Murine model of allogeneic adrenocortical cell transplantation: perspectives for the treatment of Addison's disease in man.

Background: Hormone substitution for the treatment of adrenocortical insufficiency (Addison's disease) does not adequately substitute the physiological circadian secretion of corticosteroids leading to long-term sequelae and reduced quality of life. Moreover, oral administration of corticosteroids cannot mimic the hormone peaks required in stress situations. This lack of adaptation to physical and psychological stress may lead to life-threatening Addisonian crises. Allogeneic transplantation of adrenal cortex may offer an alternative. Methods: Major histocompatibility complex (MHC) class I transgenic mice (H-2Kb) were used for the implementation of an animal model of adrenocortical transplantation. Tissue fragments or selectively isolated cell suspensions of the adrenal cortex were transplanted underneath the kidney capsule of adrenalectomized mice. Kb-transgenic murine cells as well as allogeneic adrenal cortex cells were cocultured in mixed lymphocyte cultures (MLC) in order to examine the alloimmune response. Lymphocytes from T-cell receptor transgenic mice and normal allogeneic mice respectively served as responder cells. The immune response, i.e. lymphocyte proliferation, was quantified by measuring the [[sup 3]H]thymidine uptake of responder cells. The effect of corticosteroids secreted by adrenocortical cells was antagonized by the steroid receptor antagonist Mifepristone (RU 486). Results: Without need for immunosuppressive drugs, adrenocortical grafts were demonstrated to proliferate and produce corticosteroids at physiological concentrations 20 days after transplantation. Coculture of adrenal cortical cells in MLC markedly suppressed lymphocyte proliferation. This inhibited immune response was not completely antagonized by RU 486. Conclusion: In vitro, the presence of adrenocortical cells potently suppressed allogeneic immune responses. This effect was not only due to the secretion of corticosteroids, pointing to a additional immunomodulatory pro... [ABSTRACT FROM AUTHOR]