Achieving immune tolerance in hand and face transplantation: a realistic prospect?

Abstract

Vascularized composite allotransplantation has developed rapidly during the past two decades, and while the main advances seen clinically have been in surgical technique, rehabilitation and patient selection, research leading to increased understanding of the immunobiology of vascularized composite allografts (VCAs) and development of novel protocols to control rejection is proceeding apace. The majority of VCA centers utilize conventional immunosuppressive protocols, typically derived from local solid organ transplant protocols that include antibody-mediated induction therapy with antithymocyte globulin followed by maintenance with calcineurin inhibitors (tacrolimus), an antiproliferative agent (mycofenolate mofetil), and steroids; the latter typically with a rapid wean to either low-dose maintenance or withdrawal [1]. These protocols have achieved a remarkable degree of protection against graft loss to acute rejection, with 1-year survival at 100% [1,2]. This is a feat shared by no other branch of transplantation; however, it is countered by a high incidence of acute rejection episodes, typically targeting skin, which is diagnosed in up to 90% of patients at least once within the first year [1,2]. It has been postulated that this dichotomy is due to the superficial location of VCAs, permitting rapid diagnosis and treatment of rejection episodes, which would present more slowly in solid organ transplantation. However, it may also reflect the intrinsic antigenicity of skin, which has long been recognized to pose a significant barrier to transplantation [3]. Recently, some centers have investigated modified immunosuppressive protocols for VCA with the aim of reducing the overall burden of immunosuppression. The infusion of donor bone marrow to modulate the recipient immune system has been demonstrated by the Pittsburgh/Johns Hopkins group to allow for transition to maintenance immunosuppression using single-agent tracrolimus [4]. While it is important to note that this is not a tolerance protocol, and the mechanisms by which the infusion of donor marrow without conditioning and establishment of detectable chimerism could act to reduce alloreactivity are not fully elucidated, the early results from this trial are encouraging. In contrast to this approach, where maintenance therapy, albeit at a low dose, is required and chronic rejection should be considered a possibility, the establishment of tolerance resulting in specific unresponsiveness to donor antigens, would be expected to fully control both acute and chronic rejection. The induction of tolerance of transplanted organs is considered the Holy Grail of transplant immunology research, the pursuit of which has been supported, prior to the advances in renal transplantation over the past decade, by anecdotal reports of spontaneous tolerance of liver and kidney allografts in patients noncompliant with immuno suppression [5,6]. Unfortunately, there currently does not exist a biomarker that reliably allows for Achieving immune tolerance in hand and face transplantation: a realistic prospect?