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PubMed1983

Antigenic modulation of pan-T-cell and T-cell subset-specific markers.

The time course and extent of antigenic modulation induced by monoclonal antibodies OKT3, OKT4, OKT8, BE2, and BE3 was investigated. OKT3-induced antigenic modulation could be detected as early as after 3-hr incubation with the antibody and almost total removal of the OKT3-reactive antigen was seen by 42 hr. This modulation did not decrease the expression of T-cell antigens detected by OKT4 and OKT8. OKT3-modulated cells reexpressed the antigen after 42-hr incubation in OKT3-free media. BE3 (homologue of OKT1) also caused modulation of its surface antigen after 24-hr incubation. In contrast, OKT4 did not induce modulation even after 42-hr incubation with high concentrations of OKT4 antibody. Approximately 43% of the OKT8-reactive lymphocytes could be induced to modulate this antigen. A tumor-associated antigen present on neoplastic lymphocytes from patients with cutaneous T-cell lymphoma, recognized by monoclonal antibody BE2, also was not induced to modulate. These results suggest that antigenic modulation and the fate of the modulated antibody may be of importance to immunotherapeutic applications of these reagents.

Animals↗
PubMed1992

Antigenic modulation of metastatic breast and ovary carcinoma cells by intracavitary injection of IFN-alpha.

Antigenic modulation of major histocompatibility and tumour associated antigens was observed in neoplastic cells obtained from patients with pleural and abdominal effusions of breast and ovary carcinomas following a single intracavitary dose of 18 x 10(6) U recombinant IFN-alpha. This regimen resulted in antigenic modulation in seven out of 11 tested cases, suggesting a potential, although limited, responsiveness of at least a fraction of breast and ovary carcinoma cells to in situ biomodification with IFN-alpha.

Antibodies, Monoclonal↗
PubMed1981

Antigenic modulation of lymphocytic surface immunoglobulin yielding resistance to complement-mediated lysis. II. Relationship to redistribution of the antigen.

Experiments were carried out on guinea-pig L2C leukaemic lymphocytes to investigate the mechanism of antigenic modulation of their surface immunoglobulin (Ig) defined as the conferring by anti-Ig of resistance to lysis by anti-Ig plus complement. The phenomenon reflects, and is probably a consequence of, redistribution of the Ig molecules by bivalent antibody. Fab fragments of the antibody were completely ineffective. Parallel studies by indirect immunofluorescence of the movement of th surface antigen-antibody complexes revealed that modulation for syngeneic complement was apparent when the complexes were minimally aggregated: capping and extensive endocytosis were not necessary. Modulation for xenogeneic (rabbit) complement required more extensive movement but was still appreciable while complexes persisted on the surface. Sodium azide at 10 mM, which inhibits antibody-induced redistribution of surface molecules, diminished modulation. In experiments omitting pre-incubation with antibody alone, the presence of azide during incubations with anti-Ig plus syngeneic complement increased lysis from a low and variable to a consistently high level; there was no effect on the already high level of lysis occurring with the non-modulating anti-Ia plus syngeneic complement. This effect of azide provides further evidence that antigenic modulation can be a major factor determining a cell's survival when it is confronted simultaneously by antibody and complement.

Animals↗
PubMed1980

Antigenic modulation and down regulation-their similarities suggest they may have a common origin.

Antigenic modulation, the antibody-induced disappearance of membrane-associated determinants of neoplastic cells, has a fundamental similarity to the down regulation of receptors for hormones and other ligands affecting the physiology of various nonneoplastic cell types. After hormone stimulation, cells previously responsive become refractory to further stimulation. Diminution in responsiveness correlates with a quantitative reduction in the numbers of specific complementary hormone receptors present. Murine leukemia cells, as one example "escape" antibody-mediated destruction through the mechanism of antigenic modulation. Resistance of the cells correlates with a reduction of the numbers of specific antigens present. In both down regulation and modulation, continued cellular metabolism in the absence of ligand leads to a re-expression of the hormone receptor/membrane antigen involved. It is postulated that the two phenomena have evolved from similar underlying cellular mechanisms.

Animals↗
PubMed1989

Antigenic modulation induced by four monoclonal antibodies adsorbed on gold particles (specificity anti-CD4, anti-CD5, anti-CD7, and anti-150-kDa antigen): relationship between modulation and cytotoxic activity of immunotoxins.

The present study concerns the antibody-induced antigenic modulation of CD4, CD5, CD7, and 150-kDa antigens present on cells of the CCRF-CEM human T line. The immunogold electron microscopy method was used, and it was found that the entry routes associated with the various antigen-antibody complexes were different. Thus, the anti-CD7 monoclonal antibody (MoAb) was frequently internalized via the coated structures of the cell membrane, whereas anti-CD5 MoAb was rarely internalized via those structures and anti-CD4 and anti-150-kDa antigens never used this route. The delay required for 50% internalization of the labeled MoAb-receptor complexes was 30 min. 1 h, 2 h, and 9 h for anti-CD7, anti-CD5, anti-CD4, and anti-150-kDa antigen MoAbs, respectively. A shedding of complexes from the cell surface was never observed. The internalized labeled MoAbs were sequentially transferred into endocytic vacuoles, then into fine anastomosed tubulovesicular structures, and then into lysosomes. However, the anti-150-kDa antigen MoAb proceeded directly from endocytic vacuoles to lysosomes. Among the four MoAbs studied, anti-CD7 MoAb was the most abundant in the endosomal compartment (up to 34% of internalized particles) before it proceeded to the lysosomes. The overall valency of the anti-CD7 MoAb-labeled beads (from 3.8 to 14 MoAb molecules per bead) did not modify the intracellular routing. These results suggested that the subcellular fate of MoAbs was an intrinsic property of each MoAb-antigen complex. More importantly, the comparison between the MoAb-induced modulation and the cytotoxic level of the immunotoxin built with the same MoAb suggested that receptor-mediated endocytosis via coated pits, along with an abundant occurrence of the antigen-MoAb complex within the endosomal complex, could correspond to the best set of conditions for the transfer of the toxin moiety of the immunotoxin to the cytosol.

Antibodies, Monoclonal↗
PubMed1988

Metabolic stability and antigenic modulation of nicotinic acetylcholine receptors on bovine adrenal chromaffin cells.

Bovine adrenal chromaffin cells have nicotinic acetylcholine receptors (AChRs) that are activated by the splanchnic nerve, resulting in release of catecholamines from the cells. Examination of the AChRs can provide information about the regulation and turnover of synaptic components on neurons and endocrine cells. Previous studies have shown that mAb 35 recognizes the AChR on the cells. Here we show that mAb 35 can remove AChRs from the surface of the cells by antigenic modulation, and that the modulation can be used together with other methods to examine the stability and turnover of the receptors in the plasma membrane. Unexpectedly, the results indicate a disparity between the rate at which AChRs reappear on the cells and the rate at which the ACh response recovers after preexisting AChRs have been removed. Exposure of bovine adrenal chromaffin cultures to mAb 35 results in a parallel decrease in the magnitude of the nicotinic response and the number of AChRs on the cells. The decrease depends on the concentration and divalence of mAb 35, and on the time and temperature of the incubation. The antibody induces receptor aggregation in the plasma membrane under conditions where receptor loss subsequently occurs. After binding to receptor, mAb 35 appears to be internalized, degraded, and released from the cells through a temperature sensitive pathway that requires lysosomal function. These features are characteristic of antigenic modulation. Appearance of new AChRs on the cells either after antigenic modulation or after blockade of existing AChRs with monovalent antibody fragments occurs at a rate equivalent to 3% of the receptors present on control cells per hour. The rate of receptor loss from the cells was measured in the presence of either tunicamycin or puromycin to block appearance of new receptors. Both conditions indicated a receptor half-life of approximately 24 h and a rate of loss of approximately 3%/h. The finding that the rate of receptor loss equaled the rate of receptor appearance was consistent with the observation that the total number of AChRs on untreated cells did not increase with time. In the presence of tunicamycin, loss of receptor-mediated response to nicotine also occurred with a half-time of 24 h. Paradoxically, the rate of recovery of the nicotinic response, determined using two procedures, was more than twice as great as the rate at which new AChRs appeared on the cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenal Glands↗
PubMed1984

Induction of in vitro and in vivo antigenic modulation by the anti-human T-cell monoclonal antibody T101.

Because of its implications for the therapeutic application of monoclonal antibodies, we have studied antigenic modulation in vitro and in vivo in patients receiving T101 monoclonal antibody. Incubation of normal peripheral blood T-cells, chronic lymphocytic leukemia cells, and cutaneous T-cell lymphoma cells with an excess of T101 at 37 degrees induced modulation of the T65 antigen. When assayed by indirect immunofluorescence, a change in cellular reactivity with T101 was seen after 1 hr. After 24 hr, normal T-cells showed a 94 +/- 4% (S.D.) decrease in fluorescence, compared to an 82 +/- 6% decrease for chronic lymphocytic leukemia cells and a 56 +/- 4% decrease for cutaneous T-cell lymphoma cells. When T101 was removed from the culture, the cells reexpressed T65. Modulation was inhibited by cold temperatures, suggesting that it is energy dependent. Patients with chronic lymphocytic leukemia, cutaneous T-cell lymphoma, or T-cell lymphoma have received 24-hr infusions of 3 to 500 mg T101 in therapeutic trials. After infusion, in vivo binding of T101 was observed in 39 of 43 treatments not associated with endogenous host anti-T101 antibodies. T65-target cells were seen in all 39 treatments associated with in vivo bound T101, suggesting that modulation had occurred. When cultured in vitro for 24 hr, these cells reexpressed T65. In vivo, reexpression of T65 occurred following disappearance of the serum T101 titer. The extent and duration of in vivo modulation were related to both the T101 dose and the tumor burden. These data suggest that the rapid rate of antigenic modulation may prevent potential target cell destruction by antibody-mediated cytotoxicity. However, if the process of modulation involves internalization of the antibody:antigen complex, it would be an advantage for the use of cytotoxic immunoconjugates.

Antibodies, Monoclonal↗
PubMed1981

Antigenic modulation of lymphocytic surface immunoglobulin yielding resistance to complement-mediated lysis. I. Characterization with syngeneic and xenogeneic complements.

Following previous authors, the term antigenic modulation is used to describe the induction, by antibody, of resistance to lysis by antibody plus complement. A report is given of the rapid antigenic modulation in vitro of surface immunoglobulin (Ig) on guinea-pig L2C leukaemic lymphocytes: incubation of the cells for 2 min or longer at 37 degrees with anti-Ig diminished or removed completely the lysis occurring during subsequent incubation with anti-Ig plus complement. The modulation was effective for both xenogeneic (rabbit) and syngeneic (guinea-pig strain 2) complements, but more rapid for the latter. It appeared simply to require the action of antibody on a metabolically active cell: no requirement could be demonstrated for any serum component other than antibody, and there was a need to raise the temperature to 37 degrees after attachment of the antibody. There was molecular specificity inasmuch as modulation with anti-Ig failed to confer any resistance to lysis by another antibody (anti-Ia) plus complement.

Animals↗
PubMed1993

Bacterial expression of a single-chain Fv fragment which efficiently protects the acetylcholine receptor against antigenic modulation caused by myasthenic antibodies.

Monoclonal antibodies (mAb) against the main immunogenic region (MIR) of the acetylcholine receptor (AChR) are very potent in inducing antigenic modulation of the AChR in animals and in muscle cell cultures. A recombinant antibody fragment of the rat anti-MIR mAb198 was cloned by polymerase chain reaction and expressed as soluble single-chain Fv fragment (scFv198) in E. coli and affinity purified. DNA sequencing was used to define the VH (IB) and VL (K2) chain gene usage. scFv198 was found immunologically and biologically active. Its binding affinity for the Torpedo AChR (KD = 2 +/- 0.6 nM) was very similar with that of the intact mAb198 (KD = 1.8 +/- 0.6 nM) while for the human AChR (KD = 80.7 +/- 16.6 nM) it was about four times lower than that of the intact mAb198 (KD = 21.6 +/- 6.6 nM). This fragment was capable of efficiently protecting the AChR in human cell cultures, against antigenic modulation caused by the intact mAb198 or by the antibodies from a myasthenic patient. The produced scFv198 fragment is, therefore, potentially useful in therapeutic applications for myasthenia gravis after appropriate genetic manipulations.

Amino Acid Sequence↗
PubMed2001

Experimental antigen modulation of blastocysts for mimicing dormant and invasive micrometastases.

The mouse preimplantation period can be prolonged experimentally by a delayed implantation, and this will keep the blastocyst in an inactive state. The dormancy can be interrupted by an oestrogen injection, which will make the blastocyst invasive. Thus the blastocyst mimics both dormant and invasive micrometastasis. Considering the similarities between blastocysts and micrometastases in cellular activation, we have developed methods for examining antigen modulations using the blastocyst as a model. Evaluating the total amount of antibody in the blastocyst and also the trophoblast antigen synthesis, shedding, and endocytosis, we found that dormant cells exposed to a surface-specific antibody kept the immune complexes on the cell surface for a longer time than did the invasive cells. The rate of internalization of immune complexes was low in both dormant and invasive cells, but since the shedding activity was less active in the dormant cells they contained more antibodies totally than did the invasive ones under the same conditions. When exposing the cells to an anti-cytoplamic antibody or to non-specific antibodies, the amount of antibodies in the cytoplasm of invasive cells was higher than in dormant cells. The methods used for examining the antigen modulation by the blastocyst should be useful also for studying the handling of antibodies by micrometastases.

Animals↗
PubMedDate not supplied

Antigenic modulation and receptor loss in experimental autoimmune myasthenia gravis.

Immunization of groups of rats with 0.1- 100 microgram of acetylcholine receptor (AChR) purified from the electric organ of Torpedo californica resulted in dose-dependent (1) loss of acetylcholine receptor from the rats' muscles, (2) binding of antibodies to many of the receptors remaining in muscle and (3) production of antibodies in serum capable of cross-reacting with receptor solubilized from rat muscle. Addition of antibodies from rats immunized with electric organ acetylcholine receptors to muscle cells in culture caused loss of receptor by accelerating the rate of receptor degradation. Monovalent antibody fragments did not accelerate degradation unless antiantibody was added to cross-link the monovalent antibody fragments bound to receptors. This indicates that cross-linking of receptors by antibody molecules triggers accelerated receptor degradation, leading to receptor loss. The rate of increase in receptor destruction due to antigenic modulation observed in vitro appears sufficient to account for the extent of receptor loss observed in vivo. Endocytosis of antibody cross-linked receptors may be a rate-limiting step common to antigenic modulation in vitro and in vivo.

Antigen-Antibody Reactions↗
PubMed1984

Antigenic modulation of junctional acetylcholine receptor is not sufficient to account for the development of myasthenia gravis in receptor immunized mice.

Myasthenia gravis (MG) is a disease thought to result from an autoimmune response against the nicotinic acetylcholine receptor of the neuromuscular junction. Although there is little doubt that the muscular weakness characteristic of MG can be attributed to an antibody-mediated reduction in the density of AChR, the mechanism responsible for this reduction remains uncertain. In the present studies we have used a mouse model of MG, termed experimental myasthenia gravis (EMG), to test the possibility that antigenic modulation of AChR may be the principle mechanism whereby this reduction in AChR density is achieved. We found that immunization of mice with AChR, on average, leads to a twofold increase in the rate of junctional AChR degradation. Because this effect occurred to the same extent in mice that developed severe paralysis and in those that gave no indication of muscular weakness, the role of antigenic modulation as a major pathologic mechanism in MG is questioned.

Animals↗
PubMed1986

Antigenic modulation by anti-CD5 immunotoxins.

We evaluated the modulation of T101 immunotoxins (IT) and free T101 antibody from the surface of normal and leukemic cells to determine whether the presence of toxin on antibody affected antigenic modulation. Reagents were made by conjugating T101, which binds to the T cell antigen CD5, to either intact ricin or purified ricin A chain. We found that T101-A chain modulated CD5 more efficiently than T101-ricin, which modulated CD5 more efficiently than T101 alone. Kinetic studies showed that maximal modulation of IT was reached within 3 hr. When toxicity of the reagents was tested in protein synthesis inhibition assays, T101-ricin in the presence of lactose inhibited 99% of the protein synthesis of CEM cells. T101-A chain was less toxic, inhibiting protein synthesis only 23 to 43%. The addition of the potentiating agent monensin nearly doubled the toxicity of T101-A chain, but did not affect T101-A chain modulation. To determine the fate of bound IT, T101 and T101-ricin were labeled with 125I. Cells were incubated under modulating conditions in the presence of radiolabeled reagents. T101 and T101-ricin were internalized into CEM cells. In contrast, T101, but not T101-ricin, appeared to be shed from peripheral blood mononuclear cells. Our findings show clearly that: 1) the presence of toxin on antibody does not inhibit--and may actually enhance--modulation; 2) T101-IT are internalized, not shed from the cell surface; 3) the lack of toxicity of T101-A chain is not attributed to inability to modulate; 4) there is no correlation between enhancement of T101-A chain toxicity by monensin and antigenic modulation by A chain reagents; and 5) modulation, which is undesirable in monoclonal antibody therapy, may be advantageous in the therapeutic use of IT.

Adjuvants, Immunologic↗
PubMed1993

Exploiting the lacZ reporter gene for quantitative analysis of disseminated tumor growth within the brain: use of the lacZ gene product as a tumor antigen, for evaluation of antigenic modulation, and to facilitate image analysis of tumor growth in situ.

We extend use of the lacZ reporter gene for tumor biology. Intracerebral growth of 9L/lacZ, a gliosarcoma cell line that stably expresses lacZ, was evaluated in syngeneic rats. The reporter gene product, Escherichia coli-derived beta-galactosidase (beta-gal), was detected histochemically on tissue sections. This permits visualization of disseminated tumor and, as shown here, facilitates image analysis. We show that the beta-gal marker protein itself can serve as a tumor antigen in appropriate contexts. Quantitative image analysis of tumor areas is used to show that immunization with beta-gal protects against tumor growth. Abnormal beta-gal- areas are easily detected, facilitating study of antigenic modulation. The tumor studied did not escape through this mechanism. All abnormal beta-gal- areas examined were shown to reflect accumulation of inflammatory or reactive cells, not tumor. Taken together, these findings show several ways in which the lacZ reporter gene can be exploited to facilitate quantitative analysis of disseminated tumor growth within the brain. They draw attention to the growing appreciation that tumor antigens need not be cell surface molecules.

Animals↗
PubMedDate not supplied

Evidentiation of paramyosin (Sm-97) as a modulating antigen on granulomatous hypersensitivity to Schistosoma mansoni eggs.

A Schistosoma mansoni adult worm anionic fraction (PIII) has previously been shown to protect mice against challenge infection and to reduce pulmonary and hepatic granulomatous hypersensitivity. Serum from PIII-immunized rabbit was used to screen a lambda gt11 cDNA library from S. mansoni adult worm in order to identify antigens capable of modulating granulomatous hypersensitivity. We obtained four clones with 400 (Sm-III.11), 900 (Sm-III.16), 1100 (Sm-III.10) and 1300 (Sm-III.12) bp of length. All clone-specific antibodies were able to recognize most of the PIII components. The sequence analysis showed that these clones presented high homology with S. mansoni paramyosin (Sm-97). These findings ascribe a new function to this antigen with an important role in modulation of granulomatous hypersensitivity to S. mansoni eggs.

Animals↗
PubMed1988

Mathematical modeling for antibody therapy in the setting of antigenic modulation.

The in vivo efficacy of passive monoclonal antibody therapy is limited in certain systems by the process of antigenic modulation. We describe a compartmental model which addresses the kinetics of in vivo cell binding of murine monoclonal antibody T101, modulation of the T65 target antigen, serum levels of T101, and elimination of target cells. Observed data compare favorably to that predicted by the model. The model suggests that there is no rationale for administering T101 as a prolonged, continuous infusion for passive antibody therapy.

Antibodies, Monoclonal↗