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Results for “Antigenic Modulation”

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PubMed1979

Antigenic modulation and turnover in human neutrophils.

Turnover of membrane constituents appears important in many biologic processes. We studied this process in neutrophils by immunologic methods. The capacity of neutrophils to recognize other neutrophils coated with antibodies against membrane antigens was used to determine the changes that occur after attachment of the antibody to the neutrophil membrane. Neutrophils were sensitized for 30 min at 22 degrees C with antibodies from three patients with antineutrophil autoantibodies. The sensitized neutrophils were recognized by normal neutrophils, which responded with an increase in glucose oxidation. If, after sensitization, the sensitized neutrophils were not immediately exposed to normal neutrophils, but instead were incubated at 37 degrees C for varying times, the capacity to elicit a recognition response decayed and was gone by 30 min. Additionally, the capacity of the cells to be resensitized by reexposure to antibody also decayed during this period. However, after further incubation at 37 degrees C, the neutrophils recovered the capacity to become sensitized; and this recovery was not inhibited by the addition of cycloheximide. Control incubations with normal immunoglobulin (Ig)G did not elicit a recognition response. The decay in recognition response was temperature dependent. Direct immunofluorescent studies with fluorescein-conjugated antineutrophil IgG revealed that the antibodies were cleared by aggregation and endocytosis. We conclude that: (a) neutrophils clear antibody from the cell surface by a temperature-dependent mechanism; (b) antigenicity is cleared concomitantly; (c) the mechanism of clearance involves internalization; and (d) with time, antigenicity reappears on the cell surface.

Antibodies↗
PubMed2001

An important role of CDK inhibitor p18(INK4c) in modulating antigen receptor-mediated T cell proliferation.

The inhibitors of cyclin-dependent kinase (CDK) 4 (INK4) bind CDK4/6 to prevent their association with D-cyclins and G(1) cell cycle initiation and progression. We report here that among the seven CDK inhibitors, p18(INK4c) played an important role in modulating TCR-mediated T cell proliferation. Loss of p18(INK4c) in T cells led to hyperproliferation in response to CD3 stimulation. p18(INK4c)-null mice developed lymphoproliferative disorder and T cell lymphomas. Expression of IL-2, IL-2R-alpha, and the major G(1) cell cycle regulatory proteins was not altered in p18-null T cells. Both FK506 and rapamycin efficiently inhibited proliferation of p18-null T cells. In activated T cells, p18(INK4c) remained constant, and preferentially associated with and inhibited CDK6 but not CDK4. We propose that p18(INK4c) sets an inhibitory threshold in T cells and one function of CD28 costimulation is to counteract the p18(INK4c) inhibitory activity on CDK6-cyclin D complexes. The p18(INK4c) protein may provide a novel target to modulate T cell immunity.

Animals↗
PubMed2006

Prostate-specific antigen modulates genes involved in bone remodeling and induces osteoblast differentiation of human osteosarcoma cell line SaOS-2.

PURPOSE: The high prevalence of osteoblastic bone metastases in prostate cancer involves the production of osteoblast-stimulating factors by prostate cancer cells. Prostate-specific antigen (PSA) is a serine protease uniquely produced by prostate cancer cells and is an important serologic marker for prostate cancer. In this study, we examined the role of PSA in the induction of osteoblast differentiation. EXPERIMENTAL DESIGN: Human cDNA containing a coding region for PSA was transfected into human osteosarcoma SaOS-2 cells. SaOS-2 cells were also treated with exogenously added PSA. We evaluated changes in global gene expression using cDNA arrays and Northern blot analysis resulting from expression of PSA in human osteosarcoma SaOS-2 cells. RESULTS: SaOS-2 cells expressing PSA had markedly up-regulated expression of genes associated with osteoblast differentiation including runx-2 and osteocalcin compared with the controls. Consistent with these results, the stable clones expressing PSA showed increased mineralization and increased activity of alkaline phosphatase in vitro compared with controls, suggesting that these cells undergo osteoblast differentiation. We also found that osteoprotegerin expression was down-regulated and that the receptor activator of NF-kappaB ligand expression was up-regulated in cells expressing PSA compared with controls. CONCLUSIONS: Modulation of the expression of osteogenic genes and alteration of the balance between osteoprotegerin-receptor activator of NF-kappaB ligand by PSA suggests that PSA produced by metastatic prostate cancer cells may participate in bone remodeling in favor of the development of osteoblastic metastases in the heterogeneous mixture of osteolytic and osteoblastic lesions. These findings provide a molecular basis for understanding the high prevalence of osteoblastic bone metastases in prostate cancer.

Alkaline Phosphatase↗
PubMed1999

Structural and functional consequences of antigenic modulation of red blood cells with methoxypoly(ethylene glycol).

We previously showed that the covalent modification of the red blood cell (RBC) surface with methoxypoly(ethylene glycol) [mPEG; MW approximately 5 kD] could significantly attenuate the immunologic recognition of surface antigens. However, to make these antigenically silent RBC a clinically viable option, the mPEG-modified RBC must maintain normal cellular structure and functions. To this end, mPEG-derivatization was found to have no significant detrimental effects on RBC structure or function at concentrations that effectively blocked antigenic recognition of a variety of RBC antigens. Importantly, RBC lysis, morphology, and hemoglobin oxidation state were unaffected by mPEG-modification. Furthermore, as shown by functional studies of Band 3, a major site of modification, PEG-binding does not affect protein function, as evidenced by normal SO4- flux. Similarly, Na+ and K+ homeostasis were unaffected. The functional aspects of the mPEG-modified RBC were also maintained, as evidenced by normal oxygen binding and cellular deformability. Perhaps most importantly, mPEG-derivatized mouse RBC showed normal in vivo survival ( approximately 50 days) with no sensitization after repeated transfusions. These data further support the hypothesis that the covalent attachment of nonimmunogenic materials (eg, mPEG) to intact RBC may have significant application in transfusion medicine, especially for the chronically transfused and/or allosensitized patient.

Animals↗
PubMed1979

Antigenic modulation of the cytophilic binding of guinea-pig IgG and IgM antibodies to homologous macrophages.

The cytophilic binding of immune complexes by peritoneal exudate cells (PEC) from adjuvant-stimulated guinea-pigs was studied using 125I-labelled guinea-pig IgG1, IgG2 and IgM antibodies to the dinitrophenyl (DNP) group. The influence of hapten density upon cytophilic activity was studied by the addition of DNP-conjugated antigens to antibody in 2-200 molar ratios of DNP:antibody. Only IgG2 binding was enhanced by immune complex formation, and the increased binding of IgG2 anti-DNP was dependent on the number of DNP determinants per antigen molecule. Cytophilic activity with epsilon-DNP-L-lysine (DNP-LYS), alpha,epsilon-di-DNP-L-lysine (DNP-LYS-DNP), or DNP1-8-BSA was no greater than that seen in the absence of hapten. Increased cytophilic binding was noted only with DNP20-41-BSA. The binding of IgG2 and IgG2 anti-DNP:DNP-bovine serum albumin (BSA) complexes was inhibited by monomeric IgG2. The relative cytophilic capacities of guinea-pig immunoglobulins appeared as follows: IgG greater than IgG1 greater than IgM. IgG1 and IgM binding of DNP conjugates did not enhance their cytophilic activity; therefore, IgG1 and IgM cytophilic binding to PEC was considered biologically insignificant. This investigation provides further evidence that cytophilic binding of immune complexes to macrophages is due to the co-operative action of multiple Fc sites rather than a conformational change in the IgG2 antibodies, and serum proteins, notably complement components, can alter the binding and/or phagocytosis of IgG2 anti-DNP:DNP-BSA complexes.

Animals↗
PubMed1990

Antigenic modulation of measles subacute sclerosing panencephalitis virus in a persistently infected rat glioma cell line by monoclonal anti-haemagglutinin antibodies.

Rat glioma C6 cells persistently infected with measles subacute sclerosing panencephalitis (SSPE) virus (C6/SSPE) express the viral membrane proteins haemagglutinin (HA) and F on their cell surface as well as the intracellular proteins N, P and M. Previously we have shown that the addition of a polyclonal antibody against the HA antigen to the growth medium of C6/SSPE cells led to a gradual loss of all viral antigens. Here we show that the addition of a monoclonal antibody (MAb K83) leads only to a transient decrease in viral antigens during the first three passages. After the third passage viral antigens start to increase and after five passages they produce more antigens than at the premodulation level. At this point of the MAb treatment, MAb K83 no longer recognized the HA antigen on the surface of the cells and in virus particles produced by these cells in contrast with polyclonal antibodies or other MAbs against the HA antigen. The results suggest that specific variants of the SSPE virus with an altered HA antigen were selected by the MAb treatment.

Animals↗
PubMed1977

Antigen modulation of antibody forming cells: the relationship between direct plaque size, antibody secretion rate and antibody affinity.

Using the mathematical theory of direct plaque growth, we have analyzed the expected variation of plaque size with IgM affinity and secretion rate. We use the theory to comment on recent effector cell blockage experiments and show how the theory can be used to determine the change in the secretion rate of a single antibody-forming cell subjected to blockage by a multivalent antigen. We also argue, using the mathematical theory, that under the usual experimental conditions employed in the plaque assay, cells that produce low affinity IgM antibodies will give rise to smaller plaques than cells that produce high affinity IgM antibodies.

Antibody Formation↗
PubMed2003

Schistosoma mansoni antigens modulate the activity of the innate immune response and prevent onset of type 1 diabetes.

Infection with Schistosoma mansoni (S. mansoni) or exposure to eggs from this helminth inhibits the development of type 1 diabetes in NOD mice. In this study we show that soluble extracts of S. mansoni worm or egg completely prevent onset of type 1 diabetes in these mice but only if injection is started at 4 weeks of age. T cells from diabetes-protected mice make IL-10 in recall responses to parasite antigens. These cells are furthermore impaired in their ability to transfer diabetes to NOD-SCID recipients. Bone marrow dendritic cells derived from NOD mice are found to make more IL-10 and less IL-12 following culture with S. mansoni soluble egg antigens in conjunction with lipopolysaccharides. NOD mice are deficient in NKT cells. Soluble worm and egg antigens increase the numbers of V alpha 14i NKT cells in NOD mice. These effects of schistosome antigens on the innate immune system provide a mechanism for their ability to prevent type 1 diabetes in NOD mice.

Animals↗
PubMed2004

Neuronal antigens modulate the immune response associated with experimental autoimmune encephalomyelitis.

Rats primed with bovine myelin (BM) in complete Freunds adjuvant, develop acute experimental autoimmune encephalomyelitis (EAE). We have previously described that intraperitoneal administration prior to the active induction of the disease of a bovine synaptosomal fraction (BSF) and BM were effective ways of suppressing EAE. We found that both treatments diminish the incidence of the disease and reduced biochemical and histological alterations of the central nervous system (CNS). To characterize this suppression process, in this study we examined the antigen-specific immune response in animals protected from EAE. Lymph node mononuclear cells derived from sick EAE rats, as well as from those protected by BM and BSF, showed strong myelin basic protein (MBP) proliferation. Analysis of the humoral response against MBP showed a significant diminution of IgG2b anti-MBP titres in protected BM and BSF rats in contrast to sick EAE rats whose condition could be related to a diminished anti-MBP Th1 response. Finally, cells from rats protected by BSF and BM reduced the incidence of EAE when they were adoptively transferred into animals prior to active induction of the disease. These results suggest that a mechanism based on the generation of regulatory cells and immune deviation could account for the EAE suppression mediated by myelin as well as synaptosomal antigens.

Adoptive Transfer↗
PubMed2006

Kaposi's sarcoma-associated herpesvirus-encoded latency-associated nuclear antigen modulates K1 expression through its cis-acting elements within the terminal repeats.

K1 is the first open reading frame encoded by Kaposi's sarcoma-associated herpesvirus (KSHV) and lies positionally to the immediate right of the terminal repeats. K1 is a transmembrane glycoprotein having a functional immunoreceptor tyrosine-based activation motif (ITAM) capable of activating B-cell receptor signaling. K1 is expressed mostly during the lytic cycle of the virus and its promoter lies within the terminal repeat which contains the binding sites for latency-associated nuclear antigen (LANA). The K1 promoter (K1p) having LANA binding sites assayed by reporter assay demonstrated that LANA is capable of down-regulating K1 promoter transcriptional activity. However, the KSHV replication transcription activator RTA up-regulates K1p transcriptional activity. The promoter deleted of LANA binding sites showed loss in LANA-mediated down-regulation but was unaffected for RTA-mediated up-regulation. Increasing amounts of RTA rescued LANA-mediated repression of K1p transcriptional activity in cotransfection experiments. Reporter assay data suggest that LANA binding to its cognate sequence is critical for LANA-mediated repression of K1p as a LANA construct lacking the DNA binding domain was unable to repress K1p transcription. Additionally, KSHV primary infection experiments suggest that K1 is expressed during early infection but is repressed on the establishment of latency and so follows an expression profile similar to that of RTA during infection. Analysis of the promoter sequence revealed the presence of Oct-1 transcription factor binding sites within the -116 to +76 region. Mutational analysis of the Oct-1 sites abolished RTA-mediated transcriptional activation, suggesting that RTA up-regulates K1p transcription through binding to this transcription factor.

Amino Acid Motifs↗