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Treatment of Antibody Mediated Rejection in Pediatric Heart Transplantation

Erin Albers, MD, MSCI
Seattle Children's Hospital
Seattle, WA, USA

Since the beginning of pediatric heart transplantation three decades ago, improved understanding of transplant immunology combined with more effective and less toxic immunosuppressive medications have led to lower rates of cellular rejection and excellent short-term outcomes. However, antibody mediated rejection (AMR) remains an important obstacle to long-term graft survival. Indeed, AMR is being diagnosed more often in pediatric heart transplant recipients, in part due to more refined diagnostic tools and criteria, but also as a result of a growing pool of high-risk transplant candidates, particularly those sensitized to potential donor HLA antigens from previous surgeries to repair congenital heart disease and/or mechanical support requirements. As such, AMR and its treatment is becoming an increasingly important research focus. And while advanced technology to detect and elucidate the pathophysiology of antibody-mediated graft injury has certainly offered a number of new therapeutic targets for a growing armamentarium of AMR-specific therapies, there are a few pillars of anti-rejection treatment which cannot forgotten.

Plasmapheresis, whereby proteins (including HLA antibodies) are indiscriminately removed from plasma, has been described as a method to prevent hyperacute rejection in solid organ transplant recipients since the early 1970s. Today, plasmapheresis remains the cornerstone of treatment for acute AMR with graft dysfunction, where the primary goal is rapid reduction in circulating donor-specific antibody (DSA) levels in order to halt ongoing myocardial damage. Immunoadsorption (using antibody-binding protein columns) is another option for antibody removal, although less commonly used in pediatrics. Unfortunately, these modalities typically provide only short-term reduction in circulating DSA levels, and must be used in conjunction with other treatments.

Several other traditional therapies remain mainstays for treatment of AMR. Corticosteroids provide powerful non-specific immunosuppressive effect by altering the function and distribution of all types of immunologically active cells, and remain first-line treatment for both cellular and antibody mediated rejection. The immunomodulatory effects of intravenous immunoglobulin (IVIg) are not as well understood, but theories include "neutralization" of damaging antibody activity by alteration of Fc receptor binding, disruption of antigen presentation, and inhibition of the membrane attack complex. In AMR, IVIg also serves to replenish depleted "good" antibodies and to down-regulate rebound DSA production after plasmapheresis. Finally, the T-cell depleting agent anti-thymocyte globulin (ATG), can also be used to treat hemodynamically significant AMR, as T-cells are required for antibody activation.

More recently, several AMR-specific treatments have been used to target different points in the pathway from DSA production all the way to antibody mediated cellular injury. Rituximab is an anti-CD20 monoclonal antibody which targets and destroys B cells, the precursors of antibody producing cells. While rituximab has been available and tried as an AMR treatment for many years, rituximab alone has not been shown to sufficiently lower antibody levels or reduce rates of graft loss related to AMR. Bortezomib is a proteasome inhibitor which is FDA approved for treatment of multiple myeloma, a plasma cell cancer. Proteosome inhibition interferes with the cell cycle at specific mitotic checkpoints and ultimately results in destruction of plasma cells, where DSAs are manufactured. There is growing clinical experience with Bortezomib as treatment for AMR in pediatric heart transplant recipients with initially promising results, although few formal studies exist. Eculizumab, a humanized anti-C5 monoclonal antibody, acts at the final step in antibody mediated cellular injury by blocking terminal complement activation. Eculizumab can act quickly to block antibody mediated graft injury even while antibody levels are high, potentially protecting the graft from injury while giving other therapies directed at lowering antibody levels time to work.

Several novel biological therapies are now being considered in adult and other solid organ transplant recipients which may hold promise for future AMR treatment in pediatric heart recipients. A C1-inhibitor is in the early phases of clinical trials and may work synergistically with Eculizumab to block complement mediated cell damage. Belatacept selectively binds to CD86/CD80 on antigen presenting cells and works primarily to block T-cell activation, but also acts to indirectly inhibit antibody production. Finally, several second generation proteasome inhibitors are under development for cancer treatments, which may prove useful in AMR as well.

Of course, large-scale randomized clinical trials of these therapies are not routinely being performed in children, and we must therefore rely on data from adult or smaller pediatric studies (often in other organ transplants) to guide our practice. Based on the information we have so far, no single therapy alone is adequate to treat AMR, while the perfect combination remains elusive. It is also important to remember that long-term risks of these new immunosuppressive agents are not well-documented, particularly in children, and we must remain attentive even as we become more comfortable prescribing these medications to our young patients. Finally, our ultimate goal for research and drug development should focus not only on treatment, but also on prevention of AMR and its sequelae. ■

Disclosure Statement: The author has no conflicts of interest to disclose.

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