Animal models for complement deficiencies.

The complement system plays a key role in host defense and in the development of autoimmunity. Three types of animal models of complement-mediated disease have traditionally been used: they involve normal animals, animals with spontaneously arising genetic deficiency, and animals treated with complement-inactivating agents. All of these approaches have had partial success in our attempts to understand complement mechanisms. Most animal models of genetic deficiency have been studied relatively little, as the availability of such animals is limited. C4, C2, and partial C3 deficiency in the guinea pig are well characterized, although only C4 deficiency in the guinea pig has been exclusively studied. C3 deficiency in the dog and C6 deficiency in the rabbit are well described, although studies are limited in number. C6 deficiency in the rat has been described recently and C5 deficiency in inbred mice strains has been studied fairly extensively. Factor H deficiency in the Yorkshire pig has also been described. Relatively few agents that inhibit complement are in use. Most widely used in animal studies is cobra venom factor. This inactivates the alternative complement pathway in the fluid phase and thereby depletes complement protein levels. The antigenicity of this protein, purified from the venom of cobras, limits its duration of use in most animal models. Complement-inhibiting agents are rare and, as yet, not widely used. We recently described the use of intravenous immune globulin for inhibiting complement in animal studies and present data on its use in animals, including discordant xenograft rejection, and its potential use in human disease. New developments in molecular biology provide the potential for a vast new array of deficiency models. A limited number of laboratories are actively engaged in the production of animals with inactivated genes. For example, gene knockout mice with no C3, and with no factor B, have been generated. Several complement control proteins have been prepared by genetic molecular biological techniques. Most promising among these is CR1, which limits complement damage in several animal models. Transgenic animals, which complement regulatory proteins expressed on their cells, have been prepared. As complement control proteins tend to be more efficient at regulating complement of the same species type as the regulatory protein, these animals may be useful in such areas as xenograft transplantation. The various animal models are reviewed and their potential application to understanding of human disease is emphasized.