In the attempts to understand human disease and develop therapies, the medical and associated fields have frequently relied upon analogies to observations in animals. While there are a number of similarities between non-primates and primates, there are also a large number of differences. Many of the naturally-produced agents, such as cytokines, hormones, surface membrane proteins, blood proteins, and the like, differ significantly in their composition. Most importantly, for the transduction of signals, cellular interactions, regeneration and differentiation, the molecules involved frequently have a narrow range of host specificity. Where autocrine or paracrine mechanisms are not involved, xenogeneic tissue introduced into a non-primate host must totally rely upon the host for the source of ligands not produced by the xenogeneic tissue or other xenogeneic tissue must be supplied which makes such ligands available. Furthermore, xenogeneic tissue is subject to rejection by an immunocompetent host, so that means must be provided to protect the xenogeneic tissue from degeneration as a result of immune rejection. There are no viable hosts which have no protective mechanisms against foreign entities.
There has been substantial interest in using immunosuppressive agents or immunocompromised hosts to extend the period in which xenogeneic explants may be maintained as viable functional tissue. Frequently, in order to be useful to study the effect of the agents on the xenogeneic tissue, the tissue must retain most if not substantially all of its natural characteristics. However, since the xenogeneic tissue, at best, is only a very small amount of tissue compared to the entire host, it can be subject to many modifications which may change its characteristics, so as to substantially reduce its predictive capability as to the response of the xenogeneic host.
Where the xenogeneic tissue has mobile cells, such as host organs of peripheral blood lymphocytes, such as lymph nodes, thymus, spleen, pancreas, tonsils and the like, these cells may be rapidly displaced by the xenogeneic host cells. Furthermore, vascularization and lymphatic connection can result in the xenogeneic tissue being invaded by host endothelial cells which provide the vessels. Other host cells may also invade the tissue, so as to change the characteristics of the tissue. It is therefore not sufficient that the tissue remain viable or even grow, it is necessary that the tissue retain a substantial degree of similarity to the native tissue, so as to provide responses which are predictive of the responses of the native tissue in the source host for the xenogeneic tissue.
Humans as a host are particularly unique, in the many restrictions which apply to humans and the manner in which they may be studied. Normally, one cannot induce a disease in a human to study the etiology of the disease. Nor can one treat a human with an agent, without first having gone through extensive tests with other mammals, to determine efficacy and pharmacological properties. With many diseases, there are many infectious agents which are tropic for human tissue. In other pathologic conditions, human tissue may respond quite differently from other hosts, due to the nature of its surface membrane proteins, particularly as to metabolic pathways, pharmacology, and the like.
It is therefore of substantial interest that mammalian hosts, particularly small mammalian hosts, be developed, which allow for the study of the response of human tissue to a variety of agents, particularly pathogenic agents and therapeutic agents used to treat the infection or diseased state.