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At least 883 records · Page 49Linked to original sources
PubMed1991

Granulomatous hypersensitivity to Schistosoma mansoni egg antigens in human schistosomiasis. II. In vitro granuloma modulation induced by polyclonal idiotypic antibodies.

We have previously reported on Id/anti-Id-receptor interactions in clinical human schistosomiasis. These findings support a hypothesis that anti-SEA cross-reactive Id develop in some patients during the course of a chronic infection and participate in regulation of anti-SEA cellular immune responses. We report here on experiments that extend those observations to the regulation of granulomatous hypersensitivity measured by an in vitro granuloma model. T cells from chronic intestinal schistosomiasis patients were stimulated in vitro with anti-SEA Id and assayed in an autologous in vitro granuloma assay for modulation of granuloma formation. These anti-SEA Id-reactive T cells were capable of regulating autologous in vitro granuloma formation. Both CD4 and CD8 T cells could be activated to regulate granuloma formation. This regulatory activity, initiated with stimulatory anti-SEA idiotypic antibodies, was antigenically specific and was dependent on the presence of intact F(ab')2 Ig molecules. The ability to elicit this regulatory activity appears to be dose dependent and is more easily demonstrated in chronically infected intestinal patients or SEA-sensitized individuals. These data support the hypothesis that anti-SEA cross-reactive Id are important in regulating granulomatous hypersensitivity in chronic intestinal schistosomiasis patients and these cross-reactive Id appear to play a major role in cell-cell interactions that result in the regulation of anti-SEA cellular immune responses.

Animals↗
PubMed1995

Chronic renal transplant loss.

Chronic rejection results from recurrent episodes of subclinical or clinically evident acute rejection, with or without involvement of chronic rejection-specific allogeneic immune mechanisms. The tissue damage occurs over a prolonged period of time, which allows the emergence of antigen-independent tissue repair mechanisms and intrarenal adaptations in response to progressive loss of renal mass (Fig. 1). The combination of these mechanisms leads, very likely, to the tissue remodeling of chronic rejection. The heterogeneous expression of chronic rejection may result from different types and specificities of allogeneic immune reactions as well as different contributions of antigen-independent factors that modulate the antigen-dependent tissue responses to injury. The extent to which these mechanisms participate in the overall picture is presently unknown as immunological parameters are not measured routinely in the follow-up of patients with chronic graft dysfunction. Furthermore, some grafts may undergo tissue remodeling as a consequence of predominantly antigen-independent mechanisms. Therefore, the term chronic allograft dysfunction may clinically be preferable over chronic rejection to describe the gradual decline in graft function months or years after transplantation in the absence of a well-defined mechanism or an accepted treatment.

Animals↗
PubMed1991

The effect of a chimeric mouse-human CD7 antibody on human T, natural killer, and lymphokine-activated killer cell activity in vitro.

A chimeric CD7 antibody has been constructed with mouse variable and human constant regions and is currently being assessed in the prophylaxis of renal graft rejection. In this study we have investigated if this antibody or its murine parental form inhibits the function of a number of immune effector mechanisms involved in host defense against infection and/or malignancy. Most memory T cells and all natural killer cells express the CD7 antigen and could therefore be affected by CD7 antibody. Murine and chimeric CD7 antibodies significantly inhibit the alloproliferation of naive (65 +/- 4% and 66 +/- 8%, respectively) but not memory T cells (86 +/- 2% and 98 +/- 4%, respectively) in a primary mixed lymphocyte reaction relative to the negative control CD10 antibody (P less than 0.001). The memory T cell proliferative response to recall antigen is also largely unaffected by murine and chimeric CD7 antibodies relative to the negative control antibody (91 +/- 12% and 103 +/- 10%, respectively). The CD7 antigen is almost completely modulated from the surface of NK cells after incubation for 24 hr with either the murine or chimeric CD7, but not the CD10, negative control. The modulation of CD7 antigen by antibody, however, does not affect the cytotoxic function of either the NK or lymphokine-activated killer cells significantly. Preincubation with the chimeric antibody however, consistently showed a small inhibition relative to the negative control of 75-80% in NK assays and to 80-90% in LAK assays. These data suggest that both murine and chimeric CD7 antibodies may have a selective effect on alloproliferation but may largely spare a major component of the host's innate immunity as well as memory T cell proliferation to previously encountered antigens.

Antibodies↗
PubMed2003

Enhancement of gp120-specific immune responses by genetic vaccination with the human immunodeficiency virus type 1 envelope gene fused to the gene coding for soluble CTLA4.

DNA vaccines exploit the inherent abilities of professional antigen-presenting cells to prime the immune system and to elicit immunity against diverse pathogens. In this study, we explored the possibility of augmenting human immunodeficiency virus type 1 gp120-specific immune responses by a DNA vaccine coding for a fusion protein, CTLA4:gp120, in mice. In vitro binding studies revealed that secreted CTLA4:gp120 protein induced a mean florescence intensity shift, when incubated with Raji B cells, indicating its binding to B7 proteins on Raji B cells. Importantly, we instituted three different vaccination regimens to test the efficacy of DNA vaccines encoding gp120 and CTLA4:gp120 in the induction of both cellular (CD8(+)) and antibody responses. Each of the vaccination regimens incorporated a single intramuscular (i.m.) injection of the DNA vaccines to prime the immune system, followed by two booster injections. The i.m.-i.m.-i.m. regimen induced only modest levels of gp120-specific CD8(+) T cells, but the antibody response by CTLA4:gp120 DNA was nearly 16-fold higher than that induced by gp120 DNA. In contrast, using the i.m.-subcutaneous (s.c.)-i.m. regimen, it was found that gp120 and CTLA4:gp120 DNAs were capable of inducing significant levels of gp120-specific CD8(+) T cells (3.5 and 11%), with antibody titers showing a modest twofold increase for CTLA4:gp120 DNA. In the i.m.-gene gun (g.g.)-g.g. regimen, the mice immunized with gp120 and CTLA4:gp120 harbored gp120-specific CD8(+) T cells at frequencies of 0.9 and 2.9%, with the latter showing an eightfold increase in antibody titers. Thus, covalent antigen modification and the routes of genetic vaccination have the potential to modulate antigen-specific immune responses in mice.

AIDS Vaccines↗
PubMed1992

T-cell subset analysis of Lewis lung carcinoma tumor rejection: heterogeneity of effectors and evidence for negative regulatory lymphocytes correlating with metastasis.

We have analyzed the phenotypes of the T-cell subsets generated in response to Lewis lung carcinoma clones in C57BL/6J recipients. The metastatic derivative, which expresses low levels of H-2Kb gene, predominantly elicited CD8, V beta 8, and V beta 9+ T-cells. The nonmetastatic clone expressing high levels of H-Kb gene triggered a more heterogeneous response of V beta-5, -6, -8, -9, and -11 CD8+ T-cells. Comparison of the T-cell receptor (TCR) expression of the T-cells infiltrating the tumor site with the lymphocytes in the periphery of tumor-bearing animals revealed a pattern of homing of CD4+ T-cells bearing V beta-5, -6, and -11 TCR chains and CD8+ T-cells bearing V beta-5, -6, -9, and -11. Depletion of V beta 5 or V beta 6+ T-cells correlated with accelerated tumor growth, implying their protective role as tumor-specific effectors and consistent with the cytotoxicity of T-cells with this TCR phenotype. V beta 11 TCR expression in the tumor-infiltrating lymphocytes increased with the tumor size. Depletion of V beta 11+ T-cells enhanced resistance to primary tumor growth and conferred protection from metastasis in recipients cleared of V beta 5 and V beta 6 T-cell subsets. Those results suggest that tumor-specific effectors as well as negative regulator T-cells home, infiltrate, and coexist in the tumor site.

Animals↗
PubMed1993

Epitope-specific differential modulations within the T-cell antigen receptor complex.

The feeding of cloned helper T cells by irradiated spleen cells results in the modulation of T-cell antigen receptors (TCRs) as detected by FACS. When two groups of anti-TCR antibodies--anti-idiotypic and anti-V beta--are compared, time-dependent patterns of modulation of TCR are drastically different. Whereas up to 80% of the idiotypic determinants disappear within 2 days after stimulation, almost no change is observed for the determinants recognized by V beta-specific antibodies within the same period. Sequential immunoprecipitations clearly showed that anti-idiotypic and anti-V beta antibodies recognize the same population of TCR. Moreover, surface labelling followed by immunoprecipitation of TCR did not show rapid and drastic changes in the amount of specifically precipitated material. The modulation is not significantly affected by the addition of specific antigen, but is specific for the clone's MHC restriction element. Functionally, the modulation of TCR epitopes affects the ability of anti-TCR antibody but not of the MHC/antigen complex to stimulate T cells. We conclude that the observed modulation of fluorescence intensity in the TCR complex after MHC recognition (1) is epitope specific, (2) is independent of the presence of nominal antigen and (3) does not affect the efficiency of antigen-specific stimulation.

Animals↗
PubMed1991

What determines an antigen-specific IgE isotypic response? A hypothesis.

Two models to account for an antigen-specific IgE isotypic response are proposed. Both models assume a first-tiered IgE production induced by antigen and IL-4; however, the processed IgE or Ag-IgE immune complexes stimulate T epsilon cells differently in the two models. In Model I, we propose that T epsilon cells express conventional T-cell receptors which recognize IgE isotypic determinants. Model IA proposes that IgE fragments are processed and recognized along with class II MHC molecules, and T epsilon cell preferentially act on antigen-activated IgE-committed B epsilon cells via recognition of processed membrane IgE determinants but not antigens; thus T epsilon cells are in principle capable of modulating non-antigen-specific polyclonal IgE responses. Model IB proposes that IgE function as a class-restriction determinant for nominal antigens analogous to that of class II molecules, and T epsilon cells exert stringent antigen-specific IgE isotypic responses by recognizing nominal antigens restricted to IgE. T epsilon cells thus exert antigen-specific and IgE concerted immunoregulation, and do not participate in modulating polyclonal IgE production. Model II proposes a heterotypic interaction of IgE with a cell interaction receptor (or IgE Fc receptor) on T cells. T epsilon cells modulate antigen-specific IgE isotypic responses via ligation with IgE-antigen immune complexes on B-cell surface; thus, T epsilon cells in principle contribute to polyclonal IgE responses.

Animals↗
PubMed1987

The assessment of in vitro modulation of milk fat globule membrane expression by human breast carcinomas.

Although knowledge of functional differentiation and tumour-associated changes of breast carcinomas can be gained by the application of antibodies directed against the milk fat globule membrane, more significant information may be obtained by assessment of the potential of breast carcinomas to modulate their antigenic phenotype. In this study, the extend to which primary tumours can undergo modulation in vitro has been investigated, with consideration of the suitability of organ culture in combination with the immunohistochemical detection of two milk fat globule membrane epitopes, HMFG1 and HMFG2, as methods for detecting this. The preservation of three of the 30 carcinomas assessed, all poorly differentiated, was poor after 3 days of culture. The viability of the other 27 was variable, and was greater in the better differentiated tumours and with the addition of insulin. Expression of the milk fat globule membrane epitopes was generally well maintained. Six of the carcinomas showed a significant change in antigen expression, with this being more frequent in tissues incubated with insulin. Hence, a small group of carcinomas have been identified which appear to have a greater capacity to undergo functional differentiation. Organ culture is considered to be a suitable method for maintaining the tissues in vitro for such evaluation, but the problems encountered in quantifying the immunohistochemical staining, because of antigenic heterogeneity, were such that it is suggested that other approaches be employed.

Adenocarcinoma, Mucinous↗
PubMed2001

Structural plasticity of the proteasome and its function in antigen processing.

The proteasome is the main provider of peptide ligands for major histocompatibility complex class I molecules. During an immune response to pathogens, the proinflammatory cytokine interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha are released, which induce the proteasome subunits LMP2, LMP7, and MECL-1. These replace the constitutively expressed active site subunits of the proteasome (delta, MB1, and Z) leading to a marked change in the cleavage preference of the proteasome and the production of T-cell epitopes. Proteasome activity is further changed by the IFN-gamma-mediated induction of the proteasome regulator PA28alpha/beta and the downregulation of PA28gamma. Why such an extensive exchange of proteasome active site subunits and regulators occurs is still poorly understood. In this article we discuss recent insights in the structural consequences of proteasome reorganization and their effects on epitope generation and shaping of the cytotoxic immune response. Moreover, we review the latest data on how the ubiquitin pathway targets protein antigens for peptide processing and discuss the potential of proteasome inhibitors for the modulation of antigen presentation.

Amino Acid Sequence↗
PubMed1979

Detection and partial characterization of a new murine T-lineage antigen: evidence for its enzymatic modulation.

A molecule with an apparent molecular weight of 21,000 daltons was found to be a predominating differentiation antigen of peripheral rat T lymphocytes. This antigen is also expressed on the cell surface of thymus lymphocytes though partially in masked form. The observation that these determinants could be unmasked by neuraminidase treatment in vitro suggests that enzymatic processes may play an important role in antigenic transformation along the differentiation pathway of T axis lymphocytes. Since this structure was found to be displayed also by peritoneal exudate macrophages, it is referred to as T lymphocyte-macrophage antigen. The finding that an identical antigen could be identified in the mouse suggests its more common biological significance.

Animals↗
PubMed1987

Immunoanatomic distribution of cytostructural and tissue-associated antigens in the human urinary tract.

The main objective of the present study is to define the expression and/or modulation of antigenic phenotypes in cells of the normal human kidney and urothelium according to cell type. Fourteen antibodies detecting differentiation and structural antigens expressed in the human urinary tract have been used to define the immunoanatomic distribution of these antigenic systems. They include urinary tract antigens (Tamm-Horsfall glycoprotein and prostate-specific antigen), tissue-associated antigens (epithelial membrane antigen, Factor VIII antigen, and Protein S-100), and cytoskeletal antigens of the intermediate filament classes (cytokeratins, vimentin, desmin, glial fibrillary acidic protein, and neurofilaments. Immunofluorescence and immunoperoxidase analyses performed on normal human fetal and adult tissue sections have demonstrated that these antigens are expressed by different cell types and domains of the nephron. Studies correlating normal fetal and adult tissues reveal that some of the antigens appear at distinct stages of maturation, representing early and late antigenic expression events. These antibodies offer a wide range of potential applications that include studies of embryogenesis of the human urinary tract and immunopathologic analyses of neoplastic and nonneoplastic diseases of the human kidney and urothelium.

Adult↗
PubMed1996

Anti-CD2 monoclonal antibody-induced receptor changes. II. Interaction of CD2 and CD3.

Anti-CD3 monoclonal antibodies (mAbs) and anti-CD2 mAbs each prolong allograft survival and cause transient downmodulation of homologous receptor expression. Anti-CD2 mAbs also act synergistically with anti-CD3 mAbs to prolong allograft survival and induce tolerance. The effect of combined anti-CD2 and anti-CD3 mAb treatment on receptor expression was further analyzed with an in vitro model. The anti-CD2 mAb 12-15 caused CD2 expression on purified splenic T cells to decrease from 72.6% [mean channel fluorescence (MCF) 0.68] to 41.5% (0.45) total positive cells while CD3 expression remained unchanged [69.1% (3.47) to 76.4% (4.04)]. The anti-CD3 mAb 2C11 caused CD2 expression to increase from 72.6% (0.68) to 93.0% (1.74) while CD3 expression decreased from 69.1% (3.47) to 62.6% (2.15). The combination of anti-CD2 plus anti-CD3 preserved CD2 expression (72.6 to 71.1%) while still decreasing CD3 expression [69.1% (3.47) to 69.9% (2.37)]. Modulation of CD2 and CD3 expression was similar on mixed splenic T lymphocytes and isolated CD4 and CD8 subsets. Modulation did not change with the addition of the cytokines IL-1, IL-2, IL-4, IL-6, IL-10, TNF alpha, or TGF beta. Kinetic studies showed that modulation of CD2 was rapid, persistent, and of the same magnitude from Day 1 to Day 7 of culture while CD3 downmodulation was transient. The results of transcriptional analysis and receptor distribution suggested that downmodulation was due to receptor internalization while upmodulation was due to increased transcription. Analysis of expression of other adhesion molecules demonstrated that CD11a, CD18, CD44, CD45, CD48, CD54, and CD62L were significantly increased by either anti-CD2 or anti-CD3 mAbs while the combination was not synergistic. However, anti-CD3 significantly decreased VLA-4 alpha (CD49d) expression and anti-CD2 enhanced this decrease. Conversely anti-CD3 significantly increased IL-2R (CD25) expression and anti-CD2 profoundly inhibited the increase. These results show that anti-CD2 and anti-CD3 mAbs significantly modulate CD2 and CD3 expression on T cells and modulation is accompanied by changes in the array of other T cell surface receptors. Changes in cell surface receptor display may provide an additional explanation for the synergistic effect of anti-CD2 plus anti-CD3 in prolonging allograft survival.

Animals↗
PubMed1992

Hormonal modulation of biosynthesis of prostatic specific antigen, prostate specific acid phosphatase and prostatic inhibin peptide.

Hormonal modulation of in vitro biosynthesis of three prostatic secretory proteins, prostate specific acid phosphatase (PSAP), prostate specific antigen (PSA) and prostatic inhibin peptide (PIP) by human benign hyperplasia (BPH) tissue was studied. LH and inhibins caused increase in the synthesis of all three proteins whereas FSH enhanced the synthesis of PIP and PSA only but decreased PSAP synthesis. Prolactin and thyroid releasing hormone decreased synthesis of PIP and PSAP. However, PSA synthesis was enhanced by TRH and was decreased by prolactin. Estradiol caused significant increase in PSA and PSAP but no discernible changes in PIP synthesis were noticed. Testosterone caused an increase in PIP, PSA and PSAP. These data indicate that biosynthesis of PIP, PSA and PSAP by BPH tissue is under multihormonal regulation.

Acid Phosphatase↗
PubMed2001

Human leukocyte antigen-G-expressing cells differently modulate the release of cytokines from mononuclear cells present in the decidua versus peripheral blood.

PROBLEM: To better understand the role of human leukocyte antigen (HLA)-G in regulating the T helper (Th)1/Th2 cytokine balance, one of key conditions in determining the fate of pregnancy, we asked whether the presence of HLA-G protein altered the release of cytokines from both decidual mononuclear cells and peripheral blood mononuclear cells (PBMCs). METHOD OF STUDY: The amounts of cytokines released from decidual mononuclear cells and PBMCs were compared in the presence or absence of HLA-G-expressing cells. RESULTS: When cocultured with HLA-G-expressing cells, the amounts of tumor necrosis factor-alpha and interferon-gamma released from decidual mononuclear cells and PBMCs were decreased, while the amounts of interleukin (IL)-4 from PBMCs was increased, with IL-4 release from decidual mononuclear cells being unchanged. CONCLUSIONS: Upon contact with HLA-G, decidual mononuclear cells, and PBMCs as well, modulate their ability to release cytokines in a way that may shift the Th1/Th2 balance towards relative Th2 dominance, suggesting a role for HLA-G in maintaining pregnancy.

Adult↗
PubMed2003

Reduction of the diagnostic window in three cases of human immunodeficiency-1 subtype E primary infection with fourth-generation HIV screening assays.

BACKGROUND AND OBJECTIVES: The influence of genetic variability on the sensitivity of serological diagnosis of human immunodeficiency virus (HIV) infection has, to date, been poorly investigated. The aim of the present study was to assess whether fourth-generation assays for the combined detection of HIV antigen and antibodies to HIV (anti-HIV) permit a reduction of the diagnostic window in comparison to third-generation antibody enzyme immunoassays (EIAs), which so far have shown a poor sensitivity for detection of HIV-1 non-subtype B primary infections. MATERIALS AND METHODS: Three patients with primary HIV-1 subtype E (CRF01-AE) infection were tested with different third- and fourth-generation assays, stand-alone HIV antigen (Ag) EIAs and reverse transcription-polymerase chain reaction (RT-PCR). Additionally, virus lysates from HIV-1 Group M and O and HIV-2, at concentrations of p24 Ag close to the detection limit of licensed HIV Ag EIAs, were investigated with fourth-generation EIAs and HIV Ag EIAs. RESULTS: In the first blood donor, the most sensitive fourth-generation assay detected HIV-1 infection 11 days earlier than five of the eight third-generation antibody assays. Fourth-generation EIAs, with a high sensitivity for HIV antigen, detected HIV-1 subtype E infection simultaneously or 4 days later than HIV-1 RT-PCR on pooled samples. Low concentrations of virus lysates of different HIV-1 subtypes A-H and group O, tested positive with fourth-generation EIAs, with a high sensitivity of the antigen-detection module. CONCLUSIONS: Fourth-generation EIAs, especially those with a high sensitivity for HIV-1 p24 antigen, reduce the diagnostic window for primary HIV-1 subtype E infection in comparison with third-generation antibody-screening assays. These preliminary data from seroconversions and virus lysates indicate that the genetic diversity of HIV-1 does not represent a major challenge for the most sensitive EIAs of this new assay generation.

Antigenic Variation↗
PubMed2005

Tumor-derived lactic acid modulates dendritic cell activation and antigen expression.

The tumor milieu can influence dendritic cell (DC) differentiation. We analyzed DC differentiation in a 3-dimensional tumor model and propose a new mechanism of DC modulation by the tumor environment. Monocytes were cultured in the presence of IL-4 and GM-CSF within multicellular tumor spheroids (MCTSs) generated from different tumor cell lines. Monocytes invaded the MCTSs and differentiated into tumor-associated dendritic cells (TADCs). The antigen expression was altered on TADCs independent of the culture conditions (immature/mature DCs, Langerhans cells) and IL-12 secretion was reduced. Supernatants of MCTSs could partially transfer the suppressive effect. Conditioned media from urothelial carcinoma cell lines contained high levels of M-CSF and IL-6, both cytokines known to modulate DC differentiation. In contrast, melanoma and prostate carcinoma MCTS cocultures produced little M-CSF and IL-6, but high levels of lactic acid. Indeed, addition of lactic acid during DC differentiation in vitro induced a phenotype comparable with TADCs generated within melanoma and prostate carcinoma MCTSs. Blocking of lactic acid production in melanoma MCTS cocultures reverted the TADC phenotype to normal. We therefore conclude that tumor-derived lactic acid is an important factor modulating the DC phenotype in the tumor environment, which may critically contribute to tumor escape mechanisms.

Cell Differentiation↗