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Biomedical subjects

W H Fridman

Publications and source records attributed to W H Fridman.

At least 109 records · Page 6Linked to original sources
PubMed1996

Selective in vivo recruitment of the phosphatidylinositol phosphatase SHIP by phosphorylated Fc gammaRIIB during negative regulation of IgE-dependent mouse mast cell activation.

We demonstrated previously that the low-affinity IgG receptors Fc gammaRIIB, which are coexpressed with the high-affinity IgE receptors Fc epsilonRI in mouse mast cells, can inhibit IgE-induced release of inflammatory mediators and cytokines by these cells. Inhibition was found to require the coaggregation of the two receptors and to depend on the presence of a tyrosine-based inhibition motif (ITIM) in the intracytoplasmic domain of Fc gammaRIIB. We report here that the coaggregation with Fc gammaRIIB does not prevent Fc epsilonRI from triggering activation signals in BMMC and induces the tyrosine phosphorylation of Fc gammaRIIB. Phosphorylated ITIM peptides bound in vitro to three SH2 domain-containing phosphatases present in BMMC lysates: the phosphotyrosine phosphatases SHP-1 and SHP-2. and the inositolphosphate phosphatase SHIP. Using BMMC generated from the SHP-1-deficient motheaten mice, SHP-1 was found to be dispensable for inhibition of mast cell activation. When analyzed for in vivo association, SHIP coprecipitated with phosphorylated Fc gammaRIIB, whereas SHP-1 or SHP-2 did not. These observations altogether indicate that Fc epsilonRI actively participates in its own regulation and that the mechanisms by which Fc gammaRIIB inhibit cell activation might be different in mast cells and in B-cells.

Animals↗
PubMed1996

Soluble CD16 (sCD16), a marker of malignancy in individuals with monoclonal gammopathy of undetermined significance (MGUS).

There are no well-defined host markers to determine which patients with a diagnosis of monoclonal gammopathy of undetermined significance (MGUS) will progress to multiple myeloma (MM). In this preliminary study we measured plasmatic soluble Fe gamma receptor type III (sFe gamma RIII or sCD16) in 54 individuals with MGUS. 35 patients with multiple myeloma (MM) and 29 healthy controls. We confirmed, through receiver operating characteristic (ROC) curve analysis, that a low level of sCD16 discriminates MM patients from controls. Indeed, for a sCD16 value of 1.3 micrograms/ml, the sensitivity, as well as the specificity, of this discrimination were both equal to 83%, i.e. 83% of MM patients had a plasmatic sCD16 value < 1.3 micrograms/ml compared with only 17% of controls. Moreover, ROC curve analysis showed that a low sCD16 level also identifies among MGUS patients a subgroup of patients who rapidly progress towards multiple myeloma: in this comparison, for a sCD16 level of 1.3 micrograms/ml. sensitivity and specificity were 70% and 79% respectively. Therefore a low sCD16 level in MGUS indicated a high likelihood of rapid evolution of MM. In contrast to sCD16, soluble IL-6R did not appear to be discriminant in this study.

Adult↗
PubMed1996

Predictors of clinical response to interleukin-2--based immunotherapy in melanoma patients: a French multiinstitutional study.

PURPOSE: Various parameters have been reported to be correlated with response to interleukin-2 (IL-2) therapy. A multiinstitutional study was performed to assess by multivariate analysis the predictive value of known clinical and biologic melanoma prognostic markers recorded before the onset of IL-2 therapy on the likelihood of objective clinical response. PATIENTS AND METHODS: Serum C-reactive protein (CRP), IL-6, and lactate dehydrogenase (LDH) levels were measured in 81 metastatic melanoma patients included in different IL-2-based regimens before the starting of IL-2-therapy. Clinically defined prognostic groups, i.e., patients with superficial or visceral metastases, were also analyzed for response correlates. Patients were evaluated for response to treatment 4 to 6 weeks after completion of one course of therapy. RESULTS: On univariate analysis, the pretreatment values of CRP (P = .001), IL-6 (P = .007), and LDH (P = .02) and site of metastases (P = .0004) were correlated with clinical response. However, only CRP (P < .007) and clinically defined group (P < .004) were independent predictors on multifactorial analysis. Indeed, when adjusted to CRP, IL-6 tended to improve patient selection, but did not reach statistical significance (P = .07). Furthermore, using multivariate survival analysis based on the Cox proportional hazards model, only CRP was found to be an independent prognostic factor for survival (P < .0001). CONCLUSION: In this study, patients with high serum levels of CRP and/or visceral organ involvement before therapy were unlikely to respond to IL-2 therapy. Therefore, clinical classification based on the site of metastases and serum CRP determination before the start of IL-2 therapy may help to improve selection of melanoma patients who may benefit from IL-2 and could prevent unnecessary morbidity.

Adult↗
PubMed1995

A transforming growth factor beta-like immunosuppressive factor in immunoglobulin G-binding factor.

Immunoglobulin G-binding factors (IgG-BF), which are produced by cells of the immune system, inhibit antibody production. In this paper, we show that transforming growth factor-beta (TGF-beta) suppresses secondary in vitro anti-sheep red blood cell responses of mouse splenocytes and lipopolysaccharide- or anti-IgM-stimulated mouse B cell responses in a way similar to, and with the same kinetics as, rodent IgG-BF. Moreover, the immunosuppressive activity of IgG-BF was totally neutralized by polyclonal and monoclonal anti-TGF-beta antibodies and it eluted with TGF-beta by gel exclusion chromatography, suggesting that a TGF-beta-like immunosuppressive factor is present in IgG-BF. We also show that TGF-beta behaves as an IgG-BF since it binds to insolubilized IgG, but not to insolubilized F(ab')2 or bovine serum albumin. Altogether, the data support the concept of a biological role for TGF-beta in the IgG-mediated negative feedback of antibody responses.

Animals↗
PubMed1995

Variable expression of CD3-zeta chain in tumor-infiltrating lymphocytes (TIL) derived from renal-cell carcinoma: relationship with TIL phenotype and function.

It has been reported that in mice and in humans, tumor-infiltrating lymphocytes (TIL) may exhibit a defect in CD3-zeta-chain expression. Therefore, the level of CD3-zeta was analyzed in TIL derived from patients with renal-cell carcinoma, and its correlation with TIL phenotype and function was assessed. We identified 4 out of 13 tumor-infiltrating lymphocytes derived from renal-cell carcinoma, with a significant decrease in CD3-zeta-chain expression as compared with control peripheral-blood lymphocytes. This defect was never found after culturing TIL with IL2. In one case, the low expression of zeta chain observed in TIL on day 0 was reversed when TIL were cultured with IL2. The zeta-chain level did not seem to predict the growth of TIL in response to IL2. All the TIL, irrespective of the level of zeta-chain expression, exhibited lower proliferative response when stimulated with PHA or anti-CD3 MAb in comparison with normal peripheral-blood mononuclear cells. Nevertheless, in this limited series of patients, a correlation was observed between the level of zeta-chain expression and T-cell infiltration (p = 0.02). After TIL stimulation with PHA or anti-CD3, in contrast to IL2 or IFN-gamma production, a trend towards a relationship between TNF alpha induction and the level of zeta-chain expression was observed.

CD3 Complex↗
PubMed1995

Membrane and soluble Fc gamma RII/III modulate the antigen-presenting capacity of murine dendritic epidermal Langerhans cells for IgG-complexed antigens.

Murine dendritic epidermal Langerhans cells (LC) are APC. This implies that LC take up, process, and present Ag to T cells. One way of doing so that could allow Ag internalization is provided by the low affinity receptors for the Fc region of IgG (Fc gamma R), which murine LC are known to express, although their isoform(s) and function(s) have not been defined. By using molecular biology and biochemical approaches, we demonstrated that LC expressed Fc gamma RIIb2 and Fc gamma RIII. Furthermore, LC internalized Fc gamma R by receptor-mediated endocytosis, as observed with gold-labeled anti-Fc gamma RII/III mAb or immune complexes. We demonstrated the biologic relevance of this process by observing that Fc gamma R-mediated Ag internalization improved by approximately 300-fold the Ag-presenting capacity of LC to T cells. Moreover, analysis of cell culture supernatants showed that two forms of soluble Fc gamma R (sFc gamma R) were released by LC: the first most probably was the secreted transmembrane-deleted Fc gamma RII isoform, Fc gamma RIIb3, and the second was a soluble receptor probably derived from the membrane-associated Fc gamma RII/III. The ability of two recombinant forms, corresponding to the two sFc gamma R released by LC, to inhibit Fc gamma R-mediated presentation enhancement was assayed. Preincubation of IgG-complexed Ag with either rsFc gamma R led to a dose-dependent decrease in the Ag-presenting capacity of LC. Taken together, our results suggest that, in vivo, LC express membrane Fc gamma R, which increase their Ag-presenting capacity for IgG-complexed Ag, and release sFc gamma R, which might be able to modulate this Ag presentation.

Animals↗
PubMed1995

In vitro killing of neuroblastoma cells by neutrophils derived from granulocyte colony-stimulating factor-treated cancer patients using an anti-disialoganglioside/anti-Fc gamma RI bispecific antibody.

Neutrophils isolated from cancer patients treated with granulocyte colony-stimulating factor (G-CSF) express high levels of Fc gamma RI. They exhibited an efficient killing of GD2+ neuroblastoma cells in the presence of an antidisialoganglioside (GD2) mouse monoclonal antibody (MoAb; 7A4, IgG3 kappa). However, this cytotoxicity was totally blocked by human monomeric IgG. In contrast, a bispecific antibody (7A4 bis 22/MDX-260), prepared by chemically linking an F(ab') fragment of 7A4 with an F(ab') fragment of an anti-Fc gamma RI MoAb, 22, which binds outside the Fc binding domain, triggered antibody-dependent cell cytotoxicity, even when neutrophils were preincubated with human monomeric IgG. F(ab')2 22 MoAb abrogated the MDX-260 killing without affecting that of 7A4. The 3G8 MoAb, directed against the Fc gamma RIII binding site, did not inhibit the cytotoxicity induced by either antibody. Thus, these results indicate that G-CSF-activated neutrophils exert their cytotoxic effect against neuroblastoma cells through Fc gamma RI and not Fc gamma RIII, and that the saturation of the high affinity Fc gamma RI by monomeric IgG can be overcome by the use of bispecific antibodies binding epitopes outside the IgG Fc gamma RI binding site. A combined administration of such bispecific antibodies and G-CSF may be, therefore, an efficient therapeutic approach to trigger tumor lysis by cytotoxic neutrophils in vivo.

Antibodies, Bispecific↗
PubMed1995

Release of Fc gamma RIIa2 by activated platelets and inhibition of anti-CD9-mediated platelet aggregation by recombinant Fc gamma RIIa2.

Thrombin-activated human platelets and megakaryocyte cell lines release soluble Fc gamma RII (Fc gamma RIIa2) containing the extracellular and intracellular regions of Fc gamma RIIa1, but lacking the transmembrane domain. Use of polyclonal antibodies directed either against the entire intracytoplasmic tail, or against a peptide located near the C-terminal part of the intracellular region of Fc gamma RIIa2, showed the presence of both a complete form of Fc gamma RIIa2 and a C-terminal truncated form in supernatants of platelets after release of their alpha granule contents and in culture supernatants of megakaryocyte cell lines. Furthermore, recombinant Fc gamma RIIa2 inhibited in a dose-dependent manner Fc-dependent anti-CD9 antibody-induced platelet aggregation. Thus, release of Fc gamma RIIa2 by activated platelets could play an important role in the regulation of platelet activation by immune complexes.

Antibodies, Monoclonal↗
PubMed1995

Regulation of tyrosine-containing activation motif-dependent cell signalling by Fc gamma RII.

Crosslinking of the B-cell receptor (BCR) for antigen to low-affinity receptors for IgG (Fc gamma RII) inhibits B-cell activation induced by BCR aggregation. The cell-triggering properties of the BCR depend on tyrosine-containing activation motifs (TAM), in the intracytoplasmic domain of its Ig alpha and Ig beta subunits. TAMs also account for the cell-triggering capabilities of the T-cell receptor (TCR) for antigen, in T lymphocytes, and of the high-affinity receptor for IgE (Fc epsilon RI), in mast cells. Using as a model, rat basophilic leukemia cells (RBL-2H3) stably transfected with cDNA encoding wild-type or mutated murine or human Fc gamma RIIB and chimeric molecules having the intracytoplasmic domain of the FcR gamma subunit or of TCR-CD3 zeta subunit, we found that the inhibitory properties of Fc gamma RII are neither restricted to B cells nor to BCR-dependent cell activation, but can be extended to other cells and, as a general rule, to TAM-dependent cell activation.

Animals↗
PubMed1995

Prognostic value of cytokine and soluble Fc gamma receptor assays in oncology.

The clinical course of a cancer is influenced by the interaction of tumour cells with the patient's immune system. It is thus conceivable that immunological parameters may be used as markers of prognostic or predictive value. We report here that increased serum levels of IL-6 is a signal of poor prognosis and predicts unresponsiveness to immunotherapy in patients with metastatic melanoma. In cervical cancer, IL-6 produced by infiltrating macrophages is a marker of invasive cancer. In patients with multiple myeloma, the plasmatic levels of soluble Fc gamma receptors are markers of the disease, sCD16 being drastically decreased and sCD32 being slightly increased.

Cytokines↗
PubMed1995

Ligands and biological activities of soluble Fc gamma receptors.

Soluble forms of low-affinity Fc gamma receptors (sFc gamma R) circulate in biologic fluids. Their plasmatic levels vary in immunological disorders or related diseases. They are produced by enzymatic cleavage of the membrane receptors or by alternative splicing. They bind IgG with the same isotype specificity as their cell surface counterparts and thus modulate Fc-dependent immune functions. Recent data suggest that they also bind non-Ig ligands present on leukocytes. Functional implications of these findings are discussed.

Animals↗
PubMed1995

In vivo targeting of human neuroblastoma xenograft by anti-GD2/anti-Fc gamma RI (CD64) bispecific antibody.

Antidisialoganglioside (GD2) monoclonal antibodies can target in vitro and in vivo neuroblastoma cells. However, their in vivo use is limited by the presence of high levels of circulating IgG which hamper the recruitment of effector cells through the high affinity Fc gamma RI (CD64). A bispecific Fab' x Fab' antiGD2/antiFc gamma RI antibody (7A4 bis 22), which binds outside the IgG binding site of Fc gamma RI, was therefore developed. This antibody binds both human GD2+ neuroblastoma and Fc gamma RI+ activated macrophages in vitro. It can localise a GD2 positive neuroblastoma xenografted on Nu/Nu mice. Scintigraphy tumour/muscle ratios showed that targeting with this antibody has an excellent selectivity for the tumour over normal tissues. Furthermore, although its whole body clearance is more rapid than that of the 7A4 parental antibody over the first 48 h, its selective tumour uptake is similar, as shown by immunoscintigraphy imaging. Thus, such a bispecific antibody may represent an efficient tool for in vivo therapy of neuroblastoma through its ability to recruit Fc gamma RI+ effector cells even in presence of circulating IgG and to bind concomitantly GD2+ tumour cells.

Animals↗
PubMed1995

Role of B cell receptor Ig alpha and Ig beta subunits in MHC class II-restricted antigen presentation.

The ability of the B cell antigen receptors (BCRs) to enhance MHC class II-restricted antigen presentation was ascribed to mig-associated Ig alpha/Ig beta heterodimers. The relative role of Ig alpha and Ig beta subunits in antigen presentation was investigated by fusing their cytoplasmic tails to the extracellular and transmembrane domains of Fc receptors. Ig alpha and Ig beta chimera mediate antigen internalization and increase the efficiency of antigen presentation, but they drive antigens to different endosomal compartments. Furthermore, antigens internalized by either chimera are degraded and presented with different kinetics. The cytoplasmic tail of Ig alpha targets antigen towards a major population of newly synthesized MHC class II located in class II-rich compartments. In contrast, Ig beta targets antigen towards a minor population of recycling MHC class II molecules, located in transferrin receptor-containing endosomes. Altogether, our data indicate that the composition of BCR could be therefore an important way to modulate the immune response.

Animals↗
PubMed1995

The same tyrosine-based inhibition motif, in the intracytoplasmic domain of Fc gamma RIIB, regulates negatively BCR-, TCR-, and FcR-dependent cell activation.

The cell-triggering properties of BCR, TCR and FcR depend on structurally related immunoreceptor tyrosine-based activation motifs (ITAMs). Fc gamma RIIB have no ITAM and do not trigger cell activation. When coaggregated to BCR, they inhibit B cell activation. We show here that, when coaggregated to these receptors, Fc gamma RIIB inhibit Fc epsilon RI-, Fc gamma RIIA-, and TCR-dependent cell activation. Inhibition also affected cell activation by single ITAMs, in isolated FcR or TCR subunits. The same tyrosine-based inhibitory motif (ITIM), which is highly conserved in murine and human Fc gamma RIIB and that was previously shown to inhibit BCR-dependent B cell activation, was required to regulate TCR- and FcR-dependent cell activation. Our findings endow Fc gamma RIIB, and thus IgG antibodies, with general immunoregulatory properties susceptible to act on all ITAM-containing receptors.

Amino Acid Sequence↗
PubMed1995

Lack of efficacy of low-dose subcutaneous recombinant interleukin-2 and interferon-alpha in the treatment of metastatic renal cell carcinoma.

OBJECTIVE: To evaluate the efficacy and toxicity of subcutaneous immunotherapy using a combination of recombinant interleukin-2 (r-IL2) and interferon-alpha (IFN-alpha) for the treatment of patients with metastatic renal cell carcinoma (RCC). PATIENTS AND METHODS: Initially a maximum of 45 patients with advanced RCC were to be included in the study, according to a Fleming three-stage procedure. To be included patients had to have measurable metastasis. Of a potential 45 patients with advanced RCC, 15 patients were included in the study (10 men and five women, mean age 51 years, range 25-69). From the first week of treatment r-IL2 was given subcutaneously on day 1 to 5, at 18 x 10(6) units once a day and then 9 x 10(6) units once a day for the following 5 weeks. IFN-alpha was given three times a week for the last 5 weeks. Minimum follow-up was 6 months. RESULTS: All patients initially underwent radical nephrectomy. Seven patients were found to have metastases at the time of diagnosis. All patients received ambulatory therapy, except for the first 5 days of treatment. Overall, 80% of the patients received more than 75% of the complete dose of r-IL2. One patient suffered toxicity greater than the World Health Organization (WHO) grade 2 (neutropenia). No patient had a complete or partial response, two patients had a minor response, two patients had stable disease and 11 patients had disease progression. CONCLUSIONS: Subcutaneous r-IL2 and IFN-alpha had no beneficial effect on the first 15 patients and the study was discontinued, in accordance with the Fleming rules. The dose, administration and combination of r-IL2 and IFN-alpha may explain the lack of efficacy. Other studies have shown that low doses of r-IL2 are not effective and the superiority of the combination of r-IL2 and IFN-alpha has not been proven. Therefore, a high dose of r-IL2, in association with other cytokines, chemotherapy and adoptive immunotherapy, may be the only way to improve the response rate of metastatic RCC.

Adult↗
PubMed1995

Regulation of high-affinity IgE receptor-mediated mast cell activation by murine low-affinity IgG receptors.

Allergic symptoms result from the release of granular and lipidic mediators and of cytokines by inflammatory cells. The whole process is initiated by the aggregation of mast cell and basophil high-affinity IgE receptors (Fc epsilon RI) by IgE and antigen. We report here that IgE-induced release of mediator and cytokine can be inhibited by cross-linking Fc epsilon RI to low-affinity IgG receptors (Fc gamma RII) which are constitutively expressed on mast cells and basophils. Using a model of stable transfectants in RBL-2H3 cells expressing endogeneous rat Fc epsilon RI and recombinant murine Fc gamma RII, we showed that inhibition requires that Fc epsilon RI be crosslinked to Fc gamma RII by the same multivalent ligand. Inhibition of cross-linked receptors left non-cross-linked Fc epsilon RI capable of triggering mediator release and was reversible upon disengagement. Both isoforms of wild-type Fc gamma RII were equally capable of inhibiting Fc epsilon RI-mediated mast cell activation provided they had an intact intracytoplasmic domain. Our results demonstrate that mast cell secretory responses triggered by high-affinity receptors for IgE may be controlled by low-affinity receptors for IgG. This regulation of Fc epsilon RI-mediated mast cell activation is of potential interest in mast cell physiology and in allergic pathology.

Animals↗
PubMed1995

Activation of effector functions by immune complexes of mouse IgG2a with isotype-specific autoantibodies.

Analysis of five monoclonal autoantibodies, rheumatoid factors produced by hybridomas generated from spleen cells of BALB/c mice repeatedly infected with A/PR/8/34 human influenza A virus, revealed that they recognized distinct but spatially related epitopes. The differing isoallotypic specificity of the IgM and IgA monoclonal antibodies correlated with the presence of Ile258 and Ala305, respectively. Although these data suggest that the epitopes recognized are within the CH2 domain, all antibodies failed to inhibit IgG antigen reactivity with Staphylococcus aureus protein A (SpA), C1q, mouse C3, human Fc gamma RI or mouse Fc gamma RII, activities known to be predominantly determined by CH2 domain structures. Reactivity of the IgA antibody, Z34, with IgG2b allowed further specificity studies using a panel of 26 mutant IgG2b proteins, each having single amino acid replacements over the surface of the CH2 domain. The only substitution that affected Z34 reactivity was Asn/Ala297, which destroyed the glycosylation sequon, resulting in secretion of an aglycosylated IgG molecule. The epitope recognized by Z34 therefore seems to be located outside of the Fc gamma R and C1q binding sites, but to be dependent on the presence of carbohydrate for expression. In contrast to the binding studies, complement activation by aggregated IgG2a, through classical or alternative pathways, was inhibited by the presence of autoantibodies. The functional significance of isotype-specific autoantibody in immune regulation is discussed.

Animals↗