Ann Thorac Surg 2004;77:1739
© 2004 The Society of Thoracic Surgeons
Invited commentary
David B. Ross, MD
University of Alberta Hospital, 2D4.37 Walter MacKenzie Health Sciences, 8440 112th St, Edmonton, AB, T6G 2B7 Canada
e-mail: dbross{at}cha.ab.ca
Shady and colleagues have demonstrated in this small pilot study that mycophenolic mofetil can significantly, but incompletely, reduce the development of antibodies to HLA class I (but not class II) antigens following implantation of valved allografts in children undergoing cardiac surgery. This study builds on their previous work that clearly demonstrates that implanting cardiac allograft tissue results in the development of donor specific antibodies lasting at least one year in these children. That cardiac allograft tissue elicits a powerful and sustained immunological reaction is well established. Whether attenuating this response is beneficial and worth the inevitable side-effects of therapy is less clear.
The antibody response that the authors seek to prevent has at least the theoretical potential to damage the allograft valve, thus shortening its functional life. This is logical but unproven. In animal studies using inbred and outbred strains of rats, one can demonstrate that allograft valves are damaged in the outbred strains; but this seems to be largely mediated by cellular mechanisms, is prevented by cyclosporine, and does not occur with valves implanted between inbred animals. The role of humoral immune mechanisms in this damage is less clear. Mycophenolic mofetil does inhibit proliferation of both T and B lymphocytes so its use in this study is logical. While the role of immune sensitization in the failure of allograft cardiac valves is still controversial and unproven, it is absolutely clear that such sensitization will greatly complicate the care of children who may require subsequent cardiac transplantation. Shaddy and others have shown that implantation of allograft cardiac tissue leads to virtually 100% positive PRA, which persists for at least one year. The development of a safe method to reduce this antibody response is thus important, particularly for children with lesions likely to require cardiac replacement at some point. Hypoplastic left heart syndrome repaired with allograft arch augmentation is a particular concern.
One major concern with the short-course therapy, as used in this study, is whether the antibody response is simply suppressed while the patient receives the drug. The fact that previous studies show persistently high antibody levels for at least one year suggests that the allograft tissue is the source for ongoing immune stimulation that may require continuous therapy to suppress. While one could envision accepting the side-effects of short course therapy for these children, long-term treatment would be unlikely to be acceptable. It is thus unfortunate that this present study did not assess antibody levels following cessation of the mycophenolic mofetil.
The authors deserve credit for rigorously approaching this area with their pilot study. There is at present no scientific justification for routinely giving children immmunosuppression following allograft valve implantation. There is, however, great need for further properly designed studies to determine the ultimate role of such therapy for these children.
