A Symposium on Donor‐Specific Antibodies after Transplantation Introduction

The paper by Ho et al. (1) in this issue of Pediatric Transplantation launches a symposium on donor-specific antibodies after transplantation. During the 50-or-so-year history of clinical transplantation, no subject has commanded greater attention and provoked greater controversy. The attention to donor-specific antibodies derives in part from the use of these unique reagents to define the major histocompatibility locus (2) and use in tissue typing (3) and in part from use of sera of a potential recipient for crossmatching to prevent immediate rejection (4). Today, donor-specific antibodies might offer insight into the immunological responsiveness of a recipient against their graft and hence a warning about the risk of rejection. Donor-specific antibodies also spark controversy. Some believe these antibodies cause the most important types of rejection, while others believe they merely mark the immune or inflammatory condition. Some have found these antibodies can modify grafts or the immune response to grafts that actually protects against rejection. Controversy about whether donor-specific antibodies are effectors or just markers of immunity to a graft is of more than academic import, as one now can apply specific but also expensive and potentially toxic therapies to suppress or deplete these antibodies. Whether and to what extent donor-specific antibodies elicited by transplantation determine the fate of grafts remains to be settled. The complexity of this question and the difficulties faced by those who have tried to answer it were critically and thoroughly summarized by Stetson in 1963 (5). Part of the complexity stems from the fact that antibodies can protect as well as injure grafts (6) and in part from the fact that organ grafts are far more susceptible to antibodymediated injury than cell and tissue grafts (7). Opposing the preeminence of antibody as an effector of graft outcome were the seminal studies of Mitchison (8) showing that alloreactivity is transferred by cells but not by serum and Brent et al. (9) likening the allogeneic response to the delayed-type hypersensitivity reaction. The advent and successful use in transplantation of pharmaceutical agents relatively selective for T cells appeared to resolve the argument, at least for the first 30 yr of clinical transplantation, in favor of cells. However, today, it would seem more attention is devoted to humoral than to cellular immunity to transplantation. Successful control of acute cellular immunity led to the recognition that the long-term success of organ allografts is threatened mainly by antibody-mediated chronic vascular and interstitial diseases that demonstrably resist the pharmaceutical agents so effective at suppressing cellular immunity. Moreover, today, in subjects treated with immunosuppressive agents, the outcome of transplantation correlates more closely with humoral than with cellular immune responses (10). And, improvements in overall survival, including freedom from cardiovascular disease and cancer, might today depend on finding ways to ‘‘fine-tune’’ immunosuppressive therapy, and for that purpose, donor-specific antibodies might provide a more sensitive and specific index than assays of peripheral T-cell responses. Whether antibodies provide an index that can direct and refine therapeutics is still unknown, but the results of Suciu-Foca et al. (1) and Gloor (11) suggest the answer may be ‘‘yes’’. Jeffrey L. Platt Transplantation Biology, Departments of Surgery and Microbiology and Immunology, BSRB, University of Michigan, USA Pediatr Transplantation 2011: 15: 455–457 2011 John Wiley & Sons A/S.