Hepatic natural killer and natural killer T cells markedly decreased in two cases of drug-induced fulminant hepatic failure rescued by living donor liver transplantation

The human liver contains significant numbers of innate immune cells, such as natural killer (NK) cells and natural killer T (NKT) cells, which express both T-cell receptors and NK-cell receptors simultaneously. It has been suggested that the innate immune system plays a crucial role in the liver. In this report, the distribution of NK and NKT cells in the liver and peripheral blood of two patients with drug-induced fulminant hepatic failure (FHF) who had undergone living donor liver transplantation was examined. In both the liver and peripheral blood, the proportions of NK and NKT cells markedly decreased compared with those in healthy donors. It was also revealed that, unlike murine NKT cells, human CD56(+) T cells and CD57(+) T cells did not constitutively express CD28, which is one of the important costimulatory molecules on T cells. Additionally, the residual CD56(+) T cells and CD57(+) T cells in the patients expressed more CD28 than in controls. This result suggests that NKT cells might be more activated in FHF. Although the accumulation of further cases is required, it is suggested that both NK and NKT cells might be involved in hepatic injury in FHF.     

Expression and clinical significance of CD44V5 and CD44V6 in resectable colorectal cancer

Purpose This study was conducted to evaluate the prognostic significance of CD44v5 and CD44v6 in resectable colorectal cancer.Materials and methods Membranous CD44v5 and CD44v6 levels were measured by an immunoenzymatic assay in tumors and surrounding mucosal samples obtained from 105 patients with resectable colorectal carcinomas.Results There were no significant differences of CD44v5 levels between tumors [median: 3.2 (range: 0.9–83.5) ng/mg protein) and surrounding mucosal samples (3 (3–146.2) ng/mg protein]. However, tumor samples showed significantly higher CD44v6 levels [19.5 (2.2–562.9) ng/mg protein] than mucosal samples [5 (5–230) ng/mg protein] (P=0.0001). Patients with higher CD44v5 or CD44v6 content in tumor samples had a considerably shorter relapse-free survival (P<0.05, for both). Patients with a higher CD44v6 content also had a shorter relapse-free and overall survival in the multivariate analysis (P<0.05).Conclusion The results of this study suggest a role of CD44v5 and CD44v6 in colorectal cancer progression. Membranous CD44v levels in primary tumors, measured by immunoenzymatic assay, may contribute to a more precise prognostic estimation in patients with resectable colorectal cancer.Supported by grants from ISCIII Red de Centros de Cancer RTICCC (C03/10) and Obra Social Cajastur     

Virus reactivation in high-risk non-Hodgkin’s lymphoma patients after autologous CD34+-selected peripheral blood progenitor cell transplantation

CD34⁺-selected peripheral blood progenitor cells (PBPCs) may not only reduce contaminated tumor cells but also compromise immunologic reconstitution and increase incidence of infections after transplantation. We analyzed the incidence of virus reactivation in CD34⁺-selected PBPCs autologous transplantation. From December 2001 to December 2004, ten high-risk aggressive non-Hodgkin’s lymphoma (NHL) patients were enrolled in a program of high-dose chemotherapy plus autologous CD34⁺-selected PBPCs support. Viral screening studies, including clinical symptoms, physical examinations, hepatitis B virus (HBV)-DNA, cytomegalovirus (CMV)-polymerase chain reaction (PCR), rapid diagnosis of fluorescent antibody stain for herpes-simplex virus (HSV), and viral culture from blood, fluid or tissue were performed weekly during the first 3 months and then monthly for 1 year. Two of four patients (50%) who were HBV carriers developed HBV reactivation. The other two HBV carriers who received prophylactic lamivudine therapy did not develop HBV reactivation. Two patients (20%) developed cytomegalovirus (CMV) infection, and three patients (30%) developed HSV infection in total ten serum-positive patients. The possibility of virus reactivation might increase in NHL patients undergoing autologous CD34⁺-selected PBPC transplantation. Administering prophylactic antivirus therapy and closely following patient’s clinical viral complications should be considered.     

Impaired TRAIL-dependent cytotoxicity of CD1c-positive dendritic cells in chronic hepatitis C virus infection

Dendritic cells (DCs) play a central role in antiviral immunity. Conflicting data on DC function have been reported for hepatitis C virus (HCV) infection. In addition to antigen presentation and cytokine secretion, a subset of human DCs displays direct cytotoxic activity. It has been suggested that measles virus and human immunodeficiency virus (HIV) may enhance cytotoxicity of DCs potentially leading to apoptosis of activated T cells and subsequent down-regulation of antiviral immune responses. We demonstrate that CD1c-positive myeloid DCs, but not BDCA-4-positive plasmacytoid DCs, are able to kill different target cells mainly via tumour necrosis factor-related apoptosis-inducing ligand. The ability of CD1c+ DCs to lyze target cells was found to be completely impaired in patients with chronic hepatitis C (10 chronic HCV patients vs 10 healthy controls; P < 0.001) but not in patients with primary biliary cirrhosis. Successful antiviral therapy of chronic hepatitis C rescued the cytotoxicity of DCs. Myeloid DCs of HCV patients and healthy controls had a similar phenotype and endocytotic activity, however, the frequency of mDCs in the peripheral blood was lower (P = 0.004) and the allostimulatory function was weaker (P < 0.001) in chronic hepatitis C. Thus, in contrast to HIV and measles virus studies on monocyte-derived DCs, freshly isolated myeloid DCs of patients with hepatitis C do not show an increased but a completely abolished cytotoxic activity. The impaired DC cytotoxicity could represent a novel mechanism for the increased prevalence of autoimmunity in HCV infection.     

Human hematopoietic stem/progenitor-enriched CD34(+) cells are mobilized into peripheral blood during stress related to ischemic stroke or acute myocardial infarction

The hematopoietic and non-hematopoietic stem/progenitor cells harvested directly from the bone marrow (BM) or G-CSF mobilized peripheral blood were demonstrated to play an important role in regeneration of damaged organs (1, 2). Here, we asked if the stroke- or acute heart infarct-related stress triggers mobilization of stem/progenitor-enriched CD34(+)cells from the BM into the peripheral blood, which subsequently could contribute to regeneration of damaged tissues. To address this question the peripheral blood samples were harvested from patients with ischemic stroke during the first 24 h of manifestation of symptoms and on the second and sixth day afterwards or during the first 24 h of acute cardiac pain as well as on the second and sixth day of infarct. We measured in these patients (i) percentage of circulating hematopoietic stem/progenitor-enriched CD34(+) cells in peripheral blood by employing fluorescence activated cell sorter (FACS) and (ii) number of hematopoietic progenitor cells for the granulocyte-monocytic colony-forming unit (CFU-GM) and erythoid burst-forming unit (BFU-E) lineages circulating in peripheral blood. We concluded that stress related to ischemic stroke or acute myocardial infarction triggers the mobilization of hematopoietic stem/progenitor-enriched CD34(+) cells from the BM into peripheral blood. These circulating stem/progenitor-enriched CD34(+) cells may contribute to the regeneration of ischemic tissues, however, this possibility requires further studies.     

Inhibitory effects of TSG-6 Link module on leukocyte-endothelial cell interactions in vitro and in vivo

OBJECTIVE: The authors investigated whether the anti-inflammatory protein tumor necrosis factor (TNF)-stimulated gene-6 (TSG-6) and its Link module (Link_TSG6) could affect the complex multistep process of leukocyte/endothelial cell (EC) interaction. METHODS: Mouse mesenteries were inflamed with interleukin (IL)-1beta and the extent of leukocyte rolling, adhesion, and emigration was determined after 2 h. Link_TSG6 and a single-point mutant (termed K13E) were given intraperitoneally together with the cytokine. Human neutrophil chemotaxis and transmigration were determined in vitro in response to IL-8 and/or TNF-alpha. TSG-6, Link_TSG6, and K13E were added to the leukocytes or the EC monolayers. RESULTS: Co-injection of Link_TSG6 with IL-1beta selectively inhibited cell flux, adhesion, and emigration as analyzed in mesenteric postcapillary venules. The fewer cells that rolled in the animals treated with Link_TSG6 displayed a velocity similar to that measured in vehicle-treated mice. In vitro, Link_TSG6 did not affect neutrophil chemotaxis or EC activation but did inhibit neutrophil transmigration across EC monolayers. The latter effect was shared by full-length TSG-6 and observed equally in response to IL-8 or TNF-alpha. CONCLUSIONS: These data restrict the site of action for at least some of the anti-inflammatory effects ascribed to TSG-6/Link_TSG6 to the microenvironment of the extravasating leukocyte.     

In vitro anti-tumour activity of anti-CD80 and anti-CD86 immunotoxins containing type 1 ribosome-inactivating proteins

Immunotoxins specific for the CD80 and CD86 antigens were prepared by linking three type 1 ribosome-inactivating proteins (RIPs), namely bouganin, gelonin and saporin-S6, to the monoclonal antibodies M24 (anti-CD80) and 1G10 (anti-CD86). These immunotoxins showed a specific cytotoxicity for the CD80/CD86-expressing cell lines Raji and L428. The immunotoxins inhibited protein synthesis by target cells with IC50s (concentration causing 50% inhibition) ranging from 0.25 to 192 pmol/l as RIPs. The anti-CD80 immunotoxins appeared 1-2 log more toxic for target cells than the anti-CD86 ones. Immunotoxins containing saporin and bouganin induced apoptosis of target cells. The toxicity for bone marrow haemopoietic progenitors of these conjugates was also evaluated. Bouganin and related immunotoxins at concentrations up to 100 nmol/l did not significantly affect the recovery of committed progenitors or of more primitive cells. The saporin-containing immunotoxins at concentrations >/= 1 nmol/l showed some toxicity on colony-forming unit cells (CFU-C). The expression of the CD80 and CD86 molecules is prevalently restricted to antigen-presenting cells and is also strong on Hodgkin and Reed-Sternberg cells in Hodgkin's disease. Present results suggest that immunotoxins targeting type 1 ribosome-inactivating proteins to these antigens could be considered and further studied for the therapy of Hodgkin's disease or other CD80/CD86-expressing tumours.     

Angiotensin-converting enzyme inhibition, catecholamines and hemodynamics in essential hypertension

Captopril was given to 15 unselected patients with essential hypertension (WHO II) at a dose range of 300 to 600 mg/day. Hemodynamic indexes (thermodilution) as well as levels of plasma norepinephrine, epinephrine, renin activity and aldosterone were determined simultaneously at the end of 2 weeks of placebo and after 8 weeks of captopril treatment. Systolic and diastolic arterial pressures were reduced significantly by treatment both supine (p less than 0.0025) and standing (p less than 0.0025). The diastolic arterial pressure was normalized (less than 95 mm Hg) in five patients and significantly reduced in four, whereas six patients were considered poor responders (mean arterial pressure decrease 10 mm Hg or less). The decrease in arterial pressure correlated significantly with the reduction in total peripheral resistance (r = 0.71), whereas cardiac index did not change and stroke index increased because of a slight decrease of heart rate. Plasma and urinary norepinephrine and epinephrine did not change during treatment. Moreover, the response of both heart rate and plasma catecholamines to upright posture was not altered by captopril treatment. Plasma renin activity increased and plasma aldosterone concentration decreased during treatment. These results suggest that inhibition of converting enzyme activity by captopril induces a reduction in arterial pressure through a reduction in total peripheral resistance. There was no evidence of an appreciable reduction in sympathetic nervous system activity during therapy.     

Reduction of intra- and interlaboratory variation in CD34+ stem cell enumeration using stable test material, standard protocols and targeted training. DK34 Task Force of the European Working Group of Clinical Cell Analysis (EWGCCA)

The European Working Group on Clinical Cell Analysis (EWGCCA) has, in preparation for a multicentre peripheral blood stem cell clinical trial, developed a single-platform flow cytometric protocol for the enumeration of CD34+ stem cells. Using this protocol, stabilized blood and targeted training, the EWGCCA have attempted to standardize CD34+ stem cell enumeration across 24 clinical sites. Results were directly compared with participants in the UK National External Quality Assessment Scheme (NEQAS) for CD34+ Stem Cell Quantification that analysed the same specimens using non-standardized methods. Two bead-counting systems, Flow-Count and TruCount, were also evaluated by the EWGCCA participants during trials 2 and 3. Using Flow-Count, the intralaboratory coefficient of variation (CV) was 相似文献   

Expression of human chorionic gonadotropin, CD44v6 and CD44v4/5 in esophageal squamous cell carcinoma

AIM: To study the relationship between the expression of human chorionic gonadotropin (HCG), CD44v6, CD44v4/5 and the infiltration, metastasis of esophageal squamous cell carcinoma. METHODS: By labeled streptavidin-biotin technique, the expressions of HCG, CD44v6, and CD44v4/5 in 42 patients with esophageal squamous cell carcinoma were examined. RESULTS: The positive rate of HCG expression in patients with lymph node metastasis was 85.71% (18/21), higher than that (57.14%, 12/21) in those without lymph node metastasis (P<0.05). The positive rate of CD44v6 expression was 71.43% (15/21) in lymph node metastasis group, and 38.09% (8/21) in non-metastasis group; there was a significant difference between the two groups (P<0.05). The positive rate of CD44v4/5 expression was 76.19% (16/21) in lymph node metastasis group, and 42.86% (9/21) in non-metastasis group; there was also a significant difference between them (P<0.05). From grade Ⅰ to grade Ⅲ in differentiation, the positive rate of HCG expression was 84.62% (11/13), 70.59% (12/17) and 58.33% (7/12), respectively; there was no significant difference among them (P<0.05). The positive rate of CD44v6 expression in grades Ⅰ-Ⅲ of cancer tissues was 76.92% (10/13), 52.94% (9/17), and 33.33% (4/12) respectively; there was no significant difference among them. The positive rate of CD44v4/5 expression in grades Ⅰ-Ⅲ of cancer tissues was 69.23% (9/13), 64.71% (11/17), and 41.67% (5/12) respectively; there was no significant difference among the three groups. There was no correlation between the positive rates of HCG and CD44v6, CD44v4/5 expression. Cancer cells in carcinomatous emboli and those infiltrating into vascular wall strongly expressed HCG, CD44v6, and CD44v4/5. CONCLUSION: Expression of HCG, CD44v6, and CD44v4/5 in esophageal squamous cell carcinoma is related to its infiltration and metastasis. HCG, CD44v6, and CD44v4/5 have different effects on the infiltration and metastasis of esophageal squamous cell carcinoma.