The preclinical model of choice

Abstract

Blockade of CD40-CD154 at the Time of Donor-Specific Blood Transfusion Does Not Lead to Prolonged Kidney Allograft Survival in Nonhuman Primates. Transplantation 2002; 73: 862. The article by Ringers et al. would seem to be of great interest. This group with perhaps the longest experience in primate transplantation clearly failed to reproduce the excellent results in rodents with a donor-specific blood transfusion and CD40-154 blockade. The intuitive concept here is, a classical belief, that a delivery of signal 1 (blood transfusion) coupled with a costimulatory block (anti-CD154 treatment) gives a tolerogenic signal. However, as so often happens, successful tolerogenic treatments in rodents cannot be duplicated in primates, so the results are not surprising from this point of view (1,2). This issue is somewhat muddled by the authors use of posttransplantation cyclosporine (CsA) because this agent has been shown to compromise tolerogenic models in the primate (1). However, the authors note that the synergistic effect of CsA (again, in rodents, as noted by the authors) has been seen. Another issue of some importance is the failure of the CD154 to block humoral antibody responses, an effect noted by others. The CD40-CD154 interaction was originally described as a prominent feature of the T cell-B cell interaction in humoral antibody responses. Is it possible some allogeneic humoral antibody responses are not T cell dependent? This is certainly contradicted by a wealth of literature but could be another explanation for rodent-primate disparity because rodent antibody responses are often attenuated compared with higher animals (3,4). Despite a recent suggestion that the primate models do not necessarily presage human results (5), we suggest that the primate remains the preclinical model of choice, as supported by these results and others (1,2). Perhaps we could paraphrase the issue by drawing from Churchill’s famous comment on democracy: “The primate preclinical model, like democracy, is the worst system available—except for all the others.”