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Immunomodulatory effects of mineral dust. I. Effects of intraperitoneal dust inoculation on splenic lymphocyte function and humoral immune responses in vivo.

Syngeneic PVG rats and C57BL6 mice were inoculated with liquid suspensions of UICC chrysotile A asbestos, DQ12 quartz or the inert particulate TiO2. Rats received 10 mg and mice received 2.5 mg dust intraperitoneally on day 0. Injection of the pathogenic dusts asbestos and quartz was associated with a significant reduction in mitogenic response to PHA and Con A detected in splenocytes removed from animals 14 days after inoculation. Injection of TiO2 had no significant effect on splenocyte mitogenesis. Pretreatment of C57BL6 mice with asbestos intraperitoneally also impaired subsequent production of antibody to the protein antigen KLH. These data show that intraperitoneal injection of chrysotile A asbestos and DQ12 quartz had a marked effect on generalized T lymphocyte function. An additional immunomodulatory effect of asbestos injection was shown in C57BL6 mice where in vivo humoral immune responses were suppressed.

Animals↗

Synthetic peptides as antigens for the detection of humoral immunity to Plasmodium falciparum sporozoites.

The presence of antibodies against P. falciparum sporozoites in humans living in malaria-endemic areas was measured using as antigen the synthetic peptide (NANP)3, which represents the immunodominant region of the circumsporozoite (CS) protein. By using a competitive binding assay it was determined that antibodies which recognize (NANP)3 do not react with a 22-Mer synthetic peptide representing a cross-reacting epitope present in an antigen (5.1) from the blood stages of the parasite. Antibodies present in human sera which react with the 5.1 peptide did not react with (NANP)3. This strongly suggests that antibodies to (NANP)3 found in sera of individuals living in endemic areas are a reflection of exposure to P. falciparum sporozoites. These results validate the use of (NANP)3 for epidemiological studies to detect and measure humoral immunity to P. falciparum sporozoites.

Amino Acid Sequence↗

Radioimmunotherapy with iodine-131 tositumomab in patients with low-grade non-Hodgkin's B-cell lymphoma does not induce loss of acquired humoral immunity against common antigens.

Thirty-one previously untreated patients with follicular low-grade B-cell non-Hodgkin's lymphoma expressing the CD20 antigen were treated with iodine-131 tositumomab therapy between 1996 and 1998. The therapy led to a temporary depletion of peripheral blood B-lymphocytes. Recovery of B-cells occurred in most cases by 3 to 6 months and in all patients by 12 months posttherapy. A temporary decline in T-cell subpopulations, but no reduction in serum immunoglobulin levels, could be observed. ELISA techniques were used to detect specific antibodies against rubella, mumps, varicella zoster, measles, and tetanus. Almost all patients remained seropositive against the different antigens during the 1- to 2-year follow-up. No significant reduction in antibody concentrations to tetanus or measles could be detected. The data show that acquired humoral immunity against common antigens appears to be preserved despite a temporary loss of B-lymphocytes.

Adult↗

Escherichia coli O157 fails to induce a long-lasting lipopolysaccharide-specific, measurable humoral immune response in children with hemolytic-uremic syndrome.

Escherichia coli O157 lipopolysaccharide (LPS)-specific antibodies were measured in sequential serum samples from 131 children with serologically defined E. coli O157-associated hemolytic-uremic syndrome (HUS), using an enzyme immunoassay. On the basis of evaluation of 66 children with culture-proven E. coli O157 infection and serum samples from 132 age-matched control subjects, the assay showed a sensitivity of 95%, 88%, and 74% and a specificity of 99%, 99%, and 98% for IgM, IgA, and IgG, respectively. Anti-O157 LPS antibodies decreased below the cut-off levels in >50% of the children at 11 (IgM), 5 (IgA), and 11 weeks (IgG) after onset of diarrhea and 10, 4, and 10 weeks, respectively, after the onset of HUS. Children with enteropathic HUS fail to develop a long-lasting humoral immune response to the O157 antigen. Incomplete immunity to E. coli O157 may signal a risk for recurrent infections and has implications for serodiagnostic studies.

Adolescent↗

A hemolysis-hemagglutination assay for characterizing constitutive innate humoral immunity in wild and domestic birds.

Methods to assess immunocompetence requiring only a single sample are useful in comparative studies where practical considerations prevent holding or recapturing individuals. The assay for natural antibody-mediated complement activation and red blood cell agglutination described here, requiring approximately 100 microl of blood, is highly repeatable. The effects of complement deactivation, 2-mercaptoethanol (2-ME), age, and lipopolysaccharide (LPS)-induced sickness response were examined to validate comparisons among diverse avian species. Complement deactivation by heating significantly reduces lysis and treatment with 2-ME reduces both lysis and agglutination. Lysis and agglutination both increase with age in chickens; LPS treatment does not influence these variables in 11-week-old chickens. In a comparison of 11 species, both lysis (0.0-5.3 titers) and agglutination (1.8-8.0 titers) vary significantly among species. Accordingly, this assay can be used to compare constitutive innate humoral immunity among species and with respect to age, sex, and experimental treatments within populations.

Age Factors↗

Interferon production, cellular and humoral immunity in splenectomized patients.

Undetectable levels of circulating interferon were found in 35 splenectomized patients and in 14 controls. In addition, no differences in virus, purified protein derivative (PPD), and phytohaemagglutinin (PHA) induced interferon production were observed between the patients and the controls. Virus induced lymphocyte transformation tended to be reduced after splenectomy, but only the herpes simplex virus (HSV) induced transformation index was significantly reduced in splenectomized patients without residual splenic tissue (P less than 0.05). In contrast, the PHA lymphocyte transformation was unchanged in patients and controls. The number of natural viral antibodies in splenectomized patients did not differ from that of controls. Furthermore, there were no major differences in the magnitude of the titers of the sero-positive cases between the various groups. Thus, splenectomy does not interfere with interferon production in vitro, and as seen from natural viral antibodies, no impairment of humoral immunity was observed. The reduced HSV lymphocyte transformation may indicate an impaired lymphocyte function after splenectomy.

Adolescent↗

Vaccination with recombinant N-terminal domain of Als1p improves survival during murine disseminated candidiasis by enhancing cell-mediated, not humoral, immunity.

Candida spp. are opportunistic fungal pathogens that are among the most common causes of nosocomial bloodstream infections. The mortality attributable to disseminated candidiasis is 40 to 50% despite antifungal therapy. Clearly, new strategies are needed to prevent this life-threatening infection. Because risk factors for disseminated candidiasis are well defined and frequently of limited duration, vaccination is an appealing prophylactic strategy. We have identified a cell surface protein, Als1p, that mediates adherence of Candida albicans to a variety of human substrates and plastic. Here we report that immunizing BALB/c mice with the recombinant N-terminal domain of Als1p (rAls1p-N) improved survival during a subsequent challenge with a lethal inoculum of C. albicans. The protective 20-mug dose of rAls1p-N significantly increased Candida stimulation of Th1 splenocytes and increased in vivo delayed-type hypersensitivity. In contrast, antibody titers did not correlate with protection. Finally, the vaccine was not protective in T-cell-deficient mice but was protective in B-cell-deficient mice. These data indicate that the mechanism of action of the rAls1p-N vaccine is stimulation of cell-mediated, rather than humoral, immunity against C. albicans. The majority of efforts to date have focused on the development of passive immunization strategies to prevent or treat disseminated candidiasis. In contrast, our results provide proof of principle for vaccination with an adhesin of C. albicans and emphasize the potential for cell-mediated immune modulation as a prophylactic or therapeutic strategy against disseminated candidiasis.

Animals↗

Identification of epidermal growth factor receptor-derived peptides recognised by both cellular and humoral immune responses in HLA-A24+ non-small cell lung cancer patients.

The epidermal growth factor receptor (EGFR) is one of the most appropriate target molecules for cancer therapy because of its high expression in epithelial cancers. A novel EGFR-tyrosine-kinase inhibitor, ZD1839, has been approved as a drug for non-small cell lung cancer (NSCLC), and many other agents are now being tested in clinical trials. Cytotoxic T lymphocyte (CTL)-directed epitope peptides could be another class of useful compounds in EGFR-targeted therapies. However, at present, there are no data on CTL-directed peptides of EGFR. Therefore, this study aimed to identify immunogenic EGFR-derived peptides in HLA-A24(+) NSCLC patients. We report in this study three such EGFR-derived peptides at positions 54-62, 124-132 and 800-809. These peptides were recognised by both cellular and humoral immune responses in most of the peripheral blood mononuclear cells (PBMCs) and sera from NSCLC patients that we tested. These results may provide a scientific basis for the development of EGFR-based immunotherapy.

Antibody Formation↗

Humoral immunity due to long-lived plasma cells.

Conventional models suggest that long-term antibody responses are maintained by the continuous differentiation of memory B cells into antibody-secreting plasma cells. This is based on the notion that plasma cells are short-lived and need to be continually replenished by memory B cells. We examined the issue of plasma cell longevity by following the persistence of LCMV-specific antibody and plasma cell numbers after in vivo depletion of memory B cells and by adoptive transfer of virus-specific plasma cells into naive mice. The results show that a substantial fraction of plasma cells can survive and continue to secrete antibody for extended periods of time (>1 year) in the absence of any detectable memory B cells. This study documents the existence of long-lived plasma cells and demonstrates a new mechanism by which humoral immunity is maintained.

Adoptive Transfer↗

T cells expressing delayed-type hypersensitivity can be derived from a humorally immune lymphocyte population.

Spleen cells from mice immunizied to produce a potent humoral response do not express delayed-type hypersensitivity (DTH). These cells, when cultured at low density in the presence of the specific antigen for about 6 days, are able to produce swelling of the footpads of normal mice 24 h after they are injected s.c. into the footpad with the appropriate antigen. This footpad swelling peaks 24-48 h after the injection of the cells, requires the presence of Ly-1+Ly-2- T cells in the immune population, is due to the interaction of antigen-specific cells with the appropriate antigen and is therefore due to DTH-mediating cells. The optimal generation of these cells occurs under conditions similar to those favoring the primary induction of DTH. Furthermore, the in vitro generated cells are also able to produce a systemic state of DTH when injected i.v.; a DTH reaction is elicited in recipient mice when antigen alone is injected into their footpads. The observations reported here demonstrate that a humorally immune population of spleen cells, known to contain T cells able to suppress the induction of DTH, can under appropriate conditions give rise to cells expressing this subclass of cell-mediated immunity. The decision by the immune system to mount a humoral as opposed to a cell-mediated response is therefore reversible. These findings provide grounds for believing that it should be possible to develop the means to switch an on-going in vivo humoral response to a cell-mediated one, a maneuver that would be of considerable benefit in some well-recognized clinical situations.

Animals↗

[Evaluation of humoral immune response in patients with asymptomatic and symptomatic HIV infection. Analysis of titers of anti-Hbs, antibodies against cytomegalovirus, herpes simplex virus type I, rubella virus and toxoplasma gondii].

40 asymptomatic HIV carriers and 45 AIDS patients were tested for anti-HBs (Hepatitis B Virus surface antigen), anti-RV (Rubella virus), anti-Toxo (Toxoplasma gondii), anti-CMV (Cytomegalovirus) and anti-HSV-1 (Herpes simplex virus type 1) antibody titers and compared with 83 persons characterized by risk behaviours but seronegative for HIV. The prevalence of these antibodies was very high and similar in all three groups studied, however, patients with AIDS had generally lower antibody titers when compared with asymptomatic carriers. The only exception being anti-HSV-1 which was present in high titre even in gravely ill patients. It seems that subjects with clinically overt HIV infection develop a serious disturbance in the humoral immune response with depressed specific antibody synthesis.

Acquired Immunodeficiency Syndrome↗

Regulation of aged humoral immune defense against pneumococcal bacteria by IgM memory B cell.

Elderly persons have a high incidence of lethal infections by encapsulated bacteria. However, mechanisms involved in their poor defense and maintenance of immunological memory have been poorly understood. The present study characterized the population of B cells known as IgM memory B cell compartment and their response by pneumococcal vaccine in elderly people. CD27+ memory B cells, particularly IgD+IgM+CD27+ IgM memory B cells, had dramatically declined in the aged. Their Ig syntheses by B cells and the differentiation into plasma cells were diminished in vitro compared with those in adults. A rise of anti-pneumococcal IgM in sera of elderly persons was found with lower levels compared with those in adults after pneumococcal vaccination. Although diminished function itself of aged B cells surely exist, decline of the IgM memory B cell pool is expected to result in a poor humoral immunity against pneumococcal infection in elderly people.

Adult↗

Immunomodulation by Dok Din Daeng (Aeginetia indica Roxb.) extracts in female B6C3F1 mice: II. Humoral immunity, innate immunity and hematology.

In the previous report, we have provided evidence that Aeginetia indica Roxbert (DDD) extracts enhance T cell-mediated immune responses. The study reported here was focused on the hematological and immunological effects, including B cells, natural killer (NK) cells, macrophages and neutrophils, of the whole plant extract using water (WDDD) or ethanol (EDDD) as the solvent. The extracts were administered to female B6C3F1 mice by gavage for WDDD (10-100%) and intraperitoneally for EDDD (0.25-250 mg/kg) for 28 days. In addition to hematological evaluation, several quantitative measures and functional assays (e.g., the splenic phenotypic analysis, IgM antibody-forming cell responses, natural killer cell activity, mononuclear phagocyte system [MPS] and neutrophil activity) were employed to examine the effects of DDD extracts on the innate and humoral immunities. The results from this study demonstrated that exposure to WDDD and EDDD produced minimal changes in the activities of B cells and natural killer cells, macrophages and neutrophils. Overall, hematological parameters were not affected by exposure to WDDD or EDDD. Taken together, the enhancing effect of DDD extracts on T cells may be primarily responsible for the successful and long-time use of this traditional herbal medicine in Thailand.

Administration, Oral↗

Failure of two serotype II infectious bursal disease viruses to affect the humoral immune response of turkeys.

The effect of serotype II infectious bursal disease virus (IBDV) isolates from turkeys on the homoral immune response of turkey poults was determined. Following exposure to the OH IBDV isolate, poults in two experiments were inoculated with sheep red blood cells, which is a T-dependent antigen, and poults in two other experiments were inoculated with Salmonella heidelberg O antigen, which is a T-independent antigen. Prior exposure to serotype II IBDV did not affect serum antibody titers to these antigens. IBDV infection also did not affect the concentrations of serum immunoglobulin M (IgM), IgG, or IgA in these poults. Bursa:body weight ratios of OH IBDV-infected poults were not significantly different from those of uninfected controls. In one experiment, the humoral immune response of poults to the LaSota Newcastle disease vaccine was not affected by infection with the MO IBDV isolate. Although no clinical infectious bursal disease was observed in any poult in these experiments, the serotype II IBDV isolates were infectious and transmissible in poults.

Animals↗

Auto-antibodies in prostate cancer: humoral immune response to antigenic determinants coded by the differentially expressed transcripts FLJ23438 and VAMP3.

BACKGROUND: Here we evaluate auto-antibody response against two potential antigenic determinants of genes highly expressed in low Gleason Score prostate cancer (PC) tumor samples, namely FLJ23438 and VAMP3. METHODS: RT-PCR assays were used to analyze mRNA expression profiles of FLJ23438 and VAMP3 transcripts. The auto-antibody response against FLJ23438 and VAMP3 recombinant proteins was tested by immunoblot assays using PC, benign prostate hyperplasia (BPH), healthy donors (HD), and other human cancers plasma samples. RESULTS: Our data showed that 37% (10/27) and 7.4% (2/27) of PC plasma samples presented auto-antibodies against FLJ23438 and VAMP3, respectively. Only 8.3% (1/12) of BPH plasma samples were reactive for both auto-antibodies, while none (0/12) of HD plasma samples tested were reactive. CONCLUSIONS: The prevalence of 37% of positive PC plasma samples for anti-FLJ23438 antibodies suggests that humoral immune response against this antigenic determinant could be a potential serum marker for this cancer.

Adenocarcinoma↗

Human visceral leishmaniasis: analysis of the specificity of humoral immune response to polypeptides of Leishmania donovani chagasi.

Soluble antigens from Leishmania donovani chagasi were studied in terms of their ability to react with sera from human visceral leishmaniasis. Thirty-six polypeptides, with molecular weights ranging from 14,400 to 123,000 were demonstrated by Western blot analysis. An extensive cross-reactivity with sera from patients with cutaneous leishmaniasis and Chagas' disease also was observed. Two polypeptides (Mr 119,000 and 123,000) reacted with all the sera from visceral leishmaniasis patients. When they were electroeluted from gels and evaluated with respect to specificity to the L. donovani chagasi subspecies, these components were expressed in all strains of Leishmania tested, but not in those of Trypanosoma cruzi. These results indicated that these components are shared by Trypanosomatidae of genus Leishmania. The eluted polypeptides did not react with sera from patients with Chagas' disease, indicating the feasibility of using purified antigens to discriminate between the humoral immune responses in T. cruzi and Leishmania infections.

Animals↗

Ontogeny of bursal function in chicken. 3. Immunocompletent cell for humoral immunity.

To study the occurrence of immunocompetent cells directly responsible for antibody production, cells from yolk sac, embryonic liver, bursa of Fabricius, bone marrow, spleen, or thymus were injected together with SRBC and Brucella abortus into 4-day old cyclophosphamide-treated chicks. A second stimulation was given 4 days later, and samples taken 4 days thereafter were used for antibody titrations. During ontogeny, immunocompetent cells appeared in significant numbers first in the spleen for anti-SRBC responses, but in the bursa for anti-Brucella responses. Later these cells were also found in thymus and bone marrow. In the bursa, cells immunocompetent for anti-SRBC response were not encountered in significant numbers. The slight response to SRBC by transferred bursa cells reflects the presence of stem cells and their immediate descendents in the bursa at different stages of development. These findings are compared with the development and maturation of the stem cell responsible for humoral immunity. In the bursa, development of the stem cell population precedes that of immunocompetent cells. The opposite relationship was found in bone marrow, spleen, and thymus where immunocompetent cells were always present some weeks before the appearance of cells capable of achieving a long-lasting reconstitution of bursa-dependent functions. These observations reveal that the bursa seeds out immunocompetent cells during its entire postembryonic development, but does not release the lymphoid stem cell population before this population has matured sufficiently and before the bursa itself, after fulfilling its function, starts to involute.

Animals↗

Cancer/testis antigen expression and autologous humoral immunity to NY-ESO-1 in gastric cancer.

Gastric cancer has the highest mortality rate and the second-highest morbidity rate of all malignant tumors in China. Since cancer/testis (CT) antigens are expressed in various types of human tumors but generally not in normal tissue except for testis, they are promising antigens for cancer immunotherapy. NY-ESO-1, in particular, is the most immunogenic of the CT antigens. To study the feasibility of developing a CT antigen vaccine for gastric cancer, 101 gastric cancer samples were analyzed for the presence of NY-ESO-1 mRNA and that of 10 other CT antigen genes. Twelve out of 101 samples (11.9%) were found to be NY-ESO-1 mRNA-positive, 11 of them from advanced stage patients. In 7 of the 12 NY-ESO-1 mRNA-positive samples, the NY-ESO-1 protein was also detected by immunohistochemistry. An autologous humoral immune response to NY-ESO-1 was detected in 6 of 12 advanced stage NY-ESO-1 mRNA-positive patients, indicating that NY-ESO-1 is immunogenic in advanced stage gastric cancer. The serum from a patient with an NY-ESO-1 negative but LAGE-1 positive tumor was also found to be NY-ESO-1 antibody positive, possibly due to cross-reactivity between NY-ESO-1 and LAGE-1. All NY-ESO-1 mRNA-positive gastric cancer samples also expressed one to seven additional CT genes, revealing a tendency toward a clustered expression pattern, regardless of disease stage. About 74% of the samples expressed at least one CT antigen, most frequently MAGE-3 (41.6%). NY-ESO-1 and MAGE-3 are thus potential targets for a multivalent CT antigen vaccine.

Antibody Formation↗