Effect of methylcholanthrene on human natural killer cell cytotoxicity and lymphokine production in vitro

We have developed a simple culture assay system for measuring the in vitro effects of a chemical carcinogen, 3-methylcholanthrene (MCA), on certain activities of human peripheral blood lymphocytes: blastogenesis, cell-mediated cytotoxicity by natural killer cells, interleukin-2 production, lymphotoxin release and percent T-cell subpopulations. After 72 h of treatment with different doses of MCA, blastogenesis was suppressed 23-87% and cell-mediated cytotoxicity was inhibited 45-90%. Interleukin-2 and lymphotoxin production were decreased by 64% and 38%, respectively. On the other hand, MCA treatment at the same doses caused no significant change in the percent of T-cell subsets. We conclude that MCA exerts an inhibitory effect on T-cell functional activity such as interleukin-2 and lymphotoxin production which correlate with a suppression of blastogenesis and natural killer cell activity. This in vitro assay system could be important for future studies in explaining specific inhibitory effects of chemical carcinogens on lymphoid cell function relative to tumorigenesis.     

Immune alteration associated with exposure to toxic chemicals.

Immunological abnormalities including lymphocyte subset, lymphocyte immune functional assays, chemical antibodies, and different markers for autoimmune response were examined in individuals exposed to a variety of chemicals in computer manufacturing plants. A comparison of 289 individuals exposed to chemicals to 120 controls revealed that exposed individuals had a significantly higher percentage with either increased or decreased T helper/T suppressor ratios. In addition, the individuals with abnormal T4/T8 ratios demonstrated significant elevation in chemical-hapten antibodies. Therefore, 87 exposed subjects with abnormal T4/T8 ratios were selected for further evaluation by lymphocyte phenotypic expression and T cell, B cell, NK activity, and autoimmune markers, and were compared to 60 controls. The comparison of exposed individuals with controls indicated elevation of T cell (CD3), B cell (CD19), and activated T cell (CD10, CD15, CD26, CD38), suppressed T cell and B cell function decreased or increased NK cell cytotoxic activity. Autoimmunity due to chemical exposure was evidenced by elevation of TA1 phenotype frequencies and presence of rheumatoid factor, immune complexes, ANA, and anti myelin basic protein antibodies. We conclude that chemical exposure may induce immune abnormalities including immune suppression and autoimmunity.     

Protective effect of hydroferrate fluid,MRN-100, against lethality and hematopoietic tissue damage in γ-radiated Nile tilapia,Oreochromis niloticus

Hydroferrate fluid, MRN-100, an iron-based compound derived from bivalent and trivalent ferrates, is a potent antioxidant compound. Therefore, we examined the protective effect of MRN-100 against γ-radiation-induced lethality and damage to hematopoietic tissues in fish. A total of 216 Nile tilapia fish (Oreochromis niloticus) were randomly divided into four groups. Group 1 served as a control that was administered no radiation and no MRN-100 treatment. Group 2 was exposed only to γ-radiation (15 Gy). Groups 3 and 4 were pre-treated with MRN-100 at doses of either 1 ml/l or 3 ml/l in water for 1 week, and subsequently exposed to radiation while continuing to receive MRN-100 for 27 days. The survival rate was measured, and biochemical and histopathological analyses of hematopoietic tissues were performed for the different treatment groups at 1 and 4 weeks post-radiation. Exposure to radiation reduced the survival rate to 27.7%, while treatment with MRN-100 maintained the survival rate at 87.2%. In addition, fish exposed to γ-radiation for 1 week showed a significant decrease in the total number of white blood cells (WBCs) and red blood cells (RBCs) series. However, treatment with MRN-100 protected the total WBC count and the RBCs series when compared with irradiated fish. Furthermore, significant histological lesions were observed in the hepatopancreas, spleen and gills of irradiated fish. However, treatment with MRN-100 protected the histopathology of various organs. We conclude that MRN-100 is a radioprotective agent in fish and may be useful as an adjuvant treatment to counteract the adverse side effects associated with radiation exposure.     

Incidence and prognosis of c-KIT and FLT3 mutations in core binding factor (CBF) acute myeloid leukaemias

DNA from 110 adult de novo acute myeloid leukaemia (AML) patients exhibiting either inv(16) (n = 63) or t(8;21) (n = 47) was screened for mutations in the c-KIT (exon 8 and Asp816) and FLT3 (ITD and Asp835) genes. c-KIT exon 8 mutations were found in 15/63 (23.8%) inv(16) patients and 1/47 (2.1%) t(8;21) patients. c-KIT Asp816 mutations were present in 5/63 (7.9%) inv(16) AML and 5/47 (10.6%) t(8;21) AML. FLT3 mutations were identified in five patients (7.9%) with inv(16) and three patients (5.6%) with t(8;21) AML. All mutations were mutually exclusive; 40% of inv(16) AML patients possessed either a c-KIT or FLT3 mutation. c-KIT exon 8 mutations were shown to be a significant factor adversely affecting relapse rate.     

Actinobacillus actinomycetemcomitans suppresses rat natural killer cell activity in vivo

OBJECTIVE: To examine the immune suppressive effect of Actinobacillus actinomycetemcomitans (Aa) on rat natural killer (NK) cell activity in vivo. MATERIAL AND METHODS: Sprague Dawley rats were given Aa in 2 different manners: (i) by mixing Aa with food at a dose of 10(8) cells/rat/day for 3 months; or (ii) by a single i.m. injection of live Aa at doses of 10(6) and 10(7) cells/rat/day. NK cell activity was measured by means of a 51Cr-release assay using YAC-1 tumor cells as targets. RESULTS: Rats that had been infected by Aa mixed with food experienced significant suppression of their NK cell activity; this reached approximately =50% of control values at 2 and 3 months post-Aa infection. The suppression in NK cell activity was related to decreases in the extent of conjugate formation between effectors and YAC-1 target tumor cells (51.7%) and the extent of lysis of target cells (75.7%). The results also showed that addition of an admixture of Aa-treated NK cells to the control NK cells caused 75% and 53% decreases in activity at effector:target ratios of 25:1 and 50:1, respectively. In addition, a significant increase in the extent of T-suppressor cells (154.8% of control) was detected at 3 months post-Aa infection. In contrast, the single injection of live bacteria resulted in a remarkable, dose-dependent inhibition of NK cell activity (55% and 71% at doses of 10(6) and 10(7) cells/rat/day, respectively) as early as 2 days post-treatment. This also reflected significant suppression in the effector:target conjugate formation ratio (52% of control). The data also revealed a 150-188% increase in the number of splenic lymphocytes post-Aa injection. These effects were transient and normal levels were re-established by the fifth day CONCLUSION: Aa treatment causes suppression of NK cell activity and the mode of action may be due to induction of T-suppressor cells or dilution of NK cells with other lymphoid cell populations. The degree of suppression is affected by the way in which Aa is introduced to the host. These results may contribute to the understanding of how Aa evades host defense.     

Activation of human monocyte-derived dendritic cells in vitro by the biological response modifier arabinoxylan rice bran (MGN-3/Biobran)

Arabinoxylan rice bran (MGN-3/Biobran) is a potent biological response modifier (BRM) that activates natural killer (NK) cells, T cells and monocytes. Currently, little is known regarding the effects of MGN-3 on dendritic cells (DCs), the cell type that bridges innate and adaptive immunity. Therefore, we examined the stimulatory effects of MGN-3 on DCs. Human monocyte-derived DCs were treated with MGN-3 at different concentrations (5-20 microg/ml) for 24 hours in vitro. Activation of DCs was determined by assessing the expression of co-stimulatory and maturation markers (CD40, CD80, CD83, CD86 and HLA-DR) by flow cytometry, and production of cytokines by ELISA. DC function was determined by assessing their ability to activate na?ve T cells. Activation of T cells was assessed by measuring cell proliferation and cytokine production. MGN-3 treatment, in a dose-dependent manner, resulted in: 1) up-regulation of the surface expression of CD83 and CD86, on DCs; 2) an increase in the production of pro-inflammatory and immuno-regulatory cytokines (IL-1beta, IL-6, IL-10, TNF-alpha, IL-12p40 and low levels of IL-12p70 and IL-2) by DCs; and 3) MGN-3 stimulated DC induced CD4+T cell proliferation and their production of cytokines, IFN-gamma, IL-10, IL-17. Results suggest that MGN-3 functions as a natural adjuvant for DC activation and thus may be used in DC-based vaccine strategies against infections and cancer.     

Age related changes in morphology of the thymus of the fish,Oryzias latipes

The thymus of the teleost fish Oryzias latipes is a paired structure found at the dorsoposterior part of the gill chamber. In 3-month-old fish, the thymus shows a great development. The thymus displays atrophy during aging, and the thymus involution continues until 5 years of age. Male thymus shows heavier involution than female thymus of the same age. Emigration of thymus cells takes place at all ages but increases with age.     

Modified arabinoxylan rice bran (MGN3/Biobran) enhances intracellular killing of microbes by human phagocytic cells in vitro

Phagocytic cells, comprised of neutrophils and monocytes/macrophages, play a key role in the innate immune response to infection. Our earlier study demonstrated that arabinoxylan rice bran (MGN-3/Biobran) activates murine peritoneal macrophage and macrophage cell lines. In this study, we investigated whether MGN-3 can upregulate the phagocytic activity of human phagocytes in peripheral blood to phagocytize Escherichia coli (E. coli), trigger the oxidative burst and produce cytokines. Phagocytic cells were pre-labeled with dichlorofluorescin diacetate dye and were incubated with phycoerythrin-labeled E. coli in the presence or absence of MGN-3. Phagocytosis and oxidative burst were assessed by flow cytometry. Results showed that treatment with MGN-3 enhanced the phagocytosis of E. coli by neutrophils and monocytes. This was associated with an increased oxidative burst. In addition, it caused a significant induction of cytokines (TNF-alpha, IL-6, IL-8 and IL-10); the effect was detected at 1 microg/ml and increased in a dose-dependent manner (P 相似文献   

Identification of novel genetic variations affecting osteoarthritis patients

Background

Osteoarthritis (OA) is a progressive joint disease characterized by gradual degradation of extracellular matrix (ECM) components in the cartilage and bone. The ECM of cartilage is a highly specified structure that is mainly composed of type II collagen and provides tensile strength to the tissue via aggrecan and proteoglycans. However, changes in the ECM composition and structure can lead to loss of collagen type II and network integrity. Several risk factors have been correlated with OA including age, genetic predisposition, hereditary factors, obesity, mechanical injuries, and joint trauma. Certain genetic association studies have identified several genes associated with OA using genome-wide association studies (GWASs).

Results

We identified several novel genetic variants affecting genes that function in several candidate causative pathways including immune responses, inflammatory and cartilage degradation such as SELP, SPN, and COL6A6.

Conclusions

The approach of whole-exome sequencing can be a promising method to identify genetic mutations that can influence the OA disease.