of heart failure and the processes of tolerance and accommodation occurring following transplantation.
Conclusion: Limitations of current diagnostic and predictive approaches has led many in transplantation science to assess “-Omics” platforms for more sensitive and specific, clinically helpful biomarkers. While the notion that graft integrity post-transplant may be predicted pre-surgery has existed for many years, current approaches may bring the field closer to this yet elusive goal.