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Results for “Antigenic Modulation”

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PubMed1989

Ewing's-sarcoma-associated HBA-71 tumor antigen represents a new differentiation marker of human thymocytes.

The monoclonal HBA-71 antibody recognizes a new human tumor-associated antigen of Ewing's sarcoma and peripheral neuroectodermal tumors, which is also expressed in some normal tissues, including thymus, islets of Langerhans, ependyme, adenohypophysis, Sertoli/Leydig and granulosa cells. Besides a tumor-specific reciprocal chromosomal translocation t (11:22), the expression of the HBA-71 antigen is the only marker which can be used for reliable differential diagnosis of these rare malignancies of childhood and adolescence among other small round cell tumors. The HBA-71 antigen is further characterized here by ultrastructural, functional and cell-matrix interaction studies. In immunohistochemical staining the HBA-71 reacted with the cell surface of human cortical thymocytes. The HBA-71 antigen was also found to be localized at the cell-surface glycocalyx of tumor cells using immunogold staining and electron microscopy. A panel of additional monoclonal antibodies with reactivity patterns similar to those of the HBA-71 antibody was obtained by immunization of mice with ES cell lines and boostering with thymocytes. The HBA-71 antibody triggers proliferation of thymocytes and to a lesser extent also stimulates peripheral mononuclear blood cells. Antibody-induced thymocyte cultures exhibit the phenotype of immature, CD3low thymocytes with uniform and stable expression of the HBA-71 antigen. In contrast to the thymocytes the HBA-71 antibody has an inhibitory effect on the continuous growth of the HBA-71+ tumor cell lines. The HBA-71 antigen may be involved in the regulation of growth of the positive normal and malignant tissues. Positive modulation of the antigen expression was induced in Ewing's sarcoma cell lines in response to insulin, insulin-like growth factor I (IGF-I) and by interaction of the cells with the extracellular matrix.

Animals↗

PubMed1996

Localization of DNA damage and its role in altered antigen-presenting cell function in ultraviolet-irradiated mice.

Prior ultraviolet (UV) irradiation of the site of application of hapten on murine skin reduces contact sensitization, impairs the ability of dendritic cells in the draining lymph nodes (DLN) to present antigen, and leads to development of hapten-specific suppressor T lymphocytes. We tested the hypothesis that UV-induced DNA damage plays a role in the impaired antigen-presenting activity of DLN cells. First, we assessed the location and persistence of cells containing DNA damage. A monoclonal antibody specific for cyclobutyl pyrimidine dimers (CPD) was used to identify UV-damaged cells in the skin and DLN of C3H mice exposed to UV radiation. Cells containing CPD were present in the epidermis, dermis, and DLN and persisted, particularly in the dermis, for at least 4 d after UV irradiation. When fluorescein isothiocyanate (FITC) was applied to UV-exposed skin, the DLN contained cells that were Ia+, FITC+, and CPD+; such cells from mice sensitized 3 d after UV irradiation exhibited reduced antigen-presenting function in vivo. We then assessed the role of DNA damage in UV-induced modulation of antigen-presenting cell (APC) function by using a novel method of increasing DNA repair in mouse skin in vivo. Liposomes containing T4 endonuclease V (T4N5) were applied to the site of UV exposure immediately after irradiation. This treatment prevented the impairment in APC function and reduced the number of CPD+ cells in the DLN of UV-irradiated mice. Treatment of unirradiated skin with T4N5 in liposomes or treatment of UV-irradiated skin with liposomes containing heat-inactivated T4N5 did not restore immune function. These studies demonstrate that cutaneous immune cells sustain DNA damage in vivo that persists for several days, and that FITC sensitization causes the migration of these to the DLN, which exhibits impaired APC function. Further, they support the hypothesis that DNA damage is an essential initiator of one or more of the steps involved in impaired APC function after UV irradiation.

Animals↗

PubMedDate not supplied

[Expression of surface antigens on lymphocytes stimulated by non- specific mitogens in multiple sclerosis patients].

In studies performed on 30 MS cases, as compared to 16 healthy individuals, significantly higher expression of HLA class II antigens, interleukin 2 receptor and antigens specific for lymphocytes B was observed. In MS patients after stimulation by non specific mitogens increased expression of HLA class II antigens and increased proliferation induced by PMA was found. The obtained results suggest absence of any greater modulation of surface antigens on the lymphocytes stimulated by non-specific mitogens. Our observations indicate that the number of activated T cells, as assessed by expression of Il-2 receptor, is in MS patients relatively low.

Adult↗

PubMed1995

Oral tolerance to ovalbumin in mice as a model for detecting modulators of the immunologic tolerance to a specific antigen.

Oral tolerance is thought to have a role in preventing allergic responses and immune-mediated diseases. Modulation of this tolerance by drugs and chemicals can cause or suppress them. An improved model of oral tolerance to ovalbumin (OVA) in mice was developed to detect modulators of the tolerance and to apply it to selected immunomodulating substances, cyclophosphamide (CP), Escherichia coli lipopolysaccharide (LPS) and cadmium chloride (Cd). Male C3H/HeN mice given an oral administration of 20 mg OVA were immunized 7 d later with an i.p. injection of 0.1 mg OVA in complete Freund's adjuvant. Effects of oral OVA and agents on systemic immunity were assessed by enzyme-linked immunosorbent assay (ELISA) of immunoglobulin (Ig) levels in serum collected 7 or 14 d after immunization. Oral tolerance was adequately induced on day 7 after immunization and was more effective in C3H/HeN mice than in BALB/c mice. It was primarily associated with the decreased serum levels of anti-OVA IgG (including both IgG1 and IgG2a subclasses regulated differently by T-helper subpopulations, Th2 and Th1 cells, respectively). The C3H model of oral tolerance was further examined to detect modulators of the tolerance. An i.p. injection of CP prior to oral OVA, or 5 consecutive daily oral administrations of LPS after oral OVA elevated or reduced serum levels of anti-OVA IgG in C3H mice hyposensitized by the oral OVA, respectively. Concerning IgG subclasses, CP restored anti-OVA IgG2a but not IgG1 levels, while LPS caused greater suppression of both anti-OVA IgG1 and IgG2a levels. Oral administrations of Cd for 5 d after oral OVA also suppressed anti-OVA IgG1 levels further.(ABSTRACT TRUNCATED AT 250 WORDS)

Adjuvants, Immunologic↗

PubMed1999

Reduced expression of the alphabeta T-cell antigen receptor by alveolar T-cells.

A previous study revealed that reduced expression (modulation) of the CD3 antigen is a common characteristic of alveolar T-cells in health and disease. As CD3 molecules are noncovalently bound to T-cell antigen receptors (TCR), it was hypothesized that modulation of TCR was also a feature of alveolar T-cells. To demonstrate this, lymphocytes from bronchoalveolar lavage fluid were stained with an anti-alphabeta TCR antibody and analysed by flow cytometry. The expression of alphabeta TCR by alveolar T-cells was evaluated by calculating mean fluorescence intensity (MFI) and was compared with alphabeta TCR expression by autologous blood T-cells. As anticipated from a previous study, modulation of TCR was observed not only in healthy volunteers but also in patients with pulmonary sarcoidosis, other pulmonary diseases, and nonpulmonary diseases. There were no significant differences in MFI of alveolar T-cells among the study groups. The degree of modulation assessed by the difference of MFI between blood and alveolar T-cells was greater for CD4+ cells than for CD8+ cells owing to the higher MFI of CD4+ blood T-cells. Coculture of alveolar macrophages with blood T-cells in vitro induced partial modulation of TCR. These results demonstrate the ubiquity of modulation of T-cell receptors on alveolar T-cells and suggest, in contrast to a previous report by other investigators that it is caused by some nonantigenic mechanism possibly inherent in the alveolar milieu. The implications of this phenomenon in in vivo immune responses of the lung need to be examined.

Adult↗

PubMed2001

Interferon-gamma administration after abdominal surgery rescues antigen-specific helper T cell immune reactivity.

Antigen-induced activation of T cells is determined by many factors. Among these factors are (i) the number of T-cell receptors (TCRs) triggered by TCR ligands on antigen-presenting cells (APCs), and (ii) the intrinsic cellular threshold for activation. T-cell receptor triggering is optimized by adhesion molecules that form the interaction site between T cells and APCs, i.e. the immunological synapse. In addition, signals through co-stimulatory molecules lower the intrinsic T-cell activation threshold. Immunosuppressive agents and traumatic events such as major operative procedures change physiological T-cell responses. Depressed immune functions after surgery are presumed to render patients more susceptible to pathogens. Interferon-gamma (IFNgamma) is a type II homodimeric cytokine with multiple immunostimulatory properties. Several studies have been performed to assess the effects of IFNgamma treatment in patients in need of increased immune reactivity. However, until now, the effect of IFNgamma on human antigen specific CD4(pos) T-cell reactivity after surgically-induced immunosuppression has not been reported. Therefore, a comparative trial of recombinant human (rh) IFNgamma versus placebo in patients after abdominal surgery was initiated. Antigen-specific helper T cell immune reactivity was assessed by antigen-induced cytokine production, intracellular cytokine staining and flow cytometry. A single dose of rhIFNgamma rescued down-modulation of antigen-specific CD4(pos) T-cell reactivity, concomitant with an up-regulation of TCR-ligands on antigen-presenting cells. Selected patients may benefit from the immunostimulatory properties of rhIFNgamma administration in vivo.

Abdomen↗

PubMed1984

Monocyte suppression of antigen-specific lymphocyte responses in diffuse cutaneous leishmaniasis patients from the Dominican Republic.

Patients from the Dominican Republic with diffuse cutaneous leishmaniasis showed in vivo and in vitro anergy to leishmanial antigen. Relatives of these DCL patients living in the same endemic area frequently showed skin test and lymphocyte reactivity to leishmanial antigens. This further supports the concept of specific anergy in patients with diffuse cutaneous leishmaniasis. Adherent suppressor cells modulate the antigen-specific lymphocyte proliferative response. Suppressor cells could also be isolated by Percoll gradient centrifugation. Co-culturing of lymphocytes and monocytes from HLA-identical leishmanin responders and nonresponders also identified the suppressor cell as a monocyte. In one patient, this suppression disappeared when clinical cure had been accomplished.

Adolescent↗

PubMed1997

The lymphocyte function-associated antigen 1 I domain is a transient binding module for intercellular adhesion molecule (ICAM)-1 and ICAM-3 in hydrodynamic flow.

The I domain of lymphocyte function-associated antigen (LFA)-1 contains an intercellular adhesion molecule (ICAM)-1 and ICAM-3 binding site, but the relationship of this site to regulated adhesion is unknown. To study the adhesive properties of the LFA-1 I domain, we stably expressed a GPI-anchored form of this I domain (I-GPI) on the surface of baby hamster kidney cells. I-GPI cells bound soluble ICAM-1 (sICAM-1) with a low avidity and affinity. Flow cell experiments demonstrated a specific rolling interaction of I-GPI cells on bilayers containing purified full length ICAM-1 or ICAM-3. The LFA-1 activating antibody MEM-83, or its Fab fragment, decreased the rolling velocity of I-GPI cells on ICAM-1-containing membranes. In contrast, the interaction of I-GPI cells with ICAM-3 was blocked by MEM-83. Rolling of I-GPI cells was dependent on the presence of Mg2+. Mn2+ only partially substituted for Mg2+, giving rise to a small fraction of rolling cells and increased rolling velocity. This suggests that the I domain acts as a transient, Mg2+-dependent binding module that cooperates with another Mn2+-stimulated site in LFA-1 to give rise to the stable interaction of intact LFA-1 with ICAM-1.

Animals↗

PubMed2003

The response of natural killer T cells to glycolipid antigens is characterized by surface receptor down-modulation and expansion.

CD1d-restricted natural killer T (NKT) cells are a subset of regulatory T cells that react with glycolipid antigens. Although preclinical studies have effectively targeted NKT cells for immunotherapy, little is known regarding the early in vivo response of these cells to antigenic stimulation. We have analyzed the early response of NKT cells to glycolipid antigens and bacterial infection by using specific reagents for tracking these cells. Our results demonstrate dramatic in vivo expansion and surface phenotype alterations after NKT cell activation with alpha-galactosylceramide. In addition, we show significant NK1.1 down-modulation on NKT cells in the setting of oral Salmonella infection. Our results indicate that in vivo activation of NKT cells leads to a dynamic response characterized by surface receptor down-modulation and expansion. These findings alter current understanding of NKT cell biology and should aid in the rational design of NKT cell-based immunotherapies.

Animals↗

PubMed2000

Threshold levels of gene expression of the melanoma antigen gp100 correlate with tumor cell recognition by cytotoxic T lymphocytes.

The level of expression of melanoma antigens (MA) may modulate the host immunologic response. Thus, the accurate measurement of MA expression may allow proper patient selection for antigen-specific therapies and yield important information for the evaluation of clinical results. In this study, we measured the absolute levels of MA messenger ribonucleic acid (mRNA) in tumor cell lines utilizing real-time quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). mRNA levels of MART-1, gp100, tyrosinase, TRP-1 and TRP-2 melanoma differentiation antigens and MAGE-1, MAGE-3 and ESO-1 cancer testis (CT) antigens were compared in 24 early-passage (<5 passages in culture) and 12 archival melanoma cell lines. MA mRNA expression was extremely variable among cell lines, occasionally reaching levels comparable to ribosomal RNA (rRNA). gp100 and MART-1 mRNA levels correlated with protein expression measurement obtained by FACS analysis. More significantly, a threshold of gp100 mRNA expression required for T-cell stimulation and target-cell killing was identified. This threshold level corresponded to approximately 500 mRNA copies per 10(8) copies of rRNA. Our results suggest that the measurements of MA mRNA levels may yield useful information relevant to the interpretation of clinical outcome during antigen-specific treatments.

Antigens, Neoplasm↗

PubMed2005

Reactive oxygen species are essential mediators in antigen presentation by Kupffer cells.

Kupffer cells (KC) act as APC in the liver and play a major role in the clearance of gut-derived antigens and pathogens entering the liver with portal venous blood. Antigen presentation by KC has been implicated in regulation of the local and systemic immune responses. In this study, modulation of KC antigen presentation by antioxidants and the role of reactive oxygen species (ROS) as essential mediators of antigen presentation in KC were investigated. Co-culture of KC with ovalbumin (OVA) antigens resulted in upstream intracellular endogenous ROS generation and increased expression of MHC class II and costimulator molecules, and consequent OVA-specific CD4(+) T-cell proliferation in response to antigen presentation by KC. Scavenging of KC ROS by antioxidants, or blocking of KC ROS generation by specific inhibitors of NADPH oxidase and/or xanthine oxidase, or by specific inhibitors of the mitochondrial electron transport chain, significantly decreased OVA-specific T-cell proliferation in response to antigen presentation by KC. Increased expression of MHC class II and costimulatory molecules in KC pulsed with OVA antigens was blocked by inhibiting ROS generation enzymatically. Intracellular endogenous ROS generation during antigen processing may therefore provide essential secondary signalling for KC antigen presentation.

Animals↗

PubMed1990

[HLA antigenicity of normal and pathological corneas].

Fresh human corneas and corneal buttons were studied for expression of HLA antigens. Using monoclonal antibodies in an indirect immunofluorescence assay, corneal layers were examined for class I (HLA-A, B, C) and class II (HLA-DR) histocompatibility antigens. Twenty-one human corneas were studied, 6 normal and 15 pathological: 4 buttons of allograft rejection, 9 buttons of pseudophakic bullous keratopathy. In fresh control corneas, HLA-A, B, C antigens were localized on corneal epithelium and on stromal keratocytes but were never found on endothelial cells. HLA-DR antigens were not detected on corneal epithelium, stroma or endothelium but were detected on Langerhans cells within epithelium and anterior stroma. At the corneal limbus, HLA class I-II antigens were expressed on vascular endothelium. HLA antigen distribution was modified in pathological corneas. Antigens HLA-A, B, C were induced on endothelial cells of rejected corneal allografts. Antigens HLA-DR were detected on epithelial cells, cells in the stroma of pseudophakic bullous keratopathy and also on endothelial cells of rejected corneal allografts. These results suggest that induction of class I and II antigen expression by inflammatory factors may occur in vivo. In rejected corneal allografts induction of HLA-DR antigen on corneal layers would intensify the process of rejection. This study and others have demonstrated the ability of modulation of HLA antigen expression on human corneal cells in vivo.

Cornea↗

PubMed1992

Pancreatic antigenic complex p64 69: involvement in regulation of insulin secretion and relation to glutamic acid decarboxylase.

The role of pancreatic beta-cell antigenic structures in modulation of insulin secretion in vitro was recently demonstrated by others. Here we report generation of a monoclonal antibody (mAB) ICA-1 to non-species specific beta-cell antigen(s) 64, 67 and 69 kDa. The mAB inhibits glucose stimulated insulin secretion in islet cell cultures. The ability of mAB ICA-1 to immunoprecipitate active glutamic acid decarboxylase from high speed supernatants of pancreatic and brain crude extracts was demonstrated. The 64, 67 and 69 kDa antigenic material was affinity purified from pancreatic islet cell high speed supernatants, active glutamic acid decarboxylase was found in the material. Immunoaffinity purification with mAB ICA-1 of GAD-like pancreatic beta-cell antigenic material has provided evidence of possible involvement of glutamic acid decarboxylase in modulation of insulin secretion.

Animals↗

PubMed1985

Retinal S antigen and retinoblastoma. A monoclonal antibody histopathologic study.

Using monoclonal antibody MAbA9-C6, which defines an epitope of retinal S antigen retained in fixed-tissue sections, we investigated S-antigen immunoreactivity in human fetal eyes from different gestational periods and 19 cases of retinoblastoma. S-antigen immunoreactivity was first observed in the outermost portion of the neuroblastic cell layer in the retina of a human fetus at 18 weeks' gestation, a stage preceding photoreceptor differentiation, and at all later stages examined thereafter. All adult eyes containing normal photoreceptors bound MAbA9-C6. In retinoblastomas, several different patterns of S-antigen immunoreactivity were recognized. In seven cases, S-antigen immunoreactivity appeared to be associated with normal photoreceptor elements incorporated into the growing tumor. S-antigen immunoreactivity was associated with fleurettes within the retinoblastoma in three cases and Flexner-Wintersteiner rosettes in seven cases. In 11 cases, S-antigen immunoreactivity was associated with isolated tumor cells. Our results show that S antigen may be a useful marker in the study of the embryologic development of the human retina and antigenic expression and modulation in retinoblastomas.

Adult↗

PubMed1986

T3 surface molecules on adult T cell leukemia cells are modulated in vivo.

Cells from eight patients with adult T cell leukemia (ATL) and from four patients with non-ATL were examined to see if the T3 antigen of these cells could be modulated in vitro. We found a low density of T3 antigen and the presence of Tac antigen on cells from all patients with ATL. The density of T3 antigen on non-ATL cells was normal, and Tac antigen was not detected. Modulation of T3 antigen and an increase in Tac antigen-positive cells occurred when cells from patients with T4 non-ATL were cultured with OKT3 monoclonal antibody (mAb). Those changes in T3 antigen density and the appearance of Tac antigen-bearing cells by OKT3 mAb were not so marked when ATL cells were used. But the modulation of T3 antigen and the increase in Tac antigen-bearing cells by OKT3 mAb were closely related in cells from six ATL patients. These findings suggest that T3 T cell antigen receptor complexes on ATL cells are not functionally "frozen" by leukemic changes and might be modulated in vivo. In addition, modulation of T3 surface antigen on ATL cells was not induced by cultivation with human T cell leukemia virus type I particles and envelope proteins obtained by gene technology.

Acute Disease↗

PubMed2002

Modulation of agrin binding and activity by the CT and related carbohydrate antigens.

Agrin is a nerve-derived signal that is essential for the proper organization of postsynaptic acetylcholine receptors (AChRs) at the vertebrate neuromuscular junction. It is likely that carbohydrates play a significant role in regulating agrin activity, as agrin binds multiple glycan structures and is itself a highly glycosylated protein. Here we provide support for this contention by showing that agrin can be modified with the CT antigen, a carbohydrate structure expressed at the neuromuscular junction, and by describing the resulting changes in agrin binding to neoglycoconjugates and cultured myotubes, as well as changes in agrin-dependent AChR clustering. Glycosylation of agrin with the CT antigen required the mucin domain and the dystroglycan/heparin-binding domain. The presence of the mucin domain lowered agrin binding to several N-acetyllactosaminyl-containing saccharides and C2 myotubes and lowered agrin activity in AChR clustering. Glycosylation of agrin with the CT antigen, by contrast, increased agrin binding to myotubes and potentiated its AChR clustering activity at subsaturating concentrations. Last, sialylated and nonsialylated variants of N-acetyllactosamine differentially modulated AChR clustering and agrin activity, and these changes correlated with the ability of MuSK, an agrin-stimulated kinase, to bind to these structures. These experiments demonstrate that the glycosylation state of agrin affects its activity and suggest a role for the CT antigen in modulating agrin function.

Agrin↗

PubMed2026

Parasites and allergies: a complex bidirectional relationship from evolutionary origins to modern therapeutics.

Parasites and allergic diseases are linked by a complex, bidirectional relationship shaped by long-term host-parasite coevolution. This review discusses how different parasites may either promote or attenuate allergic responses through immunological, epithelial, and microbiome-mediated mechanisms. IgE-mediated immunity, mast cell activation, eosinophilia, and pruritus may have evolved as protective responses against helminths and blood-feeding ectoparasites. In contrast, modern allergies may partly reflect misdirected responses to harmless environmental antigens. The effects of parasites on allergy are not uniform and depend on parasite type, infection site, exposure intensity and chronicity, host immune status, and the degree of host-parasite adaptation. Protozoa such as Giardia intestinalis may contribute to food allergy-related manifestations by disrupting the intestinal barrier, altering gut microbiota composition, and modifying mucosal immune responses, particularly in atopic individuals. In contrast, selected helminths may attenuate allergic inflammation by inducing regulatory T and B cells, anti-inflammatory cytokines, antigen-presenting cell modulation, and IgG4-associated mechanisms that can limit IgE-mediated effector responses. Molecular similarities between parasite-derived antigens and environmental allergens, including conserved protein families and carbohydrate epitopes, may contribute to cross-reactive IgE responses and complicate allergy diagnostics. Therefore, current research is shifting from live helminth therapy toward defined parasite-derived molecules and immunomodulatory pathways that may inspire safer and more controlled therapeutic strategies. A clearer understanding of parasite-allergy interactions may improve diagnostic interpretation and support the development of new approaches to the management of allergic disease.

Humans↗

PubMed1995

Mouse microglial cell lines differing in constitutive and interferon-gamma-inducible antigen-presenting activities for naive and memory CD4+ and CD8+ T cells.

We developed a panel of non-virus transformed cell lines derived from individual microglial precursors residing in the brains of normal mice. These colony stimulating factor-1-dependent cell lines are B7-1+ (CD80), Mac-1+, Mac-2+, Mac-3+, CD45+, MHC class I+, colony stimulating factor-1 receptor+, and they ingest antibody-coated particles. However, the cell lines differ in their expression of B7-2 (CD86), F4/80, Ly-6C and MHC class II molecules. They also differ in their ability to constitutively process and present antigens to naive CD4+ and CD8+ T cells, memory CD4+ and CD8+, and in the manner by which interferon gamma modulates their antigen-presenting activities. These cell lines should be valuable as models for studies on the immunobiology of the microglia.

Adjuvants, Immunologic↗