Toremifene has antiestrogenic and estrogenic properties in vitro and in vivo. In addition, it may have antiangiogenesis and antimicrotubule properties at higher doses. Studies have demonstrated the efficacy of this agent in the treatment of metastatic breast cancer. We performed a phase II trial of toremifene in patients with androgen-independent prostate cancer (AIPC). Patients with an increasing prostate-specific antigen level despite castrate testosterone levels and antiandrogen withdrawal were eligible. Patients could not have received prior salvage hormonal therapy or chemotherapy. Patients received toremifene at 300 mg/m2/d orally (maximum dose 640 mg/d). Fifteen patients were treated. Patients received treatment for a median of 13 weeks (range, 4-30 weeks). The median age was 72 years (range, 58-80 years). The median Eastern Cooperative Oncology Group performance status was 0. The treatment was well tolerated and toxicity was mild. Two patients had grade III hepatic toxicity; one had grade III hyperglycemia. There were no treatment-related deaths. No objective responses were demonstrated. In summary, toremifene is not effective therapy for AIPC at the dose and schedule evaluated in this trial.
B-cell-intrinsic major histocompatibility complex class II (MHCII) antigen presentation is central to the development of T-cell-dependent antibody responses. However, the physiological significance of B-cell-intrinsic MHCII signaling during homeostatic conditions and infection are unknown. Here, using a B-cell-intrinsic MHCII knockout mouse model, we demonstrate that B-cell-intrinsic MHCII signaling is important for the development of systemic IgG1 and mucosal, high-affinity IgA responses. We also show that the conditional ablation of MHCII signaling on B cells results in a change in the microbiota composition, exhibiting a significant increase in the mucin-degrading bacteria Akkermansia muciniphila. This change in the microbiome is also associated with elevated bacterial dissemination from the gut into the systemic compartment under homeostatic conditions. Additionally, using a Citrobacter rodentium model of acute gastrointestinal infection, we also demonstrate the relevance of B-cell-intrinsic MHCII signaling in limiting invasion of the systemic compartment by an opportunistic enteric pathogen. Results from these experiments demonstrate that B-cell-intrinsic MHCII signaling is an important factor minimizing the physiological cost of microbial colonization of the gut. Supported by NIH R21AI142409, R01AI155887
The diversity of protein antigens the adaptive immune system can respond to is governed by polymorphic major histocompatibility complex (MHC) molecules. Because MHC alleles are co-dominantly expressed, MHC heterozygosity should allow for a wider diversity of antigens to activate T cells. B cells present antigen via MHC molecules to T cells, and through the ensuing T cell interaction, differentiate into plasma cells. Because of this, MHC heterozygosity should result in the generation of a plasma cell pool able to generate antibodies that target a wider array of antigens. To investigate this claim, we compared B cell selection dynamics between homozygote and heterozygote MHC congenic mice within the germinal centers (GCs) of Peyer’s patches; the major secondary lymphoid tissues of the gut where plasma cells develop in response to the microbiota. I have observed differences in the distribution of GC B cells between the dark zone (DZ) and light zone (LZ) of GCs. Specifically, GC B cells in MHC heterozygotes are found in greater abundance in the LZ and lower abundance in the DZ compared the GC B cells from MHC homozygote mice, which suggests that B cells are more capable of interacting with T cells in MHC heterozygotes. MHC heterozygotes also have significantly higher abundance of GC-T FHcells in their Peyer’s patches. I have observed that MHC heterozygote mice show enhanced binding of IgA to SI-resident bacteria. Future experiments seek to sort-purify IgA-bound SI-resident bacteria from MHC heterozygotes and homozygotes for 16S analysis to determine if MHC heterozygotes bind a more diverse array of bacterial species. We will also perform IgH-sequencing to define the effect of MHC heterozygosity on repertoire diversity of plasma cell populations. Supported by grants from the NIH (R21AI142409, R01AII55887)
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