T-lymphocyte subsets in liver tissues of patients with primary biliary cirrhosis (PBC), patients with primary sclerosing cholangitis (PSC), and normal controls

T lymphocytes infiltrating hepatic tissues were typed and enumerated in liver biopsies of patients with primary biliary cirrhosis (PBC), patients with primary sclerosing cholangitis (PSC), and normal controls using monoclonal antibodies and the avidin-biotin-immunoperoxidase technique. The peripheral blood mononuclear cells were studied also by flow cytometry. In PBC, T lymphocytes were decreased (P<0.001) in the blood [absolute number was 426±200 (SE) vs 1351±416 in 15 controls], as was the helper/suppressor (T4/T8) ratio (1.0±0.1 vs normal 2.3±0.3). T lymphocytes were the most numerous mononuclear cells infiltrating portal areas of PBC livers: 749±93/5 high-power fields (HPF) in PBC vs 98±15/5 HPF (P<0.01) in controls. The T4/T8 ratios varied from 0.9 to 2.3 (mean, 1.8±0.1) in the portal triads (normal mean, 1.6±0.1), with the T4+ cells accounting for more than 75% of infiltrating T cells. In contrast, the mean T4/T8 ratio in portal triads of PSC was reduced (1.0±0.3) due to a significant increase (P<0.001) in the number of T8+ cells. The T cells around and in the walls of bile ducts in PBC were mostly T8+, and the T4/T8 ratio was 0.8±0.2. No T8+ cells were seen in this location in PSC and normal livers. Few mononuclear cells were present in hepatic lobules. Subtyping of T lymphocytes in liver tissues of patients with PBC and PSC may be helpful in the differential pathologic diagnosis. In patients with advanced PBC, a decrease in T4+ cells in the blood appeared to be accompanied by their accumulation in the portal triads. In contrast, T8+ cells accumulated preferentially around bile ducts. © 1984 Plenum Publishing Corporation

Sulindac sulfide inhibits colon cancer cell growth and downregulates specificity protein transcription factors

BACKGROUND: Specificity protein (Sp) transcription factors play pivotal roles in maintaining the phenotypes of many cancers. We hypothesized that the antineoplastic effects of sulindac and its metabolites were due, in part, to targeting downregulation of Sp transcription factors. METHODS: The functional effects of sulindac, sulindac sulfone and sulindac sulfide on colon cancer cell proliferation were determined by cell counting. Effects of these compounds on expression of Sp1, Sp3, Sp4 and pro-oncogenic Sp-regulated genes were determined by western blot analysis of whole cell lysates and in transient transfection assays using GC-rich constructs. RESULTS: Sulindac and its metabolites inhibited RKO and SW480 colon cancer cell growth and the order of growth inhibitory potency was sulindac sulfide > > sulindac sulfone > sulindac. Treatment of SW480 and RKO cells with sulindac sulfide downregulated expression of Sp1, Sp3 and Sp4 proteins. Sulindac sulfide also decreased expression of several Sp-regulated genes that are critical for cancer cell survival, proliferation and angiogenesis and these include survivin, bcl-2, epidermal growth factor receptor (EGFR), cyclin D1, p65 subunit of NFκB and vascular endothelial growth factor (VEGF). Sulindac sulfide also induced reactive oxygen species (ROS) and decreased the level of microRNA-27a in colon cancer cells, which resulted in the upregulation of the Sp-repressor ZBTB10 and this resulted in downregulation of Sp proteins. CONCLUSIONS: The results suggest that the cancer chemotherapeutic effects of sulindac in colon cancer cells are due, in part, to its metabolite sulindac sulfide which downregulates Sp transcription factors and Sp-regulated pro-oncogenic gene products

Autoimmune/inflammatory syndrome induced by adjuvants (ASIA): clues and pitfalls in the pediatric background

The development and increasing diffusion of new vaccinations and global immunization protocols have aroused burning debates about safety of adjuvants and their immunogenicity-enhancing effect in vaccines. Shoenfeld and Agmon-Levin have grouped under the term “autoimmune/inflammatory syndrome induced by adjuvants” (ASIA) a complex of variable signs and symptoms that may occur after a previous exposure to different adjuvants and also external environmental triggers, even eliciting specific overt immune-mediated disorders. This entity subsumes five medical conditions: post-vaccination phenomena, gulf war syndrome, macrophagic myofasciitis syndrome, siliconosis, and sick building syndrome, but the relevance and magnitude of the syndrome in the pediatric age is fundamentally limited to post-vaccination autoimmune or inflammatory disorders. The occurrence of vaccine-triggered phenomena represents a diagnostic challenge for clinicians and a research conundrum for many investigators. In this paper, we will analyze the general features of ASIA and focus on specific post-vaccination events in relation with the pediatric background. In the presence of a favorable genetic background, many autoimmune/inflammatory responses can be triggered by adjuvants and external factors, showing how the man himself might breach immune tolerance and drive many pathogenetic aspects of human diseases. Nonetheless, the elective application of ASIA diagnostic criteria to the pediatric population requires further assessment and evaluations. Additional studies are needed to help clarify connections between innate or adaptive immunity and pathological and/or protective autoantibodies mostly in the pediatric age, as children and adolescents are mainly involved in the immunization agendas related to vaccine-preventable diseases