Effects of lasofoxifene and bazedoxifene on B cell development and function

Abstract

The third generation selective estrogen receptor modulators lasofoxifene (las) and bazedoxifene (bza) are indicated for treatment of postmenopausal osteoporosis. 17β-Estradiol (E2) and the second generation SERM raloxifene (ral) have major effects on the immune system, particularly on B cells. Treatment with E2 or ral inhibits B lymphopoiesis and treatment with E2, but not ral, stimulates antibody production. The effects of las and bza on the immune system have not been studied. Therefore, the aim of this study was to investigate their role in B cell development, maturation, and function. C57BL/6 mice were sham-operated or ovariectomized (ovx) and treated with vehicle, E2, ral, las, or bza. All substances increased total bone mineral density in ovx mice, as measured by peripheral quantitative computed tomography. In uterus, bza alone lacked agonistic effect in ovx mice and even acted as an antagonist in sham mice. As expected, E2 decreased B cell numbers at all developmental stages from pre-BI cells (in bone marrow) to transitional 1 (T1) B cells (in spleen) and increased marginal zone (MZ) B cells as determined by flow cytometry. However, treatment with las or bza only decreased the last stages of bone marrow B cell development and splenic T1 B cells, but had no effect MZ B cells. E2 increased antibody-producing cells quantified by ELISPOT, but las or bza did not. In conclusion, las and bza differ from E2 by retaining normal number of cells at most B cell stages during B lymphopoiesis and maturation and by not increasing antibody-producing cells.

Effects of Bu-Shen-Ning-Xin Decoction on immune cells of the spleen and bone marrow in ovariectomized mice

“…In fact, in human males made hypogonadal and selectively replaced with either estrogen or testosterone, estrogen is associated with an increase in the percentage of bone marrow CD19 + B cells (40)(41)(42)(43). In our study, we found that ovariectomy induced an increase in CD19 + and B220 + B cells, but BSNXD treatment decreased B cell numbers in the BSNXD+OVX group.…”

Tamoxifen persistently disrupts the humoral adaptive immune response of gilthead seabream (Sparus aurata L.)

“…The higher number of IgM þ cells observed in naïve and hemocyaninstimulated head kidney leukocytes from Tmx-treated fish during the recovery period would suggest a pivotal role for this compound in the homeostasis of the immune responses. However, further studies will be necessary to gain a deeper understanding of the mechanism underlying the immunotoxicology effects caused by this compound in this cell type in fish taking into account that E 2 , but not SERMs, increased the Ig production and the number of Igproducing cells in the bone marrow and spleen (Bernardi et al, 2014;Erlandsson et al, 2002).…”

“…In mammals five antibody isotypes have been identified (IgA, IgD, IgE, IgG and IgM), while in fish IgM has been identified as the most common Ig in the serum of teleosts, although IgD (Hordvik et al, 1999;Stenvik and Jorgensen, 2000;Wilson et al, 1997), IgT/IgZ (Hansen et al, 2005;Ryo et al, 2010) have also been identified. It has been previously demonstrated that natural and synthetic estrogens, including SERMs, have major effects on the immune system, particularly on B cells (Bernardi et al, 2014). In gilthead seabream it has been previously demonstrated that total IgM levels decreased at 3 and 7 days after E 2 post-injection (Cuesta et al, 2007).…”

Selective estrogen receptor modulators in T cell development and T cell dependent inflammation

“…It has previously been shown that mice treated with E2 in doses similar to the one used here obtain serum E2 levels corresponding to low diestrus levels (10-25 pg/ml) (Offner et al, 2000). The doses of ral, las and bza, were chosen based on our previous finding that they cause a significant increase in total bone mineral density in ovx mice (Bernardi et al, 2014). In addition, body surface area calculations ensured that doses of ral, las and bza used in mice were similar to those used in humans (Reagan-Shaw et al, 2008).…”

“…Interestingly, preliminary data from our lab show that also las and bza have beneficial effects on disease development and associated bone loss in postmenopausal collagen-induced arthritis (Andersson et al, submitted). We recently reported that las and bza inhibit B lymphopoiesis at a later developmental stage compared to E2, and that they do not increase the number of antibody-producing cells or the marginal zone B cell population (Bernardi et al, 2014). However, no previous studies have explored the effects of las and bza on T cell development.…”