Modulation of fetal antigen(s) in mouse leukemia cells.
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Animals↗
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Modulation of surface antigens of a human monocyte cell line, U937, during incubation with T lymphocyte-conditioned medium: detection of T4 antigen and its presence on normal blood monocytes.
The human monocyte line, U937, derived from an individual with histiocytic lymphoma, undergoes morphological and functional changes when incubated with medium conditioned by lectin-stimulated cloned human T lymphocytes. Using monoclonal antibodies and flow cytometry, we therefore analyzed alterations in surface components that might accompany these morphological changes, in comparison with components present on normal blood monocytes. The U937 cells possess three surface antigens in common with blood monocytes, detected with OKM1, 4F2, and anti-monocyte.2 (the last monocyte specific). DR antigen was not detectable on U937 cells with three anti-DR framework antibodies but was detected on blood monocytes. Unexpectedly, OKT4, a monoclonal antibody to T4 antigen previously believed to be restricted to helper T lymphocytes, also reacted with U937 cells. Six monoclonal antibodies to other epitopes on T4 also reacted with U937 cells. None of these could be inhibited by blocking of Fc receptors. T4 with its various epitopes were also expressed on normal human blood monocytes. Other lymphocyte surface markers (T3, T8, T6) and fibronectin were not detectable on U937 cells or monocytes. An individual, whose lymphocytes lacked the epitope detected with OKT4 but had epitopes detected with OKT4 A, B, C, and D, had monocytes with identical reactivity, evidence that the T4 on monocytes and lymphocytes are products of the same structural gene. Stimulation of U937 cells for 24 hours with supernatants from Con A-stimulated T lymphocyte clones caused an increase in expression of OKM1 and Fc receptor activity and a decrease in expression of T4, consistent with a more mature phenotype of blood monocytes. Although the function of the T4 molecule is unknown, it is notable that it is displayed by two cells of distinct lineage which interact in the response to soluble antigens.
Animals↗
Modulation of the antigenicity of C1r and C1s by C1 inactivator.
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Angioedema↗
Modulation of antigen-presenting cell function as a potential regulatory mechanism in tumor-host immune reactions.
A growing body of information suggests that immunological defense mechanisms against newly emerging tumors may exist within the skin. In this regard, the recognition and presentation of tumor-associated antigens by cutaneous antigen presenting cells is a prerequisite for the establishment of specific tumor immunity. However, despite the recently demonstrated ability of normal I-A+ epidermal cells (Langerhans cells) to effectively present tumor-associated antigens in vivo, even tumors with recognizable antigenic epitopes can grow progressively in situ. Therefore, regulatory mechanisms within the local microenvironment may exist that control the ability of resident epidermal APC to initiate and to elicit protective immunity against incipient cutaneous neoplasms. This report reviews the role of APC in tumor immunity and the effects of cytokines and ultraviolet radiation (UVR) on tumor antigen presentation by epidermal APC. Our data suggest that these agents can significantly modify the ability of epidermal cells to present tumor-associated antigens and may therefore control the type and effectiveness of tumor immune responses in situ. Furthermore, the induction of primary tumor immunity and the elicitation of secondary immune responses are independently regulated and respond differently to cytokine application.
Antibody Formation↗
Secretion of bioactive interleukin-1beta by dendritic cells is modulated by interaction with antigen specific T cells.
The role of interleukin-1beta (IL-1beta) as a regulator of the immune response, although extensively investigated, is still debated. We then studied the expression of IL-1beta by human dendritic cells (DCs), the professional antigen presenting cells, and its modulation during immune reactions in vitro. Our results show that, on maturation or tetanus toxoid presentation to specific CD4(+) CD40L(+) T lymphocytes, DCs begin to accumulate IL-1beta precursor (pro-IL-1beta) but do not secrete bioactive IL-1beta. In contrast, interaction with alloreactive T cells results in both stimulation of pro-IL-1beta synthesis and secretion of processed isoforms of the cytokine, that display biologic activity. Both CD4(+) and CD8(+) subsets of allospecific T lymphocytes are required: CD4(+) T cells drive the synthesis of pro-IL-1beta through CD40 engagement but have no effects on pro-IL-1beta processing; CD8(+) T cells, unable to induce synthesis of pro-IL-1beta per se, are responsible for the generation of mature IL-1beta by pro-IL-1beta-producing DCs. Interleukin-1beta-converting enzyme (ICE) inhibitors do not prevent the recovery of IL-1beta bioactivity after allorecognition, indicating that allospecific CD8(+) T cells may induce the release of bioactive IL-1beta via mechanism(s) other than ICE activation. Altogether, these findings suggest that CD4(+) and CD8(+) T-lymphocyte subsets have distinct roles in the induction of IL-1beta secretion by DCs and support the hypothesis that IL-1beta plays a role in cell-mediated immune responses. (Blood. 2000;95:3809-3815)
CD4-Positive T-Lymphocytes↗
Pseudomonas aeruginosa B-band O-antigen chain length is modulated by Wzz (Ro1).
The wbp gene cluster, encoding the B-band lipopolysaccharide O antigen of Pseudomonas aeruginosa serotype O5 strain PAO1, was previously shown to contain a wzy (rfc) gene encoding the O-antigen polymerase. This study describes the molecular characterization of the corresponding wzz (rol) gene, responsible for modulating O-antigen chain length. P. aeruginosa O5 Wzz has 19 to 20% amino acid identity with Wzz of Escherichia coli, Salmonella enterica, and Shigella flexneri. Knockout mutations of the wzz gene in serotypes O5 and O16 (which has an O antigen structurally related to that of O5) yielded mutants expressing O antigens with a distribution of chain lengths differing markedly from that of the parent strains. Unlike enteric wzz mutants, the P. aeruginosa wzz mutants continued to display some chain length modulation. The P. aeruginosa O5 wzz gene complemented both O5 and O16 wzz mutants as well as an E. coli wzz mutant. Coexpression of E. coli and P. aeruginosa wzz genes in a rough strain of E. coli carrying the P. aeruginosa wbp cluster resulted in the expression of two populations of O-antigen chain lengths. Sequence analysis of the region upstream of wzz led to identification of the genes rpsA and himD, encoding 30S ribosomal subunit protein S1 and integration host factor, respectively. This finding places rpsA and himD adjacent to wzz and the wbp cluster at 37 min on the PAO1 chromosomal map and completes the delineation of the O5 serogroup-specific region of the wbp cluster.
Bacterial Proteins↗
Modulation by interferons of HLA antigen, high-molecular-weight melanoma associated antigen, and intercellular adhesion molecule 1 expression by cultured melanoma cells with different metastatic potential.
The effect of leukocyte (IFN-alpha), fibroblast (IFN-beta), and immune (IFN-gamma) interferon and/or mezerein on the expression of HLA antigens and melanoma-associated antigens by the melanoma cell line MeWo and its metastatic variant MeM 50-10 was investigated, since this information may contribute to our understanding of the molecular mechanism(s) underlying the metastatic process and of the role of cell differentiation and growth suppression in the antigenic changes induced by interferon (IFN). The three types of IFN had no effect on the expression of high-molecular-weight melanoma-associated antigen, but enhanced that of HLA Class 1 antigens and of intercellular adhesion molecule 1 on MeWo and MeM 50-10 cells. The enhancing effect of IFN-gamma was more marked than that of IFN-alpha and IFN-beta. Furthermore IFN-gamma enhanced the expression of intercellular adhesion molecule 1 by MeM 50-10 cells more than by MeWo cells. IFN-beta was shown for the first time to induce HLA Class II antigens; the effect of IFN-beta, like that of IFN-gamma, is differential on the two cell lines and on the gene products of the HLA-D region. Like IFN-gamma, IFN-beta induced only HLA-DR antigens on MeM 50-10 cells. The results of Northern blot analysis with HLA-DR beta, -DQ beta, and -DP beta probes suggest that the differential modulation of the gene products of the HLA-D region by IFN-beta and IFN-gamma reflects transcriptional and posttranscriptional events. The differential susceptibility to modulation by IFN-beta and IFN-gamma of HLA Class II antigens on MeWo and MeM 50-10 cells is an intrinsic property of each cell line, since only small differences were detected in the number and/or affinity of receptors on the two cell lines. Furthermore, the lack of marked effects of mezerein on the antigen-modulating activity of the three types of IFN, in spite of an enhancement of their differentiating activity, suggests that the changes in the antigenic profile induced by IFN do not represent a differentiation-related phenomenon.
Antigens, Neoplasm↗
Schistosomal granuloma modulation. II. Specific immunogenic carbohydrates can modulate schistosome-egg-antigen-induced hepatic granuloma formation.
To further investigate the factors involved in the modulation of the schistosomal granuloma, mice were primed with immunogenic carbohydrates which were common to soluble egg antigen (SEA) and adult worm antigen. Mice sensitized with LewisX trisaccharide or lacto-N-fucopentaose-III (LNFP-III) displayed an increased cellular response towards SEA-coupled beads implanted in the liver by mesenteric injection, resulting in the formation of larger periparticular granulomas. When animals were sensitized with bovine serum albumin or a structurally related carbohydrate, an accelerated response was not seen. Since LNFP-III is built up of LewisX molecules, and LewisX carbohydrates are common to SEA and worm antigens such as the gut-secreted antigens CCA and CAA (two antigens that could prime egg-antigen-induced granuloma formation), this may explain why adult, live Schistosoma mansoni worms positively modulate egg-antigen-induced hepatic granuloma formation in the murine host. These observations provide new insights into the role of carbohydrates in parasite-host immunity and may yield important implications for choosing worm-derived antigens for the development of anti-schistosome vaccines.
Animals↗
Modulation by interferon alpha and gamma of the expression of a melanoma-associated antigen detected by autologous antibody.
Interferons (IFN) are known to alter the expression of histocompatibility and tumour-associated antigens. We have reported the isolation and purification of a 66-kD melanoma-associated antigen (MAA) that is recognized by the host. Competitive binding with MAA reduced autologous antibody binding to five melanoma cell lines, suggesting that a similar antigen is detected by other patients with melanoma. Nine melanoma cell lines were incubated for 3 days with 0.01-100 units/ml of interferon alpha (IFN-alpha) or interferon gamma (IFN-gamma) and the maximum titre of autologous antibody reactivity was determined by protein A haemadsorption. Incubation with IFN-alpha or IFN-gamma resulted in a decrease in maximum titre of autologous antibody reactivity directed against all melanoma cell lines. A 3-day incubation of three melanoma cell lines with IFN-gamma augmented the expression of HLA-DR, as has been reported by others. Incubation with spent media from autologous melanoma cells exposed to IFN-alpha inhibited autologous antibody binding less than control media from melanoma cells to which no IFN was added, indicative of decreased production or internalization of MAA. Conversely, incubation with spent media obtained after exposure to IFN-gamma inhibited autologous antibody binding to a greater degree than control spent media, consistent with increased shedding of antigen. These results suggest that IFN-alpha and IFN-gamma down-regulate the expression of MAA detected by autologous antibody by different mechanisms of action.
Antigenic Modulation↗
Modulation of a surface antigen of Entamoeba histolytica in response to bacteria.
Changes in the cell surface of Entamoeba histolytica, a human intestinal parasite and the causative agent of amebic dysentery, were examined with a monoclonal antibody, 2D7.10, which selectively recognizes carbohydrate epitopes in some axenic amebic strains. While high-level expression of this epitope was observed in axenic amebae, it was either absent or present only in small amounts in xenic amebae. Furthermore, reassociation of the axenic amebae with intestinal flora resulted in loss of the 2D7.10 epitope. Our data suggest that surface antigens of E. histolytica can be modulated in response to bacteria and may provide an explanation for the observed influence of bacteria on amebic virulence.
Animals↗
Modulation of human leukocyte antigen class I expression by gamma interferon in head and neck cancer cell lines.
One possible mechanism explaining the action of interferon (IFN) on squamous cell carcinoma (SqCC) of the head and neck is the modulation of major histocompatibility antigen expression on tumor cells. We tested the ability of gamma interferon (gamma-IFN) to modulate major histocompatibility class I antigens and beta 2-microglobulin (beta 2-M) on two carcinoma cell lines derived from SqCC of the head and neck. Major histocompatibility class I antigens and beta 2-M were detected using a two-step immunochemical stain; antigen expression was quantified using flow cytometry. gamma-IFN increased constitutive antigen expression by as much as five times on both cell lines. Maximum modulation was seen within 72 hours of exposure to gamma-IFN at clinically attainable doses (10 U/mL to 100 U/mL). The presence of gamma-IFN in cell cultures was necessary for continued modulation of surface antigens. These findings suggest a possible mechanism of action and encourage further clinical trials with gamma-IFN.
Carcinoma, Squamous Cell↗
Modulation of tumour associated antigen expressed on human squamous cell carcinoma cell lines by recombinant interferon-alpha.
Our earlier studies have shown that monoclonal antibody (Mab) 3F8E3 generated against a head and neck cancer cell line LICR-LON-HN2 showed reactivity with squamous cell carcinoma (SCC) irrespective of the tissue of origin and identified antigens on SCC cell lines AW 13516 and AW 8507. The affinity constants (Ka) for binding of Mab 3F8E3 to AW 13516 and AW 8507 cell lines were 6.2 x 10(8) and 4.3 x 10(8) mol/l and it identified 6.8 x 10(4) and 3.77 x 10(4) sites/cell, respectively, as determined by Scatchard analysis. Treatment of both the cell lines with recombinant human interferon-alpha (rHu-IFN alpha) increased the binding affinity of the Mab but did not increase the number of binding sites on the SCC cell lines. Shedding of antigen recognised by the Mab in the culture supernatant of the cell lines was reduced after rHu-IFN alpha treatment. The results suggest that rHu-IFN alpha may bring about a firm anchorage of the tumour associated antigen on the SCC cells. Cells modulated with rHu-IFN alpha may serve as better targets for assessing cell mediated as well as Mab mediated cytotoxicity in oral cancer patients.
Animals↗
Modulation of the severity of experimental autoimmune encephalomyelitis by gammadelta T lymphocytes activated by mycobacterial antigens.
Immunity to mycobacterial antigens may contribute to the maintenance of self-tolerance. Exposure of the immune system to mycobacterial antigen might well stimulate the immune system to exert control over unwanted self-reactive clones. We demonstrated that in vivo administration of Mycobacterium tuberculosis, PPD, and PPD peptide (180-196) prior to immunization with Myelin Basic Protein (MBP) led to a moderate increase of gammadelta T cells, suppression of the immune response, and reduction in the severity of Experimental Autoimmune Encephalomyelitis. The immunosuppression observed is due, at least in part, to the production of Transforming growth factor-beta (TGFbeta) by the gammadelta T lymphocytes.
Adoptive Transfer↗
Isopentenyl pyrophosphate, a mycobacterial non-peptidic antigen, triggers delayed and highly sustained signaling in human gamma delta T lymphocytes without inducing eown-modulation of T cell antigen receptor.
The Vgamma9Vdelta2 T cell subset, which represents up to 90% of the circulating gammadelta T cells in humans, was shown to be activated, via the T cell receptor (TcR), by non-peptidic phosphorylated small organic molecules. These phosphoantigens, which are not presented by professional antigen-presenting cells, induce production of high amounts of interferon-gamma and tumor necrosis factor (TNF-alpha). To date, the specific signals triggered by these antigens have not been characterized. Here we analyze proximal and later intracellular signals triggered by isopentenyl pyrophosphate (IPP), a mycobacterial antigen that specifically stimulates Vgamma9Vdelta2 T cells, and compare these to signals induced by the non-physiological model using an anti-CD3 antibody. During antigenic stimulation we noticed that, except for the proximal p56(lck) signal, which is triggered early, the signals appear to be delayed and highly sustained. This delay, which likely accounts for the delay observed in TNF-alpha production, is discussed in terms of the ability of the antigen to cross-link and recruit transducing molecules mostly anchored to lipid rafts. Moreover, we demonstrate that, in contrast to anti-CD3 antibody, IPP does not induce down-modulation of the TcR.CD3 complex, which likely results in the highly sustained signaling and release of high levels of TNF-alpha.
Antigens, Bacterial↗
Modulation of melanoma-associated antigens by monoclonal antibodies as visualized by radioimmunoelectron microscopy and radioantibody binding assay.
There is a wealth of information about monoclonal antibody (MAb) specificity and function on fixed tissues, yet little is known about formation and release of antigen-antibody complexes and their functional behavior in vivo. We analyzed the pathway of radiolabeled MAbs directed against melanoma-associated antigens by radioimmunoelectron microscopy (RIEM) on metabolically active cells of the melanoma cell lines SK-MEL-28, MeWo and Colo 38 at different time intervals. In parallel, binding and release of MAbs were investigated by the radioantibody binding assay (RBA). Both procedures gave essentially concordant results. Preferentially stable binding of immune complexes (ICs) to the cell surface after 30 and 120 min was shown for the MAb L10. Internalization was demonstrated for the MAb M.2.9.4. At the ultrastructural level, direct evidence of this phenomenon was obtained by visualization of radioactivity within the cytoplasm after 120 min. In the RBA this process was indicated by resistance of bound MAbs to acid buffer desorption. RIEM pointed to different transport mechanisms: constitutive internalization by endocytotic vesicles, or receptor-mediated endocytosis by coated vesicles. Shedding was indicated for the MAb R24 by release of the ICs from the cell membrane. It was demonstrated that stable fixation of ICs on the cell surface or modulation by internalization led to high accumulation rates, while shedding of antigen-antibody complexes resulted in a low accumulation of the MAb in tumor cells. Assuming that the potential of MAbs for clinical application is determined by the biological behavior of antigen-antibody complexes, these methods are suitable for demonstration of antigenic modulation by MAbs and eventually enable us to predict the localization, penetration and distribution pattern of individual MAbs in the melanoma patient.
Antibodies, Monoclonal↗
Modulation of neuroendocrine surface antigens in oncogene-activated small cell lung cancer lines.
Small cell lung cancer (SCLC) manifests a number of neuroendocrine differentiation features and antigenic characteristics that distinguish the tumour from non-small cell lung cancer (NSCLC). Several surface antigens on SCLC cells, identified by clusters of monoclonal antibodies (MAbs), distinguish SCLC and other neuroendocrine tumours of NSCLC. Stable transfection of the c-myc proto-oncogene has been reported to confer upon classic SCLC cells the growth properties and morphology of the variant subtype of SCLC (SCLC-v). Furthermore, insertion of the v-Ha-ras oncogene into such SCLC-v cells has been found to induce features typical of NSCLC. We have used classic SCLC cells transfected with c-myc, or co-transformed with c-myc and v-Ha-ras, to examine the expression of characteristics SCLC cluster antigens. Flow cytometric assays reveal that SCLC cells co-transformed with c-myc and v-Ha-ras oncogenes down-modulate SC-1, SC-2 and SC-5A surface antigens to levels approaching, in some cases, those seen with NSCLC cells. The SC-4 surface antigen is not modulated by activation of these oncogenes. These findings support clinical and laboratory observations that important transitions can occur between subtypes of human lung cancer cells, and that these shifts may play a role in the clinical progression of lung cancer.
Adenocarcinoma↗
In vivo treatment with anti-I-A antibodies: differential effects on Ia antigens and antigen-presenting cell function of spleen cells and epidermal Langerhans cells.
The in vivo activation of T cells by a variety of antigens can be inhibited by the administration of anti-I-A antibodies (Ab) at the time of antigen priming. This inhibition can partially be explained by the temporary loss of Ia molecules from Ia-bearing antigen-presenting cells (APC) in the spleen. In this study, the effects of i.p. injected monoclonal Ab specific for I-A glycoproteins of different H-2 haplotypes on Ia antigen expression and APC function of spleen cells and epidermal Langerhans cells were compared. It was found that anti-I-A Ab quickly bound to both spleen cell and Langerhans cell Ia antigens. Although spleen cell Ia antigens were modulated and thus temporarily disappeared, Ia antigen expression by epidermal Langerhans cells was not modulated. In functional studies, the capacity of spleen cells and epidermal cells from anti-I-A Ab treated vs control animals to function as APC for antigen-specific, I-A- or I-E-restricted T cell clones was tested. A single injection of anti-I-A Ab completely abolished the APC function of spleen cells as shown in several inbred mouse strains, F1 animals, and with the use of several different Ab and T cell clones. In contrast, Langerhans cell-dependent APC function of epidermal cells remained completely unaltered. Even multiple injections of high doses of Ab never caused any inhibition of Langerhans cell function. Experiments with anti-I-Ak or anti-I-Ad Ab in an (H-2k X H-2d)F1 animal showed abrogation of APC function of spleen cells, but again not of Langerhans cells. Thus in vivo anti-I-A Ab administration appears to differentially affect Ia antigen expression and APC function from spleen and epidermis: Ia antigens are modulated from spleen cells but not from epidermis, and APC function disappears in the spleen but not in the epidermis. The abrogation of splenic but not of Langerhans cell APC function with anti-I-A Ab will facilitate the dissection of the relative contributions of Langerhans cells as compared with other APC in the generation of cutaneous immune responses.
Animals↗
Prostate-specific membrane antigen regulates angiogenesis by modulating integrin signal transduction.
The transmembrane peptidase prostate-specific membrane antigen (PSMA) is universally upregulated in the vasculature of solid tumors, but its functional role in tumor angiogenesis has not been investigated. Here we show that angiogenesis is severely impaired in PSMA-null animals and that this angiogenic defect occurs at the level of endothelial cell invasion through the extracellular matrix barrier. Because proteolytic degradation of the extracellular matrix is a critical component of endothelial invasion in angiogenesis, it is logical to assume that PSMA participates in matrix degradation. However, we demonstrate a novel and more complex role for PSMA in angiogenesis, where it is a principal component of a regulatory loop that is tightly modulating laminin-specific integrin signaling and GTPase-dependent, p21-activated kinase 1 (PAK-1) activity. We show that PSMA inhibition, knockdown, or deficiency decreases endothelial cell invasion in vitro via integrin and PAK, thus abrogating angiogenesis. Interestingly, the neutralization of beta(1) or the inactivation of PAK increases PSMA activity, suggesting that they negatively regulate PSMA. This negative regulation is mediated by the cytoskeleton as the disruption of interactions between the PSMA cytoplasmic tail and the anchor protein filamin A decreases PSMA activity, integrin function, and PAK activation. Finally, the inhibition of PAK activation enhances the PSMA/filamin A interaction and, thus, boosts PSMA activity. These data imply that PSMA participates in an autoregulatory loop, wherein active PSMA facilitates integrin signaling and PAK activation, leading to both productive invasion and downregulation of integrin beta(1) signaling via reduced PSMA activity. Therefore, we have identified a novel role for PSMA as a true molecular interface, integrating both extracellular and intracellular signals during angiogenesis.
Animals↗