Strategies to Prevent Cellular Rejection in Pediatric Heart Transplant Recipients

Abstract

Despite more than 40 years' experience in pediatric heart transplantation, cellular rejection remains a significant cause of morbidity and mortality. In this review, strategies and agents to prevent acute cellular rejection are discussed. Strategies to prevent rejection are divided into two phases - induction and maintenance therapies. Currently, the most commonly used induction agents are polyclonal antibodies (rabbit or equine antithymocyte globulin) and interleukin-2 receptor antibodies (daclizumab or basiliximab). Induction therapies have reduced early rejection, are renal sparing, and can reduce corticosteroid exposure, but have not yet been shown to have a longer term survival benefit. Multiple maintenance immunosuppressants are available. Nearly all regimens include a calcineurin inhibitor (either ciclosporin [cyclosporine] or tacrolimus). Most combinations in pediatric heart transplantation include an antiproliferative agent (azathioprine, mycophenolate mofetil or, less commonly, sirolimus). Everolimus has seen increasing use in adult heart transplant patients in Europe but, to date, its use is rare in pediatric heart transplantation. The use of corticosteroids as a third agent is still common, but strategies to avoid or minimize their use are increasing. The 'best' combination of therapies varies between studies. By gaining a better understanding of individuals' genetic and environmental risk factors, we may in the future be able to better predict the course of cardiac allografts and enhance our ability to tailor immunosuppression to individual patient variables with the ultimate goal of inducing a state of immune tolerance.

Everolimus in Heart Transplantation: An Update

“…While early withdrawal of steroids is a well established strategy in pediatric transplant recipients, there is only limited experience with-reduced-CNI or CNI-free regimens [33, 34]. Everolimus is not currently licensed in children and its use in pediatric heart transplant patients is largely restricted to high-volume centers [35]. There are no randomized trials.…”

Pediatric heart transplantation: Looking forward after five decades of learning

“…However, they are associated with many adverse effects, especially in the pediatric population. 21,22 Prednisone use in children is decreasing with ISHLT registry data revealing that 66% of recipients were discharged on prednisone in the most recent era (January 2010-June 2018) compared to 74% in the previous era (January 2005-December 2009). 23 Multiple registry analyses have reported that corticosteroids can be avoided in children with excellent freedom from rejection and overall post-transplant survival outcomes.…”

Cardiac allograft vasculopathy: A review

“…MMF is an anti‐proliferative agent and an antimetabolite that interrupts purine metabolism in T and B lymphocytes 60 . It is used as an adjunctive agent to CNI and has largely replaced the use of azathioprine.…”

“…PSI, otherwise known as mTOR inhibitors, are used for the prevention of both acute and chronic rejection. Sirolimus is a macrolide antibiotic with a structure similar to that of tacrolimus, and everolimus is an analog of sirolimus that differs by one hydroxyl group 60 . With the arrival of PSIs there has been multiple studies assessing whether this class of drugs offer further advantages in preventing and treating CAV; however, multiple adult studies have shown mixed results.…”

“…MMF is an anti-proliferative agent and an antimetabolite that interrupts purine metabolism in T and B lymphocytes. 60 It is used as an adjunctive agent to CNI and has largely replaced the use of azathioprine. MMF directly prevents proliferation of intimal muscle cells and fibroblasts involved in the formation and development of CAV.…”