SEARCH · Search PubMed

Results for “Antigenic Modulation”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

SourceResearch connectionFrom yearThrough year

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 523 records · Page 29Linked to original sources

PubMed1993

Immunologic monitoring during OKT3 therapy.

The monoclonal antibody OKT3 is a potent immunosuppressant inducing both T-cell depletion and antigenic modulation of the CD3/T-cell receptor complex. CD3 + lymphocytes are cleared from the circulation within 1 hour of intravenous administration of OKT3. Periodic monitoring of remaining or reappearing CD3 + lymphocytes gauges the adequacy of OKT3 dosing and OKT3 consumption by anti-OKT3 antibodies. The maximum acceptable concentration of CD3 + lymphocytes for maintaining the effectiveness of OKT3 therapy remains controversial due to variable sensitivity of the methods used. Intravenously administered OKT3 has a half-life of approximately 18 hours and results in trough serum levels ranging from 500 to 1000 ng/ml in 3 to 4 days. The antibody response to OKT3 is oligoclonal, and both IgM and IgG antibodies to OKT3 may develop, showing restricted specificity; anti-isotypic and/or anti-idiotypic antibodies can be detected. The IgG anti-idiotypic antibodies are the ones that neutralize the therapeutic activity of OKT3, and their specific detection involves the use of an immunofluorescence method that tests their ability to block the binding of OKT3 to normal T cells. The production of OKT3 antibodies has been shown to be affected by concomitantly administered immunosuppressive agents. Studies have demonstrated that OKT3 can be successfully reused in allograft recipients who do not present anti-idiotypic blocking antibodies. The acute clinical syndrome regularly observed upon the first OKT3 injection is related to massive, although transient, release of several cytokines, which may be easily monitored with currently available radioimmunologic or immunoenzymatic tests.

Cytokines↗

PubMed2000

Soluble HLA-G circulates in maternal blood during pregnancy.

OBJECTIVE: Soluble isoforms of the HLA class Ib gene HLA-G have been identified at the maternal-fetal interface. Because soluble forms of other HLA class I antigens modulate T-cell reactivity and induce cellactivated apoptosis, our goal was to determine whether soluble HLA-G circulates in maternal or fetal blood and to identify the specific isoform. STUDY DESIGN: Capture enzyme-linked immunosorbent assays with mouse monoclonal antibodies directed toward an epitope present on all isoforms of soluble HLA-G were constructed to identify soluble HLA-G in 44 serum samples from nonpregnant control subjects, 129 serum samples from pregnant women, and 10 samples of term cord blood. Distinguishing between soluble HLA-G1, which is composed of heavy chains complexed with light chains (beta(2)-microglobulin), and soluble HLA-G2, which consists only of heavy chains, was achieved by substituting a monoclonal antibody that requires beta(2)-microglobulin for binding (W6/32) in the capture phase of the enzyme-linked immunosorbent assay. RESULTS: Capture enzyme-linked immunosorbent assays with mouse anti-soluble HLA-G showed that soluble HLA-G was present at all stages of gestation and that levels of soluble HLA-G were statistically significantly higher in serum samples from pregnant women than in serum samples from nonpregnant women. In contrast, W6/32 failed to detect soluble HLA-G in serum samples from pregnant women. Cord serum samples did not contain detectable soluble HLA-G. CONCLUSION: Collectively, the data indicate that pregnancy is characterized by the presence of soluble HLA-G circulating in maternal blood and strongly suggest that the major isoform is soluble HLA-G2.

Animals↗

PubMed2006

Short-term treatment with anti-CD3 antibody reduces the development and progression of atherosclerosis in mice.

BACKGROUND: Atherosclerosis is a chronic inflammatory disease of the large arteries that is the primary cause of heart disease and stroke. Anti-CD3-specific antibodies suppress immune responses by antigenic modulation of the CD3 antibody/T-cell receptor complex. Their unique capacity to restore self-tolerance in a mouse model of diabetes and, importantly, in patients with recent-onset type 1 diabetes involves transforming growth factor-beta-dependent mechanisms via expansion and/or activation of regulatory T cells. We hypothesized that treatment with anti-CD3-specific antibodies might inhibit atherosclerosis development and progression in mice. METHODS AND RESULTS: Low-density lipoprotein receptor-deficient mice were fed a high-cholesterol diet for 13 or 24 weeks. Anti-CD3 antibody was administered on 5 consecutive days beginning 1 week before or 13 weeks after the high-cholesterol diet was initiated, respectively. Control mice were injected in parallel with phosphate-buffered saline. Anti-CD3 antibody therapy reduced plaque development when administered before a high-cholesterol diet and markedly decreased lesion progression in mice with already established atherosclerosis. We found increased production of the antiinflammatory cytokine transforming growth factor-beta in concanavalin A-stimulated lymph node cells and enhanced expression of the regulatory T-cell marker Foxp3 in spleens of anti-CD3 antibody-treated mice. A higher percentage of apoptotic cells within the plaques of anti-CD3 antibody-treated mice was also observed. CONCLUSIONS: Altered disease progression, combined with the emergence of this particular cytokine pattern, indicates that short-term treatment with an anti-CD3 antibody induces a regulatory T-cell phenotype that restores self-tolerance in a mouse model of atherosclerosis.

Animals↗

PubMed1982

Pilot studies using melanoma tumor-associated antigens (TAA) in specific-active immunochemotherapy of malignant melanoma.

Highly purified melanoma TAA which induce melanoma-related cellmediated immune responses have been further characterized using hyperimmune TAA antisera after affinity chromatography for double immunodiffusion-immunoelectrophoresis and indirect immunofluorescence studies. An additional study of antigenic modulation was performed in 23 nonanergic and seven anergic melanoma patients, tested simultaneously with melanoma TAA prepared from primary and metastatic tumors, which had been obtained from one patient at different time periods. The results of pilot clinical trials are reported, including toxicity, timing and dosage studies in 20 patients and subsequent studies of patients with metastatic melanoma treated at three separate centers, using a single lot of purified, allogeneic melanoma TAA. The results of these latter studies in 51 patients with Stage III (distantly metastatic) melanoma and in five patients with earlier stages of disease indicate that: (1) when the interval from primary therapy to recurrence is greater than one year and when liver, bone and brain are not involved, partial or total clinical regression may be noted in up to 25% of patients with metastatic disease receiving immunochemotherapy; (2) when total regression does occur, the effect usually lasts from one to three years; (3) cytoreductive (debulking) surgery, when possible, in cutaneous, nodal retroperitoneal, and visceral regions may enhance the response to specific active immunochemotherapy, although some debulked patients had less tumor burden and this factor alone may lead to an improved prognosis in patients undergoing any subsequent treatment; (4) when circulating inhibitory factors are modified through preimmunization chemotherapy, an enhanced host response may be seen; and (5) Cancer Serum Indices (CSI) may be useful in predicting recurrence and in following tumor load and response to therapy. Information obtained from these studies suggest the need for further trials to determine the effect of immunization on patients with earlier stages of disease where recurrence rates remain high, and to evaluate the mechanisms of tumor rejection or tumor progression in the face of immune stimulation.

Adult↗

PubMed1997

Keratinocyte-lymphocyte interaction in cutaneous T-cell lymphoma. Modulation of keratinocyte antigen My7 by a soluble factor produced by T lymphocytes.

OBJECTIVE: To test the hypothesis that the modulation of My7 antigen in the basal keratinocytes is directly related to the effect of dermal lymphocyte infiltrate of epidermotropic cutaneous T-cell lymphoma (CTCL). DESIGN: In vitro study with reconstituted skin model. SETTING: Department of Dermatology of University Hospital, Nantes, France. PATIENTS: Lymphocytes extracted from 11 skin samples with lesions of epidermotropic CTCL (mycosis fungoides, stages IIa to IV) and 6 skin samples with lesions of atopic dermatitis (control population) together with the supernatants of these infiltrating lymphocytes were incubated with normal reconstituted skin samples either alone or in the presence of interferon alfa-2a (10(2) IU/ mL). Moreover, normal peripheral blood mononuclear cells of 7 patients and 4 controls were incubated with reconstituted skin. INTERVENTION: None MAIN OUTCOME MEASURES: None. RESULTS: Ten of 11 samples of lymphocytes extracted from CTCL and 7 of 11 of their supernatants inhibited partially or completely My7 expression by basal cells. NO inhibition was noted for lymphocytes extracted from inflammatory skin or their supernatants. Addition of interferon alfa-2a in a culture medium of extracted lymphocytes or their supernatants blocked inhibition of My7 expression by keratinocytes in 8 of 10 reconstituted skin samples. No abrogation of My7 expression was noted with peripheral mononuclear cells. CONCLUSIONS: Our in vitro study demonstrated a direct and specific interaction between the tumor infiltrate of CTCL and keratinocytes. Moreover, this interaction appeared to be closely associated with a soluble factor produced by the tumor T-cell infiltrate and was at least partially blocked by interferon alfa-2a.

Antibodies, Monoclonal↗

PubMed1999

Effect of pressure on antigen-antibody complexes: modulation by temperature and ionic strength.

Changes in the equilibrium binding affinity of antigen-antibody complexes subjected to hydrostatic pressures of about 2000 bar provide a potential means for the separation and recovery under mild conditions of biological molecules from immunoadsorbents or immunosensors. We have investigated the ability of temperature and ionic strength to modulate the pressure sensitivity of several antigen-antibody complexes in solution. For two different protein:monoclonal antibody complexes (BSA:9.1 and HEWL:HyHEL-10) exhibiting pressure-induced dissociation (positive association volume), we find little temperature dependence to the association volume. For another complex (digoxigenin:26-10) exhibiting pressure-induced association, the association volume increases with temperature, which, via a Maxwell relation, indicates that enthalpic changes drive the pressure effect. An increase in ionic strength decreases the affinity of binding the HEWL:HyHEL-5 complex, which contains several salt bridges. At low ionic strengths (<0.3 M), no pressure dependence of the free energy of association is observed, but at higher ionic strengths, significant pressure-induced association is observed, suggesting that positive contributions to the association volume provided by the salt bridges are counterbalanced by other (e.g., aromatic stacking) interactions that lead to negative association volumes. These results suggest that ionic strength may be used to modulate the pressure sensitivity of antigen antibody complexes, which may be useful in designing processes that exploit this phenomenon for immunoseparations.

Animals↗

PubMed1984

Unusually restricted anti-isotype human immune response to OKT3 monoclonal antibody.

The unusual anti-mouse immunoglobulin (Ig) sensitization of a renal allograft recipient who was treated prophylactically with the anti-T cell monoclonal antibody OKT3 (IgG2a) is reported. Whereas in most patients, the injection of OKT3 (5 mg/day, i.v. for 13 days) induces the rapid appearance of neutralizing anti-OKT3 antibodies, the patient reported here did not show the signs of conventional anti-OKT3 sensitization. High levels of circulating OKT3 persisted and no OKT3+ lymphocytes reappeared during the whole treatment period. Moreover, no IgG or IgM anti-OKT3 antibodies were detected at any time, using a specific enzyme-linked immunosorbent assay. However, an atypical anti-isotype response was evidenced in this subject whose Ig were shown by indirect fluorescence to bind to normal T cells coated with OKT3 or with other anti-T cell murine monoclonal antibodies carrying the IgG2a isotype (no reactivity was observed with IgG1 or IgG2b molecules). The patient's Ig did not bind to normal T cells coated with F(ab')2 fragments of OKT3 and did not inhibit the binding of OKT3 to its target antigen indicating that they reacted with the Fc fragment of the OKT3 molecule. Additionally, and probably explained by this unusual anti-OKT3 response, the patient's Ig were shown to inhibit the phytohemagglutinin-induced proliferation of normal lymphocytes, to bind under selected in vitro conditions to normal T cells and lastly to enhance the antigenic modulation induced in vitro by OKT3 on its membrane receptor.

Antibodies, Monoclonal↗

PubMed1994

Monoclonal antibodies to murine CD40 define two distinct functional epitopes.

Two rat IgG2a antibodies which define distinct epitopes on murine CD40 have been generated. These antibodies specifically bind recombinant murine CD40 expressed on L cells, and the soluble extracellular domain of murine CD40 coated onto microtiter plates. Both antibodies bind B220+ but not B220 murine spleen cells, and immunoprecipitate a 45-kDa protein from the surface of purified murine splenic B cells. These antibodies exhibit separate functional properties, consistent with the notion that they define two distinct CD40 epitopes. One of the monoclonal antibodies (designated 1C10) directly induces a specific proliferative response from mature murine B cells, up-regulates several B cell surface antigens, and rescues immature B lymphoma cells from anti-IgM-induced growth arrest. The other monoclonal antibody (designated 4F11) exhibits none of these properties, but is capable of synergizing with suboptimal amounts of either anti-IgM antibodies or the 1C10 agonistic anti-CD40 antibody to produce an optimal proliferative response of purified small dense B cells. Furthermore, 4F11 antibody synergizes with suboptimal amounts of 1C10 antibody to rescue B lymphoma cells from anti-IgM-induced growth arrest. The 1C10 and 4F11 antibodies were unable to cross-block each other's binding to recombinant CD40 expressed in L cells, providing strong support for the notion that the antibodies recognize distinct epitopes on CD40. The potential implications of two functionally distinct CD40 epitopes are discussed.

Animals↗

PubMed2005

Isolation of potent human Fab fragments against a novel highly immunogenic region on human muscle acetylcholine receptor which protect the receptor from myasthenic autoantibodies.

In the autoimmune disease myasthenia gravis (MG), antibodies against the muscle nicotinic acetylcholine receptor (AChR) cause loss of functional AChR in the neuromuscular junction. To isolate AChR-specific human antibody fragments (Fab), a phage-display library was constructed from an MG patient's thymic B lymphocytes. The first Fab isolated had a low affinity for human AChR, but two sequential antibody chain shufflings using the MG donor heavy and light chain gene repertoires resulted in isolating two new Fab with an approximately 30-fold higher binding ability. The selected Fab contained extensively mutated heavy and light chains and probably represent intraclonal variants of a common progenitor having diverged in vivo by somatic hypermutation. Interestingly, the isolated Fab bound to an extracellular highly immunogenic region located either on an alpha-subunit site affected by the gamma/epsilon-subunits or on the interface between alpha- and gamma/epsilon-subunits. This region is not the previously described "main immunogenic region" (MIR), although it seems to be close to it, as one improved Fab and an anti-MIR mAb competed for AChR binding with distinctly different subpopulations of MG sera. Furthermore, this Fab protected surface AChR in cell cultures against MG autoantibody-induced antigenic modulation, suggesting a potential therapeutic use in MG, especially in combination with a human anti-MIR Fab.

Amino Acid Sequence↗

PubMed1988

Problems and prospects in the use of lymphoma idiotypes as therapeutic targets.

The infusion of anti-idiotypic antibody in patients with lymphoma has proved a relatively innocuous procedure, but in general had yielded only partial, short-lived remissions of disease. A major problem is that xenogeneic antibody is simply not well-fitted to destroying mammalian cells: complement and cellular effectors (K cells and phagocytes) are not efficiently recruited, and the target cells in any case present some excellent defense mechanisms. Antigenic modulation is particularly prominent among these defenses, and we present evidence here for modulation of idiotype being much more efficient in vivo than in vitro. Two broad types of antibody derivative are under development to improve the killing of neoplastic targets. One type relies on recruiting natural effectors, and is exemplified by univalent chimeric antibody. The other relies on delivering an exogenous effector such as a drug or toxin, and is exemplified by bispecific anti-Id/anti-saporin F(ab'gamma)2 antibody. Both types of derivative have been able to suppress animal lymphoma to the extent that tumor escape occurs largely through the emergence of idiotype-negative mutants.

Aged↗

PubMed1993

Roferon-A (interferon alpha 2a) combined with Tigason (etretinate) for treatment of cutaneous T cell lymphomas.

Many treatments are used for epidermotropic cutaneous T cell lymphomas (CTCL) such as mycosis fungoides (MF) and Sézary syndrome (SS). All pretend to be effective, but none is really curative. As single drug therapy provides a response rate of about 55% with interferon alpha and about 45% with etretinate, we studied the effectiveness of combining these two drugs for immunomodulatory therapy in epidermotropic CTCL. A review of four reports, including a multicenter study performed in 45 patients, indicates a response rate of 56%, with better results for MF than SS. Side effects are generally moderate when low doses are used. The mechanism of action of this combined therapy on cutaneous lesions remains unclear. In vitro, a synergistic effect of retinoids on interferon alpha antiviral activity has been demonstrated, and in vivo an immunohistochemical study showed that the combined therapy modulates antigens expressed by keratinocytes and increases cytotoxic cells in dermis without modifying the number of Langerhans cells in epidermis.

Drug Synergism↗

PubMed1981

Heterogeneity, position, and functional capability of the macrophages in Peyer's patches.

Peyer's patches are thought to be deficient in macrophages capable of sustaining the induction of an immune response. The present study examined the position, morphology, and phagocytic activity of Peyer's-patch macrophages, and their ability to take up, in situ, a tracer antigen introduced through the intestinal lumen. Peyer's-patch macrophages were isolated in vitro, and nonspecific esterase activity of individual cells was quantitated. Macrophages concentrated within the epithelium overlying Peyer's patches and in the subepithelial zone showed phagocytic activity and the ability to take up exogenous ferritin. Adherent macrophages demonstrated heterogeneity of esterase activity, with approximatley 15% having none. However, esterase activity in macrophages from lymph nodes was equally heterogeneous. The profile of esterase activity of Peyer's-patch macrophages seemed intermediate between those of macrophages from submandibular and mesenteric nodes. Tingible body macrophages were concentrated in germinal centers and were poorly adherent. The results of this study indicate that macrophages similar to those in lymph nodes are concentrated in the region where they may intercept antigens entering through overlying specialized epithelium. The presence of plasma cells in the same region suggests that local reaction to antigens, perhaps modulating further antigen entry, is supported by these macrophages. Perhaps the proportion of functional macrophages in the entire Peyer's patch is too low to support immune induction in in vitro-tests.

Animals↗

PubMedDate not supplied

Preparation and properties of FabIgG, a chimeric univalent antibody designed to attack tumour cells.

In order to promote the killing of tumour cells by antibody a derivative has been synthesized in which Fab'gamma from xenogeneic antibody is thioether-bonded to half-cystine on normal IgG of the species to be treated. The resulting entity, FabIgG, is obtained with about a 40% yield of the starting Fab'gamma. Being univalent it evades antigenic modulation. It activates complement efficiently, is minimally immunogenic, and appears to be catabolized at the slow rate characteristic of autologous IgG.

Animals↗

PubMed1997

Myasthenia gravis as a prototype autoimmune receptor disease.

Myasthenia gravis (MG) is an organ-specific autoimmune disease in which autoantibodies against nicotinic acetylcholine receptors (AChR) at the postsynaptic membrane cause loss of functional AChR and disturbed neuromuscular transmission. The immunopathogenic mechanisms responsible for loss of functional AChR include antigenic modulation by anti-AChR antibodies, complement-mediated focal lysis of the postsynaptic membrane, and direct interference with binding of acetylcholine to the AChR or with ion channel function. The loss of AChR and subsequent defective neuromuscular transmission is accompanied by increased expression of the different AChR subunit genes, suggesting a role for the target organ itself in determining susceptibility and severity of disease. Experimental autoimmune myasthenia gravis (EAMG) is an animal model for the disease MG, and is very suitable to study the immunopathogenic mechanisms leading to AChR loss and the response of the AChR to this attack. In this article the current concepts of the structure and function of the AChR and the immunopathological mechanisms in MG and EAMG are reviewed.

Animals↗

PubMed1984

The clinical use of monoclonal anti-T-cell antibodies.

Monoclonal anti-T-cell antibodies are progressively replacing other T-cell markers in clinical immunology. A number of problems persist however, that urge for caution in interpreting the data issued from their in vitro use. Several antibodies directed against the same molecule may give different results according to the subject (due to genetic variants) or according to stage T-cell differentiation. The expression of antigenic determinants (epitopes may vary under the effect of drugs, positively (cimetidine, thymic hormones) or negatively (indomethacin). Lastly the correlation between phenotype and function of T-cell subsets may be very poor in the same pathological settings. In spite of these pitfalls, monoclonal anti-T-cell antibodies have proven to be very useful in several circumstances. Thus, in renal allograft recipients immunological monitoring with monoclonals helps the diagnosis of rejection in patients treated with conventional immunosuppression and permits early detection of antigenic modulation and xenosensitization in patients treated with the anti-T-cell OKT3 antibody.

Antibodies, Monoclonal↗

PubMed1984

Chimeric univalent antibodies for treating lymphoid malignancies.

A more effective use of antibody in treating cancer appears to require derivatives with enhanced cytotoxic potential. Working with anti-idiotype antibodies directed against neoplastic lymphocytes, we have shown previously that univalent antibody derivatives with intact Fc-regions can avoid antigenic modulation while retaining the ability to recruit cytotoxic effectors such as complement. Chimeric univalent antibodies represent an extension of this approach. To prepare them Fab' gamma from antibody is linked by thioether bonds to half-cystine in normal Ig of the species to undergo immunotherapy. The derivatives FabIgG and FabFc utilize IgG and Fc gamma respectively as the effector partners of the antibody Fab' gamma. They appear superior to parent antibody in their ability to invoke complement and K-cell killing of target lymphocytes. They show promise of being minimally immunogenic and, because they present homologous Fc, should prove efficient recruiters of host effector functions.

Animals↗

PubMed1991

The main immunogenic region (MIR) of the nicotinic acetylcholine receptor and the anti-MIR antibodies.

Myasthenia gravis (MG) is caused by autoantibodies against the nicotinic acetylcholine receptor (AChR) of the neuromuscular junction. The anti-AChR antibodies are heterogeneous. However, a small region on the extracellular part of the AChR alpha subunit, called the main immunogenic region (MIR), seems to be the major target of the anti-AChR antibodies, but not of the specific T-cells, in experimental animals and possibly in MG patients. The major loop of the overlapping epitopes for all testable anti-MIR monoclonal antibodies (MAbs) was localized within residues 67-76 (WNPADYGGIK for Torpedo and WNPDDYGGVK for human AChR) of the alpha subunit. The N-terminal half of alpha 67-76 is the most critical, Asn68 and Asp71 being indispensable for binding. Yet anti-MIR antibodies are functionally and structurally quite heterogeneous. Anti-MIR MAbs do not affect channel gating, but they are very potent in mediating acceleration of AChR degradation (antigenic modulation) in cell cultures and in transferring experimental MG in animals. Fab fragments of anti-MIR MAbs bound to the AChR prevent the majority of the MG patients' antibodies from binding to and causing loss of the AChR. Whether this inhibition means that most MG antibodies bind on the same small region or is a result of broad steric/allosteric effects is under current investigation.

Adult↗

PubMed1986

Anti-C3b-receptor (CR1) antibodies in patients with systemic lupus erythematosus.

Using an enzyme-linked immunoadsorbent assay, IgG in the plasma and purified IgG from 2 patients with systemic lupus erythematosus (SLE) were found to strongly react with purified C3b receptor (CR1) insolubilized on microtiter plates. The amount of IgG that bound to CR1 in 201 plasma samples from 179 other patients with SLE did not significantly differ from that which bound in 72 control samples from normal individuals. Purified IgG from the patients with anti-CR1 reactivity did not inhibit CR1 function in vitro. The number of CR1 antigenic sites expressed on erythrocytes from both patients was much lower than that observed in a normal population and in the lowest range of the decreased numbers found in patients with SLE. The occurrence of anti-CR1 antibodies in patients with SLE could provide an acquired mechanism for decreased expression of CR1 through antigenic modulation of the receptor on precursor cells and/or alter the function of cells of the immune system bearing C3b receptors.

Animals↗