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PubMed1998

The activity of topoisomerase I is modulated by large T antigen during unwinding of the SV40 origin.

When simian virus 40 (SV40) large T antigen binds to the virus origin of replication, it forms a double hexamer that functions as a helicase to unwind the DNA bidirectionally. We demonstrate in this report that T antigen can unwind and release an origin DNA single strand of less than full length in the presence of purified human topoisomerase I. The sites nicked by topoisomerase I in the strands released by T antigen during DNA unwinding were localized primarily to the "late" side of the origin, and the template for lagging strand synthesis was preferred significantly over the one for leading strand synthesis. Importantly, these sites were, for the most part, different from the sites nicked by topoisomerase I in the absence of T antigen. These data indicate that T antigen activates topoisomerase I nicking at discrete sites and releases these nicked strands during unwinding. We hypothesize that a single molecule of topoisomerase I can form a functional complex with a double hexamer of T antigen to simultaneously relax and unwind double-stranded origin-containing DNA.

Antigens, Viral, Tumor↗
PubMed1997

Independent regulation of Fuc-TIV and Fuc-TVII genes leading to modulation of cell surface antigen expression in developing myeloid cells.

Fucosylated antigen expression, fucosyltransferase activities and expression of Fuc-TIV and Fuc-TVII genes have been measured in the human leukemic cell lines KG1a, arrested at the undifferentiated myeloblast stage of maturation and KG1, arrested at the myeloblast and early promyelocytic stage. The results are compared with those we earlier found for the later promyelocytic cell line HL-60 and the myelocyte form into which HL-60 cells can be induced to differentiate. These leukemic cell lines, and the differentiated HL-60 cells, are believed to correspond to four successive stages of myeloid maturation in the bone marrow. Fuc-TVII mRNA was strongly expressed in the myeloblastic KG1a cells but expression was less in KG1 and HL-60 cells. In contrast to the sharp fall in Fuc-TIV expression observed on differentiation of HL-60 cells, the expression of Fuc-TIV mRNA showed a progressive increase from KG1a to HL-60 cells; thus the peak of expression of this gene was at the HL-60 promyelocyte stage. This peak correlated with an increase in fucosyltransferase activity with nonsialylated acceptors and the transitory downregulation of cell surface sialyl-Le(x) expression and upregulation of Le(x), VIM-2 and Le(y) expression. The variations in levels of expression of the fucosylated antigens on the surface of the developing myeloid cells therefore correlate with variations in mRNA expression arising from the independent regulation of Fuc-TIV and Fuc-TVII genes.

Animals↗
PubMed2004

Dietary polyunsaturated fatty acids modulate in vivo, antigen-driven CD4+ T-cell proliferation in mice.

Our objective was to determine whether dietary lipids affect in vivo, antigen-driven, proliferation of naïve CD4(+) T lymphocytes. To accomplish this, we adoptively transferred lymphocytes from T-cell receptor (TCR) transgenic DO11.10 (i.e., donor) mice into syngeneic, nontransgenic BALB/c (i.e., recipient) mice. Before adoptive transfer, recipient mice were fed for 4 wk AIN93G-type diets that differed only in fat source: lard, low in PUFA, fish oil, rich in (n-3) PUFA, and soybean oil, rich in (n-6) PUFA. One week after transfer, recipient mice were immunized with antigen (i.e., ovalbumin), and expansion of CD4(+) T(DO11.10) cells in the spleen and draining lymph nodes (LN) was measured by flow cytometry. Five days postimmunization (p.i.), at the peak of expansion, CD4(+) T(DO11.10) cells in the draining LN and spleen were 5- to 10-fold higher than in unimmunized mice, then quickly declined during the contraction phase (i.e., 7 and 10 d p.i.). Recipients fed the (n-6) PUFA rich diet had approximately 25% greater in vivo expansion of CD4(+) T(DO11.10) cells than lard- and fish oil-fed recipient mice at 5 d p.i. (P < 0.05). However, at 7 and 10 d p.i., CD4(+) T(DO11.10) cells in the draining lymph nodes did not differ between groups, nor in the spleen at 5, 7, and 10 d p.i. In summary, we are the first to demonstrate that dietary PUFAs affect antigen-driven expansion of naïve CD4(+) T cells in vivo. Surprisingly, (n-3) PUFA consumption did not reduce CD4(+) T-cell expansion.

Animals↗
PubMed1995

Prostanoid modulation of synovial antigen-specific CD4+ T-cell cytotoxic function in rheumatoid arthritis.

The recent demonstration of cytolytic mediators within synovial CD4+ T-cells of patients with rheumatoid arthritis (RA) has suggested an additional role for these cells in the pathogenesis of the disease. In this study we have investigated the function and regulation of antigen-specific class II-restricted cytotoxic T-cells from the synovial fluid (SFMNC) and peripheral blood (PBMNC) of 20 seropositive RA patients, and correlated in vitro findings with clinical data. Regulatory factors including prostaglandin E2 (PGE2), interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) were measured in cell supernatants. A diversity in SFMNC antigen-specific cytotoxicity that correlated with therapy and PGE2 production was found, and shown to be mediated by synovial prostanoid (products of cyclooxygenase metabolism) inhibition of effector function. Our findings indicate that SFMNC cytotoxicity may be important in the pathogenesis and treatment of RA. Cyclooxygenase inhibition as the sole treatment early in RA may reduce the potentially beneficial inhibitory effect of synovial prostanoids on antigen-specific SFMNC cytotoxicity.

Adult↗
PubMed1993

Evidence that anti-CD8 abrogates anti-CD4-mediated clonal anergy but allows allograft survival in mice.

Monoclonal antibodies directed against different T cell subpopulations have been used in several rodent models of transplantation to induce long-term unresponsiveness to allografts by a variety of mechanisms. To investigate whether different mechanisms may be operative when different regimens of mAb therapy are used, we studied the effects of various combinations of anti-T-cell antibody treatment on the induction of tolerance in a mouse islet allograft model. Anti-CD4 mAb alone, anti-CD8 mAb alone, anti-CD4 mAb plus anti-CD8 mAb, and anti-Thy1.2 mAb alone were given at the time of engraftment. Only the anti-CD4 mAb and the anti-CD4 mAb plus anti-CD8 mAb regimens were successful in inducing permanent unresponsiveness to islet allografts. We have previously shown that anti-CD4 mAb alone induces permanent unresponsiveness to islet allografts by a mechanism of clonal anergy, as demonstrated by unresponsiveness of potentially alloreactive T cells to anti-T-cell receptor-specific cross-linking. Interestingly, the potentially alloreactive T cell subsets of recipient mice (V beta 5+ and V beta 11+) made unresponsive to islet allografts by anti-CD4 mAb plus anti-CD8 mAb therapy were not found to be anergic using the same assay. Differences between the repopulation kinetics of CD8+ T cells of anti-CD4 mAb plus anti-CD8 mAb treated recipient mice, which accepted islet allografts, and anti-Thy1.2 treated recipient mice, which rejected islet allografts despite similar levels of initial T cell depletion, suggest that unresponsiveness to alloantigen may have been induced in anti-CD4 mAb plus anti-CD8 mAb treated recipients by clearance of donor passenger leukocytes during prolonged CD8+ T cell depletion.

Animals↗
PubMed1990

Modulation of bullous pemphigoid antigens by gamma interferon in cultured human keratinocytes.

We report the effects of human recombinant gamma interferon (gamma-IFN) on the expression of bullous pemphigoid (BP) antigens by human cultured keratinocytes. Secondary epidermal cell cultures were grown on 3T3 mouse fibroblasts; when confluent, some cultures were maintained in control medium while others were exposed to various concentrations of gamma-IFN (100, 200, 400 U/ml) for 14 days. The expression of BP antigens was analyzed by indirect immunofluorescence on epithelial sheets and immunoblotting of Tris, SDS, beta-mercaptoethanol culture extracts using different BP sera. Our results show that gamma-IFN alters the expression of BP antigens in a way varying according to the skin donor: we observed results ranging from complete loss and decreased expression to unchanged reactivity patterns. Thus, gamma-IFN modifies BP antigen expression; this behavior has been previously shown for other adhesion molecules such as fibronectin and thrombospondin. However, the observed variability of the expression of BP antigens according to the skin donor suggests an unexpected variability in keratinocyte sensitivity to gamma interferon, which remains to be explored both in vitro and in vivo.

Aged↗
PubMed1992

Modulation of bullous pemphigoid antigen gene expression by gamma-interferon in cultured keratinocytes.

Bullous pemphigoid (BP) is characterized by the production of autoantibodies against BP antigens. gamma-interferon (gamma-IFN), a T-cell lymphokine, is known to enhance the expression of several cell-surface proteins. In this study, keratinocytes were cultured in the presence of gamma-IFN, the expression of BP antigen protein was examined by flow cytometry and BP antigen messenger RNA (mRNA) (encoding 230-kDa protein) was quantified by slot-blot hybridization. The results indicated that BP antigen gene expression by keratinocytes was upregulated by gamma-IFN. This enhancement of gene expression was detected at both the protein and mRNA level, suggesting pretranslational regulation. These results imply the involvement of not only humoral immunity but also cell-mediated immunity in the development of BP.

Animals↗
PubMed1991

HIV induces modulation of functionally important cellular antigens.

Infection of T lymphoblastoid CEM cells with the IIIB isolate of HIV-1 results in modulation of the expression of several cellular antigens in addition to the CD4 molecule. The intercellular adhesion receptor LFA-1 (CD11a/CD18) and HLA-DR are markedly induced in the cytoplasm and at the cell surface, and the CD7 antigen is down-regulated, being virtually undetectable by sensitive immunocytochemical techniques in the infected cell population. These modulatory effects are to some degree dependent on the virus isolate examined, as the CBL-1 British isolate did not induce comparable phenotypic changes in the CEM cell line. Furthermore, these effects are not reproduced by recombinant gp120 (IIIB isolate) or p24 added exogenously to uninfected CEM cells. The CD7 molecule appears to play a regulatory role in T cell proliferation, and the LFA-1 integrin molecule is involved in a wide range of immunologically important cell-cell interactions, as well as HIV-induced syncytium formation. The possible contributions of such effects to the pathogenesis of HIV infection are considered.

Antibodies, Monoclonal↗
PubMed1991

CD3-induced T-cell proliferation and interleukin-2 secretion is modulated by the CD45 antigen.

In the present study we have investigated the effect of CD45, CD45RA and CD45RO monoclonal antibodies (MoAbs) on the CD3 receptor-mediated proliferation of human T lymphocytes. It is shown that CD3-induced proliferation of purified resting T cells and quiescent T lymphoblasts (QTL) is promoted via all of the investigated CD45-associated epitopes. It is also shown that the CD45 molecules are required to be cross-linked for costimulation. The MoAbs enhance the interleukin-2 (IL-2) production of CD3-stimulated QTL. The elevation of the IL-2 production correlates with the increase in CD3-induced cell proliferation suggesting that the CD45-driven regulation of T lymphocyte activation is linked to the IL-2 pathway.

Animals↗
PubMed1995

Modulation of mite antigen-induced immune responses by lecithin-bound iodine in peripheral blood lymphocytes from patients with bronchial asthma.

1. Dermatophagoides farinae (Df) mite antigen induced IgE synthesis associated with an imbalance of cytokine production in mite-sensitive patients with bronchial asthma; increased production of interleukin 4 (IL-4), and decreased production of interferon-gamma (IFN-gamma) was specifically induced in these patients' lymphocytes. 2. Lecithin-bound iodine (LBI), with which children with bronchial asthma have been successfully treated in the range of 0.5 to 5 microM, concentrations comparable to LBI blood levels in medicated individuals, modified mite antigen-induced immune responses, thereby decreasing abnormal lymphocyte functions. 3. In Df antigen-driven immune responses, inhibition of IgE generation accompanied by suppression of IL-4 and the recovery of IFN-gamma production was successful when LBI was used in vitro. 4. LBI also acted on normal PBMCs by downregulating the IL-4-induced IgE synthesis, phytohaemagglutin (PHA)- and phorbol myristate acetate (PMA) plus calcium ionophore (CaI)-induced IL-4 secretion, and by upregulating purified protein derivatives (PPD)-induced IFN-gamma production. Therefore, LBI was capable of inhibiting the IgE and IL-4 responses and of enhancing IFN-gamma production both from allergen-stimulated atopic cells and from non-atopic cells appropriately stimulated. 5. The expression of human histocompatibility leukocyte antigen (HLA), class II antigens and intercellular adhesion molecule 1 (ICAM-1) on monocytes, crucial molecules for T cell-monocyte interactions, was not altered by LBI. 6. LBI probably acts as an immunomodulator to ameliorate mite antigen-induced abnormal cell-mediated immune responses in patients with bronchial asthma caused by Df antigen thereby leading to improvement of their clinical status.

Animals↗
PubMed1990

Structural factors modulate the activity of antigenic poliovirus sequences expressed on hybrid hepatitis B surface antigen particles.

We have studied the functional expression of antigenic poliovirus fragments carried by various hybrid hepatitis B surface antigen (HBsAg) particles. Several constructions were made by using two different insertion sites in the HBsAg molecule (amino acid positions 50 and 113) and two different sequences, one derived from poliovirus type 1 (PV-1) and the other from PV-2. The inserted fragments each encompassed residues 93 to 103 of the capsid protein VP1, a segment which includes the linear part of the neutralization antigenic site 1 of the poliovirus. The antigenicity and immunogenicity of the hybrid particles were evaluated and compared in terms of poliovirus neutralization. A high level of antigenic and immunogenic activity of the PV-1 fragment was obtained by insertion at position 113 but not at position 50 of HBsAg. However, a cooperative effect was observed when two PV-1 fragments were inserted at both positions of the same HBsAg molecule. Antibodies elicited by the PV-2 fragment inserted at amino acid position 113 did not bind or neutralize the corresponding poliovirus strain. They did, however, bind a chimeric poliovirus in which the homologous antigenic fragment of PV-1 had been replaced by that of PV-2. The only virions that were neutralized by these antibodies were certain mutants carrying amino acid substitutions within the PV-2 fragment. These results show that position, constraints from the carrier protein, and nature of the inserted sequences are critically important in favoring or limiting the expression of antigenic fragments as viral neutralization immunogens.

Amino Acid Sequence↗
PubMed1991

Pharmacological modulation of the antigen-induced expression of the low-affinity IgE receptor (Fc epsilon RII/CD23) on rat alveolar macrophages.

Brown-Norway (BN) rats were sensitized by 3 aerosol exposures to ovalbumin (OA; 10 mg/ml) at days 1, 3 and 14. At day 21, the rats were challenged with the antigen or vehicle by aerosol. Alveolar macrophages (AM) were obtained by bronchoalveolar lavage and the expression of Fc epsilon RII/CD23 was assessed by flow cytometry after staining with the BB10 monoclonal antibody. A maximum of 74% of the AM from sensitized and challenged BN rats expressed FC epsilon RII/CD23 24 h after OA exposure, compared to 12% of the cells from rats exposed to vehicle. Sprague-Dawley rats were passively sensitized by intravenous injection of 0.1 or 0.05 ml/kg mouse ascitic fluid containing dinitrophenyl (DNP)-specific monoclonal IgE (2682-1) and after 24 h exposed to an aerosol of 5 mg/ml of DNP-bovine serum albumin for 30 min. In this case also, antigen exposure induced the expression of Fc epsilon RII/CD23 on 75% AM, compared to 17% AM from saline-challenged rats. Such an induction of Fc epsilon RII/CD23 on AM was, however, not observed when the animals were challenged with either histamine, serotonin or acetylcholine by aerosol. The antigen-induced expression of Fc epsilon RII/CD23 on AM was inhibited upon treatment of the rats with ketotifen or beclomethasone. In addition, oral or aerosol administration of respectively BN 50730 or BN 52021 (two structurally unrelated platelet-activating factor antagonists), inhibited the antigen-induced Fc epsilon RII/CD23 expression on AM, indicating the participation of this lipid mediator in this process.

Animals↗
PubMed2001

Modulation of inhaled antigen-induced IgE tolerance by ongoing Th2 responses in the lung.

The normal response to inhaled Ag is the absence of Ag-specific IgE and cytokine production to later Ag challenges. Although the mechanism of this aerosol-induced IgE tolerance is not completely understood, it may prevent sensitization to inhaled Ags, which could otherwise lead to allergy and asthma. We examined the consequences of ongoing Th1 and Th2 responses in the lungs of mice during OVA inhalation to mimic conditions that may subvert tolerance and lead to sensitization. We found that concurrent, secondary Th2 lung responses to keyhole limpet hemocyanin or primary responses to Nippostrongylus larvae or Asperigillus fumagatus extract prevented establishment of IgE tolerance to aerosolized OVA. Intranasal rIL-4 given before OVA aerosolization also prevented establishment of tolerance, whereas concurrent Th1 responses to influenza virus or Mycobacterium bovis bacillus Calmette-Guérin had no effect. However, once established, aerosol tolerance to OVA could not be completely broken by OVA rechallenge concurrent with a secondary Th2 response to keyhole limpet hemocyanin or A. fumagatus extract, or by intranasal rIL-4. These data suggest that the immune status of the lung of an individual may profoundly influence the initial response to inhaled Ag, and that aerosol-induced IgE tolerance may not be appropriately established in individuals undergoing concurrent, Th2-mediated responses to Ags or pathogens.

Administration, Inhalation↗
PubMed2004

Soy isoflavones do not modulate prostate-specific antigen concentrations in older men in a randomized controlled trial.

Mortality rates for prostate cancer are low in Asia but high in the West. One explanation is the high level of soy consumption in Asia. Soy isoflavones reduce prostate tumor growth in many, but not all, animal models. Elevated levels of serum prostate-specific antigen (PSA) are a marker of prostate tumor growth. Our objective was to determine whether 12-month soy isoflavone supplementation would alter serum PSA concentrations in healthy, older men. The parent study was a double-blinded, parallel-arm, randomized trial in which participants were assigned to consume either a soy protein drink providing 83 mg/day isoflavones (+ISO) or a similar drink with isoflavones removed (-ISO). Participants in the parent study were 85% men. Of the 128 men enrolled in the trial, 112 completed. These men were later contacted for consent to allow their stored sera to be analyzed for PSA and 81 men consented. We measured PSA in serum collected at 0 and 12 months using a commercial radioimmunometric assay. Serum PSA concentrations increased in both groups over the 12-month intervention, but the changes were similar: Geometric mean PSA concentration increased 0.5% more in the +ISO group than in the -ISO group (P = 0.94; 95% confidence interval = -17.3 to 22.2). The proportion of participants having a serum PSA velocity greater than 1 ng/ml/year was similar in the +ISO and -ISO groups (17.6% versus 12.8%; P = 0.54). We found no evidence that a 12-month 83 mg/day isoflavone treatment alters serum PSA concentration or velocity in seemingly healthy men aged 50-80 years.

Aged↗
PubMed1990

B-cell growth factor-induced and alpha-interferon-inhibited proliferation of hairy cells coincides with modulation of cell surface antigens.

alpha-Interferon (IFN-alpha) induced unique ultrastructural alterations in peripheral blood and splenic hairy cell leukemia (HCL) cells (14 of 20 cases) treated in vitro. To further investigate the effects of B-cell growth factor (BCGF) and IFN-alpha on target hairy cells (HCs), we utilized immunogold labeling in conjunction with scanning electron microscopy. This methodology, in contrast to other immunological methods, facilitated direct view of the expression, density, and rearrangement of selected antigens/receptors on individual cells before and after BCGF or IFN-alpha treatment. In addition to inducing proliferation of HCL cells, BCGF enhanced the expression of interleukin 2 receptors (CD25; T-activated cell antigen) with no change in the expression of class I and class II human leukocyte antigen. On the other hand, IFN-alpha did not exert a noticeable proliferative effect on HCL cells but rather inhibited the proliferation of BCGF-treated cells. In addition, IFN-alpha treatment revealed an enhanced expression of class I (4 of 9) and class II (12 of 15) human leukocyte antigen on target HCs. Two-day exposure of HCs to IFN-alpha resulted in enhanced expression of CD25 (11 of 14), whereas a decrease in CD25 expression was recorded in 4 of 5 cases treated with IFN-alpha for 3 days. Also, no significant change in the expression of two other HCL-related surface antigens, CD22 (S-HCL-1; Leu-14) and CD11c(S-HCL-3; Leu-M5), was recorded following up to 3 days of IFN-alpha or BCGF treatment. However, a 5-day exposure to IFN-alpha resulted in a significant decrease in expression of CD11c on treated HCs. Finally, the IFN-alpha-induced immunoultrastructural changes in target HCs were primarily encountered in cells from HCL cases classified as responders to in vivo IFN-alpha therapy. Our data add support to the concept that the effect of IFN-alpha in HCL is mediated by impairment of the response to B-cell growth factors and induction of further differentiation of the target cells.

Aged↗
PubMed1985

Modulation of apolipoprotein B antigenic determinants in human low density lipoprotein subclasses.

To investigate the effect of low density lipoprotein (LDL) heterogeneity on the conformation of LDL apolipoprotein B (apo-B), the immunoreactivities of 6 monoclonal antibodies against LDL apo-B were measured in 3 LDL subfractions isolated by equilibrium density gradient ultracentrifugation. To ensure a broad range of LDL particles, the LDL subfractions were prepared from normal subjects and patients with hyperapobetalipoproteinemia. With 3 of the antibodies, 1D1, 5E11, and 3A10, LDL fractions 1 (the most buoyant), 2 (the intermediate), and 3 (the densest) were equally immunoreactive and competed similarly with reference whole LDL. In contrast, with 3 other antibodies, 2D8, 3F5, and 4G3, fraction 1 was significantly more reactive than fraction 3; that is for each in turn, 290, 250, and 150% more of the densest LDL protein was required to achieve the same displacement as with fraction 1. Further, the immunoreactivities of the 3 LDL fractions with antibodies 2D8, 3F5, and 4G3 were negatively correlated with their LDL cholesterol to LDL protein ratio with r values of 0.727, 0.898, and 0.870, respectively, suggesting that as LDL particle size decreases, the conformation of the LDL apo-B changes progressively. It is of interest that the antigenic determinants recognized by 3F5 and 4G3 are close to the LDL receptor recognition site on LDL apo-B. Therefore, it is possible that the reduced immunoreactivity of these determinants in dense LDL may be the in vitro correlate of the reduced fractional catabolics rate of dense LDL compared to buoyant LDL previously observed in vivo.

Antibodies, Monoclonal↗