Immunosuppressive Drugs in Paediatric Liver Transplantation

Abstract

Orthotopic liver transplantation is established treatment for children with acute and chronic liver failure. Despite advances in pre- and postoperative management, innovative surgical techniques and new immunosuppressive drugs, acute and chronic rejection remains a problem. In addition, well established adverse effects of commonly used immunosuppressive drugs are no longer accept able. More potent, but less toxic, immunosuppressive agents have been developed and some novel compounds are now entering routine practice. Cyclosporin was the cornerstone of immunosuppressive therapy until the introduction of its novel pharmaceutical form (Neoral) with improved bioavailability, lower inter- and intraindividual pharmacokinetic variability and improved graft survival. Recently, tacrolimus, a macrolide drug with a similar mode of action, but much higher potency, was introduced and, at present, is the only agent which can successfully replace cyclosporin as a first-line immunosuppressive drug. Mycophenolate mofetil has recently been approved for use in adult and paediatric renal transplant recipients. It has a similar mode of action to cyclosporin and tacrolimus, but acts at a later stage of the T cell activation pathway. Administration with standard immunosuppressive drugs reduces the incidence of acute rejection and enables cyclosporin and tacrolimus dose reduction, thus reducing the risk of associated toxic effects. Phase I and II trials with sirolimus (rapamycin), a macrolide antibiotic, have shown comparable immunosuppressive action, when administered in conjunction with standard immunosuppressants. Further clinical trials need to be carried out to establish efficacy, tolerability and pharmacokinetics in paediatric transplant recipients. Monoclonal antibody therapy (daclizumab and basiliximab) is an exciting new development whereby T cell proliferation is inhibited by selective blockade of interleukin (IL)-2 receptors. Preliminary results, when used in combination with a standard immunosuppressive regimen, are good with respect to incidence of acute graft rejection, host immune response and adverse effects. FTY720 is a novel synthetic immunosuppressive compound which induces a reduction in peripheral blood lymphocyte count through apoptotic T cell death or accelerated trafficking of T cells into lymphatic tissues. Experimental animal studies demonstrated synergistic action in combination with low dose cyclosporin or tacrolimus, potentiating their immunosuppressive effects. Further studies are being carried out to determine its potential for application in organ transplantation. Despite this rapid development of novel compounds, it will take many years before they may become part of standard protocols in paediatric transplantation medicine. Further development and research of efficacy and tolerability of existing drugs is, therefore, vital.

Daclizumab as useful treatment in refractory acute GVHD: a paediatric experience

“…This T-cell inhibition proved to be effective when Dac was used in the rejection prophylaxis of patients undergoing solid organ transplant. 11,12 Dac was also found to be effective as second-line treatment of steroid-resistant GVHD in a limited number of reports that mostly referred to adult populations. [5][6][7][8][9][10] Response rates for aGVHD ranged between 29 and 68% in these series; however, data regarding the children who were included in these studies were not evaluable separately because they were not stratified by age.…”

“…In studies involving exclusively adults, or both adult and paediatric populations, [5][6][7][8][9][10] Dac is reportedly safe when used in children as rejection prophylaxis after organ transplantation, 11,12 and effective in the second-line treatment of refractory acute GVHD (aGVHD) and chronic GVHD (cGVHD).…”

Mycophenolate mofetil monotherapy in the management of paediatric uveitis

“…[11][12][13] Over the past decade, several studies have demonstrated a similar clinical effectiveness of MMF in paediatric transplant patients. [14][15][16] MMF has also been proven effective in autoimmune diseases in children. [17][18][19][20] Here, we report our experience with MMF in paediatric patients with autoimmune uveitis.…”

“…Nine of them achieved inflammation control on MMF without concomitant corticosteroids or other IMTs for a median of 15 months (range: [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]. During this follow-up period, 8 out of the 9 patients experienced no uveitis relapse; 1 patient experienced one relapse that was treated with 4 weeks of topical corticosteroids.…”

Daclizumab for children with corticosteroid refractory graft-versus-host disease

“…2 Daclizumab has been shown to be safe in children when used to prevent rejection after solid organ transplantation. 3,4 A few small studies have shown daclizumab to be effective in treating refractory acute and chronic GVHD in adults. 2,[5][6][7] Three of these studies included a small number of children; 2,6,7 however, results were not stratified by age.…”