Anti-tumor immunity in adult T-cell leukemia

Adult T-cell leukemia (ATL) occurs in a small population of human T-cell leukemia virus type I (HTLV-I)-infected individuals. It has been noted that ATL is incidentally associated with mother-to-child infection which occurs mainly through breast-feeding, elevated levels of proviral load, and insufficiency in HTLV-I-specific cytotoxic T lymphocyte (CTL) responses. Among these, anti-tumor potentials of HTLV-I-specific CTL have been shown in ex vivo analysis of human HTLV-I-infected individuals and also in vivo experiments by using rat models of HTLV-I-infected lymphomas. In another rat model of HTLV-I-infection, orally infected rats showed significantly higher HTLV-I proviral load but lower HTLV-I-specific cellular immune responses than in intraperitoneally infected rats. As a result, persistent viral load was inversely correlated with levels of virus-specific T-cell responses. HTLV-I-specific T-cell responses in orally infected rats recovered by re-immunization. Conversion of Tax-specific T-cell responses from low to high levels was also observed in an ATL patient who obtained complete remission after hematopoietic stem cell transplantation. These findings suggest that HTLV-I-specific immune unresponsiveness associated with oral HTLV-I infection may be a potential risk factor for development of ATL, allowing expansion of the infected cell reservoir in vivo, and that immunological strategies targeting Tax may potentially reduce the risk of ATL and induce therapeutic effects on ATL.     

Lower expression of mRNA for interferon-gamma in T helper cells of children with newly diagnosed lymphomas

The complex interactions between cancer and host cells are far from being fully elucidated. Assessment of Th1/Th2/Th3/Tr1 balance is an interesting approach to explain immunological disturbances in lymphomas. The aim of our study was to assess mRNA for pro- and anti-inflammatory cytokines in T-cells in 20 children with Hodgkin- and non-Hodgkin lymphomas. CD4+ and CD8+ cells were isolated from whole peripheral blood and four different cytokine mRNA levels (IFN-gamma, IL-10, IL-4, TGF-beta) were determined by real-time PCR technique. Comparing to the control group, we found lower expression of mRNA for IFN-gamma in CD4+ cells at the time of lymphoma diagnosis. It may be one of the pathogenetic mechanisms of impaired immunity in these patients.     

Timing of dietary fat exposure and mammary tumorigenesis: Role of estrogen receptor and protein kinase C activity

The possible association between a high fat diet and increased breast cancer risk has remained controversial. This largely reflects the conflicting data obtained from migrant, case control and animal studies, which generally support this association, and cohort studies which often fail to show a link between fat and breast cancer. The mammary gland is particularly sensitive to estrogens during the fetal development, leading us to hypothesize that dietary fat levels during this period may significantly influence breast cancer risk. Using chemically-induced mammary tumors in rats as our experimental model, we have demonstrated the ability of a maternal diet, high in the polyunsaturated fatty acid (PUFA) linoleic acid, to alter mammary gland differentiation, accelerate the onset of sexual maturation, and increase breast cancer risk. The mammary glands of female rats exposed to a highfat diet in utero have more of the undifferentiated structures (terminal end buds) and fewer of the differentiated structures (alveolar buds) than the glands of rats exposed to a low-fat diet in utero. Furthermore, these mammary glands contain lower levels of total estrogen receptors and have reduced total protein kinase C activity. These effects appear to be mediated by an increase in tne serum estradiol levels of pregnancy, which are elevated at least 30% in pregnant dams fed a high fat diet. Furthermore, the administration of estradiol to pregnant dams produce effects on mammary gland development, onset of puberty and sensitivity to chemical carcinogenesis comparable to those seen in the offspring of rats fed a high fat diet during pregnancy. Our results, thus, support the hypothesis based on epidemiological data that high maternal estrogen levels increase daughters' breast cancer risk. The results also suggest that a high-fat diet may be an important factor in increasing pregnancy estrogenic activity.     

Mechanisms of gastrointestinal CD4+ T-cell depletion during acute and early human immunodeficiency virus type 1 infection

During acute and early human immunodeficiency virus type 1 (HIV-1) infection (AEI) more than 50% of CD4+ T cells are preferentially depleted from the gastrointestinal (GI) lamina propria. To better understand the underlying mechanisms, we studied virological and immunological events within the peripheral blood (PB) and GI tract during AEI. A total of 32 AEI subjects and 18 uninfected controls underwent colonic biopsy. HIV-1 viral DNA and RNA levels were quantified in CD4+ T cells derived from the GI tract and PB by using real-time PCR. The phenotype of infected cells was characterized by using combinations of immunohistochemistry and in situ hybridization. Markers of immunological memory, activation, and proliferation were examined by flow cytometry and immunohistochemistry, and the host-derived cytotoxic cellular response was examined by using immunohistochemistry. GI CD4+ T cells harbored, on average, 13-fold higher HIV-1 viral DNA levels and 10-fold higher HIV-1 RNA levels than PB CD4+ T cells during AEI. HIV-1 RNA was detected in both "activated" and "nonactivated" mucosal CD4+ T cells. A significantly higher number of activated and proliferating T cells were detected in the GI tract compared to the PB, and a robust cytotoxic response (HIV-1 specificity not determined) was detected in the GI tract as early as 18 days postinfection. Mucosal CD4+ T-cell depletion is multifactorial. Direct viral infection likely accounts for the earliest loss of CD4+ T cells. Subsequently, ongoing infection of susceptible CD4+ T cells, along with activation-induced cellular death and host cytotoxic cellular response, are responsible for the persistence of the lesion.     

Tumor markers (CEA, TPA and CA 19-9) in urine of bladder cancer patients

This study was carried out to evaluate the usefulness of determining urinary levels of carcinoembryogenic antigen (CEA), tissue-polypeptide antigen (TPA), and gastro-intestinal cancer antigen (Ca19-9) in addition to the usual diagnostic procedures for bladder cancer. Sixty-seven patients with transitional bladder cancer, 40 healthy controls and 20 patients with inflammatory diseases of the urinary tract were considered. All urine samples were obtained from patients with intact renal function and no urinary tract infection. TPA and Ca19-9 urinary levels in patients with G3 bladder tumors were significantly higher than in those with lower graded neoplasms. The sensitivity, specificity, and predictive value of a positive (PV+) or negative (PV-) test and the diagnostic accuracy were also evaluated. Ca19-9 was the best urinary marker for bladder cancer (sensitivity 71.6%, specificity 91.6%, PV+ 90.5%, PV- 74.3%, diagnostic accuracy 81%).     

血清sTREM-1、肺功能指数与肺癌患者术后肺部感染的关系及其预测价值研究

目的:探讨血清髓样细胞触发受体-1(sTREM-1)、肺功能指数与肺癌患者术后肺部感染的关系及其预测价值。方法:回顾性分析2016年1月-2019年1月在我院进行手术治疗的115例肺癌患者的临床资料,根据患者术后72 h是否发生肺部感染将其分为感染组(n=28)及未感染组(n=87)。对比两组患者临床资料、术后6 h血清s TREM-1、降钙素原(PCT)水平及术前肺功能指数[第一秒用力呼气量(FEV1)、呼气流量峰值(PEF)]变化,记录感染组患者痰细菌培养结果,采用Logistic分析肺癌患者术后感染的影响因素,并采用受试者工作特征(ROC)曲线分析s TREM-1、FEV1、PEF在肺癌术后感染的预测价值。结果:感染组术后入住ICU比例大于未感染组,感染组TNM分期为IV期的比例大于未感染组(P0.05),感染组术后6 h血清s TREM-1、PCT水平高于未感染组,术前FEV1、PEF水平低于未感染组(P0.05)。感染组痰培养结果提示G-菌为17例,占60.71%;G+菌10例,占35.71%;真菌1例,占3.57%。二元多因素Logistic分析提示术后6 h血清s TREM-1水平升高、术前FEV1下降及PEF下降、术后入住ICU为肺癌患者术后感染的独立影响因素。三者联合预测曲线下面积为0.850(95%CI:1.350～1.745,P=0.000),敏感度与特异性分别为91.3%与80.6%,优于s TREM-1、FEV1、PEF的单独预测效能。结论:s TREM-1水平升高,术前FEV1、PEF水平降低与肺癌患者术后肺部感染密切相关,对s TREM-1、FEV1、PEF三者联合分析对于预测肺癌患者术后肺部感染的发生具有较高的预测价值。     

Tumour Induction by Cell-free Extracts derived from Mice with Graft versus Host Disease

A SUBSTANTIAL proportion of inbred mice, in which a protracted form of the graft versus host reaction (GVHR) is induced, eventually develop lymphoreticular tumours¹. This experimental mouse model can be used to study the role of immune reactions in cancer induction. One possibility is that the immune disturbance activates a latent oncogenic virus. That such activation can occur has been demonstrated in C57BL mice². In this strain, with its low spontaneous leukaemic incidence, thymic lymphomas are induced by an irradiation-activated leukaemogenic virus. In man, there is suggestive evidence that Burkitt's lymphoma may be caused by a combination of virus infection and immunological stimulation³.     

Children's exposure to environmental pollutants and biomarkers of genetic damage. II. Results of a comprehensive literature search and meta-analysis

The present review is based on findings from 178 publications retrieved through an extensive search of the MedLine/PubMed database for a 25 years time period (1980-2004) and 10 manually identified papers. Among the cytogenetic biomarkers that are frequently used in field studies, chromosome aberrations (CA) and micronuclei (MN) but not sister chromatid exchanges (SCE) were found consistently increased in children exposed to environmental pollutants. Meta-analysis of the studies reporting SCE in cord blood showed similar levels of SCE in exposed and in non-exposed newborns. Exposure to airborne pollutants, soil and drinking water contaminants, mostly increased CA and, to a lesser extent, MN levels in children. The effect of exposure to airborne urban pollutants was consistently reported by field studies measuring DNA, albumin and hemoglobin adducts. Prenatal (in utero) and postnatal exposure (environmental tobacco smoke, ETS) to tobacco smoke compounds were associated with increased frequencies of DNA and hemoglobin adducts and CA. The limited number of field studies measuring DNA fragmentation (Comet assay), hypoxanthine-guanine phosphoribosyltransferase (HPRT) and the glycophorinA (GPA) mutation frequency in environmentally exposed children precluded a meaningful evaluation of the usefulness of these assays. Meta-analyses performed in children exposed to ETS and in newborns exposed in utero to their mothers' smoke showed 1.3 and 7 times higher levels of hemoglobin adducts compared to referent subjects, respectively. These increases are consistent with the epidemiological evidence of higher lung cancer risks reported in adults who had never smoked and were exposed to ETS during childhood and with 7-15 times higher lung cancer risks reported in smokers than in non-smokers. Higher levels of PAH-DNA adducts were found in fetal than in maternal tissue, suggesting a specific susceptibility of the fetus to this class of ubiquitous environmental pollutants. According to these findings, future research and biomonitoring programs on children would greatly benefit from the inclusion of selected biomarkers that could provide biologically based evidence for the identification of intervention priorities in environmental health.     

Comparison of human immunodeficiency virus type 1 viral loads in Kenyan women,men, and infants during primary and early infection

Steady-state levels of human immunodeficiency virus type 1 (HIV-1) RNA in plasma reached at approximately 4 months postinfection are highly predictive of disease progression. Several studies have investigated viral levels in adults or infants during primary and early infection. However, no studies have directly compared these groups. We compared differences in peak and set point plasma HIV-1 RNA viral loads among antiretrovirus-naive Kenyan infants and adults for whom the timing of infection was well defined. Peak and set point viral loads were significantly higher in infants than in adults. We did not observe any gender-specific differences in viral set point in either adults or infants. However, infants who acquired HIV-1 in the first 2 months of life, either in utero, intrapartum, or through early breast milk transmission, had significantly higher set point HIV-1 RNA levels than infants who were infected after 2 months of age through late breast milk transmission or adults who were infected through heterosexual transmission.     

Monoclonal B-cell hyperplasia and leukocyte imbalance precede development of B-cell malignancies in uracil-DNA glycosylase deficient mice

Ung-deficient mice have reduced class switch recombination, skewed somatic hypermutation, lymphatic hyperplasia and a 22-fold increased risk of developing B-cell lymphomas. We find that lymphomas are of follicular (FL) and diffuse large B-cell type (DLBCL). All FLs and 75% of the DLBCLs were monoclonal while 25% were biclonal. Monoclonality was also observed in hyperplasia, and could represent an early stage of lymphoma development. Lymphoid hyperplasia occurs very early in otherwise healthy Ung-deficient mice, observed as a significant increase of splenic B-cells. Furthermore, loss of Ung also causes a significant reduction of T-helper cells, and 50% of the young Ung(-/-) mice investigated have no detectable NK/NKT-cell population in their spleen. The immunological imbalance is confirmed in experiments with spleen cells where the production of the cytokines interferon gamma, interleukin 6 and interleukin 2 is clearly different in wild type and in Ung-deficient mice. This suggests that Ung-proteins, directly or indirectly, have important functions in the immune system, not only in the process of antibody maturation, but also for production and functions of immunologically important cell types. The immunological imbalances shown here in the Ung-deficient mice may be central in the development of lymphomas in a background of generalised lymphoid hyperplasia.     

Breast cancer in women with primary biliary cirrhosis.

The occurrence of extrahepatic malignancy was studied in 195 unselected patients who satisfied predetermined biochemical, immunological, and histological criteria for the diagnosis of primary biliary cirrhosis. The incidence of breast cancer in women with primary biliary cirrhosis was found to be significantly higher than in an age and sex matched control population from the same well defined geographical area (p less than 0.0015). The association of breast cancer and primary biliary cirrhosis remains unexplained, though diminished immunological surveillance, fat soluble vitamin deficiency, or endocrine dysfunction may play a part.     

Effect of immunotherapy on lymphocyte function in acute lymphatic leukemia]

During the immunotherapy children suffered from acute leukaemias will have a significantly higher transformation rate than at the beginning of the immunotherapy. This may be explained by an increase of the immunological competence as well as by an enhanced mobilization of lymphatic cells. Leukaemic blasts used for immunoinduction-therapy will have no higher transformation rates as antigens than those cells never contacted by children. During the immunotherapy an increase of transformation rates may be observed after administering unspecific antigens and in mixed cultures. In a retrospective manner the indication for immunotherapy may be checked again in children with immunotherapy on the basis of the clinical course and evaluation of the cellular immunoreaction.     

Rhesus rhadinovirus infection in healthy and SIV-infected macaques at Tulane National Primate Research Center

Rhesus rhadinovirus (RRV) infection was quantified in peripheral blood mononuclear cells (PBMC) from healthy and simian immunodeficiency virus (SIV)-infected rhesus macaques (Macaca mulatta) at the Tulane National Primate Research Center and in a large collection of simian acquired immunodeficiency syndrome--(SAIDS)-associated lymphomas. Quantification of RRV load was performed by real-time PCR using amplification primers specific for the RRV interleukin-6 homologue (RRV vIL-6). RRV infection was detected infrequently and at low levels in PBMC of randomly selected healthy animals. Examination of longitudinally collected PBMC from 22 SIV-infected animals throughout progression to SAIDS revealed similarly low RRV loads that sometimes increased with advancing disease. RRV infection was detected more frequently in the peripheral blood of SIV-infected animals than in healthy animals. Examination of SAIDS-associated lymphomas showed that RRV is rare within the tumor mass, likely representing infection in an occasional tumor-infiltrating cell or contaminating blood. The results indicate that RRV infection in PBMC is not predictive of, and is apparently not required for, development of lymphoma or hyperplastic lymphadenopathy in SIV-infected animals at TNPRC.     

Exposure to lard-based high-fat diet during fetal and lactation periods modifies breast cancer susceptibility in adulthood in rats

The present study investigated whether early life exposure to high levels of animal fat increases breast cancer risk in adulthood in rats. Dams consumed a lard-based high-fat (HF) diet (60% fat-derived energy) or an AIN93G control diet (16% fat-derived energy) during gestation or gestation and lactation. Their 7-week-old female offspring were exposed to 7,12-dimethyl-benzo[a]anthracene to induce mammary tumors. Pregnant dams consuming an HF diet had higher circulating leptin levels than pregnant control dams. However, compared to the control offspring, significantly lower susceptibility to mammary cancer development was observed in the offspring of dams fed an HF diet during pregnancy (lower tumor incidence, multiplicity and weight), or pregnancy and lactation (lower tumor multiplicity only). Mammary epithelial elongation, cell proliferation (Ki67) and expression of NFκB p65 were significantly lower and p21 expression and global H3K9me3 levels were higher in the mammary glands of rats exposed to an HF lard diet in utero. They also tended to have lower Rank/Rankl ratios (P=.09) and serum progesterone levels (P=.07) than control offspring. In the mammary glands of offspring of dams consuming an HF diet during both pregnancy and lactation, the number of terminal end buds, epithelial elongation and the BCL-2/BAX ratio were significantly lower and serum leptin levels were higher than in the controls. Our data confirm that the breast cancer risk of offspring can be programmed by maternal dietary intake. However, contrary to our expectation, exposure to high levels of lard during early life decreased later susceptibility to breast cancer.     

A study of chromosomal fragility in peripheral blood lymphocytes in patients with lymphomas

Patients with lymphomas were shown to have authentically a higher frequency of fragile sites, both spontaneous and induced by aphidikoline expression, in comparison with the control group. Differential sensitivity of chromosomes caused by the action of aphidikolin was revealed. The fragility of chromosomes 9 and 11 in patients with lymphomas on sites 9q31-32 and 11p13-14 was authentically higher (alpha = 0.05) than that in healthy individuals. Site 9q31-32 appeared to be strictly specific for lymphoma disease.     

Elevated plasma IL-6 associates with increased risk of advanced fibrosis and cholangiocarcinoma in individuals infected by Opisthorchis viverrini

Opisthorchis viverrini is considered among the most important of the food-borne trematodes due to its strong association with advanced periductal fibrosis and bile duct cancer (cholangiocarcinoma). We investigated the relationship between plasma levels of Interleukin (IL)-6 and the risk of developing advanced fibrosis and bile duct cancer from chronic Opisthorchis infection. We show that IL-6 circulates in plasma at concentrations 58 times higher in individuals with advanced fibrosis than age, sex, and nearest-neighbor matched controls and 221 times higher in individuals with bile duct cancer than controls. We also observed a dose-response relationship between increasing levels of plasma IL-6 and increasing risk of advanced fibrosis and bile duct cancer; for example, in age and sex adjusted analyses, individuals with the highest quartiles of plasma IL-6 had a 19 times greater risk of developing advanced periductal fibrosis and a 150 times greater risk of developing of bile duct cancer than individuals with no detectable level of plasma IL-6. Finally, we show that a single plasma IL-6 measurement has excellent positive predictive value for the detection of both advanced bile duct fibrosis and bile duct cancer in regions with high O. viverrini transmission. These data support our hypothesis that common mechanisms drive bile duct fibrosis and bile duct tumorogenesis from chronic O. viverrini infection. Our study also adds a unique aspect to the literature on circulating levels of IL-6 as an immune marker of hepatobiliary pathology by showing that high levels of circulating IL-6 in plasma are not related to infection with O. viverrini, but to the development of the advanced and often lethal pathologies resulting from chronic O. viverrini infection.     

Importance of B-cell responses for immunological control of variant strains of simian immunodeficiency virus

The properties of three variants of cloned simian immunodeficiency virus strain 239 (SIV239) were compared. One strain (M5) lacked five sites for N-linked carbohydrate attachment in variable regions 1 and 2 (V1 and V2) of the gp120 envelope protein, one strain (DeltaV1-V2) completely lacked V1 and V2 sequences, and another (316) had nine mutations in the envelope that impart high replicative capacity for tissue macrophages. All three strains were capable of significant levels of fusion independent of CD4, and all three were considerably more sensitive to antibody-mediated neutralization than the parent strain from which they were derived. Upon experimental infection of rhesus monkeys, these three variant strains replicated to viral loads at peak height around day 14 that were indistinguishable from or only slightly less than those observed in monkeys infected with the parental SIV239 strain. Viral loads at the set point 20 to 50 weeks after infection, however, were more than 400- to 10,000-fold lower with the variant strains. Depletion of B cells around the time of infection with M5 resulted in less effective immunological control and much higher viral loads at the set point in two of three monkeys. The differences between SIV239 infection, where there is not effective immunological control, and SIVM5 infection, where there is effective immunological control, cannot be easily explained by differences in the inherent replicative capacity of the viruses; rather, they are more readily explained by differences in the effectiveness of the antibody response. These results suggest that resistance of SIV239 to antibody-mediated neutralization is very important for evading effective immunological control, for allowing continuous viral replication, for maintenance of moderate-to-high viral loads at set point, and for disease progression.     

Fetal immunization of baboons induces a fetal-specific antibody response

Neonates face a high risk of infection because of the immaturity of their immune systems. Although the transplacental transfer of maternal antibodies to the fetus may convey improved postnatal immunity, this transfer occurs late in gestation and may fail to prevent in utero infection. Both fetal immunization and in utero exposure to antigen can result in a state of immunologic tolerance in the neonate. Tolerance induction of fetal and premature infant lymphocytes has become a paradigm for neonatal responsiveness. However, fetal IgM responses have been demonstrated to maternal immunization with tetanus toxoid and to congenital infections such as rubella, toxoplasma, cytomegalovirus and human immunodeficiency virus. Moreover, 1-week-old infants can respond to standard pediatric vaccination, and neonates immunized with polysaccharide antigens do not develop immunologic tolerance. Here, direct immunization of the baboon fetus with recombinant hepatitis B surface antigen produced a specific fetal IgG antibody response. No specific maternal antibody response was detected, eliminating the possibility of vertical antibody transmission to the fetus. Some infants also responded to later vaccinations with hepatitis B surface antigen, indicating that no immunological tolerance was induced by prior fetal immunization. These results characterize the ability of the fetal immune system to respond to in utero vaccination. We demonstrate that active fetal immunization can serve as a safe and efficient vaccination strategy for the fetus and neonate.     

Loss of Hymenolepis diminuta from the rat

One, 5, 15 and 30 worm infections of Hymenolepis diminuta were established in juvenile or adult male (Hooded Rowett or Sprague-Dawley) rats. Worm numbers and weight, and egg output were determined from day 15 to day 85 post infection. Gradual worm loss occurred only from 15 and 30 worm infections. In 5, 15 and 30 worm infections worm weight decreased from day 19 to day 50 but no weight loss occurred in single worm infections. The size range of individual worms from a multiple infection of a single rat increased markedly following infection. Adult rats showed a greater worm loss and harboured smaller worms than juvenile rats. The data will fit either a competitive or an immunological model.