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PubMed1986

Alveolar macrophage stimulation of T-cell proliferation in autologous mixed lymphocyte reactions. Role of HLA-DR antigens.

Alveolar macrophages act as accessory cells in lymphocyte response to mitogens or alloantigens. Because the autologous mixed lymphocyte reaction (MLR), in which HLA-DR-positive non-T cells stimulate the proliferation of autologous T lymphocytes, represents a good model to study macrophage-T cell interaction, we examined and compared the ability of human alveolar macrophages and peripheral blood-derived monocytes to induce T-cell proliferation in autologous MLR. Maximal T lymphocyte proliferation was observed in both alveolar-macrophage- and blood-monocyte-stimulated autologous MLR at a T cell to alveolar macrophage or blood monocyte ratio of 4:1, but the ability to stimulate T-cell proliferation was lower for alveolar macrophages than for blood monocytes (p less than 0.01). Because HLA-DR antigens modulate monocyte-T cell interaction, we quantified the proportions of HLA-DR-positive cells in alveolar macrophage and blood monocyte suspensions and determined the inhibitory effects on T-cell proliferation of masking HLA-DR antigens on stimulator cells with monoclonal antibodies. The proportions of HLA-DR-positive cells were higher in alveolar macrophage than in blood suspensions (p less than 0.01); interestingly, however, the preincubation of the stimulator cells with anti-HLA-DR monoclonal antibodies inhibited to a similar extent both alveolar-macrophage- and blood-monocyte-stimulated autologous MLR (p greater than 0.2). These studies indicate that alveolar macrophages are less effective than blood monocytes are as stimulator cells in autologous MLR and that, although the masking of HLA-DR molecules results in inhibition of autologous MLR, T-cell proliferation is not dependent on the numbers of stimulator cells bearing HLA-DR antigens. The autologous MLR may represent a good model to study the functions of alveolar macrophages during their interaction with autologous T cells in health and disease.

Adult↗

PubMed1983

Definition of antigenic heterogeneity and modulation among human mammary carcinoma cell populations using monoclonal antibodies to tumor-associated antigens.

Murine monoclonal antibodies, prepared against human metastatic mammary tumor cells, were used to demonstrate differential expression of several tumor-associated antigens (TAAs) among various mammary carcinomas and within a given tumor mass. Using the immunoperoxidase technique on serial sections of 39 human primary mammary carcinomas, a spectrum of antigenic phenotypes of TAAs was observed: 13% of the tumors reacted with all of a panel of four monoclonal antibodies; while 10% of the mammary tumors scored negative with all four antibodies. The remaining 30 tumors could be divided into several additional groups based on their differential reactivity with some, but not all, of the monoclonal antibodies. Furthermore, variation among mammary carcinomas was also observed in the cellular localization of antigens. Antigenic phenotypic diversity of mammary tumor cell populations within a given tumor mass was also observed; this was noted with respect to (a) antigenic expression in one area of a tumor mass and not another and (b) a "patchwork" effect in which antigens were expressed on cells immediately adjacent to cells which scored negative. Antigenic phenotypic diversity was also observed in established mammary tumor cell lines grown in vitro. A differential loss of some cell surface TAAs was observed as a function of continued cell passage; consistent with this finding, MCF-7 mammary tumor cell lines obtained from four sources could be differentiated from each other by their pattern of cell surface TAA expression. Single-cell clones derived from the MCF-7 mammary tumor cell line exhibited at least four distinct antigenic phenotypes; a change in cell surface phenotype of some of the clones was seen during subsequent passage. This definition of phenotypic variation and modulation of TAA expression among, and within, human mammary carcinomas has implications towards both the design and the outcome of studies involving the in situ immunodetection and therapy of breast cancer.

Adenocarcinoma↗

PubMed1987

Down regulation of human monocyte differentiation antigens by interferon gamma.

The role of IFN-gamma in the activation and differentiation of human peripheral blood monocytes was investigated. Recombinant IFN-gamma induced a decrease in the expression of monocyte differentiation antigens (Mo2 and 63D3) and, to a lesser extent, the C3bi receptor. Conversely, class II histocompatibility antigen expression increased on monocytes exposed to IFN-gamma. The antigen modulating effect of IFN-gamma was maximal on freshly isolated monocytes, with diminished potency if added to monocytes that had been cultivated in vitro for 1 to 3 days. Experiments to determine the fate of the down-regulated antigens on interferon-treated cells failed to demonstrate intracellular antigen due to internalization. We suggest that Mo2 and 63D3 may be considered "inverse" activation antigens; i.e., their expression is decreased in monocytes activated by interferon.

Antibodies, Monoclonal↗

PubMed2005

CD3-specific antibodies restore self-tolerance: mechanisms and clinical applications.

The treatment of autoimmune diseases using conventional chemical immunosuppressants has short-term effects, imposing the need for chronic treatment with its risks of over-immunosuppression. CD3-specific monoclonal antibodies can restore self-tolerance in a durable fashion after a single short-term treatment, as demonstrated in several experimental models and clinically in recent-onset insulin-dependent diabetes. Disease remission involves first an immediate 'freezing' of the autoimmune response, which is linked to CD3-specific antibody-induced antigenic modulation of CD3-TCR complex at the T lymphocyte surface, followed by 'resetting' of TGF-beta-dependent T-cell mediated immunoregulation. Tolerance induction is demonstrated by persisting disease protection in spite of recovery of full immunocompetence to unrelated antigens.

Animals↗

PubMed1982

Altered expression of Plasmodium knowlesi variant antigen on the erythrocyte membrane in splenectomized rhesus monkeys.

Variant antigens are present on the surface of Plasmodium knowlesi malaria-infected erythrocytes as detected by the schizont-infected cell agglutination (SICA) assay. We found that parasitized erythrocytes passaged in splenectomized monkeys did not agglutinate with immune sera. On the first passage from intact to splenectomized monkeys, the SICA titers decreased 4- to 16-fold; after the second and subsequent passages in splenectomized monkeys, the infected cells became nonagglutinable to all sera tested, including sera from animals infected with the nonagglutinating parasites. This loss of agglutinability could have resulted from selection of a genetically distinct subpopulation of the original parasites or the ability of the original parasites to alter their phenotypic expression. We have designated the new nonagglutinable phenotype, SICA [-], and the agglutinable phenotype, SICA [+]. The loss of agglutinability indicates that the variant antigen normally expressed on the erythrocyte membrane of infected cells is altered or absent. Because SICA [-] parasites developed in the absence of the spleen, the major organ of host defense against malaria, then this organ may in some manner influence or modulate antigenic expression in P. knowlesi and possibly other malaria parasites.

Animals↗

PubMed2002

Cellular responses to murine CD40 in a mouse B cell line may be TRAF dependent or independent.

Engagement of CD40 by its ligand induces IKK and mitogen-activated protein kinase (MAPK) phosphorylation and transcriptional activation, leading to activation and differentiation of B cells. These events are most likely transduced by adaptor molecules that are recruited to the CD40 cytoplasmic domain, called TNF receptor-associated factors (TRAF). We have engineered a chimeric CD40 molecule using the human extracellular sequence and the murine cytoplasmic domain to assess the contribution that specific TRAF binding domains provide to the cytoplasmic signaling functions of CD40. The data presented here show that the shared binding site for TRAF2 and TRAF3 accounts for receptor internalization, and the majority of signaling through CD40, but is redundant with the TRAF6 binding site for activation of p38 and NFkappaB signaling pathways. Disruption of the TRAF2/3 binding site results in a delayed and diminished kinase pathway induction, but complete preclusion of all signals requires the disruption of more than the two known TRAF binding sites. The specific TRAF dependency of CD40-induced growth arrest, TNF-alpha production, and phosphorylation of signaling molecules are shown, while p38 MAPK activation and cell surface antigen modulation suggest TRAF independent CD40 signaling in B cells.

Animals↗

PubMed1998

Ratio of IgG:IgM antibodies to sialyl Lewis(x) and GM3 correlates with tumor growth after immunization with melanoma-cell vaccine with different adjuvants in mice.

Human melanoma cells (from biopsies and culture) express sialyl-Lewis(x) and sialyl Lewis(a), the ligands for ECAM. These ligands may facilitate tumor progression and metastasis in human cancers. To test whether the antibodies to these ligands inhibit tumor progression, IgG and IgM responses to sLe(x) and sLe(a) were induced in C57BL/6j mice (n = 76) by immunization with human melanoma cells, with or without adjuvants (BCG, MPL, KLH). Control mice were treated with saline or BCG. Tumor growth and antigen expression were monitored after challenge with B16 mouse melanoma cells expressing sLe(x), sLe(a) and the ganglioside GM3. Tumor growth was reduced in mice immunized with BCG alone or cells with BCG or MPL, while tumors in mice receiving cells without adjuvants grew larger than in the control. Augmentation of IgM titers to sLe(x) and GM3 after immunization with BCG, or with cells with BCG or MPL correlated with retarded tumor growth, while increased IgG titers to sLe(x) significantly correlated with aggressive tumor growth in mice immunized with cells without adjuvants. SLe(x), sLe(a) and GM3 were expressed in tumors from mice treated with saline or BCG. SLe(x) expression, in particular, was lost in tumors growing in mice immunized with cells with or without adjuvants. Anti-sLe(x) antibodies may promote or prevent tumor growth by antigenic modulation or by cytotoxic killing of tumor cells. Since early anti-sLe(x) IgM correlated with tumor regression, in contrast to anti-sLe(x) IgG, it may serve as a potential early endpoint for the effectiveness of melanoma vaccines expressing the antigens.

Animals↗

PubMed1999

Intracellular traffic to compartments for MHC class II peptide loading: signals for endosomal and polarized sorting.

In this review we focus on the traffic of MHC class II and endocytosed antigens to intracellular compartments where antigenic peptides are loaded. We also discuss briefly the nature of the peptide loading compartment and the sorting signals known to direct antigen receptors and MHC class II and associated molecules to this location. MHC class II molecules are expressed on a variety of polarized epithelial and endothelial cells, and polarized cells are thus potentially important for antigen presentation. Here we review some cell biological aspects of polarized sorting of MHC class II and the associated invariant chain and the signals that are involved in the sorting process to the basolateral domain. The molecules involved in sorting and loading of peptide may modulate antigen presentation, and in particular we discuss how invariant chain may change the cellular phenotype and the kinetics of the endosomal pathway.

Amino Acid Motifs↗

PubMed1981

Response of cutaneous T cell lymphoma to therapy with hybridoma monoclonal antibody.

A murine hybridoma monoclonal anti-T-cell antibody was given to a patient with advanced cutaneous T cell lymphoma. The patient tolerated seventeen treatment courses over ten weeks without symptoms of toxicity. Each treatment caused a reduction in circulating T cells which reached a stable level after two weeks of therapy. Antigenic modulation was observed after each treatment but was fully reversed within three to four days; therefore the treatment was given twice weekly. Monoclonal antibody produced a striking clinical response in skin, lymph nodes, and blood but complete remission was not achieved. Since the remaining disease was antigen positive, failure to eradicate all tumour cells was not a result of immunoselection. At no time did the patient show an antimouse immune response.

Aged↗

PubMed1987

Penetration and binding of radiolabeled anti-carcinoembryonic antigen monoclonal antibodies and their antigen binding fragments in human colon multicellular tumor spheroids.

The binding and penetration of two 125I-labeled anti-carcinoembryonic antigen (CEA) monoclonal antibodies (MAb) and their F(ab')2 and Fab fragments were measured in multicellular spheroids of poorly (HT29) and moderately well differentiated (Co112) human colon adenocarcinomas which express different amounts of CEA. Spheroids cultured in vitro model tumor microenvironments where poor vascular supply may modulate antigen expression and accessibility. The two MAb studied, 202 and 35, were shown previously to react with different CEA epitopes and to have high affinities of 1.2 and 5.8 X 10(9) M-1, respectively. MAb 202 has also been shown to cross-react with antigens present on human granulocytes and normal epithelial cells from human lung and pancreas. Specific binding of intact MAb and fragments of both antibodies was demonstrated for both types of human colon carcinoma spheroids compared to mouse colon carcinoma (CL26) and mammary tumor (EMT6/Ro) spheroids. Total binding of MAb and fragments was greater (1.5- to 2.5-fold) after 4 h compared to 1 h of exposure; the amount of binding compared to control IgG1 was 5- to 30-fold greater after 1-h incubation and 15 to 200 times greater after 4 h. This binding was stable as demonstrated by short and long wash experiments at 37 degrees and 4 degrees C. The binding of F(ab')2 and Fab fragments of the anti-CEA MAb 35 to spheroids of human colon Co112 was almost 2-fold greater than that of the intact MAb. However, for MAb 202, the binding of intact MAb and F(ab')2 was greater than that of Fab fragments. In addition the binding of both intact and F(ab')2 fragments of MAb 202 was greater than that obtained with MAb 35. Specific binding of both antibodies to HT29 spheroids, which express less CEA, was decreased for MAb and fragments of both 202 and 35. Autoradiography and immunoperoxidase experiments were performed to determine the penetration of MAb and fragments after incubation with intact spheroids. Comparisons were made with labeled MAb directly applied to frozen sections of spheroids. F(ab')2 and Fab fragments of both antibodies were bound at the surface of intact spheroids and penetrated to eight to ten cells, but the intact MAb were localized mainly at the spheroid surface and the outer one to three cell layers. There was much less binding at the surfaces of HT29 compared to Co112 spheroids. An enzyme immunoassay using MAb 35 and 202 demonstrated that Co112 spheroids produced about 8-fold more CEA/mg of cell protein than did monolayer cultures.(ABSTRACT TRUNCATED AT 400 WORDS)

Antibodies, Monoclonal↗

PubMed1987

HLA antigens in Behçet's disease with refractory ocular attacks.

HLA class I, II, and III antigens were studied in Japanese patients with Behçet's disease with refractory ocular attacks. In addition to the increased frequency of B51, DQw3, especially TA10-negative DQw3, was increased and DQw1 was decreased significantly in this subgroup of Behçet's disease. As for complement markers, C4A Q0 was increased. A rare variant of BF S07 was first observed in Japanese. Although the mechanism for the DQw3 association is obscure, a possible hypothesis is that an immune-response or immune-suppression gene linked to the DQ antigens modulates the disease severity and the efficacy of treatments.

Behcet Syndrome↗

PubMed1997

Flagellin, a major protein present in SDS-PAGE profiles of Sarkosyl-OMP-enriched fractions from Bordetella bronchiseptica Bvg- or modulated Bvg+ strains.

The bvg or vir locus positively regulates the expression of many Bordetella virulence-associated determinants (encoded by vag genes), including cell envelope proteins, in response to environmental stimuli. On the other hand, several genes named vrg genes are negatively controlled by the bvg regulon (Knapp and Mekalanos, 1988). Flagellin is encoded by a vrg gene, which is expressed when the principal virulence factors are eliminated during antigenic modulation or in phase variants (Akerley et al., 1992). We have previously analyzed SDS-PAGE profiles of Sarkosyl-outer membrane protein (OMP)-enriched fractions from B. bronchiseptica Bvg- and modulated Bvg+ strains and reported a major band associated with the avirulent phenotype (Passerini de Rossi et al., 1995). In order to characterize this band we have purified flagellar filaments from Bvg- and modulated Bvg+ strains, and analyzed them by SDS-PAGE. These profiles revealed a single major band of 40 or 45 kDa depending on the strain. The N-terminal amino acid sequence of the putative flagellin expressed by BB7200a was identical over the first 21 residues analyzed to that of the flagellin from the modulated strain BB7865 reported by Akerley et al. (1992). Comparison of the SDS-PAGE profile of flagellar filaments with that of the OMP-enriched fraction of the corresponding strain showed that the flagellum-associated polypeptide had the same electrophoretic mobility as that of the characteristic band of the avirulent phenotype. Furthermore, this band was absent in the OMP-enriched fraction profile from a Bvg- strain subjected to a treatment that removes flagella. Our results indicate that the major protein observed in SDS-PAGE profiles of Sarkosyl-OMP-enriched fractions from B. bronchiseptica Bvg- and modulated Bvg+ strains corresponds to flagellin.

Amino Acid Sequence↗

PubMed1986

Influence of avidity and idiotope recognition on the modulation of surface immunoglobulin on malignant human B cells by rat monoclonal anti-idiotype antibodies.

Immunoglobulin (Ig) was obtained from the tumor cells of patients with B cell malignancies by somatic cell hybridization to mouse-human heteromyeloma cells. The human Ig secreted by one of these hybridomas was used as an immunogen for the production of rat monoclonal antibodies (mAb). A panel of mAb specific for the idiotype (Id) was produced and characterized. Competitive binding studies that made use of [Se]-labeled anti-Id mAb (MAID) demonstrated several distinct yet topographically related Id on the Id-bearing Ig. These antibodies were shown to have avidities ranging from 0.38 to 45.3 X 10(8) l/mol. Additional studies demonstrated varying degrees of antigenic modulation of surface Id in vitro by MAID. The degree of modulation correlates with antibody avidity.

Animals↗

PubMed1993

CD44 is not directly involved in the binding of lymphocytes to cultured high endothelial cells from peripheral lymph nodes.

The Ager assay was adapted to a porcine lymphocyte-rat high endothelial cell (HEC) system. Using this in vitro assay, the role of porcine CD44 in lymphocyte binding to HEC was examined. The results show that the presence of soluble CD44 molecules did not inhibit the binding of porcine lymphocytes to the cultured rat HEC. Treatment of lymphocytes with anti-CD44 monoclonal antibodies (mAb), or with papain, which removes a 45,000 MW peptide from the intact CD44 molecule, did not inhibit the binding. Binding to the rat HEC did not induce modulation of CD44 molecules on the cell surface. Furthermore, modulation of the CD44 molecule by biotinylated anti-CD44 antibody followed by streptavidin-phycoerythrin, which had caused the molecule to cap on the cell surface, did not prevent the cells binding to the HEC. Similarly, cells denuded of CD44 by anti-CD44 antibody retained the capacity to bind to HEC. Moreover, the binding cells were mainly those which had been stripped of CD44 by the antigenic modulation. It is concluded that CD44 is not directly involved in the binding of lymphocytes to the cultured HEC from peripheral lymph nodes (PLN).

Animals↗

PubMed1993

Targeting of an activated T-cell subset using a bispecific antibody-toxin conjugate directed against CD4 and CD26.

We have developed a bispecific antibody that recognizes the CD4 and CD26 antigens simultaneously and that was examined for its ability to target CD4+CD26+T cells. These latter cells constitute the activated component of the CD4+ CD29highCD45RO+ memory T-cell subset that provides help for B-cell Ig synthesis and help for responses against recall antigens. The purified bispecific antibody exhibited an estimated dissociation constant (kd) of 2.4 x 10(-9) mol/L, on comparison with 1.1 x 10(-9) mol/L for anti-CD26, and 1.6 x 10(-10) mol/L for anti-CD4. Surface plasmon resonance was used to show the bifunctional capacity of the antibody. On binding 125I-bispecific antibody to phytohemagglutinin (PHA)-activated T cells, 54.4% of the bound antibody was internalized. This was the result of bispecific binding, because monovalent fragments of anti-CD4 and anti-CD26 were not able to modulate antigen or induce internalization using both a fluorescent assay and an 125I-internalization assay. The ability of the bispecific antibody to be internalized was used to deliver a toxin, blocked ricin, specifically to cells that are CD4+CD26+. The inability of monovalent fragments to be internalized formed the basis for our hypothesis that monovalent binding by the bispecific immunotoxin would not result in internalization. Against resting E+ T cells, the bispecific immunotoxin developed a minimal effect. On preactivating the same cells, using phorbol myristate acetate (PMA)/ionomycin on concanavalin A (ConA) or especially PHA, levels of CD26 were upregulated and the immunotoxin effectively inhibited the ability to provide help for B-cell Ig synthesis while leaving intact the CD4-CD26+ and CD4+CD26- populations; an effect observed both functionally and by phenotype. The bispecific antibody proved to be most effective at inhibiting a heterologous mixed leukocyte reaction. We propose that this reagent may form the basis for the rational design of toxins designed to modulate activated T cells from, or directed against, tissue grafts.

Antibodies, Monoclonal↗

PubMed1996

Differential expression of T cell antigens in normal peripheral blood lymphocytes: a quantitative analysis by flow cytometry.

AIMS: To obtain reference values of the level of expression of T cell antigens on normal lymphocyte subsets in order to disclose differences which could reflect their function or maturation stages, or both. METHODS: Peripheral blood from 15 healthy donors was processed by flow cytometry with triple colour analysis. For each sample phycoerythrin (PE) conjugated CD2, CD4, CD5, CD8, and CD56 monoclonal antibodies were combined with Cy5-R-phycoerythrin (TC) conjugated CD3 and fluorescein isothiocyanate (FITC) conjugated CD7; CD2- and CD7-PE were also combined with CD3-TC and CD4-FITC. Standard microbeads with different capacities to bind mouse immunoglobulins were used to convert the mean fluorescence intensity (MFI) values of the lymphocyte subsets identified by multiparametric flow cytometry into the number of antigen molecules per cell, measured as antibody binding capacity (ABC). RESULTS: CD4+ (helper/inducer) T cells exhibit a higher CD3 antigen expression compared with CD8+ (suppressor/ cytotoxic) T lymphocytes. Within the CD4+ T cells, the CD4+CD7- subset expressed a lower level of CD3 compared with CD4+CD7+ and CD8+CD7+ cells, and higher CD2 and CD5 expression than the main CD3+CD7+ subset. Major differences in antigen expression were also detected between CD3+ T cells and CD3-CD56+ natural killer (NK) cells: NK cells exhibited higher levels of CD7 and CD56 and lower levels of CD2 and CD5 than T cells. Significantly lower CD5 expression was also detected in the small CD5+ B lymphocyte subset compared with T cells. CONCLUSIONS: Quantitative flow cytometry with triple colour analysis may be used to detect antigen modulations in disease states and to increase the accuracy of diagnosis by comparison with findings in normal counterparts.

Adult↗

PubMed1981

Use of monoclonal antibodies as diagnostic and therapeutic reagents in acute lymphoblastic leukemia.

A monoclonal antibody specific for a common acute lymphoblastic leukemia (ALL) antigen has been generated and characterized. This antibody (J-5) is reactive with leukemic cells from most patients with non-T-cell ALL and some patients with chronic myelocytic leukemia in blast crisis. J-5 antibody is not reactive with leukemic cells from patients with either T-cell ALL, chronic lymphocytic leukemia, acute myeloblastic leukemia, or stable-phase chronic myelocytic leukemia. In addition to diagnostic applications, anti-common ALL antigen monoclonal antibody has been used to study the effect of specific serotherapy in the treatment of ALL. In the first patient with ALL treated with J-5 antibody, a 90% reduction in circulating lymphoblasts occurred within 1 hr of starting antibody infusion. Despite continued serotherapy, however, lymphoblasts persisted in peripheral blood and bone marrow. Analysis of cell surface markers during serotherapy suggested that resistance to antibody-mediated lysis in vivo may have been due to antigenic modulation of leukemic cells in response to J-5 monoclonal antibody.

Acute Disease↗

PubMed2000

Heterogeneity found in the cagA gene of Helicobacter pylori from Japanese and non-Japanese isolates.

We analyzed cagA genes from Helicobacter pylori strains isolated from Japanese and non-Japanese individuals for differences that could be associated with variations in virulence. The cagA genes from Japanese isolates (n = 12) and non-Japanese American Type Culture Collection (ATCC) strains (n = 4) were sequenced and compared with three published sequences. Phylogenetic analysis resolved two distinct clusters with a genetic distance of 0.1602. Similarity plot analysis of the amino acid sequences identified two highly variable regions of which each was unique to the Japanese and non-Japanese isolates, respectively. Furthermore, nucleic acid sequence analysis revealed that the multiple repeated sequences present in cagA may have been generated by homologous recombination and/or misaligned replication to promote variation in the cagA gene products. Our data indicate that alleic variations in the H. pylori genome exist between isolates from Japanese and non-Japanese subjects and that distinct H. pylori populations may be circulating in different geographical regions. Phylogenetic analysis did not reveal any association of a specific CagA type with a particular disease. Although extensive alterations were found in the cagA gene, none of the isolates contained a prematurely terminated CagA protein. The cagA gene may be advantageous to H. pylori, possibly by aiding its escape from host immune recognition by antigen modulation. Thus, this ability to elude the host immune system may contribute to an increased risk for gastric disease.

Algorithms↗