Tamoxifen alleviates disease severity and decreases double negative T cells in autoimmune MRL‐lpr/lpr mice

Some polyacetylenes from the plant Bidens pilosa have been reported to treat diabetes. In this study, we report that the cytopiloyne from B. pilosa, which is structurally different from the above-mentioned polyacetylenes and inhibits CD4+ T cell proliferation, effectively prevents the development of diabetes in nonobese diabetic mice as evidenced by a normal level of blood glucose and insulin and normal pancreatic islet architecture. Cytopiloyne also suppresses the differentiation of type 1 Th cells but promotes that of type 2 Th cells, which is consistent with it enhancing GATA-3 transcription. Also, long-term application of cytopiloyne significantly decreases the level of CD4+ T cells inside pancreatic lymph nodes and spleens but does not compromise total Ab responses mediated by T cells. Coculture assays imply that this decrease in CD4+ T cells involves the Fas ligand/Fas pathway. Overall, our results suggest that cytopiloyne prevents type 1 diabetes mainly via T cell regulation.

Section: H]thymidine Incorporation Assayssupporting

confidence: 93%

Cytopiloyne, a Polyacetylenic Glucoside, Prevents Type 1 Diabetes in Nonobese Diabetic Mice

Chang

Lee

et al. 2007

“…In agreement with this idea, raloxifene negatively regulated B lymphopoiesis in BM in two separate studies (24,25), and tamoxifen treatment was shown to reduce the severity of autoimmune disease in mouse models (18,22,26). However, the observation that tamoxifen has beneficial effects on autoimmune disease are contradicted by data suggesting that tamoxifen can augment lymphocyte activation (22,27). Regardless, because ER are expressed by many cells of the immune system, including DC (28 -31), it should not be surprising that SERM possess immunomodulatory properties.…”

Section: Endritic Cells (Dc)mentioning

confidence: 86%

“…Furthermore, in vivo exposure of mice to tamoxifen (22) or raloxifene (23) reduced lymphoid organ weights suggesting that these SERM may dampen immune responses. In agreement with this idea, raloxifene negatively regulated B lymphopoiesis in BM in two separate studies (24,25), and tamoxifen treatment was shown to reduce the severity of autoimmune disease in mouse models (18,22,26). However, the observation that tamoxifen has beneficial effects on autoimmune disease are contradicted by data suggesting that tamoxifen can augment lymphocyte activation (22,27).…”

Section: Endritic Cells (Dc)mentioning

confidence: 99%

The Selective Estrogen Receptor Modulators, Tamoxifen and Raloxifene, Impair Dendritic Cell Differentiation and Activation

Nalbandian

Paharkova-Vatchkova

Mao

et al. 2005

104

Most immune cells, including myeloid progenitors and terminally differentiated dendritic cells (DC), express estrogen receptors (ER) making these cells sensitive to estrogens. Our laboratory recently demonstrated that 17-β-estradiol (E2) promotes the GM-CSF-mediated development of CD11c+CD11bint DC from murine bone marrow precursors. We tested whether the therapeutic selective estrogen receptor modulators (SERM), raloxifene and tamoxifen, can perturb DC development and activation. SERM, used in treatment of breast cancer and osteoporosis, bind to ER and mediate tissue-specific agonistic or antagonistic effects. Raloxifene and tamoxifen inhibited the differentiation of estrogen-dependent DC from bone marrow precursors ex vivo in competition experiments with physiological levels of E2. DC differentiated in the presence of SERM were assessed for their capacity to internalize fluoresceinated Ags as well as respond to inflammatory stimuli by increasing surface expression of molecules important for APC function. Although SERM-exposed DC exhibited increased ability to internalize Ags, they were hyporesponsive to bacterial LPS: relative to control DC, they less efficiently up-regulated the expression of MHC class II, CD86, and to a lesser extent, CD80 and CD40. This phenotype indicates that these SERM act to maintain DC in an immature state by inhibiting DC responsiveness to inflammatory stimuli. Thus, raloxifene and tamoxifen impair E2-promoted DC differentiation and reduce the immunostimulatory capacity of DC. These observations suggest that SERM may depress immunity when given to healthy individuals for the prevention of osteoporosis and breast cancer and may interfere with immunotherapeutic strategies to improve antitumor immunity in breast cancer patients.

“…It also decreases serum levels of soluble TNF receptors 55 and 75 (16). In MRL/lpr mice, treatment with tamoxifen decreases the number of CD4 Ϫ CD8 Ϫ T cells (17), whereas in murine lupus induced by 16/6 Id, tamoxifen normalizes the levels of IL-1, IL-2, IL-4, and IFN-␥ (18,46). Other studies investigating the mechanism of action of tamoxifen have shown that tamoxifen decreases CD5 ϩ B cells and inhibits dendritic cell maturation, thereby decreasing T cell activation (16).…”

Section: Discussionmentioning

confidence: 99%

Tamoxifen Blocks Estrogen-Induced B Cell Maturation but Not Survival

Peeva

Jeganathan

Diamond

2005

Estrogen treatment has been shown not only to exacerbate disease activity and accelerate death in spontaneous murine models of lupus but also to induce a lupus-like phenotype in nonspontaneously autoimmune mice. In mice transgenic for the H chain of an anti-DNA Ab, estrogen rescues naive autoreactive B cells that normally are deleted and causes them to mature to a marginal zone phenotype. Estrogen further leads to the activation of this population causing an elevation of serum anti-DNA Ab titers and renal disease. This study was designed to evaluate the therapeutic potential of tamoxifen, a selective estrogen receptor modulator, on estrogen-induced lupus. Mice treated with both estradiol and tamoxifen showed no elevation in anti-DNA Ab titers and consequently no glomerular IgG. The DNA-reactive B cell population that is rescued by estrogen was present in an anergic state in mice treated with both estradiol and tamoxifen. Estradiol enhances transitional B cell resistance to apoptosis and expands the population of marginal zone B cells; tamoxifen did not impede the enhanced resistance to apoptosis, but prevented the development of autoreactive cells as marginal zone B cells. Thus, estrogen-induced autoimmunity proceeds through two distinct molecular pathways, one affecting survival and the other maturation. Activation, but not survival, of autoreactive B cells can be abrogated by tamoxifen. Drugs that modulate even some of the effects of estrogen may be beneficial in patients with lupus. Eventually, understanding the pathways involved in survival and activation of autoreactive B cells will permit the development of therapeutics that target all relevant pathways.