(1/3240) Prolonged eosinophil accumulation in allergic lung interstitium of ICAM-2 deficient mice results in extended hyperresponsiveness.
ICAM-2-deficient mice exhibit prolonged accumulation of eosinophils in lung interstitium concomitant with a delayed increase in eosinophil numbers in the airway lumen during the development of allergic lung inflammation. The ICAM-2-dependent increased and prolonged accumulation of eosinophils in lung interstitium results in prolonged, heightened airway hyperresponsiveness. These findings reveal an essential role for ICAM-2 in the development of the inflammatory and respiratory components of allergic lung disease. This phenotype is caused by the lack of ICAM-2 expression on non-hematopoietic cells. ICAM-2 deficiency on endothelial cells causes reduced eosinophil transmigration in vitro. ICAM-2 is not essential for lymphocyte homing or the development of leukocytes, with the exception of megakaryocyte progenitors, which are significantly reduced. (+info)
(2/3240) Effects of soybean oil emulsion and eicosapentaenoic acid on stress response and immune function after a severely stressful operation.
OBJECTIVE: To investigate the effects of soybean oil emulsion and oral or enteral administration of eicosapentaenoic acid (EPA) on stress response, cytokine production, protein metabolism, and immune function after surgery for esophageal cancer. SUMMARY BACKGROUND DATA: It has been reported that safflower oil, rich in n-6 polyunsaturated fatty acid (n-6 PUFA), affects the survival rate of septic animals and decreases the immune function. It has also been reported that the administration of fish oil, in contrast, reduces these stress responses and stress-induced immunosuppression. In humans, the effects of soybean oil emulsion and the administration of EPA on stress response and immune function after surgery have not been established. METHODS: Patients who underwent esophagectomy with thoracotomy were divided into three groups. Seven patients were fed by total parenteral nutrition (TPN) with soybean oil emulsion, which accounted for 20% of total calories. Seven patients were given oral or enteral administration of 1.8 g/day EPA, in addition to TPN with soybean oil emulsion. Nine patients served as the control group; these patients received fat-free TPN. Serum interleukin-6 (IL-6), C-reactive protein, concanavalin A (con A)- or phytohemagglutinin (PHA)-stimulated lymphocyte proliferation, natural killer cell activity, and stress hormones were measured. RESULTS: The postoperative level of serum IL-6 was significantly higher in the group receiving soybean oil emulsion than in the fat-free group. Oral or enteral supplementation of EPA with soybean oil emulsion significantly reduced the level of serum IL-6 compared with the patients receiving soybean oil emulsion. Con A- or PHA-stimulated lymphocyte proliferation decreased significantly on postoperative day 7 in all groups of patients. The supplementation of EPA with soybean oil emulsion significantly improved the lymphocyte proliferation and natural killer cell activity on postoperative day 21 compared with the group receiving soybean oil emulsion. CONCLUSIONS: Soybean oil emulsion amplifies, and the supplementation of EPA reduces, the stress response and stress-induced immunosuppression. (+info)
(3/3240) N,N'-Diacetyl-L-cystine-the disulfide dimer of N-acetylcysteine-is a potent modulator of contact sensitivity/delayed type hypersensitivity reactions in rodents.
Oral N-acetyl-L-cysteine (NAC) is used clinically for treatment of chronic obstructive pulmonary disease. NAC is easily oxidized to its disulfide. We show here that N,N'-diacetyl-L-cystine (DiNAC) is a potent modulator of contact sensitivity (CS)/delayed type hypersensitivity (DTH) reactions in rodents. Oral treatment of BALB/c mice with 0.003 to 30 micromol/kg DiNAC leads to enhancement of a CS reaction to oxazolone; DiNAC is 100 to 1000 times more potent than NAC in this respect, indicating that it does not act as a prodrug of NAC. Structure-activity studies suggest that a stereochemically-defined disulfide element is needed for activity. The DiNAC-induced enhancement of the CS reaction is counteracted by simultaneous NAC-treatment; in contrast, the CS reaction is even more enhanced in animals treated with DiNAC together with the glutathione-depleting agent buthionine sulfoximine. These data suggest that DiNAC acts via redox processes. Immunohistochemically, ear specimens from oxazolone-sensitized and -challenged BALB/c mice treated with DiNAC display increased numbers of CD8(+) cells. DiNAC treatment augments the CS reaction also when fluorescein isothiocyanate is used as a sensitizer in BALB/c mice; this is a purported TH2 type of response. However, when dinitrofluorobenzene is used as a sensitizer, inducing a purported TH1 type of response, DiNAC treatment reduces the reaction. Treatment with DiNAC also reduces a DTH footpad-swelling reaction to methylated BSA. Collectively, these data indicate that DiNAC in vivo acts as a potent and effective immunomodulator that can either enhance or reduce the CS or DTH response depending on the experimental conditions. (+info)
(4/3240) An epidemiological study on the association between the total leukocyte and neutrophil counts, and risk factors of ischemic heart disease by smoking status in Japanese factory workers.
Several epidemiologic studies have shown the association between total leukocyte count and the risk of developing myocardial infarction. The purpose of this study was to assess the association between the total leukocyte and neutrophil counts and risk factors of ischemic heart disease in 1,384 Japanese factory workers. Total leukocyte and neutrophil counts were significantly higher in current smokers than in non-smokers. Among current smokers, the total leukocyte and neutrophil counts were positively associated with the number of cigarettes smoked daily and the duration of cigarette smoking and alcohol consumption. Being independent of smoking habit, the total leukocyte and neutrophil counts were also related to several characteristics recorded at the physical examinations. The total leukocyte and neutrophil counts were positively associated with serum total cholesterol, serum triglyceride and hematocrit levels, and inversely associated with the serum HDL-cholesterol level. No significant associations of the total leukocyte or neutrophil counts were found with the red blood cell count and hemoglobin level. These results suggest that the total leukocyte and neutrophil counts may represent the metabolic condition with a high coronary risk among apparently healthy people. (+info)
(5/3240) Immunodeficiency due to a unique protracted developmental delay in the B-cell lineage.
A unique immune deficiency in a 24-month-old male characterized by a transient but protracted developmental delay in the B-cell lineage is reported. Significant deficiencies in the number of B cells in the blood, the concentrations of immunoglobulins in the serum, and the titers of antibodies to T-dependent and T-independent antigens resolved spontaneously by the age of 39 months in a sequence that duplicated the normal development of the B-cell lineage: blood B cells followed by immunoglobulin M (IgM), IgG, IgA, and specific IgG antibodies to T-independent antigens (pneumococcal polysaccharides). Because of the sequence of recovery, the disorder could have been confused with other defects in humoral immunity, depending on when in the course of disease immunologic studies were conducted. Investigations of X-chromosome polymorphisms suggested that the disorder was not X linked in that the mother appeared to have identical X chromosomes. An autosomal recessive disorder involving a gene that controls B-cell development and maturation seems more likely. In summary, this case appears to be a novel protracted delay in the development of the B-cell lineage, possibly due to an autosomal recessive genetic defect. (+info)
(6/3240) Predictive value of CD19 measurements for bacterial infections in children infected with human immunodeficiency virus.
We investigated the predictive value of CD19 cell percentages (CD19%) for times to bacterial infections, using data from six pediatric AIDS Clinical Trials Group protocols and adjusting for other potentially prognostic variables, such as CD4%, CD8%, immunoglobulin (IgA) level, lymphocyte count, prior infections, prior zidovudine treatment, and age. In addition, we explored the combined effects of CD19% and IgG level in predicting time to infection. We found that a low CD19% is associated with a nonsignificant 1.2-fold increase in hazard of bacterial infection (95% confidence interval: 0.97, 1.49). In contrast, a high IgG level is associated with a nonsignificant 0.87-fold decrease in hazard of infection (95% confidence interval: 0.68, 1.12). CD4% was more prognostic of time to bacterial infection than CD19% or IgG level. Low CD19% and high IgG levels together lead to a significant (P < 0. 01) 0.50-fold decrease in hazard (95% confidence interval: 0.35, 0. 73) relative to low CD19% and low IgG levels. Similarly, in a model involving assay result changes (from baseline to 6 months) as well as baseline values, the effect of CD19% by itself is reversed from its effect in conjunction with IgG. In this model, CD19% that are increasing and high are associated with decreases in hazard of infection (P < 0.01), while increasing CD19% and increasing IgG levels are associated with significant (at the P = 0.01 level) fourfold increases in hazard of infection relative to stable CD19% and decreasing, stable, or increasing IgG levels. Our data suggest that CD19%, in conjunction with IgG level, provides a useful prognostic tool for bacterial infections. It is highly likely that T-helper function impacts on B-cell function; thus, inclusion of CD4% in such analyses may greatly enhance the assessment of risk for bacterial infection. (+info)
(7/3240) Dose-escalation study of docetaxel in combination with mitoxantrone as first-line treatment in patients with metastatic breast cancer.
PURPOSE: To define the maximum-tolerated dose (MTD) and the dose-limiting toxicities (DLTs) of docetaxel in combination with mitoxantrone in patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: Forty-one chemotherapy-naive patients with MBC (median age, 61 years) were enrolled. Thirty-eight (93%) had performance status (World Health Organization [WHO]) 0, 29 (71%) were postmenopausal, and 21 (51%) had estrogen receptor-negative tumors. Patients received escalated doses of docetaxel (75 to 100 mg/m2) on day 1 and mitoxantrone (8 to 22 mg/m2) on day 8. Treatment was repeated every 3 weeks. RESULTS: A total of 217 chemotherapy cycles were administered. Without recombinant human granulocyte colony-stimulating factor (rhG-CSF) support, the MTD1 occurred at the first dose level (docetaxel 75 mg/m2 and mitoxantrone 8 mg/m2); DLTs were febrile neutropenia, grade 4 neutropenia lasting more than 5 days, and grade 3 diarrhea. With prophylactic rhG-CSF, the MTD2 was docetaxel 100 mg/m2 and mitoxantrone 20 mg/m2; DLTs were febrile neutropenia and grade 4 neutropenia. Nine (22%) patients developed neutropenia after the first cycle of treatment. A total of 19 episodes of febrile neutropenia (9% of the cycles) occurred during the whole period of the study; there were no toxic deaths. At high docetaxel (100 mg/m2) and mitoxantrone (> 12 mg/m2) dose levels, a significant decrease of the absolute lymphocyte number was observed; immunophenotyping revealed that all lymphocyte subpopulations were reduced. Grades 2 and 3 neurosensory toxicity occurred in six patients (15%) and one patient (2%), respectively. No cardiac toxicity was observed. Nine complete responses (22%) and 23 partial responses (56%) were achieved (overall response rate, 78%; 95% confidence interval, 62.5% to 88.8%). The median duration of response was 12.5 months, and the median time to tumor progression was 14.5 months. CONCLUSION: The reported combination of docetaxel and mitoxantrone with G-CSF support is a safe, intensified, well-tolerated, and effective regimen as first-line treatment in patients with MBC. (+info)
(8/3240) Development of CD8+ effector T cells is differentially regulated by IL-18 and IL-12.
We investigated the effects of IL-18 on the development of CD8+ effector T cells in DBA/2 anti-BDF1 whole spleen cell MLC and compared the results with those of IL-12. Addition of IL-18 to the MLC resulted in a twofold increase in CD8/CD4 ratios compared with the control cultures when cells were expanded in IL-2-containing medium following MLC. Purified CD8+ T cells recovered from the IL-18-stimulated MLC produced 20- to 30-fold more IFN-gamma after secondary stimulation with C57BL/6 spleen cells or anti-CD3 mAb, and exhibited strong allospecific CTL activity. Neither IL-18 nor IL-18-supplemented culture supernatants from DBA/2 anti-BDF1 MLC induced type I CD8+ effector T cells when purified CD8+ T cells were used as responder cells in primary MLC. Furthermore, CD4+ T cell depletion from the responder cells abrogated the IL-18-induced increase in secondary IFN-gamma production by CD8+ T cells, suggesting that IL-18-induced type I effector CD8+ T cell development was CD4+ T cell dependent. In marked contrast, adding IL-12 to primary MLC decreased CD8/CD4 ratios by 50% and suppressed secondary IFN-gamma production and CTL activity by CD8+ T cells regardless of concentration, whereas Th1 development was promoted by IL-12. Moreover, both IL-12 and IL-18 efficiently induced type I CD8+ effector T cells in C57BL/6 anti-BDF1 MLC. These findings show that IL-18 plays an important role in the generation of type I CD8+ effector T cells, and further suggest that functional maturation of CD8+ T cells is differentially regulated by IL-18 and IL-12. (+info)