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At least 721 records · Page 40Linked to original sources
PubMed2000

Selective Modulation of Paracortical Dendritic Cells and T-Lymphocytes in Breast Cancer Sentinel Lymph Nodes.

Sentinel nodes (SNs), the nodes nearest a primary tumor on the direct lymphatic drainage path, are the site of earliest metastases, and in melanoma show striking immune modulation. We evaluated SNs from breast cancer patients for evidence of similar immune perturbation. The purpose of this study was to evaluate whether SNs from patients with breast cancer show the alterations in the histology and cytology of the paracortical areas seen in SNs from patients with melanoma. Formalin-fixed and paraffin-embedded sections from 32 SNs and 32 nonsentinel nodes (NSNs) from patients with breast cancer were evaluated. Sections were stained with hematoxylin and eosin and with antibodies to S-100 protein and HLA-DR, DQ, and DP to identify interdigitating dendritic cells (IDCs), and by an antibody to CD43RA to delineate T lymphocytes. By computerized image analysis we evaluated the distribution, frequency, immunophenotype, and activation status of IDCs and associated T lymphocytes in SNs and NSNs. Average areas occupied by S-100-positive dendritic cells (DCs) in SNs and NSNs were 0.13% and 19.98%, respectively, of total nodal area (p < 0.0001). The average density of S-100-positive IDCs in SNs was 11.00/mm2 and in NSNs was 257.88/mm2 (p < 0.0001). In SNs 43.55% of DCs (4.93/mm2) were nondendritic, 51.92% (5.69/mm2) had short dendrites, and 5.2% were mature with long dendrites (0.62/mm2). In SNs the ratio of immature to mature IDCs was 7.95:1. In NSNs, 8.09% of DCs (8.5/mm2) were nondendritic, 28.22% (67.46/mm2) had short dendrites, and 63.07% (145.96/mm2) were mature DCs with long dendrites. The ratio of immature to mature DCs in NSNs was 1:6.66. The average areas occupied by HLA class II-positive DCs in SNs and NSNs were 4.21% and 31.82%, respectively, of total nodal area. The frequency of coexpression of S-100 and HLA class II by immature IDCs without dendrites was 11.27% in SNs and 15.00% in NSNs. In both SNs and NSNs (p < 0.001) all mature S-100-positive IDCs with long dendrites expressed HLA class II. CD43RA-positive T lymphocytes occupied 20.06% of total nodal area in SNs and 63.57% in NSNs (p < 0.0001). The SNs from breast cancer patients are profoundly immune modulated with, by comparison to NSNs, markedly reduced paracortical areas, densities of paracortical DCs, frequency of S-100-positive IDCs coexpressing HLA class II, and a predominance of immature nondendritic and poorly dendritic DCs.

Journal Article↗
PubMed2003

CD40 ligand (CD154) improves the durability of respiratory syncytial virus DNA vaccination in BALB/c mice.

Respiratory syncytial virus (RSV) infection is the single most important cause of serious acute respiratory illness in children <1 year of age worldwide, and is associated with life-threatening pneumonia or bronchiolitis in the elderly. Current vaccine strategies include live, attenuated virus, subunit and DNA vaccines, however, none have been sufficiently safe, or shown to induce satisfactory long-term immunity, thus immune modulators are being considered to enhance the effectiveness of RSV vaccines. In this study, we examine CD40 ligand (CD40L) as an immune modulator to enhance the durability of DNA vaccines encoding RSV F and/or G glycoproteins in BALB/c mice. The addition of CD40L to DNA vaccines encoding the F glycoprotein enhanced virus clearance and some aspects of the immune response to RSV challenge, suggesting that CD40L may enhance the durability of RSV DNA vaccines.

Animals↗
PubMed1985

Dextran as a modulator of immune and coagulation activities in trauma patients.

Low Mr dextran has been utilized as a prophylactic therapy in treatment of coagulopathy. There is evidence that monocyte dysfunctions are important contributors to hypercoagulability episodes, as well as to immunoincompetence post-trauma. Dextran is a known monocyte modulator. Consequently, we evaluated the efficacy of dextran infusion in moderating immune dysfunction, monocyte aberrations, and hypercoagulability episodes. Twenty-eight trauma patients were randomly divided into two groups. One group of 15 received dextran at 1 g/kg wt/24 hr for 5 days in addition to standard resuscitation and treatment. The control or nontreated patient group received only standard treatment. Trauma patients in the two groups were retrospectively matched by injury severity score (ISS) to ensure comparability. Blood samples were collected daily for some studies and at 3-day intervals for other assays. In vivo coagulation status was evaluated by assessing the changes in intravascular fibrinopeptide A (FPA). Immune reactivity to the mitogen phytohemagglutinin (PHA) was also evaluated. Both monocyte production of plasminogen activator (PA) and monocyte production of procoagulant activity (PCA) have been shown to correspond to and be augmented by monocyte-T lymphocyte interactions. Consequently, monocyte production of plasminogen activator and procoagulant activity were assessed as measures of monocyte immune activity as well as indicators of monocyte function in controlling the balance between fibrinolysis and coagulation. Only patients with ISS of greater than 25 experienced significant immune, coagulation, or monocyte aberrations. Of those having an injury severity score (ISS) score of 25-35, all of the control and two of the dextran patients had significant perturbations in their immune and monocyte functions.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Coagulation↗
PubMed1995

Transcription factors as drug targets: opportunities for therapeutic selectivity.

Many traditional drugs target cell surface receptors. Medicinal chemists and pharmacologists have not ventured into the field of transcription regulation due to the fear that drugs that interfere with transcription regulation may not be selective or efficacious. The past 5 years have seen some exciting developments in the field of signal transduction in general, and transcription regulation in particular. Our understanding of mechanisms of regulated and basal transcription is advanced to a degree that it should be possible to selectively modulate a target gene directly. In this review we have argued that sufficient diversity exists in the combinatorial interplay of the transcription factors to offer opportunities for selective therapeutic intervention. We have focused our attention on transcriptional factors that play a role in three different therapeutic areas: osteoporosis, immune modulation, and cardiovascular diseases. Human estrogen receptor is considered as a model transcription factor. The role of estrogen in bone remodeling is discussed. Opportunities for tissue-specific modulation of estrogen receptors are described. For selective immune modulation, we have discussed the role of NF-AT (nuclear factors for activated T cells) transcription factors in interleukin-2 gene regulation. The last section focuses on the transcriptional mechanisms conferring tissue specificity in regulated expression of the apoAI gene, a major component of HDL, in liver. We have highlighted opportunities for rational development of transcription-based drugs useful for raising HDL plasma levels and atherosclerosis prevention.

Cardiovascular Diseases↗
PubMed1987

[Tumor cell immunogenicity and T-cell-mediated antitumor immune reactions. Modulation and application to immunotherapy].

Several approaches to increase tumor cell immunogenicity and anti-tumor T-cell reactivity have been reviewed. In contrast to unspecific immune stimulation, the activation of specific T-cell reactivity can lead to long-lasting anti-tumor immunity. In several instances, immunization with modified tumor cells led to the induction of tumor immunity against the original non-modified tumor cells. In our own studies two types of approaches were also effective with the highly metastatic mouse tumor line ESb which carries a weak tumor associated antigen. Postoperative immunization with either virus modified ESb cells or with mutagenized variants of ESb cells led to the survival of a significant proportion of the treated animals. These animals had been cured of their micrometastases and developed long lasting anti-tumor immunity. It is hoped that such modified tumor cells could become useful reagents for tumor immunotherapy, especially in situations where the tumor burden is low. Future efforts should be directed towards testing the effectiveness of immunogenic modified tumor variants in combination with surgery or chemotherapy for treatment of micrometatases.

Animals↗
PubMed2004

Platelet count, previous infection and FCGR2B genotype predict development of chronic disease in newly diagnosed idiopathic thrombocytopenia in childhood: results of a prospective study.

About 25-30% of children with acute idiopathic thrombocytopenia (ITP) develop chronic disease. It is not well known which patient characteristics influence the course of the ITP. A prospective study in 60 children with newly diagnosed ITP was performed. The aim of the study was to identify patient characteristics at the onset of thrombocytopenia that predicts the progression to chronic ITP. Clinical data and blood samples were collected at several time points during the first 6 months of the disease. Variables predicting chronic disease, as calculated in a multivariate logistic regression analysis, were a platelet count >10 x 10(9)/l at the onset [odds ratio (OR) 1.1, 95% confidence interval (CI) 1.01-1.14], the absence of infection shortly before the onset of the disease (OR 4.8, CI 1.16-19.57) and FGR2B-232I/T genotype (OR 7.9, CI 0.96-65.27). The latter may point at an immune-modulating role of Fc gamma RIIb in ITP. Although only three patients had serious bleeds, 35 patients received immune-modulating treatment for low platelet counts only. Seventeen patients were treated with intravenous immunoglobulin (IVIG) and 18 patients received corticosteroids. Patient variables did not differ between these treatment groups. However, patients receiving IVIG had significantly lower risk for chronic disease.

Adolescent↗
PubMed2003

Dang-Gui-Bu-Xai-Tang modulated the immunity of tumor bearing mice.

Dang-Gui-Bu-Xai-Tang (DGBXT), which includes Radix Angelicae Sinensis and Radix Astragali Membranaceus, is a traditional Chinese medicine used to modulate the lymphocyte activity of cancer patients after chemotherapy and radiotherapy. In the present study, we examined the cytotoxicity of DGBXT on transformed cells and the immunomodulating effects of DGBXT in a tumor-bearing murine model. DGBXT markedly inhibited the growth of the EJ-Ha-ras transformed LZEJ and LZEJ-C2 cells lines. Oral administration of DGBXT for three weeks significantly prevented the tumor development in mice that injected with LZEJ-C2 cells subcutaneously. Moreover, DGBXT effectively increased the population of cytotoxic T lymphocytes (CTLs) and NK cells, and down-regulated activated T helper cells (CD4+/CD25+) in spleen and tumor-draining lymph nodes (TDLN). Furthermore, DGBXT stimulated the production of tumor necrosis factor-alpha in in vitro cultured splenocytes. These results might explain the antitumor effects of DGBXT.

3T3 Cells↗
PubMed2006

Effects of organochlorine contaminants on loggerhead sea turtle immunity: comparison of a correlative field study and in vitro exposure experiments.

Several laboratory and field studies indicate that organochlorine contaminants (OCs), such as polychlorinated biphenyls (PCBs) and pesticides, modulate immune responses in rodents, wildlife, and humans. In the present study we examined the effects of OCs on immunity in free-ranging loggerhead sea turtles (Caretta caretta). Mitogen-induced lymphocyte proliferation responses, lysozyme activity, and OC concentrations were measured from blood samples. Mitogens chosen in the lymphocyte proliferation assay were phytohemagglutinin (PHA) and concanavalin A (ConA) for T-lymphocyte stimulation, and lipopolysaccharide (LPS) and phorbol 12,13-dibutyrate (PDB) for B-lymphocyte stimulation. Lysozyme activity was significantly and negatively correlated with whole-blood concentrations of 4,4 -dichlorodiphenyldichloroethylene (4,4 -DDE) and the sum of chlordanes. Lymphocyte proliferation responses stimulated by PHA, LPS, and PDB were significantly and positively correlated with concentrations of the sum of PCBs measured in whole blood. LPS- and PDB-induced proliferation were also significantly and positively correlated with 4,4 -DDE blood concentrations. These correlative observations in free-ranging turtles suggest that current, chronic exposure to OCs may suppress innate immunity and enhance certain lymphocyte functions of loggerhead sea turtles. To further test this hypothesis, lymphocyte proliferation was measured after in vitro exposure of peripheral blood leukocytes from 16 turtles to Aroclor 1254 (0-13.5 microg/mL) or 4,4 -DDE (0-13.4 microg/mL). Both contaminants increased PHA- and PDB-induced proliferation at concentrations below those that affected cell viability. Moreover, the concentrations that enhanced PDB-induced proliferation in vitro were similar to concentrations measured in turtles with the highest proliferative responses. The similarities between the in vitro experiments and the correlative field study suggest that OC exposure modulates immunity in loggerhead turtles.

Animals↗
PubMed2003

Portal to the interior: viral pathogenesis and natural compounds that restore mucosal immunity and modulate inflammation.

Most antigens, particularly viruses, enter the body through the mucosal epithelia where they are carried by afferent lymphatics to regional lymph nodes for presentation to the immune system. Although they share immunological similarities, immune processes that protect the mucosa are distinct from innate and acquired immunity. The barrier formed by the intestinal mucosa is the most studied, with its microenvironment having a marked influence on both local and systemic immune responses. A healthy microenvironment and resilient neighboring tissue provide protection against inflammation known to dampen mucosal immunity, promote carcinogenesis, contribute to systemic inflammatory processes, and result in autoimmune diseases. Numerous natural substances improve this microenvironment and thereby enhance immunity against microbial infections. Since mucosal immunity forms the first line of defense against many commonly transmitted pathogens, restoring and maintaining mucosal immunity is critical for disease prevention and intervention. This article discusses the nature of mucosal immunity and its relationship to viral infections and other conditions, and reviews natural compounds that help restore mucosal immunity.

Dietary Supplements↗
PubMed1987

Endorphinergic modulation of immune function: potent action of the dipeptide glycyl-L-glutamine.

Glycyl-L-glutamine (GLG), the carboxy terminal dipeptide of B-endorphin, inhibits brainstem neuronal activity. It also occurs along with B-endorphin in pituitary secretory vesicles suggesting a neurosecretory role for this dipeptide. We have evaluated potential immunoregulatory actions of this compound using the Phytohemaglutinin (PHA) blastogenesis and the concanavalin A (ConA) suppressor cell induction assays. GLG in low doses (10(-12) M) enhanced the response of human lymphocytes to PHA induced blastogenesis, however; with higher doses of the dipeptide (10(-7) M) immunosuppression was consistently observed. In the suppressor cell induction assay, when GLG was used together with ConA, we observed a dose-dependent inhibition of suppressor activity. These results clearly indicate that GLG produces a dose dependent bidirectional modulation of at least two indicies of immune function, and confirm the presence of a second pituitary peptide with the potential for potent immunomodulatory action.

Concanavalin A↗
PubMed2003

Effect of bisphenol A on murine immune function: modulation of interferon-gamma, IgG2a, and disease symptoms in NZB X NZW F1 mice.

To investigate the effects of the estrogen receptor-binding molecule bisphenol A (BPA) on murine immune function in vivo, we fed a low dose of 2.5 micro g BPA/kg body weight/day to both normal C57BL/6 and lupus-prone NZB X NZW F(1) (NZB/NZW) 5-week-old mice for 1 week. Analysis of concanavalin A (ConA)-stimulated splenic mononuclear cells by ELISA demonstrated that BPA-fed C57BL/6 males produced, on average, 40% less interferon-gamma (IFN-gamma; p < 0.01) and C57BL/6 females 28% less IFN-gamma (p < 0.05) compared with controls. Treated female NZB/NZW mice were monitored for lupus disease symptoms, defined as proteinuria (> 100 mg/dL albumin in urine for 2 consecutive weeks). Before the development of proteinuria, BPA-fed NZB/NZW mice produced significantly less ConA-stimulated IFN-gamma than did controls and displayed an average reduction of 50% in immunoglobulin G2a (IgG2a) antibody production from lipopolysaccharide (LPS)-stimulated splenocytes (p < 0.05). It is striking that 5-week-old female NZB/NZW mice fed a 7-day low-dose course of BPA developed proteinuria an average of 7 weeks later than did controls. Once proteinuria developed, splenocytes were stimulated with ConA for cytokine analysis. The BPA-fed mice showed a dramatic reduction of 64% in IFN-gamma production and a 32% reduction in ConA-stimulated interleukin-10 (p < 0.05). The long-lasting effects of BPA on IFN-gamma and IgG2a production likely contributed to the increased symptom-free period of the NZB/NZW mice.

Animals↗
PubMed1989

Immune complex modulation by plasma proteins. With special reference to the complement system and autoimmune diseases.

The complement (C) system consists of two activation pathways, the classical and the alternative, which may both be activated by immune complexes (IC). C activation products become attached to the IC during activation leading to profound changes in the properties of the complexes. The common terminal C pathway is not involved in activation mediated by fluid phase IC. The interaction between IC and C may lead to: 1) Increased solubility of the IC. 2) Enhanced phagocytosis and clearance of the IC. 3) Altered tissue distribution of the IC. 4) Generation of soluble C fragments which mediate inflammation. 5) Tissue damage by activation and/or lysis of bystanding cells. 6) Modulation of B-cell proliferation and differentiation. Activation of the C system by IC is an essential normal component in the clearance of invading foreign material. However, in conditions with a persistent high concentration of IC in the circulation or tissues, this activation may lead to chronic inflammatory disease. This thesis reviews certain aspects of the interactions between IC and C. The earlier work describes our development of an assay for measuring the C activity in patient sera by its ability to solubilize preformed, fluid phase IC (CMS assay). The CMS was found to be dependent upon the alternative pathway of C and facilitated by the classical. Further studies concerning the influence of C deficiencies or depletion of C factors, the concentration of divalent metallions, the temperature and the ionic strength were performed to characterize the reaction. The CMS assay, showed that serum from patients with SLE and other systemic persistent inflammatory diseases and infections exhibited a reduced capacity to solubilize IC. The CMS values correlated inversely to the disease activity in SLE patients. It was also for the first time demonstrated that serum from some SLE patients contained a CMS inhibitor and it is suggested that this inhibitor of CMS is endogenously formed incompletely C solubilized IC. This suggestion is based upon several lines of indirect evidence, and by HPLC size distribution analysis of the IC in SLE sera, which showed a reduction in IC size upon incubation with C. A negative correlation between the CMS capacity and the content of CMS inhibitory material was found. The CMS capacity did not correlate to the serum concentration of any of the C factors C3b/C3c, C4, Clq, factor B, factor H or factor I, nor did it correlate to the concentration of the degradation product C3dg. But a low concentration of one of the native C factors was associated with a reduced CMS.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1995

Association of changes in monocyte antigen presentation and cytokine production in haemophilic boys with treatment and blood-borne virus infection.

Aspects of monocyte function (antigen presentation and cytokine production (e.g. IL-1, IL-6) have been studied in a normal control population and three groups of haemophilic boys: group 1 HIV and HCV seronegative and treated only with a single heat-treated factor VIII (FVIII) concentrate; group 2 HIV seronegative but HCV seropositive; group 3 all HIV and HCV seropositive. Groups 2 and 3 have been previously treated with unheated and heated FVIII concentrate. Group 1 boys (HIV/HCV uninfected) showed no significant reduction in monocyte antigen presentation function nor IL-1 or IL-6 production when compared with a control population. Group 2 boys (HCV infected) showed a reduced monocyte antigen presentation activity (P < 0.05), but no significant reduction in IL-1 or IL-6 production. Group 3 boys (HIV and HCV infected) showed a significantly reduced monocyte antigen presentation activity (P < 0.001) and an impairment of IL-1 and IL-6 production (P < 0.05). A significant reduction of IL-1 and IL-6 production was only seen in the HIV and HCV infected haemophilic boys, implicating HIV as an aetiological agent. In contrast, reduced monocyte antigen presentation activity was seen in haemophilic boys with both HIV and HCV infection or HCV alone. The HIV and HCV seronegative boys had normal antigen presentation. The absence of immune modulation in haemophilic boys that have not acquired HIV and HCV infection suggests that chronic blood-borne virus infections as contributory to immune modulation seen in haemophiliacs with virus infections.

Adolescent↗
PubMed2004

Immune response modulation to DPT vaccine by aqueous extract of Withania somnifera in experimental system.

Immunopotentiation on oral feeding of standardized aqueous extract of Withania somnifera (Linn. Dunal, Family Solanaceae) was evaluated in laboratory animals immunized with DPT (Diphtheria, Pertussis, Tetanus) vaccine. The immunostimulation was evaluated using serological and hematological parameters. Treatment of immunized animals with test material (100 mg/kg/day) for 15 days resulted in significant increase of antibody titers to B. pertussis (P=0.000007). Immunized animals (treated and untreated) were challenged with B. pertussis 18,323 strain and the animals were observed for 14 days. Results indicate that the treated animals did show significant increase in antibody titers as compared to untreated animals after challenge (P=0.000003). Immunoprotection against intracerebral challenge of live B. pertussis cells was evaluated based on degree of sickness, paralysis and subsequent death. Reduced mortality accompanied with overall improved health status was observed in treated animals after intracerebral challenge of B. pertussis indicating development of protective immune response. Present study indicates application of the test material as potential immunopotentiating agent possible applications in immunochemical industry. The test material also offers direct therapeutic benefits resulting in reduced morbidity and mortality of experimental animals.

Animals↗
PubMed2003

Modulation of immune response in Plasmodium falciparum malaria: role of IL-12, IL-18 and TGF-beta.

The interaction between pro- and anti-inflammatory cytokines such as interleukin 12 (IL-12), interleukin 18 (IL-18) and transforming growth factor beta (TGF-beta) plays an important role in malaria pathogenesis and outcome, modulating the immunoresponse in Plasmodium falciparum malaria. In our previous studies, we analyzed the plasmatic levels of IL-12, IL-18 and TGF-beta in 105 African children with different degrees of malaria and we correlated the production of these cytokines with the severity of the disease. The aim of the present study was to analyze with a mathematical model, taking into account all the relationships between these cytokines and the parameter variations involved in malaria pathogenesis that influence the results of each type of treatment or therapeutic protocol on patients at different stages of the disease. A mathematical correlation was demonstrated between the levels of pro-inflammatory and anti-inflammatory cytokines, and from this it was possible to build curves of reference in which each patient was positioned based on IL-12 level. Our data, obtained in patients with mild and severe diseases, demonstrate that the levels of IL-12 represent a reliable parameter to predict the progression of the disease, which may be complemented or modulated by administration of IL-18 and TGF-beta. Our findings provide future implications for an immune therapy against the P. falciparum malaria infection, especially in the early phase of the disease showing that a more aggressive outcome may be due to the lack of a balanced immune response.

Animals↗
PubMed1986

Immune interferon modulation of in vitro murine anti-human T cell monoclonal antibody-mediated cytotoxicity.

Limited antitumor effects have been achieved in clinical trials with murine monoclonal antibody T101, perhaps because of its limited ability to effect complement-mediated or cell-mediated cytotoxicity. We explored the effects of recombinant immune interferon on T101-mediated cytotoxicity in vitro. Interferon failed to enhance expression of the antigen detected by T101 on target cells, but it did increase Fc receptor binding of T101 and other IgG2A and IgG3 murine proteins, but not IgG1 or IgG2B. Preincubation of U937, HL60, and human mononuclear cells with 100 U of immune interferon for 48 hr, while T101 was preincubated with various T cell line targets or human CLL cells at 4 degrees C for 30 min before combining effectors and targets for 4 hr at 37 degrees C, resulted in cytotoxicity of 18 to 44% of maximum. Cytotoxicity in the absence of interferon or T101 was less than 5%. Unfortunately, rapid modulation of antigen-antibody when T101 was preincubated with targets at 37 degrees C prevented any increase in cytotoxicity under those conditions. We conclude that immune interferon can augment T101-mediated cytotoxicity in vitro, but it is unlikely that it would enhance T101-mediated cytotoxicity via complement or cell-mediated mechanisms in vivo.

Animals↗