Lessons and limits of mouse models

Abstract

Seminal studies in rabbits and rodent transplantation models by Peter Medawar revealed that cellular processes, rather than humoral antibodies, are central to the acute rejection of transplanted organs, and much of basic transplantation research continues to be focused on the biology and control of these cells, which were subsequently shown to be T cells. However, the success of current immunosuppression at controlling T-cell-mediated rejection has resulted in an increasing awareness of antibody-mediated rejection in the clinic. This, in turn, has fueled an emerging interest in the biology of allospecific antibodies, the B cells that produce these antibodies, and the development of mouse models that allow their investigation. Here we summarize some of the more widely used mouse models that have been developed to study the immunobiology of alloreactivity, transplantation rejection and tolerance, and used to identify therapeutic strategies that modulate these events.

Figure 1.

(A) Skin transplantation: Technically simple, a good model for acute T-cell-mediated rejection, and considered a stringent model of tolerance. (B) Heterotopic heart transplantation: Moderate technical difficulty, a good model for acute T-cell-mediated rejection, can model acute and chronic antibody-mediated rejection, notable differences in the pathology of chronic rejection from human chronic rejection, and most common model to investigate immunological tolerance. (C) Orthotopic kidney transplantation: Technically difficult, can be a life-sustaining graft, and can model spontaneous graft acceptance and chronic rejection. (D) Orthotopic liver transplantation: Technically very difficult, life-sustaining graft, and clinically relevant model of spontaneous graft acceptance.