Analysis of Historical Outcomes of Composite Tissue Allograft Transplants in Nonhuman Primates

In this issue of Transplantation, Cendales and co-authors have introduced a sensate osteocutaneous radial forearm flap as a model of composite tissue allograft (CTA) transplants in nonhuman primates (NHP) 0168(1). In a series of experiments on 19 monkeys evaluating autologous and allogeneic CTA transplants, the authors have proven technical feasibility of the model. They have characterized the immunologic and histologic pattern of the CTA rejection in transplant recipients without immunosuppressive therapy and have described the pattern of delayed rejection (up to 76 days) in the recipients receiving triple therapy of tacrolimus, mycophenolate mofetil, and methylprednisolone. This study confirms results of some previous experiments carried on the radial forearm and partial hand allograft transplants in NHPs (2–5). Although extension of the CTA survival and tolerance can be readily induced in rodent transplant models, it is still difficult to induce tolerance and extend CTA survival in the large animals. It seems logical that clinical strategies for tolerance induction in the CTA transplants should rely on the large animal models. The NHPs have the obvious advantage of genetic similarity to humans. Specifically, the MHC class I and class II loci share structural homology between the rhesus macaques and humans (5). Despite these similarities, there are some significant problems encountered by the researchers studying CTA transplants in primates. Previous reports carried on CTA a transplants in NHPs included: full hand transplantations in baboons, the radial forearm/thumb allograft transplantations in rhesus monkeys, and the composite mandibular allograft in cynomolgus monkeys (2–6). It was shown that hand transplantation in NHPs is technically feasible and the functional results were promising (2, 3). However, a common problem encountered in all these studies was the lack of predictability of timing of allograft rejection or survival despite application of the same immunosuppressive regimens (2–6). In 1986, Daniel et al. reported four hand transplants and seven neurovascular free-flap allograft transplants in baboons (2). The authors used high doses of CsA and steroids as the immunosuppressive therapy. Despite the same immunosuppressive protocol, three out of four hand allografts rejected, and only one survived up to 304 days posttransplant. However, four digital free flaps survived for more than 4 months again on the same protocol of combined CsA and steroid therapy. There was reinnervation of the transplanted skin confirmed by electrophysiological tests and reinnervation of donor muscles was demonstrated by response to electrical stimulation of the recipient's median and ulnar nerves (2). In 1987, Stark et al. used CsA (20 mg/kg) and prednisolone (1.5 mg/kg) as an immunosuppressive regimen in the hand transplantation model in baboons. They reported long-term survival in one transplant recipient up to 296 days, and the other six animals rejected hand allografts within 15 days posttransplant (3). In 1990 Stevens et al. reported their results of 12 partial hand transplantations in rhesus monkeys (4). The transplant model was anatomically based on the radial side of the hand and included: the radial forearm flap which was combined with the first ray of the hand including thumb, in order to study sensory recovery and motor function. S.E.R. Hovius summarized this work in his PhD thesis on the functional and immunological aspects of the partial hand transplantation in nonhuman primates (5). The shorter (21 to 33 days) survival periods were achieved under combined protocol of CsA and prednisolone. The rejection was reversed by increased dosages of prednisone and survival increased up to 79 and 179 days (4, 5). The return of sensation in this model was observed between 27–64 days posttransplant as assessed by the withdrawal reflex in response to the electrode stimulation. First signs of motor recovery assessed by Compound Motor Action Potentials (CMAP) were recorded between 31 and 56 days posttransplant and electromyography of the thenar muscles showed recovery between 72 and 79 days posttransplant in long-term survivals. Unfortunately, at longer follow-ups all grafts were lost due to sepsis, formation of lymphoid tumors or due to animals' death (5). Finally in 1991, Gold et al., in a study on four cynomolgus monkeys, showed that a composite mandibular allograft transplant consisting of the mandible with attached muscle, skin and mucosa was technically feasible. CTA recipients received a daily dose of 15 mg/kg of CsA monotherapy. As a result two of the recipients rejected as early as 13 and 27 days posttransplant and two other survived up to 63 and 65 days respectively (6). The cause of early versus late rejection was not detected. In their current study, Cendales et al. have confirmed the unpredictability of rejection and survival time of the CTA transplant recipients, indicating that animals submitted to the same triple protocol of immunosuppressive therapy have rejected grafts at very different time points starting as early as 5, 8, 15, 17, 24 days posttransplant and showing extended graft survival up to 73 and 76 days in two allograft recipients. Common to all previous reports is the fact that, immunosuppression was used in a nonselective manner, which inevitably could have deleterious side effects on the recipients when used chronically. Furthermore, when the high antigenic load of primate skin is taken into account, the amount of immunosuppressive regimens may need to be either considerably increased or should include more specific protocols such as costimulation based therapies to guarantee longer CTA transplant survival (7). The triple regimen of immunosuppressive therapy used by Cendales et al. was, as the authors stated, “subtherapeutic,” so considering previous reports, the achievement of long-term allograft survival was unlikely and authors were interested in studying progression and resolution of CTA rejection. Dr. Cendales and colleagues have to be commended on carrying such a challenging experimental study on the largest in the literature series (19 primates) of the CTA transplants in the NHP model. Their study has confirmed 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 (2, 3). Interestingly, much better outcomes are reported worldwide after human hand allograft transplantation (24 cases) and so far only two rejection cases were reported (8, 9). The first U.S. hand transplant recipient is currently at the seventh year of follow-up, presenting a satisfactory clinical outcome. In contrast to the protocols used in primate studies, most of the human CTA recipients received induction therapy followed by standard immunosuppressive protocols for kidney transplant recipients (8, 9). Considering the encouraging outcomes of the CTA transplants in humans, the question remains of how, from an ethical point of view, we should approach future studies on CTA transplants in nonhuman primates to achieve reproducible results.