The importance of large animal models in transplantation

Abstract

Animal models have been extensively used in transplantation research. However, animal experimentation is contentious and subject to legal and ethical restrictions. Most experiments are carried out on rodents, but crucial prerequisites for the development of safe pre-clinical protocols in biomedical research are needed through suitable large animal models. In transplantation particularly, large animal models have developed dramatically. This article provides an overview of the large animal models commonly used to evaluate organ transplant experiments and analyzes the specificity of several models in various situations such as induction of allospecific tolerance and xenotransplantation. The key determination that remains be addressed is the most appropriate species and strains to model human immune and physiological systems. Because of their phylogenetic and physiologic similarities to man, non-human primates play an increasingly important role in pre-clinical testing. Nevertheless, a number of studies have shown the pig to be a reliable large animal model for transplantation research, and the availability of genetically defined or modified pigs establishes a stronger position for pigs as a large animal model.

The utility of animal models in developing immunosuppressive agents

“…They are also anatomically very similar to humans. The tempo and histological findings of organ rejection are also very similar to humans (Dehoux and Gianello, 2007).…”

“…Much important information about pharmacologic agents is gleaned from rodent studies, but there remain important constraints in the applicability to humans. Drug absorption is greatly different between large animals and humans (Anderson and Kirk, 2013;Dehoux and Gianello, 2007). Drug distribution also differs between species.…”

“…Dogs also poorly absorb sirolimus, and are much more prone to tacrolimus toxicity. Pigs, in contrast, tolerate very high levels of calcineurin inhibitors, even to the extent of inducing tolerance in some transplant models (Dehoux and Gianello, 2007).…”

“…This may be because of dogs being used older when they have more immunological memory, and dogs being perhaps more outbred than pigs/primates. Thus dogs are often regarded as more immunologically stringent than pigs and primates because it is difficult to achieve tolerance (Dehoux and Gianello, 2007).…”

“…This contrasts with research primates, for example, which are captured in the wild having had exposure to environmental pathogens which allow generation of immunological memory. Although experiments on outbred rodents bred in non-specific pathogen free circumstances are useful, large animal models bear more similarities to humans (Dehoux and Gianello, 2007).…”