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Results for “Antigenic Modulation”

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PubMed1992

Adverse effect of chronic tonsillitis on clinical course of sarcoidosis in relation to HLA distribution.

We examined the effect of chronic inflammatory foci in the upper respiratory tract and/or HLA class 2 antigens on the clinical course of sarcoidosis. Sarcoidosis resolved spontaneously in 6 of 27 (22 percent) patients with CTL and in 19 of 29 (66 percent) without CTL (p less than 0.01). The clinical course became favorable after TLT in 7 of 14 cases with CTL. Patients with HLA-DR9 and DRw8 showed the highest ratio of patients who had protracted clinical course; those with HLA-DR2, DR5 and DR6 showed the lowest; and those with HLA-DR4, DRw52 and Drw53 were between these levels. A high responsiveness to SCW antigens was seen more frequently in sarcoidosis patients with protracted clinical course. The high responsiveness to SCW antigens was related to HLA-DR4, DRw8, DR9 and DRw53 in sarcoidosis patients. HLA antigens, especially HLA-DR, modulate the immune response to inhaled antigenic agents. Immune response seemed to affect the clinical course of sarcoidosis.

Adult↗

PubMed1985

Retinal S-antigen and retinoblastoma: a monoclonal antibody and flow cytometric study.

Retinal S-antigen was demonstrated in the WERI-Rb1 and to a lesser extent the Y-79 tissue cultured retinoblastoma cell lines as well as an ethanol-fixed, paraffin-embedded retinoblastoma by an indirect immunoperoxidase technique using monoclonal antibody MAbA9-C6, and by flow cytometric analysis (FCM) using MAbA9-C6 and MAbA1-G5. In fixed tissue sections, S-antigen immunoreactivity was restricted and localized to small numbers of retinoblastoma cells, including Flexner-Wintersteiner rosettes. By FCM, MAbA9-C6 bound to 15.4% of WERI-Rb1 cells and to 10.99.7% of Y-79 cells whereas MAbA1-G5 bound to 14.66% of WERI-Rb1 and to 4.23% of Y-79 cells respectively. Cell cycle analysis showed that S-antigen was predominately expressed in the resting (G0/G1) phase. The usefulness of MAbA9-C6 in studying the embryological development of the retina and as a marker protein for studying antigenic expression and modulation in retinoblastomas is discussed.

Animals↗

PubMed1988

Blood group-related antigens in human urothelium: enhanced expression of precursor, LeX, and LeY determinants in urothelial carcinoma.

Seven mouse monoclonal antibodies and the lectin from Ulex europaeus, detecting blood group specificities of the ABH and Lewis systems, have been used to define the expression and/or modulation of these antigenic structures in human normal urothelium and tumors of the urinary bladder. The reagents employed recognize the following blood group related antigens: A, B, H, Lewisa (Lea), Lewisb (Leb), Lewisx (Lex), Lewisy (Ley), and type 1 precursor chain. Immunohistochemical studies have demonstrated that these antigenic systems are differentially expressed in the urothelium of secretor and nonsecretor individuals. The normal urothelium of secretors is particularly rich in ABH blood group antigens as well as Leb and Ley specificities. Nonsecretors, however, either lack or show decreased and patchy expression of H, Leb, and Ley antigens. In general, areas affected by carcinoma in situ showed deletion of ABH, as did invasive carcinomas, as demonstrated by other investigators. This was not a universal observation, however, as variable expression of ABH antigens occurred in a few invasive tumors. Lex antigen was not expressed in normal urothelium except for occasional umbrella cells, but was demonstrated in the majority of invasive tumors, regardless of blood type and secretor status of the individuals studied. Ley determinant, which was poorly expressed in the normal urothelium of nonsecretor individuals, was found in all tumors analyzed. An accumulation of non-fucosylated precursor structure was also a feature of invasive carcinoma, particularly in secretor individuals. A panel of anti-blood group antibodies, encompassing A, B, Lex, Ley and type 1 precursor chain specificities for use in patients of known secretor status, may provide useful early markers of malignant change in the urothelium.

Adult↗

PubMed2005

Peripheral "CD8 tuning" dynamically modulates the size and responsiveness of an antigen-specific T cell pool in vivo.

In this study, we suggest that CD8 levels on T cells are not static, but can change and, as a result, modulate CD8(+) T cell responses. We describe three models of CD8 modulation using novel weak-agonist (K1A) and super-agonist (C2A) altered peptide ligands of the HY smcy peptide. First, we used peripheral nonresponsive CD8(low) T cells produced after peripheral HY-D(b) MHC class I tetramer stimulation of female HY TCR transgenic and wild-type mice. Second, we used genetically lowered CD8(int) T cells from heterozygote CD8(+/0) mice. Finally, we used pre-existing nonresponsive CD8(low) T cells from male HY TCR transgenic mice. In CD8(low) and CD8(high) mice, presence of a lower level of CD8 greatly decreased the avidity of the peptide-MHC for HY TCR as reflected by avidity (K(D)) and dissociation constant (T(1/2)) measurements. All three models demonstrated that lowering CD8 levels resulted in the requirement for a higher avidity peptide-MHC interaction with the TCR to respond equivalently to unmanipulated CD8(high) T cells of the same specificity. Additionally, direct injections of wild-type HY-D(b) and C2A-D(b) tetramers into female HY TCR or female B6 mice induced a high frequency of peripheral nonresponsive CD8(low) T cells, yet C2A-D(b) was superior in inducing a primed CD8(+)CD44(+) memory population. The ability to dynamically modulate the size and responsiveness of an Ag-specific T cell pool by "CD8 tuning" of the T cell during the early phases of an immune response has important implications for the balance of responsiveness, memory, and tolerance.

Animals↗

PubMed2000

Epstein-barr virus nuclear antigen 2 retards cell growth, induces p21(WAF1) expression, and modulates p53 activity post-translationally.

The Epstein-Barr virus (EBV) nuclear antigen 2 (EBNA2) has been shown to be required for promotion of cell-cycle progression in EBV-immortalized B-lymphocytes. However, other studies have indicated that EBNA2 alone, in the absence of other EBV genes, may retard cell growth. To resolve this discrepancy, we investigated the effect of EBNA2 on the growth of various cells, including EBV target nasopharyngeal carcinoma cells, NPC-TW01 and NPC-TW04. We found that EBNA2 could retard cell growth, in stable Vero, HEp-2, and U2OS cell clones expressing EBNA2, and in Vero, 293, NPC-TW01, and NPC-TW04 cells transiently transfected with EBNA2. While investigating the mechanism underlying the growth-retarding function of EBNA2, we found that EBNA2 induced p21(WAF1) expression in these cells. This induction of p21(WAF1) expression was mediated through p53. EBNA2 was found to stimulate p53 to bind to the p53-response element within the p21(WAF1) promoter, possibly by promoting p53 phosphorylation. This enhancement of p53 sequence-specific DNA-binding activity may be the mechanism through which EBNA2 activates the expression of p53-regulated genes, including p21(WAF1) and mdm-2. Together, these studies reveal a possible intrinsic function of EBNA2 in cell-growth regulation and elucidate a novel mechanism by which EBNA2 modulates transcription.

Animals↗

PubMed1988

Modulation of lymphocyte nuclear matrix organization in vivo by 5,6-dichloro-1-beta-D-ribofuranosyl benzimidazole: an autoradiographic and immunofluorescence study.

Assembly of active nuclei in lymphocytes stimulated by mitogen is paralleled by the elaboration of a structurally and biochemically complex nuclear matrix (NM). To examine the dynamics of individual NM polypeptide components during blastogenesis, we have applied immunofluorescence labelling with anti-NM antibodies to concanavalin A-stimulated mouse splenocytes. Whereas peripherin and PI2 antigens did not reorganize during stimulation, labelling of PI1 and small nuclear ribonucleoprotein (snRNP) antigens increased markedly in intensity and redistributed in concert with the previously reported NM restructuring. Double-labelling showed, furthermore, that snRNPs and the internal staining component of PI1 were largely co-localized. As an approach to studying the role of RNA and RNA synthesis in NM organization, we have further examined the effects of the inhibitor of RNA synthesis, 5,6-dichloro-1-beta-D-ribofuranosyl benzimidazole (DRB), on NM antigen distribution. The rapid inhibition of 3H-uridine incorporation by DRB was accompanied by coordinate aggregation of snRNPs and of the internal PI1 component into large, brightly stained patches. Both 3H-uridine incorporation levels and antigen localization were readily reversed upon removal of DRB. We conclude that NM antigens behave independently during nuclear and NM assembly and that NM organization, as reflected by NM antigen distribution, is modulated by con A- and DRB-induced alterations in RNA synthesis. We propose, furthermore, that the PI1 antigen plays a role in RNA metabolism, and is possibly involved in RNA transport to the nuclear periphery.

Animals↗

PubMed1985

Region of peptide 125-147 of acetylcholine receptor alpha subunit is exposed at neuromuscular junction and induces experimental autoimmune myasthenia gravis, T-cell immunity, and modulating autoantibodies.

A major antigenic region of native nicotinic acetylcholine receptors (AcChoR) has been identified by using a synthetic disulfide-looped peptide corresponding to alpha-subunit residues 125-147 of Torpedo electric organ AcChoR: Lys-Ser-Tyr-Cys-Glu-Ile-Ile-Val-Thr-His-Phe- Pro-Phe-Asp-Gln-Gln-Asn-Cys-Thr-Met-Lys-Leu-Gly. The peptide bound 26-56% of polyclonal antibodies induced in rat, rabbit, and dog by immunization with native AcChoR. Rats inoculated with 50 micrograms of unconjugated peptide developed helper T-cell responses, delayed hypersensitivity, and antibodies to native AcChoR. Anti-peptide antibodies were more reactive with native than denatured AcChoR and bound to the alpha subunit. Some reacted exclusively with mammalian muscle AcChoR, some induced modulation of AcChoR on cultured myotubes, but none inhibited binding of alpha-bungarotoxin to solubilized or membrane-associated AcChoR. Repeated immunization induced experimental autoimmune myasthenia gravis: clinical signs in one rat and electrophysiologic and/or biochemical signs in 10 of 11 rats. Thus, at least part of the corresponding region of the mammalian AcChoR alpha subunit is extracellular at the neuromuscular junction and a potential target for pathogenic autoantibodies in patients with acquired myasthenia gravis.

Amino Acid Sequence↗

PubMed1991

Expression and capping of a proliferation-associated surface membrane p34 kDa antigen on different human hematopoietic cell lines.

A novel surface membrane nonglycosylated acidic polypeptide (34 kDa), encoded by a structural gene on chromosome 11, has been identified using murine monoclonal antibody (MoAb) 53.6 (IgG2a). MoAb 53.6, raised against uninduced cells of a human erythroleukemia line (HEL), recognizes a surface membrane antigen that is displayed on proliferating (cell cycle phase G1, S, and M + G2 phase) human leukocytes. The expression and redistribution (i.e., patching and capping) of the p34 kDa antigen on 27 different long-term human hematopoietic cell (HHC) lines was defined by fluorescence microscopy. These lines had been established from patients with leukemia or healthy donors and included phenotypically defined populations of T cells, B cells, and myelomonocytic cells. Almost all (greater than 95%) of the leukocytes of the 27 lines reacted strongly with MoAb 53.6. The majority of the leukocytes displayed p34 kDa antigen patching (26/27 lines; patched cells, 96-100%); moreover, 20 of 27 lines exhibited p34 kDa antigen capping (capped cells, 8-96%). Presentation of the p34 kDa antigen on surface membrane ultrastructures, imaged with immunogold using an indirect antibody labeling procedure, was illustrated by scanning electron microscopy, and endocytosis of the gold-tagged antigen-antibody complex was studied by transmission electron microscopy. The HHC lines are thought to represent immortalized populations of different human leukocyte subsets that are in different stages of maturation and/or differentiation; thus these lines should prove useful as models for further characterizing this unique p34 kDa proliferation-associated antigen and for defining the mechanisms and significance of surface membrane antigen redistribution and modulation that has been associated with leukocyte activation and propagation.

Antibodies, Monoclonal↗

PubMed1993

Antigenic variation of pilin regulates adhesion of Neisseria meningitidis to human epithelial cells.

Pili have been shown to play an essential role in the adhesion of Neisseria meningitidis to epithelial cells. However, among piliated strains, both inter- and intrastrain variability exist with respect to their degree of adhesion to epithelial cells in vitro (Virji et al., 1992). This suggests that factors other than the presence of pili per se are involved in this process. The N. meningitidis pilin subunit undergoes extensive antigenic variation. Piliated low- and high-adhesive derivatives of the same N. meningitidis strain were selected and the nucleotide sequence of the pilin gene expressed in each was determined. The highly adhesive derivatives had the same pilin sequence. The alleles encoding the pilin subunit of the low-adhesive derivatives were completely different from the one found in the high-adhesive isolates. Using polyclonal antibodies raised against one hyperadhesive variant, it was confirmed that the low-adhesive piliated derivatives expressed pilin variants antigenically different from the highly adhesive strains. The role of antigenic variation in the adhesive process of N. meningitidis was confirmed by performing allelic exchanges of the pilE locus between low- and high-adhesive isolates. Antigenic variation has been considered a means by which virulent bacteria evade the host immune system. This work provides genetic proof that a bacterial pathogen, N. meningitidis, can use antigenic variation to modulate their degree of virulence.

Amino Acid Sequence↗

PubMed2002

DNA adenine methylase overproduction in Yersinia pseudotuberculosis alters YopE expression and secretion and host immune responses to infection.

Yersinia pseudotuberculosis mutants that overproduce the DNA adenine methylase (Dam) are highly attenuated, confer fully protective immune responses, and secrete several Yersinia virulence proteins (Yersinia outer proteins [Yops]) under conditions that are nonpermissive for secretion in wild-type strains. We examined here the effects of Dam overproduction on Yersinia virulence determinant expression and secretion, as well as the host immune response to Yersinia antigens. Western blot analysis with convalescent antisera identified several low-calcium-responsive antigens whose synthesis was affected by Dam overproduction. One of these antigens was shown to be the type III secretion effector protein, YopE, a cytotoxin involved in antiphagocytosis. Dam overproduction disrupted both the thermal and calcium regulation of YopE synthesis and relaxed the thermal but not the calcium dependence of YopE secretion. Altered expression and/or secretion of Yersinia proteins in Dam-overproducing strains may contribute to the decreased virulence and heightened immunity observed in vaccinated hosts and may provide a means by which to deliver heterologous antigens and/or immune modulators of the inflammatory response.

Animals↗

PubMed1999

Antigen-dependent and -independent IFN-gamma modulation by penicillins.

The activation of CD4+ T lymphocytes upon Ag stimulation plays a critical role in adverse immune responses including drug-specific hypersensitivity reactions. We examined the modulation of T cell phenotype induced by hapten-specific stimulation using the model of beta-lactam antibiotics such as penicillin G (Pen G), Pen V, and ampicillin (Amp). When PBMC of donors suffering from hypersensitivity reactions against beta-lactams were stimulated in vitro with different doses of Pen G, a preferential expansion of IL-4-producing TCR alphabeta+ cells was detected. A panel of T cell clones was then prepared from Pen G-specific lines after two cycles of restimulation with the hapten. For the majority of these clones, we found that high doses of Pen G induced optimal IL-4 secretion, whereas the amount of IFN-gamma secreted was inversely correlated with the dose of Pen G, thus leading to a hapten-inducible shift of the functional phenotypes for some of the clones. Finally, Pen V and Amp were used to modulate different Ag-induced immune responses. We found that Amp had no influence on the cytokine pattern induced by specific Ag or mitogens. In contrast, Pen V inhibited the secretion of IFN-gamma, but not IL-4, most likely by Ag-independent mechanisms. This last finding may open new applications for immune intervention in those diseases in which polarized Th1 responses are involved in the development of the pathology.

Amino Acid Sequence↗

PubMed2005

Functional avidity directs T-cell fate in autoreactive CD4+ T cells.

Major histocompatibility complex class II tetramer staining and activation analysis identified 2 distinct types of antigen-specific CD4+ T cells in the peripheral blood of humans with type 1 (autoimmune) diabetes. T cells with low-avidity recognition of peptide-MHC ligands had low sensitivity to activation and inefficient activation-induced apoptosis. In contrast, high-avidity T cells were highly sensitive to antigen-induced cell death through apoptotic mechanisms, and both apoptosis-resistant high- and low-avidity T cells that survived prolonged tetramer treatment were rendered anergic to restimulation by antigen. In addition, however, apoptosis-resistant high-avidity T cells acquired regulatory features, being able to suppress both antigen-specific and nonspecific CD4+ T-cell responses. This suppression was contact-dependent and correlated with the down-regulation of HLA class II and costimulatory molecules on antigen-presenting cells, including B cells and dendritic cells. T cells face a variety of fates following antigen exposure, including the paradoxic maintenance of high-avidity autoreactive T cells in the peripheral circulation, perhaps due to this capability of acquiring anergic and suppressive properties. Regulation via down-modulation of antigen-presenting cell function, a form of cell-to-cell licensing for suppression, also offers possibilities for the application of peptide-MHC therapeutics.

Adolescent↗

PubMed1986

Differentiation antigens on rhesus monkey lymphocytes. II. Characterization of RhT3, a CD3-like antigen on T cells.

A monoclonal antibody FN18 is described, which is specific for mature rhesus monkey T lymphocytes. It defines a cell surface antigen, composed of two polypeptide chains with a molecular mass of 22 and 27 kDa. In view of these and other similarities with the human T3 or CD3 antigen, it was designated as RhT3. Expression, distribution and certain functions of RhT3 were compared with those of its human counterpart. Analogous to anti-CD3 antibodies in man, FN18 is able to modulate its target antigen, has mitogenic properties and is able to block the pokeweed mitogen and concanavalin A-driven cell proliferation, but not that caused by phytohemagglutinin. In spite of such minor dissimilarities the available data strongly suggest that the RhT3 antigen is the rhesus monkey's homologue of the human CD3 antigen.

Animals↗

PubMed1998

Do noninherited maternal antigens (NIMA) enhance renal graft survival?

To test the hypothesis that noninherited maternal antigens (NIMA) can modulate the alloreactivity of infant cells and provide protection for renal transplant recipients, a study of renal transplantations performed between 1980 and 1991 was undertaken. The survival rate of grafts with a mismatched antigen identical to the NIMA was compared to that of grafts in which the mismatched antigen was not identical to the NIMA. In the case of HLA-A mismatches, graft survival rates were significantly better for NIMA-mismatched transplants: 94% and 83% at 1 and 3 years, respectively, for single NIMA HLA-A mismatched transplants, and 83% and 67% when both HLA-A antigens were mismatched, compared to 76% and 68% (one non NIMA HLA-A mismatch) and 67% and 45% (two non-NIMA HLA-A mismatches). Our results suggest that some class I NIMA-mismatched antigens are not harmful to renal transplant recipients.

Adult↗

PubMed2003

Feedback regulation of pathogen-specific T cell priming.

MHC class I-restricted antigen presentation is an essential step in the priming of CD8 T lymphocytes during immune responses to infection. While microbial growth and clearance have been accurately measured in mammalian hosts, the duration of functional antigen presentation during infection remains undefined in vivo. Herein we characterize the activation of naive and memory T cells at different times during bacterial infection. Surprisingly, the host's ability to prime T cells is of much shorter duration than bacterial infection, inversely correlating with the development of pathogen-specific cytolytic T lymphocytes. Our studies demonstrate a feedback mechanism that limits the duration of effective in vivo antigen presentation, thereby modulating T cell responses by temporally restricting recruitment of naive T cells into the immune response.

Animals↗

PubMed1989

Genetic control of immune response to a purified Schistosoma mansoni antigen. II. Establishment and characterization of specific I-A and I-E restricted T-cell clones.

T-cell lines and clones specific for a partially protective schistosome antigen (9B antigen) were established from mice immunized with such antigen. The H-2 congenic strains B10.A which express both I-A and I-E class II gene products of the major histocompatibility complex (MHC) and B10.A(4R) which only express I-A molecules were used in these studies. The specific T-cell lines recognized the 9B antigen in the context of either A or E molecules, but both class II antigens were necessary for maximal stimulation of the T-cell lines in lymphocyte proliferation assays. T-cell clones were derived from these lines and their MHC restriction was investigated. Both I-A and I-E restricted clones could be isolated. All clones were specific for 9B antigen showing different degrees of cross-reactivity with a total schistosome extract (CA sonicate). A correlation between the fine specificity of the clones and the expression of class II antigens was demonstrated. Clones specific for 9B antigen, or which reacted to the same extent with 9B antigen and CA sonicate, were I-A restricted, whereas clones which proliferated more in the presence of CA sonicate were all I-E restricted. This suggests that I-E restricted clones recognize more cross-reactive epitopes than I-A restricted clones. These antigen-specific T-cell clones should provide a useful tool for examining the role of class II antigens in the modulation of protective immune response during Schistosoma mansoni infection.

Animals↗

PubMed1990

Effects of mitogens and lymphokines on the regulation of the immune response to HBs antigen in vitro.

We studied the immunoregulatory mechanisms of responsiveness and non-responsiveness to hepatitis B (HB) vaccine by analysing the influence of HB surface antigen (HBsAg) on lymphokine- or mitogen-stimulated peripheral lymphocytes from healthy volunteers. Stimulation with pokeweed mitogen (PWM) led to a reduced production of polyclonal IgG from responder cells compared to non-responder lymphocytes. PWM did not enhance the HBs-specific IgG production from responder lymphocytes when the cells were obtained at Day 10 after the last vaccination. A slight reduction of the proliferative response was observed when lymphocytes of non-responders were stimulated with phytohaemagglutinin (PHA) or concanavalin A (Con A). Production of HBs-specific antibodies was enhanced by incubating responder lymphocytes with interleukin-4 (IL-4). The HBs antigen itself did not modulate the expression of the CD23 B-cell differentiation antigen in unseparated lymphocytes. However, CD23 expression induced by low doses of IL-4 was markedly enhanced in an antigen-specific way. Our data indicate that HBs antigen enhances the lymphokine-induced CD23 expression, whereas the mitogen-induced CD23 expression is not affected. Lymphocytes obtained from non-responders exerted a reduced expression of CD25 surface antigen compared to responder lymphocytes. Exogeneous addition of IL-2 in the absence or presence of HBsAg induced a marked enhancement of the IL-2 receptor expression in responder lymphocytes. Furthermore, no significant modulation of CD25 expression was observed in non-responder lymphocytes.

Cell Division↗

PubMed1995

Additive effects of copolymer-1 and interferon beta-1b on the immune response to myelin basic protein.

Copolymer-1 (Cop-1) inhibits the T cell response to myelin basic protein (MBP), suppresses experimental autoimmune encephalomyelitis in many animal species, and was recently shown to be effective in the treatment of multiple sclerosis (MS). Interferon beta-1b (IFN-beta), an immune modulator with no antigenic specificity, is already approved for treatment of relapsing-remitting MS. We investigated the combined effect of these two agents on the cellular immune response to MBP. Antigen-specific Th1-like cell lines were generated from two healthy individuals with different MHC phenotypes. Cop-1 inhibited the proliferation of all MBP-specific lines but had no suppressive effect on tuberculin (PPD) or tetanus toxoid (TT)-specific T cell lines from either donor, while IFN-beta non-specifically reduced proliferation of all T cell lines. When combined in vitro, Cop-1 and IFN-beta had additive suppressive effects on proliferation of MBP-specific T cell lines, with 70-100% inhibition depending on the concentration of antigen. Synthesis of the pro-inflammatory cytokines interleukin-2 and IFN-gamma by MBP-specific lines was also inhibited additively (up to 100%). When antigen-presenting cells (APC) were pretreated with Cop-1, IFN-beta or both, T cell proliferation was inhibited in the same additive pattern, even though the inhibitors were not present in culture, indicating that they acted primarily through modulation of APC function. Additive effects were not found with PPD- or TT-specific cell lines. Pretreatment of APC with IFN-beta resulted in dose-dependent reduction in HLA-DR and HLA-DQ expression, which paralleled inhibition of T cell proliferation.(ABSTRACT TRUNCATED AT 250 WORDS)

Antigen-Presenting Cells↗