98 research outputs found
Next-generation pathology detection of T cell–antigen-presenting cell immune synapses in human liver allografts
No full textBackground and Aims: In otherwise near-normal appearing biopsies by routine light microscopy, next-generation pathology (NGP) detected close pairings (immune pairs; iPAIRs) between lymphocytes and antigen-presenting cells (APCs) that predicted immunosuppression weaning failure in pediatric liver transplant (LTx) recipients (Immunosuppression Withdrawal for Stable Pediatric Liver Transplant Recipients [iWITH], NCT01638559). We hypothesized that NGP-detected iPAIRs enrich for true immune synapses, as determined by nuclear shape metrics, intercellular distances, and supramolecular activation complex (SMAC) formation. Approach and Results: Intralobular iPAIRs (CD45high lymphocyte–major histocompatibility complex II+ APC pairs; n = 1167, training set) were identified at low resolution from multiplex immunohistochemistry–stained liver biopsy slides from several multicenter LTx immunosuppression titration clinical trials (iWITH; NCT02474199 (Donor Alloantigen Reactive Tregs (darTregs) for Calcineurin Inhibitor (CNI) Reduction (ARTEMIS); Prospective Longitudinal Study of iWITH Screen Failures Secondary to Histopathology). After excluding complex multicellular aggregates, high-resolution imaging was used to examine immune synapse formation (n = 998). By enriching for close intranuclear lymphocyte–APC distance (mean: 0.713 μm) and lymphocyte nuclear flattening (mean ferret diameter: 2.1), SMAC formation was detected in 29% of iPAIR-engaged versus 9.5% of unpaired lymphocytes. Integration of these morphometrics enhanced NGP detection of immune synapses (ai-iSYN). Using iWITH preweaning biopsies from eligible patients (n = 53; 18 tolerant, 35 nontolerant; testing set), ai-iSYN accurately predicted (87.3% accuracy vs. 81.4% for iPAIRs; 100% sensitivity, 75% specificity) immunosuppression weaning failure. This confirmed the presence and importance of intralobular immune synapse formation in liver allografts. Stratification of biopsy mRNA expression data by immune synapse quantity yielded the top 20 genes involved in T cell activation and immune synapse formation and stability. Conclusions: NGP-detected immune synapses (subpathological rejection) in LTx patients prior to immunosuppression reduction suggests that NGP-detected (allo)immune activity usefulness for titration of immunosuppressive therapy in various settings.</p
Postoperative Monitoring: Biomarkers and Alloimmune Responses and Their Relevance to Vascularized Composite Allotransplantation
No full text
Immune-Mediated Liver Disease in the Transplanted Liver
No full textLiver transplantation has evolved as the treatment of choice for many patients with end-stage liver disease. Currently, survival posttransplant is excellent, with 10-year survival exceeding 65%. Causes of graft failure include recurrent disease, in particular autoimmune disease, alcoholic liver disease, and NAFLD. Immune-mediated injury is also a cause for graft failure, but this cause has proved to be less common nowadays. With the actual range of potent immunosuppressive agents and a greater use of a tailored approach, rejection is seen less frequently. Rejection may take the form of T-cell-mediated rejection (TCMR), antibody-mediated rejection (AMR), and plasma cell-rich hepatitis. On the opposite end of the spectrum, operational tolerance develops in a small proportion of liver transplant recipients. Finally, as indicated earlier, some autoimmune diseases can recur in the allograft
From immunosuppression to tolerance
No full textSummaryThe past three decades have seen liver transplantation becoming a major therapeutic approach in the management of end-stage liver diseases. This is due to the dramatic improvement in survival after liver transplantation as a consequence of the improvement of surgical and anaesthetic techniques, of post-transplant medico-surgical management and of prevention of disease recurrence and other post-transplant complications. Improved use of post-transplant immunosuppression to prevent acute and chronic rejection is a major factor in these improved results. The liver has been shown to be more tolerogenic than other organs, and matching of donor and recipients is mainly limited to ABO blood group compatibility. However, long-term immunosuppression is required to avoid severe acute and chronic rejection and graft loss. With the current immunosuppression protocols, the risk of acute rejection requiring additional therapy is 10–40% and the risk of chronic rejection is below 5%. However, the development of histological lesions in the graft in long-term survivors suggest atypical forms of graft rejection may develop as a consequence of under-immunosuppression. The backbone of immunosuppression remains calcineurin inhibitors (CNI) mostly in association with steroids in the short-term and mycophenolate mofetil or mTOR inhibitors (everolimus). The occurrence of post-transplant complications related to the immunosuppressive therapy has led to the development of new protocols aimed at protecting renal function and preventing the development of de novo cancer and of dysmetabolic syndrome. However, there is no new class of immunosuppressive drugs in the pipeline able to replace current protocols in the near future. The aim of a full immune tolerance of the graft is rarely achieved since only 20% of selected patients can be weaned successfully off immunosuppression. In the future, immunosuppression will probably be more case oriented aiming to protect the graft from rejection and at reducing the risk of disease recurrence and complications related to immunosuppressive therapy. Such approaches will include strategies aiming to promote stable long-term immunological tolerance of the liver graft
Emergent transcriptomic technologies and their role in the discovery of biomarkers of liver transplant tolerance.
No full textLiver transplantation offers a unique window into transplant immunology due, in part, to the considerable proportion of recipients who develop immunological tolerance to their allograft. Biomarkers able to identify and predict such a state of tolerance, and thereby able to establish suitable candidates for the minimisation of hazardous immunosuppressive therapies, are not only of great potential clinical benefit, but might also shed light on the immunological mechanisms underlying tolerance and rejection. Here we review the emergent transcriptomic technologies serving as drivers of biomarker discovery, we appraise efforts to identify a molecular signature of liver allograft tolerance, and we consider the implications of this work on the mechanistic understanding of immunological tolerance
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