| Summary: | 博士 === 國立臺灣大學 === 微生物學研究所 === 88 === The goal of this study is to try to find out the mechanisms for the therapeutic effects of tamoxifen (TAM) on the severity of autoimmune disease. The preliminary study using normal female BALB/c mice showed that administration of a different dose of TAM had no significant side effects in mice. To investigate further the regulatory mechanisms of TAM in female MRL-lpr/lpr mice, we administrated 200mg TAM to each mouse four times every two weeks and then evaluated the serological parameters and cellular functions. As compared to control mice, the TAM-treated female MRL-lpr/lpr mice showed: (1) smaller spleen and lymph nodes, (2) a smaller percentage of T cells and double negative T cells (DN T cells, CD4- CD8- T cells) among splenocytes, (3) no difference in cytokine production, (4) higher IL-2 production in mitogen-stimulated lymph node cells, (5) higher 3H-incorporation of lymph node DN T cells in proliferate assay, (6) inhibition of in vitro IL-2 activated proliferation of lymph node DN T cells by TAM treatment in a dose dependent manner, and (7) alleviation of the disease in both male and female MRL-lpr/lpr mice through administration of TAM. In parallel, we studied the effects of TAM on female NZB/W F1 mice, which developed a natural course of lupus symptoms much closer to human SLE. We found that after treatment with TAM (800mg TAM / mouse / every two weeks) for 5 months, TAM-treated NZB/W F1 mice had less severe proteinuria and an increased survival rate compared to controls. TAM-treated NZB/W F1 mice showed: (1) a significantly lower percentage of splenic B cells and CD5+ B cells, (2) a significantly lower serum level of soluble TNF receptor I and II molecules, and (3) less pathological change in the kidney. Collectively, our findings demonstrated that TAM may influence T cells and consequently modulate the immune function in MRL-lpr/lpr mice. Moreover, TAM treatment may affect immune function, influence the B cell count, modulate the expression of cytokine receptors and thereby subsequently alleviate the symptoms of lupus nephritis in NZB/W F1 mice. The compelling data presented here indicate that TAM suppresses the circulatory IGF-I levels in lupus strains of mice. We also hypothesize that TAM may have its regulatory effect through a pathway other than oestrogen effect; it may affect the translocation of protein kinase C on cell membrane or inhibit the secretion of IGF-1 growth factor. It has yet to be determined whether a similar mechanism can be generalized to explain the effect of TAM on the in vitro lymphocyte culture system. TAM may interfere with the actions of GH and IGF-I on effector cells of the immune system and direct the existed neuron- endocrine-immune axis, and IGF-I may play a critical role in the pathogenesis of renal disease in lupus. Further understanding the mechanisms of TAM is important for the future application of this particular drug for autoimmune diseases other than breast cancer, as well as for designing new derivatives of the drug with higher potency and less deleterious side effects.
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