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Biomedical subjects

W L Sibbitt

Publications and source records attributed to W L Sibbitt.

At least 55 records · Page 3Linked to original sources
PubMed1986

Reversible inhibition of lymphokine-activated killer cell activity by lipoxygenase-pathway inhibitors.

Natural killer (NK) cells and lymphokine-activated killer (LAK) cells are anomalous cytotoxic cells which are potentially important in host defense against cancer. Several studies have demonstrated that natural killer (NK) cell activity can be suppressed by chemical inhibitors of the lipoxygenase pathway through inhibition of the production of leukotriene B4 (LTB4). The present study investigated the effects of the lipoxygenase inhibitors BW755C and nordihydroguaiaretic acid (NDGA) on NK and LAK cell activity. NK cell function of fresh peripheral blood mononuclear cells (PBMC) was determined via a standard chromium release assay employing K562 as the tumor target. The LAK cell activity of PBMC which had been stimulated with 10 IU of interleukin-2 for 72 hr was determined against the NK-resistant cell line Daudi. Both BW755C and NDGA inhibited NK and LAK cell function at a variety of concentrations. Indomethacin, a prostaglandin synthesis inhibitor, did not bring about an appreciable diminution in NK or LAK cell activity. Inhibition of NK and LAK cell activities by BW755C and NDGA could be reversed by washing the effector cell suspensions prior to the cytotoxic assay or by adding LTB4 (10(-11)-10(-8) M) directly to the effector:target suspensions. These data indicate that certain arachidonic acid oxidation products of the lipoxygenase pathway are essential for the function of LAK cells.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1986

Immunoglobulin from systemic lupus erythematosus serum induces interferon release by normal mononuclear cells.

Ig fractions from patients with systemic lupus erythematosus (SLE) were tested with cultured normal peripheral blood mononuclear cells for induction of interferon release. Lymphocyte eluates, euglobulins containing IgG and IgM, and IgG or IgM from DEAE or sucrose gradients all induced interferon production. Lymphocytotoxic antibody in SLE sera showed a high correlation with capacity of isolated Ig fractions to induce interferon. Most interferon produced was of the gamma type. Monoclonal SLE IgM antilymphocyte antibody induced interferon synthesis.

Antibodies, Monoclonal↗
PubMed1986

Inert particles inhibit natural killer cell function in vitro.

Aqueous suspensions of inert particles were found to inhibit the baseline and interferon-enhanced natural killer (NK) cell activity of peripheral blood mononuclear cells (PBMC) and large granular lymphocytes (LGLs). This inhibition was induced with latex, silica, and Sephadex particles. The suppression of NK activity was not related to effector cell death as determined by trypan blue exclusion. The inhibition of NK cell function was more pronounced with prolonged incubation and could be partially reversed with monocyte depletion or the addition of indomethacin, a prostaglandin synthesis inhibitor, but not with the addition of the lipoxygenase inhibitors nordihydroguaiaretic acid and BW755C. Similarly, particle exposure inhibited the NK cell function of monocyte-depleted large granular lymphocytes with and without the add-back of glass adherent cells, implying that monocyte-independent NK suppressive mechanisms were also present. These data demonstrate that inert particles are immunosuppressive in vitro and can inhibit baseline and interferon-stimulated NK cell function of LGLs and PBMC through monocyte-dependent and independent pathways.

Humans↗
PubMed1986

Serum factors which suppress natural cytotoxicity in cancer patients.

Spontaneous cytotoxicity mediated by natural killer (NK) cells is potentially an important mechanism of immunosurveillance against tumor or virus-infected cells. NK activity is impaired in many cancer patients. This study investigated the possibility that humoral factors are responsible for depressed NK activity in cancer patients and examined whether these factors were anti-lymphocyte antibodies (ALA) or immune complexes. The degree of NK suppression induced by 20 cancer patients' sera was determined by preincubating normal peripheral blood mononuclear cells with cancer sera. Eight of the 20 serum samples from cancer patients had NK-suppressive humoral factors. Elimination of immune aggregates by ultracentrifugation did not remove the inhibitory factors. The degree of NK suppression induced by cancer sera correlated with the extent of NK impairment in the serum donors (p less than 0.05). The cancer sera was examined for the presence of ALAs using flow cytometry. All cancer sera tested contained only low ALA reactivity to NK cell-enriched suspensions (less than 15%). This is in marked contrast to previous reports regarding NK-inhibitory systemic lupus erythematosus sera which contained large amounts of large granular lymphocyte (LGL) reactive ALAs. This study demonstrates that certain cancer sera suppress NK cell function. These inhibitory serum factors do not appear to be LGL-reactive ALAs or immune aggregates.

Adult↗
PubMed1985

The effect of an aldose reductase inhibiting agent on limited joint mobility in diabetic patients.

Improvement in range of motion and in strength of digital flexion and extension is reported in three diabetic subjects with the syndrome of limited joint mobility. Therapy was accomplished with sorbinil, an inhibitor of the enzyme aldose reductase, which inhibits the polyol pathway. We propose that reduction in collagen hydration secondary to reduced tissue content of polyols may participate in the clinical response.

Adult↗
PubMed1985

Relationship between circulating interferon and anti-interferon antibodies and impaired natural killer cell activity in systemic lupus erythematosus.

Interferon (IFN) production and response are impaired in a high percentage of systemic lupus erythematosus (SLE) patients. In addition, elevated serum levels of alpha-IFN or anti-alpha-IFN antibodies are present in some SLE patients. This study examined the relationship of circulating IFN and anti-IFN antibodies to the impairment of natural killer (NK) cell function in SLE. All 15 SLE patients studied had measurable circulating alpha-IFN, while the normal controls had minimal serum IFN. Neither patient nor control sera contained any detectable anti-alpha-IFN activity. However, most of the SLE patients demonstrated defects in NK cell function. Because these defects in NK cell function appeared to be associated with circulating IFN, but not anti-IFN, antibodies, the effect of prolonged in vitro IFN exposure on NK cell function of peripheral blood mononuclear cells was determined. It was found that prolonged exposure to IFN induced both an apparent defect in IFN response and a definite impairment of baseline NK cell function. These results suggest that prolonged elevation of circulating alpha-IFN levels could be responsible, in part, for the defects in natural cytotoxicity present in SLE.

Autoantibodies↗
PubMed1985

Generation of natural killer cells and lymphokine-activated killer cells in human AB serum or fetal bovine serum.

Interleukin 2 (IL-2) can induce or enhance the cytotoxic activity of natural killer (NK) cells and lymphokine-activated killer (LAK) cells. The effects of fetal bovine serum (FBS) and human AB serum (HABS) on the IL-2-induced NK cell and LAK cell activities of large granular lymphocytes (LGL) were measured, respectively, against the NK-sensitive cell line K562 and the LAK-sensitive cell line Daudi. FBS and HABS were essentially equivalent in their effects on IL-2-dependent NK activity with prolonged culture. However, with prolonged incubation from 1 to 5 days of PBMC in the presence of IL-2, there was considerably less generation of LAK cell activity in FBS (Day 3: 5.3 +/- 3.4 LU/10(7) cells) compared to HABS (Day 3: 44.6 +/- 4.2 LU/10(7) cells) (P less than 0.05). These differences in IL-2-dependent LAK cell generation did not appear to be due to the lot of the FBS or to activating factors present in individual samples of HABS. Similarly, the suppressive effects of FBS could not be reversed with increasing concentrations of IL-2 ranging from 10 to 100 U/ml. Importantly, the presence of FBS in the cultures resulted in more cell death (15.9 +/- 5.6%) at 4 days of culture compared to HABS (1.8 +/- 1.0%) (P less than 0.05). These results suggest that FBS may inhibit generation of LAK effector cells, but not NK cells in cultures containing IL-2 and that the use of HABS as a culture supplement is preferable to FBS in studies of human LAK cell function.

Animals↗
PubMed1985

Natural killer cells in connective tissue disorders.

NK cells may be important in the elimination of cells infected by virus, in the regulation of antibody production, and in tissue destruction. The significance of NK cells in rheumatic disorders is unknown, but NK cells and NK-like cells have been found in the peripheral blood and synovial tissues of patients with autoimmune disease. In particular, defects in NK cell activity have been reported in SLE, RA, PSS and SS. Of these diseases, SLE appears to be the best characterized with obvious abnormalities in NK cell numbers, impaired cytotoxicity of individual NK cells, decreased release of cytotoxic factors, deranged IFN modulation of the NK cell, and associated abnormalities in the IL-2 system. The association of these abnormalities with the underlying disease process is currently under investigation.

Arthritis, Rheumatoid↗
PubMed1984

Impaired release of a soluble natural killer cytotoxic factor in systemic lupus erythematosus.

Disease states characterized by abnormalities in immune regulation often demonstrate concomitant abnormalities in cytotoxicity mediated by natural killer (NK) cells. For example, some patients with systemic lupus erythematosus (SLE) have depressed NK activity despite the presence of normal numbers of effector cell:target cell conjugates. This study was designed to determine if defects in NK cell function were directly related to impaired release of a soluble cytotoxic factor. NK activity of peripheral blood mononuclear cells and large granular lymphocytes was measured using 51Cr-labeled K562 target cells in 4-hour release assays. The SLE patients had significantly decreased NK activity relative to normal controls. However, the number of effector cell:target cell conjugates was not different in SLE patients versus control subjects. The release of a soluble natural killer cytotoxic factor (NKCF) by peripheral blood mononuclear cells was measured by cytotoxicity induced in K562 cells. NKCF was released preferentially by suspensions enriched in NK cells (large granular lymphocytes). At a 1:1 dilution, NKCF release was significantly lower in SLE patients than in controls. The release of NKCF correlated well with NK activity. Thus, this study shows that the defect in NK cell activity in SLE patients may be related to an impairment in release of a soluble cytotoxic factor with specificity for NK cell-sensitive targets.

Adult↗
PubMed1984

Interferon-alpha regulation of lymphocyte function in systemic lupus erythematosus.

Interferon (IFN) production and responsiveness are abnormal in some patients with systemic lupus erythematosus (SLE). The present investigation was designed to further delineate these abnormalities of IFN response. The response to IFN-alpha was determined in peripheral blood mononuclear cells (PBMC) using the natural killer (NK) cell assay, the concanavalin A (Con A)-induced T-cell proliferation assay, and the pokeweed mitogen (PWM) blastogensis system. The average NK cell activity was impaired in SLE patients (19.7 +/- 3.8 LU/10(7) cells; n = 22) compared to 24 normal controls (45.6 +/- 7.2 LU/10(7) cells; n = 24) (P less than 0.05). In addition, the response to IFN in the NK cell system was impaired in SLE (110.0 +/- 38.0% enhancement) compared to controls (320.0 +/- 94.0% enhancement; +/- SD P less than 0.05). In contrast to the impaired IFN response of the NK cell in SLE, the effect of IFN on Con A- and PWM-induced blastogenesis in SLE was normal (P greater than 0.1). Thus, the defect in IFN response in SLE appeared to be confined to the NK cell system, but was not present in the other assay systems. To determine if the impaired IFN response might be secondary to impaired release of natural killer cytotoxic factor (NKCF) induced by IFN, NKCF was generated from PBMC in the presence of IFN. IFN-induced NKCF release was markedly impaired in SLE (8.9 +/- 11.7%) relative to normal controls (22.3 +/- 11.2%) (P less than 0.05). IFN-induced release of NKCF in SLE also closely correlated with IFN-induced NK enhancement (r = .83, P less than 0.05). No depletion of NK cells was noted using the monoclonal antibody HNK-1. Thus, this study demonstrates for the first time that the insensitivity to IFN in SLE is not a universal lymphocyte defect but appears to be isolated to the NK cell which is functionally abnormal.

Adult↗
PubMed1984

Lymphokines in autoimmunity: relationship between interleukin-2 and interferon-gamma production in systemic lupus erythematosus.

Interleukin-2 (IL-2) and interferon (IFN) are potent immunoregulatory factors. Recently, it has been demonstrated that IL-2 production is necessary for IFN-gamma synthesis. Thus, defects in IL-2 production could lead to defects in IFN-gamma production. Indeed, in systemic lupus erythematosus, defects in IFN-gamma and IL-2 production have been noted. To test this hypothesis, IL-2 and IFN-gamma production rates by peripheral blood mononuclear cells PBMC were measured simultaneously after stimulation by concanavalin A (Con A) and phorbol myristic acetate (PMA). IL-2 activity was determined employing HT-2, a cell line with an absolute growth requirement for IL-2. IFN-gamma activity was assessed using a standard viral plaque inhibition assay. IL-2 production in normal controls (n = 6) was 14.7 +/- 9.4 units/ml and in SLE patients (n = 10), 18.0 +/- 10.5 units/ml (P greater than 0.05). IFN-gamma production in controls was 74.7 +/- 43.7 units/ml and in SLE patients, 68.8 +/- 35.4 units/ml (P greater than 0.05). Only one SLE patient, who had moderately active disease, demonstrated defects in IL-2 synthesis (less than 4 units/ml) and IFN-gamma production (16 units/ml). Thus, production of these lymphokines in SLE patients was largely normal in response to Con A-PMA. These results imply that the intrinsic pathways of IFN and IL-2 production are basically normal in most SLE patients although defects in production of these lymphokines can occur. The defects in IL-2 and IFN production in SLE previously reported may be secondary to an impaired cellular response to the selected inducing agent rather than a primary defect in the actual ability to produce these important lymphokines.

Autoantibodies↗
PubMed1984

Defects in natural killer cell activity and interferon response in human lung carcinoma and malignant melanoma.

The natural killer (NK) activity of peripheral blood mononuclear cells from 25 patients with squamous cell carcinoma of the lung, malignant melanoma, or epitheloid cancers of the gastrointestinal tract was measured by the lysis of 51Cr-labeled K562 target cells. NK activities of many patients with lung cancer or malignant melanoma were decreased relative to normal controls. This abnormality was significantly correlated with advancing stage of disease and the percentage of monocytes in the cell suspensions. Addition of indomethacin or removal of monocytes did not restore depressed NK function to normal levels. Abnormalities of NK function did not appear to be secondary to the presence of mononuclear suppressor cells. The response to interferon was also impaired in patients with advanced disease. The number of effector:target conjugates was normal even in patients with depressed NK function; however, the number of active lytic effectors was decreased. These results imply that the cells which bind tumor targets are present in patients with advanced cancers, but these cells are either immature or functionally inactive.

Humans↗
PubMed1983

Enrichment of natural killer cells by negative selection: comparison to Percoll gradient separation method.

A method is described for the preparation of human peripheral blood mononuclear cell (PBMC) suspensions containing highly enriched natural killer (NK) cell cytotoxicity. The technique involved the negative selection of OKM1+ cells by the selective removal of nylon wool nonadherent PBMC which are reactive with the Leu-1 monoclonal antibody. The Leu-1+ cells are removed by subsequent rosette formation with anti-mouse IgG coated bovine erythrocytes. The resultant OKM1+ cell suspension had a greater number of large granular lymphocytes, K562 target binding effector cells, and lytic activity than concomitantly prepared fractions of Percoll gradients.

Antibodies, Monoclonal↗
PubMed1983

Human alpha-interferon enhances in vitro IgM rheumatoid factor synthesis by lymphocytes from normal subjects and rheumatoid arthritis patients.

Alpha-interferon (alpha-IFN) was added to pokeweed mitogen (PWM) or Epstein-Barr virus stimulated human peripheral blood mononuclear cell cultures from normal subjects or patients with rheumatoid arthritis (RA). Alpha-IFN enhanced in vitro production of PWM induced IgG and IgM, and significantly enhanced PWM induced IgM rheumatoid factor (IgM-RF) production by lymphocytes both from normal subjects and RA patients. Enhancement was recorded whether cells were preincubated with alpha-IFN for 16 hours or with alpha-IFN present throughout the culture period. Alpha-IFN did not enhance IgM-RF production in the absence of PWM or T cells. Enhancement of IgM-RF production was not seen in Epstein-Barr virus stimulated cultures.

Adult↗
PubMed1983

Impaired natural killer cell function in systemic lupus erythematosus. Relationship to interleukin-2 production.

Immune regulation requires clonal expansion of regulatory T cells which is dependent on the presence of interleukin-2 (IL-2). Previously, both natural killer (NK) cell function and IL-2 production were found to be depressed in systemic lupus erythematosus (SLE). This study was designed to determine the relationship between IL-2 production and NK cell activity in SLE. NK activity as determined by a standard 4-hour 51Cr-release assay was impaired in SLE (11.0 +/- 5.1 lytic units/10(7) cells) compared with controls (25.1 +/- 7.1 lytic units/10(7) cells) (P less than 0.05). IL-2 production was induced with concanavalin A and phorbol ester and quantitated using the IL-2 dependent cell line HT-2. IL-2 production was impaired in only 1 SLE patient, despite concomitant abnormalities in NK function in the SLE group as a whole. Moreover, in patients with impaired NK activity, incubation of lymphocytes with exogenous IL-2 did not restore NK activity to normal levels. These findings demonstrate that impaired NK activity in SLE is independent of IL-2 production and that defects in IL-2 production in SLE may not be as common as previously reported.

Humans↗
PubMed1983

Abnormal interferon modulation of natural cytotoxicity in systemic lupus erythematosus. Relation to suppressive serum factors.

In the present study we examined one aspect of the derangement in natural cytotoxicity (natural killer, NK) activity observed in some patients with systemic lupus erythematosus (SLE), i.e., the lack of enhancement of NK activity usually seen with interferon (IFN). NK activity of SLE patients as a group was 23.0 +/- 3.9 lytic units (LU)/10(7) cells (mean +/- SE). This contrasted with the NK activity found in normal controls (45.0 +/- 3.8 LU/10(7) cells) (P less than 0.05). The enhancement seen with IFN was an increase of 15.4 +/- 4.0 LU/10(7) cells in SLE patients compared with 104.6 +/- 192 LU/10(7) cells in control subjects (P less than 0.05). SLE sera and aggregated IgG (Agg-IgG) also inhibited the increase in NK activity of normal peripheral blood mononuclear cells after IFN priming. The results reported here support the hypothesis that the impaired baseline NK activity and poor response to IFN noted in SLE are secondary, in part, to the presence of inhibitory serum factors and preactivation by IFN.

Cells, Cultured↗