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Biomedical subjects

M Linker-Israeli

Publications and source records attributed to M Linker-Israeli.

At least 37 records · Page 2Linked to original sources
PubMed1991

Elevated levels of endogenous IL-6 in systemic lupus erythematosus. A putative role in pathogenesis.

Elevated spontaneous IgG production is characteristic of SLE. To identify the factors that support it, IL-6, a cytokine with an important role in the differentiation of IgG-secreting cells, was studied in SLE patients. Higher than normal levels of IL-6 were found, by a B9 assay, in sera of 63 of 70 patients (p less than 0.05). IL-6 was detected in 36 of 37 active SLE sera in higher titers (p = 0.009) than those for inactive SLE (n = 33), which were higher (p less than 0.05) than healthy controls (n = 15). IL-6 mRNA was detected in freshly isolated PBMC of 11 of 11 patients but not in normal PBMC, whereas IL-1 mRNA was detected only in patients with active disease. IL-6 activity was recovered from PBMC of four SLE patients, but not from four normal donors. By immunoperoxidase, IL-6 was detected in the cytoplasm of SLE monocytes and lymphocytes. When SLE PBMC were grown in short term cultures with no deliberate stimulation, expression of the IL-6 gene declined rapidly. Accordingly, the spontaneous production of IgG by SLE PBMC could be enhanced by exogenous IL-6. Spontaneous IgG production was diminished by 20 to 65% in the presence of neutralizing antibodies to IL-6, TNF-alpha, or IL-1. In contrast, neutralization of endogenous IL-4 increased production by approximately 40%. Anti-TNF-alpha treatment decreased IL-6 content of PBMC cultures, whereas anti-IL-4 augmented it, and exogenous IL-6 reversed anti-TNF-alpha effects on IgG production. Therefore, it is possible that the neutralization of TNF-alpha and IL-4 affected IgG production by modulating the synthesis/activity of IL-6. These results support the concept that SLE B cell hyperactivity is promoted by dysregulation of endogenous cytokines and suggest that IL-6, in particular, has an important pathogenic role.

Blotting, Northern↗
PubMed1991

Inhibition of immunoglobulin production by parathyroid hormone. Implications in chronic renal failure.

Available data indicate that B cell proliferation is inhibited in chronic renal failure and this is due to excess blood levels of PTH. This defect may also affect immunoglobulin production. We examined production of IgG, IgM and IgA by B cells stimulated with Staphylococcus aureus Cowan I (SAC) or with pokeweed mitogen (PWM) after eight days of culture and evaluated the effect of PTH on this process in 34 hemodialysis patients and 44 normal subjects. IgG, IgM and IgA production by B cells from patients was lower (P less than 0.01) than by B cells from normal subjects. Both 1-34 and 1-84 PTH inhibited (P less than 0.01) immunoglobulin production by B cells from normal subjects and dialysis patients. However, this inhibitory effect was evident in dialysis patients only with the higher dose of PTH. The inhibition of immunoglobulin production by PTH occurred only when the hormone was added at the initiation of the B cell culture. Inactivation of PTH abolished its inhibitory effect on immunoglobulin production. Agents that stimulate cAMP production (forskolin, cholera toxin) and the cAMP analogue, 8-bromoadenosine 3',5' cyclic monophosphate inhibited immunoglobulin production by B cells from both normal and dialysis patients, and the degree of inhibition was not different between the two groups. The calcium inophore A23187 also inhibited IgG, IgA and IgM production by B cells from normal subjects and dialysis patients; there was no significant difference in the degree of inhibition between the two groups. The resting levels of cytosolic calcium in B cells of dialysis patients was significantly (P less than 0.01) higher than that of B cells from normal subjects. The data show that: (1) immunoglobulin production is impaired in dialysis patients; (2) B cells of dialysis patients have elevated resting levels of cytosolic calcium; (3) PTH inhibits IgG, IgA and IgM production and this effect is at least partly mediated by PTH-induced cAMP production and alterations in cytosolic calcium into B cells; (4) this inhibitory effect is mediated by events that affect initial stages of B cell proliferation and maturation; (5) the requirement for high dose of PTH for its inhibitory effect on B cells from dialysis patients is probably due to desensitization and/or down-regulation of PTH receptors on B cells. The results are consistent with the proposition that impaired immunoglobulin production by B cells from dialysis patients is at least partly due to the state of secondary hyperparathyroidism in these patients.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1990

CD8+ lymphocytes from patients with systemic lupus erythematosus sustain, rather than suppress, spontaneous polyclonal IgG production and synergize with CD4+ cells to support autoantibody synthesis.

The cellular requirements for B cell hyperactivity in systemic lupus erythematosus (SLE) were studied. Removal of either CD8+ or CD4+ lymphocyte markedly decreased the spontaneous in vitro production of polyclonal IgG and of antigen-specific (anti-double-stranded DNA and antinucleoprotein) antibodies by SLE peripheral blood mononuclear cells (PBMC). The CD8+ lymphocytes that sustained IgG production were CD3+, HLA-DR+, and their activity was abrogated by preincubation with anti-HLA-DR monoclonal antibody. When both CD4+ and CD8+ cells were removed, the readdition of either subset partially restored polyclonal IgG production, but both cell subsets were required to reconstitute autoantibody production. Purified SLE B cell cultures, which generated only 15% of the IgG produced by unseparated PBMC, were fully reconstituted only by mixtures of CD4+ with CD8+ cells, and with CD8-, CD4-, CD16+ cells. At least part of the support for spontaneous IgG production can be attributed to endogenous interleukin-2 and interleukin-6.

Antibody Formation↗
PubMed1990

Effect of parathyroid hormone on human T cell activation.

Lymphocytes have receptors for PTH and patients with chronic renal failure have high blood levels of PTH and impaired lymphocyte function. It is possible, therefore, that PTH affects lymphocyte function. We studied the interaction between PTH and proliferation of human lymphocytes in vitro and examined potential mechanisms for such an interaction. 1-84 PTH stimulated in a dose dependent manner PHA-induced proliferation of T cells but had no effect on PWM-induced proliferation. The hormone did not alter CD4/CD8 ratio. Inactivation of PTH abolished its stimulatory effect. PTH augmented IL-2 production by PHA-activated T cells but did not increase expression of IL-2R. 1-34 PTH also stimulated PHA-induced T cell proliferation. TPA augmented PHA-induced T cell proliferation but the addition of PTH to the culture stimulated by PHA and TPA did not augment further the proliferation of T cells. Staurosporin reversed the stimulation by PTH of the PHA-induced lymphocyte proliferation. Both 1-34 and 1-84 PTH stimulated cyclic AMP production by lymphocytes. Forskolin did not affect PHA-induced T cell proliferation although it stimulated cyclic AMP generation. The results show that: 1) PTH acts on T cells; 2) acute exposure to PTH augments PHA-induced T cell proliferation and IL-2 production; 3) this action of PTH is related to its biological activity and is most likely due to the ability of PTH to enhance entry of calcium into cells and/or stimulation of protein kinase C but is independent of cyclic AMP generation.

Adult↗
PubMed1990

Evidence of impaired T cell function in hemodialysis patients: potential role for secondary hyperparathyroidism.

Previous studies in our laboratory showed that the T cell is a target for parathyroid hormone (PTH) action. It is theoretically possible, therefore, that chronic exposure of the T cells to high blood levels of PTH in patients with chronic renal failure may adversely affect T cell function. We examined in both normal subjects and dialysis patients several aspects of T cell function, including (1) T cell proliferation in response to phytohemagglutinin (PHA) mitogen with and without PTH and with and without exogenous interleukin 2 (IL-2); (2) the IL-2 production induced by PHA with and without PTH, and (3) resting levels of cytosolic calcium--[Ca2+]i--and the increment in [Ca2+]i in response to anti-CD3 antibody. Although PHA significantly (p less than 0.01) stimulated proliferation of T cells from both normal subjects and dialysis patients, the magnitude of the stimulation was significantly (p less than 0.01) smaller in the latter group. In both normal subjects and dialysis patients, exogenous IL-2 alone stimulated T cell proliferation, and the magnitude of the stimulation was similar to that produced by PHA. Also, IL-2 augmented PHA-induced proliferation of T cells from normal subjects, but failed to do so in T cells from dialysis patients. PHA did not augment IL-2 production by T cells from dialysis patients, and PTH did not correct this defect. The resting levels of [Ca2+]i in T cells from dialysis patients were significantly (p less than 0.01) higher, and the increments in [Ca2+]i in response to anti-CD3 antibody were significantly (p less than 0.01) lower than in T cells from normal subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Parathyroid hormone inhibits B cell proliferation: implications in chronic renal failure.

B cell proliferation is impaired in patients with chronic renal failure, but the mechanisms underlying this defect are not known. Lymphocytes have receptors for parathyroid hormone, and it is possible that the state of secondary hyperparathyroidism of renal failure is responsible for the B cell defect. Our studies were designed to (a) examine T cell-independent B cell proliferation [3H)thymidine incorporation) induced by Staphylococcus aureus Cowan 1 after 5 days of culture, (b) evaluate the effect of parathyroid hormone on S. aureus Cowan I-induced B cell proliferation, and (c) investigate the mechanisms through which parathyroid hormone may exert its effect on B cell proliferation. Lymphocytes were obtained from 37 normal subjects and 21 dialysis patients. S. aureus Cowan I induced significant stimulation (P less than 0.01) of the proliferation of B cells from both groups, but the effect was smaller on B cells from dialysis patients (10.0 x 10(3) +/- 1.4 x 10(3) cpm) than on those from normal subjects (21.8 x 10(3) +/- 2.0 x 10(3) cpm). Both the intact molecule of parathyroid hormone (1-84 PTH) and its amino-terminal fragment (1-34 PTH) caused significant inhibition of proliferation of B cells from normal subjects in a dose-dependent manner, with the effect being significantly greater (P less than 0.01) with an equimolar concentration of 1-84 PTH than that of 1-34 PTH. Inactivation of 1-84 PTH by oxidation abolished most of its inhibitory effect on B cell proliferation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Inhibition of autoimmune uveitis by anti-CD4 antibody.

In this study, rats with S-antigen-induced uveitis were treated with W3/25, a monoclonal antibody that recognizes the CD4 molecule expressed by helper/inducer cells. Treatment was started on day 5 after administration of S-antigen. Groups of animals were killed 18 or 31 days after S-antigen injection. The enucleated globes were studied histologically, and in vitro T-cell response and anti-S antibody levels were determined. Results showed that the antibody treatment prevented development of experimental autoimmune uveitis (EAU) in all animals. Furthermore, there was no evidence of disease development for 14 days after cessation of therapy. These results suggest that CD4+ cells are important in the initiation of EAU, and that monoclonal antibodies directed to this subset may provide effective treatment of autoimmune uveal inflammation.

Animals↗
PubMed1989

Inhibitory effects of anti-CD2 monoclonal antibodies on interleukin 2 production and interleukin 2 receptor expression in anti-CD3-induced T cell activation.

The effects of anti-CD2 monoclonal antibodies (mAb) on anti-CD3-driven interleukin 2 (IL2) production and IL2 receptor (IL2R) expression were investigated. Two anti-CD2 mAb, which had previously been shown to inhibit in vitro anti-CD3-induced T cell proliferation, also inhibited anti-CD3-induced IL2 production. However, it seemed unlikely that this was the crucial mechanism in the inhibition of anti-CD3-driven proliferation, since anti-CD2 mAb also partially inhibited T cell proliferation induced by the anti-CD3 mAb 446 which does not induce detectable IL2 levels. Anti-CD2 mAb also inhibited anti-CD3-induced surface IL2R expression as measured by immunofluorescence staining with an anti-IL2R mAb against the p55 chain. Inhibition of IL2R expression paralleled inhibition of proliferation. This anti-CD2-mediated inhibition involved a block in the generation of normal numbers of IL2R+ cells rather than a direct inhibitory effect on the IL2R+ cells themselves, since IL2R+ cells isolated from anti-CD2-containing cultures responded normally to IL2. Exogenous IL2 and IL4, singly or in combination, could reverse neither the anti-CD2-mediated inhibition of anti-CD3-induced proliferation nor the anti-CD2-mediated inhibition of anti-CD3-induced IL2R expression. Taken together, these observations suggest that anti-CD2 mAb inhibit anti-CD3-driven proliferation by inhibiting the generation of IL2R+ cells at a maturational stage proximal to their expression of surface IL2R. This inhibition cannot be overcome by exogenous IL2 or IL4, suggesting that the underlying biochemical mechanism involves an IL2- and IL4-independent pathway.

Antibodies, Monoclonal↗
PubMed1989

Suppression of experimental uveitis in rats by anti-I-A antibodies.

I-region-associated (Ia) class II major histocompatibility complex (MHC) products are known to play a major role in autoimmunity. Effects of anti-I-A and anti-I-E monoclonal antibodies on development of experimental autoimmune uveitis (EAU) were investigated in Lewis rats. Prior to sensitization with S-antigen, seven groups of rats, six in each group, were injected intraperitoneally with one of the following agents. Groups 1, 2, and 3 (controls) received saline, RPMI and mouse immunoglobulin G (IgG), respectively. Groups 4 and 5 were injected with anti-I-E antibodies, 80 micrograms and 1000 micrograms, respectively. Similarly, groups 6 and 7 received anti-I-A, 100 micrograms and 750 micrograms, respectively. The treatments were repeated on days 1, 2, 5, 8, and 11 after S-antigen injection. All these animals were killed on day 18. In addition, two groups of rats sensitized with S-antigen were treated with 750 micrograms anti-I-A antibodies on days 5, 6, and 7 (group 8) and on days 7, 8 and 9 (group 9). An additional group (group 10) of Lewis rats was treated with 750 micrograms anti-I-A 1 day prior to and on days 1 and 2 after S-antigen injection. These group-10 animals were killed on day 31. Histopathologically, the enucleated globes of animals treated with high dose anti-I-A revealed marked suppression or inhibition of uveitis development. Such inhibition was virtually complete when the antibody was administered within a week of S-antigen injection, and the inhibitory effect lasted for at least 31 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Monoclonal antibodies to different sites on human transcobalamin II.

Two IgG1K monoclonal antibodies to human transcobalamin II (TC II) were generated. These antibodies, 16.1 and 16.6, did not cross-react with the other two types of human cobalamin-binding proteins, intrinsic factor and R binder (TC I). Both antibodies cross-reacted with orangutan and simiang TC II but not with TC II from cynomolgus and howler monkeys, who are less closely related to humans. This finding suggests close structural similarity of human to ape TC II. The antibodies also did not react with TC II of lower mammals which included the horse, dog, guinea pig, and mouse; in particular, reaction did not occur with rabbit TC II, which has been considered structurally close to human TC II. Neither of the two antibodies was directed at the cobalamin-binding site of TC II. However, antibody 16.6 hindered TC II binding to cell receptor. This reactivity with the receptor-binding site should prove particularly useful in studies of that region of the TC II molecule.

Animals↗
PubMed1988

Characterization of lymphocytes that suppress IL-2 production in systemic lupus erythematosus.

IL-2 production by peripheral blood mononuclear cells (PBM) is decreased in patients with systemic lupus erythematosus (SLE). This defect can be reversed by the removal of CD8+ lymphocytes. The purpose of these studies was to determine whether the CD8+ IL-2 suppressor cells comprise a specific subset or whether all CD8+ cells have this activity. Lymphocyte subsets were identified and separated by two-colour flow cytometry prior to a 48 h mitogen stimulation. The CD8+ cells that suppressed IL-2 production co-expressed HLA DR and were radiosensitive. Other markers co-expressed by CD8+ cells which are found on suppressor cells such as Leu 15 (CD11), Leu 11 (CD16), and Leu 7 were also found on the CD8+ IL-2 suppressor cell population in SLE. In healthy subjects, removal of CD16+, but not of CD8+ cells markedly elevated the production of IL-2. The CD8- CD16+ non-T cell subset suppressed IL-2 production by normal and SLE PBM in autologous and allogeneic combinations. This subset may be a human equivalent of the murine natural suppressor cells. These results demonstrate that the cells that suppress IL-2 production in SLE are heterogeneous, and suggest that they belong to more than one lineage.

Antigens, Differentiation↗
PubMed1988

Further characterization of interleukin-2 production by lymphocytes of patients with systemic lupus erythematosus.

To further characterize the mechanisms responsible for defective interleukin-2 (IL-2) production in patients with systemic lupus erythematosus (SLE), we studied the effect of irradiation on the capacity of lymphocytes to produce this lymphokine when stimulated with phytohemagglutinin (PHA), or with a combination of PHA and a phorbol myristic acid ester (PMA). Irradiation increased PHA induced IL-2 production in patients with SLE and normal controls, and reached normal levels in 10 of 16 patients with SLE. This effect was due to inactivation of CD8+ suppressor cells. When PMA was used as a costimulant, maximal enhancement of IL-2 production was observed in both groups, but values in SLE remained significantly lower than in normals. These differences were not overcome by irradiation, raising the possibility that SLE suppressor cells act upon a site proximal to protein kinase C. Our studies have confirmed that active endogenous suppression may be responsible for most of the defective PHA induced IL-2 production in SLE and that this suppression is radiosensitive.

Adult↗
PubMed1988

Partial purification and characterization of systemic lupus erythematosus derived factors that suppress production of interleukin-2.

We report here on interleukin-2 (IL-2) suppressive factors, synovial fluid (SF) peripheral blood mononuclear cells (PBM), derived from short term cultures of unstimulated PBM of patients with systemic lupus erythematosus (SLE). SF PBM suppressed production of IL-2, but not proliferative responses to this lymphokine. It was sensitive to acid (pH 2.6), heat (56 degrees C), and tryptic digestion. It retained activity in the presence of 2-mercaptoethanol (2-ME), had no interferon activity and no non-specific cytotoxicity. Although crude SF PBM contained IgG and PGE2, these were not associated with its 2 active fractions. SF PBM was partially purified on a G-200 Sephadex column. IL-2 suppressive activity was detected in 2 fractions of molecular weights corresponding to greater than 150 kD and 40-60 kD, the latter acting only in the presence of monocytes. SF PBM appear to affect directly the IL-2 producer cell, since it suppressed IL-2 production by (1) mitogen stimulated PBM depleted of CD8+ suppressor cells and by (2) mitogen induced Jurkat cells. These "spontaneous" suppressive factors were ubiquitous in SLE, and may be important tools for studying the defective IL-2 production in SLE and its significance in the development of the disease.

Cells, Cultured↗
PubMed1987

Characterization of immunologic function in homosexual men with persistent, generalized lymphadenopathy and acquired immune deficiency syndrome.

A syndrome of persistent, generalized lymphadenopathy (PGL), related to the acquired immune deficiency syndrome (AIDS), has been described in homosexual men. To further characterize and correlate the immunologic status of patients with PGL with those in AIDS, we studied spontaneous and pokeweed mitogen (PWM)-induced IgG synthesis by B-cells, T-cell subsets in peripheral blood (PB), natural cytotoxicity (NC), and Interleukins (IL)-1 and IL-2 production in 39 homosexual patients (21 PGL; 13 AIDS; five asymptomatic homosexual men), in whom 32 of 35 tested (91%) had antibodies to human T-lymphotropic virus-III (HTLV-III). A profound abnormality in B-cell function was found in AIDS and PGL, consisting of high spontaneous IgG production, with paradoxic suppression of IgG synthesis after PWM. IL-2 values were more often low in AIDS when compared with PGL (P less than 0.001). The PB lymphocyte count was normal in PGL and reduced in AIDS (P less than 0.001). OKT4 "helper" cells were decreased in PGL, but even lower in AIDS (P less than 0.001), while OKT8 "cytotoxic/suppressor" cells were normal in AIDS and increased in PGL (P less than 0.01). The T4:T8 ratio was reversed in both, but more abnormal in AIDS (P less than 0.001). A decrease in NC killing was observed in AIDS when compared with heterosexual controls. Thus, patients with PGL and AIDS both demonstrate a spectrum of immunologic dysfunction, involving the cellular and humoral arms of the immune system.

AIDS-Related Complex↗
PubMed1987

Evidence of an activated T-cell system with augmented turnover of interleukin 2 in rheumatoid arthritis. Stimulation of human T lymphocytes by dendritic cells as a model for rheumatoid T-cell activation.

The stage of activation of synovial inflammatory T cells was studied in rheumatoid arthritis and compared with that of normal T cells stimulated in vitro by dendritic cells. Increased numbers of rheumatoid inflammatory T cells expressed activation antigens such as HLA-DR, interleukin 2 receptors (Tac), and transferrin receptors. These T cells also had high spontaneous proliferation. Peripheral blood T cells stimulated by autologous dendritic cells showed a similar expression of activation antigens and had high proliferation. Resting T cells and T cells cocultured with monocytes expressed much less activation markers. Exogenous interleukin 2 significantly increased the proliferation of the various T cells. All responses were inhibited by an antibody which blocks the interleukin 2 receptor. Supernatants from mitogen-stimulated rheumatoid inflammatory mononuclear cells and mitogen-stimulated T cells preactivated by dendritic cells usually contained less interleukin 2 than supernatants from mitogen-stimulated normal T cells. Furthermore, the various in vivo and in vitro-activated Tac-positive T cells, in contrast to nonactivated Tac-negative T cells from peripheral blood of patients and controls, significantly absorbed interleukin 2. The results indicate a turnover of interleukin 2 in rheumatoid inflammatory T cells comparable to that of T cells activated by dendritic cells.

Arthritis, Rheumatoid↗
PubMed1987

Functional properties of CD8 positive lymphocyte subsets in systemic lupus erythematosus.

CD8+ lymphocytes comprise several cell subpopulations that differ phenotypically and functionally. Although the percentage of T cytotoxic/suppressor cells (CD3+ CD8+) is usually increased in patients with active SLE, these lymphocytes are unable to suppress immunoglobulin (Ig) synthesis. However, freshly prepared lymphocytes from patients with SLE contain CD8+ DR+ cells which spontaneously suppress lymphocyte production of mitogen induced interleukin 2 (IL-2). Furthermore, CD8+ Leu 11+ non-T cells which comprise only 5% of total lymphocytes are also potent suppressors of IL-2 production. At the present time it is not known whether CD8+ suppressors of Ig synthesis and CD8+ suppressors of IL-2 production represent different maturation stages of common precursor cells or represent true heterogeneity of CD8+ lymphocytes.

Humans↗
PubMed1986

Natural killer-cell immunodeficiency in patients with chronic myelogenous leukemia. I. Analysis of the defect using the monoclonal antibodies HNK-1 (LEU-7) and B73.1.

Quantitative evaluation of natural killer (NK) cells using the HNK-1 (Leu-7) and B73.1 monoclonal antibodies (MAbs) was correlated with NK activity in 13 patients with chronic myelogenous leukemia (CML) and compared to normal donor controls. A consistent observation was the presence of normal absolute numbers of B73.1+ lymphocytes as well as normal to increased absolute numbers of HNK-1+ lymphoid cells in the peripheral blood of chronic-phase CML patients. Despite normal to increased numbers of B73.1+ and HNK-1+ lymphoid cells, these patients consistently demonstrated a significant impairment of lymphocyte-mediated NK activity in their peripheral blood. Further experiments demonstrated that chronic-phase CML patients, in contrast to normal controls, had significantly increased percentages of HNK-1+, E+ and B73.1+, E+ lymphoid cells and significantly decreased percentages of HNK-1+, E- and B73.1, E- lymphoid cells, which resulted in significant reversals of the HNK-1+, E+ to HNK-1+, E- and B73.1+, E+ to B73.1+, E- lymphoid cell ratios. (HNK-1+ [E+/E-] greater than B73.1+ [E+/E-]). Furthermore, as compared to normals, both FACS-sorted HNK-1+ and B73.1+ lymphoid cells from the E+ fraction of CML patients were consistently defective in NK activity, and could not be substantially augmented with alpha-interferon preparations. Although markedly defective in their ability to lyse K-562, HNK-1+ lymphoid cells from the E+ fraction of CML patients were not defective in their ability to bind to the NK-sensitive target, K-562. In contrast, NK-defective B73.1+ lymphoid cells were partially defective in their ability to bind to K-562.

Antibodies, Monoclonal↗