Nonhuman primates for the study of composite tissue allotransplantation.

In a recent editorial, Siemionow analyzes historical outcomes of composite tissue allotransplantation (CTA) transplants in nonhuman primates (NHPs) in response to our manuscript (1). We appreciate the commentary and commend Siemionow for her contributions with rodents (2, 3). Siemionow highlights limitations of the NHP model, specifically “the lackofpredictabilityof timingofallograft rejection or survival despite application of the same immunosuppressive regimens” (4). Humans and, to a lesser extent, experimental animals are exposed throughout their lives to factors that condition their immune responses (infections, pregnancy, transfusions). These shape unique antigen responses and markedly alter each individual’s threshold to respond to any immune event. Thus, variability is a hallmark of an increasingly complex immune system and grows with phylogenetic advancement (5). Our practice continuously encounters unpredictability and indeed, its focus is to understand rejection and improve drug efficiency amid this irregularity. To date, the number of transplants performed in primates (human or nonhuman) is too few to draw any generalizations and certainly is not such that increased variability should be viewed as an unrepresentative of the clinic. Siemionow emphasizes, “so far, only two rejection cases of human hand transplantation have been reported and current outcomesarebettercomparedtoNHPstudies. ” A commendable publication by the hand registry reported 17 recipients (6) of whom the majority (not two) experienced rejection within the first year. Rescue therapy (which was not attempted in our NHPs) was typically successful. A systematic evaluation of the infiltrate is being under study in NHPs, and our group would argue that variability is best evaluated experimentally prior to subjecting humans to experimentation. Clearly, no single model will answer all research questions, although many avenues are only approachable through NHPs systems. Their general physiology and anatomy, and the histology and cadence of unmodified rejection, are comparable to that of humans (7). Conversely, functional outcomes (e.g., range of motion) after hand transplantation are difficult to assess in NHPs (8) and all animal models. Although other parameters related to function are possible to evaluate, neurophysiologic studies have shown normal proprioceptive and motor responses after hand transplants in baboons (8). Siemionow stresses that “despite development and application of new immunosuppressive therapies, primates are still resistant to accepting CTA transplants in a pattern similar to what was reported almost 20 years ago” (8, 9). These studies and ours are comparable in that they include different tissues. However, they differ in the research questions: one includes the entire hand and the second one was designed to address long-term survival and its functional reinnervation under cyclosporine A. The first study concluded, “Long-term survival of limb allografts can be achieved if the immunosuppression is combined with continuous methylprednisolone administration. In the presence of high serum levels of CyA, long-term survival of limb allografts can be achieved with continuous methylprednisolone administration. ” The second includes longterm survival in five animals, reversible rejection in three, chronic rejection in one, and uncontrollable rejection in two (9). Although rejection has been presumed to be mediated by mechanisms similar to solid organ transplantation, a systematic examination of the inflammatory infiltrate has not been performed. Furthermore, models for testing of humanspecific immunosuppressants are also needed. However, before any question can be answered in NHPs, the model itself needs to be established. This includes maneuvers like allowing subtherapeutic immunosuppressive levels to evaluate rejection and its relationship to human rejection (10). CTA is an emerging field and as with other transplant fields, large-animal models are necessary to test hypotheses before systematically study in humans (7, 11). The alternative, to embark on blind human experimentation for a nonlife-threatening condition, is unnecessary and untenable.