Hypophysitis Research Center

Future Directions and Animal Models

The availability of a biomarker capable of distinguishing autoimmune hypophysitis from other masses occupying the sella turcica would greatly improve patient management. At the moment this distinction is not possible. Researchers have used animal models through the years to improve our understanding of autoimmune diseases. Of the total 315 journal articles we could find on AH, 6 made use of animal models (Table). Beutner et al in 1964 immunized rabbits with rabbit anterior pituitary extracts, mixed with complete Freund's adjuvant. They were able to demonstrate specific antibody responses, but no pituitary pathology. Levine published in Science the first successful model of experimental AH. He immunized young rats with rat anterior pituitary extract emulsified in complete Freund's adjuvant and was able to show diffuse infiltration of the pituitary gland with mononuclear cells (lymphocytes, monocytes and occasional epitheliod cells) in 6 out of 14 rats (43%). Disease incidence could be increased to 75% (15 out of 20 rats) by addition of a second immunologic adjuvant, pertussis toxin. In his 1969 publication, he then went on to show that pituitary extracts from guinea pig were the most potent inducer of experimental AH (6/6 rat recipients), whereas human and cow extracts were poorly effective, and dog and rabbit extracts not effective at all.

In 1982 Klein induced lympho-plasmacytic infiltration of the anterior pituitary by injecting rabbits 3 times, at 2 weeks interval, with 2 mg of rabbit pituitary extracts, emulsified in complete Freund's adjuvant. He was the first to show that T cells play an important role in the pathogenesis of this disease. Ten years later, Yoon et al showed that rubella virus E1 and E2 glycoproteins, produced by recombinant DNA technology in mammalian cells, induced antibodies against pituitary cells and diffuse lymphocytic infiltration throughout the pituitary gland. None of the hamster that had received the control protein (nonglycosylated rubella nucleoprotein C) showed such lesions in the pituitary. The disease could be prevented by neonatal thymectomy, and could not be produced be passive transfer of the autoantibodies, thus indicating that T cells are critical for disease induction and that antibodies are more like an important marker of disease, rather than a pathogenic player. Finally, Watanabe et al in 2001 immunized Lewis rats with rat pituitary extract and showed minimal lymphocytic infiltration in the pituitary and antibodies directed against growth hormone, thyreotrope and luteinizing hormone.

A notable absent in these animal models is the mouse, probably the most frequently used animal models in autoimmune diseases, because of the enormous amount of information and material available on this species (such as a complete genome, numerous genetically modified strains and immunological reagents).

Year Author Host Immunogen Results
1964 Beutner Rabbit Rabbit anterior pituitary Production of antibodies, but no pituitary pathology
1967 Levine Rat Rat anterior pituitary Antibodies not studied. Diffuse lymphocytic infiltration in the anterior pituitary
1969 Levine Rat Rat anterior pituitary Antibodies not studied. Guinea pig extracts induce the most severe pathology
1982 Klein Rabbit Rabbit pituitary Antibodies negative. Diffuse lymphocytic infiltration in the anterior pituitary
1992 Yoon Hamster Recombinant E1 and E2 rubella virus proteins Induction of pituitary antibodies and diffuse lymphocytic infiltration
2001 Watanabe Rat Rat pituitary Induction of pituitary antibodies and focal lymphocytic infiltration