Immunomodulatory properties of steroid hormones

Sammanfattning: Recent epidemiological, clinical and experimental evidence have suggested that steroid hormones play an important role in immune responses and in immune-mediated diseases. Many autoimmune diseases are treated with corticosteroids. Also, oestrogen has been shown to have beneficial effects when administered to patients suffering from rheumatoid arthritis. In this thesis, we focus on the impact of combined treatment with suboptimal doses of corticosteroids and oestradiol on T lymphocyte mediated delayed type hypersensitivity (DTH), granulocyte-mediated inflammatory responses and immunoglobulin production. We also examined the cellular requirements for the development of DTH in severe combined immunodeficiency (SCID) mice in order to differentiate the influence of steroid hormones on the participating cell populations. In further experiments we studied the kinetics of corticosteroid and oestradiol induced thymic atrophy and alteration of the phenotype distribution of lymphocytes in the thymus and in the spleen. It was shown that combined treatment with suboptimal doses of corticosteroids and oestradiol had additive effects on the suppression of DTH, but not on granulocyte-mediated inflammation. The immunoglobulin production was increased after exposure to oestradiol but suppressed by corticosteroids. It was further shown that for the development of DTH a H-2 restricted APC-T cell interaction is required, whereas B cells are not mandatory. In transfer experiments it was shown that SCID mice receiving oestradiol-exposed spleen cells from syngeneic or allogeneic donor mice displayed lower DTH response. The opposite was seen when oestradiol-exposed syngeneic thymocytes were transferred. Oestradiol-treated SCID mice, transferred with syngeneic spleen cells or thymocytes, displayed significantly lower DTH response. Interestingly, corticosteroid-treated SCID mice, transferred with syngeneic thymocytes, displayed increased DTH response and SCID mice receiving corticosteroid-exposed thymocytes did not change their DTH response. However, corticosteroids significantly decreased DTH response when given one day before challenge. Exposure of adult mice to corticosteroids led to a rapid and pronounced thymic atrophy compared to their oestradiol treated counterparts. Corticosteroids induced thymic atrophy resulted from a proportional loss of the CD4/CD8 double positive subset of T cells. Oestrogen treatment caused an increase of spleen weight and cellularity and both hormones led to decreased numbers of B220+ B cells.In conclusion, it is shown that oestradiol and corticosteroids have additive effects on suppression of DTH. T lymphocytes are not the target for oestradiol-mediated suppression of DTH. Corticosteroids suppress the effector phase of DTH response in mice possibly by their anti-inflammatory properties or by effects on activated memory T cells. The results concerning thymic atrophy and lymphocyte phenotypic alteration in mice, following oestradiol and corticosteroid treatment, imply differences in both kinetics and in the mechanisms by which these compounds elicit their respective effects on thymus. Our findings may form a basis for future combination therapy with corticosteroids and oestradiol in patients suffering from rheumatic diseases such as RA, Sjögren´s syndrome, and certain vasculitides.