Publications

Abstract

Aging of the world population significantly impacts healthcare globally and specifically, the field of transplantation. Together with end-organ dysfunction and prolonged immunosuppression, age increases the frequency of comorbid chronic diseases in transplant candidates and recipients, contributing to inferior outcomes. Although the frequency of death increases with age, limited use of organs from older deceased donors reflects the concerns about organ durability and inadequate function. Cellular senescence (CS) is a hallmark of aging, which occurs in response to a myriad of cellular stressors, leading to activation of signaling cascades that stably arrest cell cycle progression to prevent tumorigenesis. In aging and chronic conditions, senescent cells accumulate as the immune system's ability to clear them wanes, which is causally implicated in the progression of chronic diseases, immune dysfunction, organ damage, decreased regenerative capacity, and aging itself. The intimate interplay between senescent cells, their proinflammatory secretome, and immune cells results in a positive feedback loop, propagating chronic sterile inflammation and the spread of CS. Hence, senescent cells in organs from older donors trigger the recipient's alloimmune response, resulting in the increased risk of graft loss. Eliminating senescent cells or attenuating their inflammatory phenotype is a novel, potential therapeutic target to improve transplant outcomes and expand utilization of organs from older donors. This review focuses on the current knowledge about the impact of CS on circulating immune cells in the context of organ damage and disease progression, discusses the impact of CS on abdominal solid organs that are commonly transplanted, and reviews emerging therapies that target CS.

View details for DOI 10.1097/TP.0000000000004838

View details for PubMedID 37953486

View details for Web of Science ID 001094086301480

View details for DOI 10.1097/01.tp.0000993400.94644.c0

View details for PubMedID 37845955

Abstract

Solid organ transplant remains a life-saving therapy for children with end-stage heart, lung, liver, or kidney disease; however, ∼33% of allograft recipients experience acute rejection within the first year after transplant. Our ability to detect early rejection is hampered by an incomplete understanding of the immune changes associated with allograft health, particularly in the pediatric population. We performed detailed, multilineage, single-cell analysis of the peripheral blood immune composition in pediatric solid organ transplant recipients, with high-dimensional mass cytometry. Supervised and unsupervised analysis methods to study cell-type proportions indicate that the allograft type strongly influences the post-transplant immune profile. Further, when organ-specific differences are considered, graft health is associated with changes in the proportion of distinct T cell subpopulations. Together, these data form the basis for mechanistic studies into the pathobiology of rejection and allow for the development of new immunosuppressive agents with greater specificity.

View details for DOI 10.1016/j.xcrm.2023.101147

View details for PubMedID 37552988

Abstract

The International Pediatric Transplant Association convened an expert consensus conference to assess current evidence and develop recommendations for various aspects of care relating to post-transplant lymphoproliferative disorders after solid organ transplantation in children. In this report from the Viral Load and Biomarker Monitoring Working Group, we reviewed the existing literature regarding the role of Epstein-Barr viral load and other biomarkers in peripheral blood for predicting the development of PTLD, for PTLD diagnosis, and for monitoring of response to treatment. Key recommendations from the group highlighted the strong recommendation for use of the term EBV DNAemia instead of "viremia" to describe EBV DNA levels in peripheral blood as well as concerns with comparison of EBV DNAemia measurement results performed at different institutions even when tests are calibrated using the WHO international standard. The working group concluded that either whole blood or plasma could be used as matrices for EBV DNA measurement; optimal specimen type may be clinical context dependent. Whole blood testing has some advantages for surveillance to inform pre-emptive interventions while plasma testing may be preferred in the setting of clinical symptoms and treatment monitoring. However, EBV DNAemia testing alone was not recommended for PTLD diagnosis. Quantitative EBV DNAemia surveillance to identify patients at risk for PTLD and to inform pre-emptive interventions in patients who are EBV seronegative pre-transplant was recommended. In contrast, with the exception of intestinal transplant recipients or those with recent primary EBV infection prior to SOT, surveillance was not recommended in pediatric SOT recipients EBV seropositive pre-transplant. Implications of viral load kinetic parameters including peak load and viral set point on pre-emptive PTLD prevention monitoring algorithms were discussed. Use of additional markers, including measurements of EBV specific cell mediated immunity was discussed but not recommended though the importance of obtaining additional data from prospective multicenter studies was highlighted as a key research priority.

View details for DOI 10.1111/petr.14471

View details for PubMedID 37294621