Search PubMed⌕ Search

Biomedical subjects

N Talal

Publications and source records attributed to N Talal.

At least 181 records · Page 10Linked to original sources
PubMed1982

Decreased syngeneic mixed lymphocyte reaction in autoimmune susceptible mice.

The syngeneic mixed lymphocyte reaction (SMLR) is a proliferative response mediated by murine splenic thymus-derived (T) lymphocytes after stimulation by syngeneic non-T cells. Several murine strains genetically susceptible to autoimmune diseases have decreased SMLR compared with normal strains. This diminished SMLR occurs before the onset of clinical disease and is most pronounced in those autoimmune mice that express a severe form of the disease. For example, in NZB/NZW F1 hybrid (B/W) mice, the SMLR is lower at 7 than at 2 months of age. The SMLR is lower in BXSB males, which develop more accelerated autoimmune disease, than in BXSB females. The defect in these autoimmune strains resides within the responding Lyt 1+,2,3-T-cell population. These results suggest the presence of a common T-cell defect in several murine strains that spontaneously develop autoimmunity.

Animals↗
PubMed1982

Thymic influences on autoimmunity in MRL-lpr mice.

We have examined the role of the thymus in the development of autoimmunity in MRL/Mp-lpr/lpr (MRL-lpr) mice. MRL-lpr mice develop a lymphoproliferative disorder characterized by features of systemic lupus erythematosus and by massive proliferation of a subpopulation of Lyt-1+23- T cells. Using fluorescein-conjugated monoclonal antibodies and the fluorescence-activated cell sorter, we have found an abnormal pattern of differentiation within the MRL-lpr thymus characterized by a loss of Lyt-123+ thymocytes and an increased frequency of Lyt-1+23- thymocytes. Neonatal thymectomy retarded lymphoproliferation, reduced autoantibody concentrations, improved renal function, and prolonged life. Furthermore, neonatal thymectomy resulted in a relatively specific elimination of the subset of T cells involved in the lymphoproliferative process. These findings suggest that thymic maturation of T cells with alloantigenic characteristics of a helper subpopulation may contribute to the marked lymphoproliferation and severe autoimmunity of MRL-lpr mice. Neonatal thymectomy may protect against autoimmunity by preventing the maturation of this helper subpopulation.

Animals↗
PubMed1982

Suppression of natural killing in vitro by monocytes and polymorphonuclear leukocytes: requirement for reactive metabolites of oxygen.

Natural killer cells spontaneously lyse certain tumor cells and may defend against malignancy. We have previously shown that natural killing (NK) by human peripheral blood mononuclear cells (PBMC) is suppressed in vitro by phorbol diester tumor promoters, including 12-O-tetradecanoylphorbol-13-acetate (TPA). We here demonstrate that suppression of NK is mediated by monocytes or polymorphonuclear leukocytes (PMN) and that suppression is dependent on the generation of reactive forms of molecular oxygen (RO), particularly hydrogen peroxide (H2O2). NK was suppressed not only by TPA but also by opsonized zymosan (yeast cell walls), which, like TPA, was not toxic to PBMC. Both TPA and zymosan stimulated the production of superoxide anion (O2-) and H2O2 by PBMC. Production of RO correlated with suppression of NK. When PBMC were depleted of monocytes, the production of RO and the suppression of NK were both markedly reduced. Suppression could be restored by monocytes or PMN, both of which produced RO in response to TPA or zymosan. Suppression of NK was dependent on RO. Monocytes or PMN from a patient with chronic granulomatous disease, whose cells cannot generate RO, did not mediate suppression of NK. Suppression was also reduced in glucose-free medium, which did not support the generation of RO. Suppression of NK by TPA was inhibited by catalase. Bovine superoxide dismutase had a limited effect on suppression, even in high concentration, and tyrosine-copper (II) complex, which also enhances dismutation of O2- to H2O2, had almost no effect on suppression. When H2O2 was directly generated enzymatically from glucose oxidase and glucose, NK was suppressed and suppression was reversed by catalase. NK was also suppressed by the enzymatic generation of O2- from xanthine oxidase and xanthine, but suppression under these conditions was again inhibited by catalase and not by superoxide dismutase, indicating that suppression was due to the secondary formation of H2O2 from O2-. These results indicate that H2O2 is important in suppression of NK. Myeloperoxidase did not appear to play a role in suppression because inhibition of this enzyme by sodium azide, cyanide, or aminotriazole did not prevent suppression of NK. Suppression of NK was reversible; after exposure to zymosan, NK could be partially restored by the addition of catalase and superoxide dismutase or by the removal of zymosan. These studies demonstrate cellular regulation of NK by monocytes or polymorphonuclear leukocytes and indicate a role for RO in immunoregulation.

Cell Communication↗
PubMed1982

An increase in peripheral blood Ia-positive T cells in Sjögren's syndrome correlates with a decrease in the autologous mixed lymphocyte response.

The defective autologous MLR was studied in Sjögren's syndrome (SS) in relation to Ia+ cells as determined by reactivity with a monoclonal anti-human Ia antibody. By indirect immunofluorescence, the percentage of Ia+ T lymphocytes was increased in nine of 15 patients. There was no correlation with clinical features or drugs. The percentage of Ia+ T cells in the non-T cell preparations was normal. An inverse correlation was found between the percentage of Ia+ T cells and the proliferative response to autologous non-T cells. Removal of Ia+ T cells enhanced both the autologous MLR and the allogeneic MLR. Thus Ia+ T cells contain suppressor cells in the MLR, but this may not be the sole explanation for the defective autologous MLR.

Adult↗
PubMed1981

Deficient interleukin 2 activity in MRL/Mp and C57BL/6J mice bearing the lpr gene.

Spleen cells from MRL-lpr and B6-lpr mice have a marked defect in the ability to produce interleukin 2 (IL-2) in response to concanavalin A stimulation. This defect precedes the onset of clinical illness, increases with age, and eventually becomes virtually absolute. It is not due to cellular suppression of IL-2 production, nor does it reflect the presence of a soluble inhibitor of IL-2 activity. Failure to restore IL-2 production with macrophage-replacing factors, such as interleukin 1 and phorbol myristic acetate, suggests that IL-2 deficiency reflects a primary T cell defect rather than a macrophage defect. MRL-lpr and B6-lpr spleen cells also have an age-dependent reduction in IL-2 response that apparently results from a deficiency of cell surface receptors for IL-2. Congenic MRL-+/+ and B6-+/+ mice, which lack the lpr gene responsible for accelerated autoimmunity and lymphoproliferation, have normal IL-2 activity. These findings suggest that a defect in IL-2 activity may contribute to impaired immunoregulation in mice bearing the lpr gene. The absence of such a defect in MRL-+/+ and B6-+/+ mice further suggests that a single autosomal recessive gene is responsible for IL-2 deficiency.

Absorption↗
PubMed1981

Treatment of NZB/NZW F1 hybrid mice with Mycobacterium bovis strain BCG or type II interferon preparations accelerates autoimmune disease.

NZB/NZW F1 hybrid mice develop a spontaneous autoimmune disease characterized by the appearance of antinuclear antibodies and premature death due to immune complex glomerulonephritis. To investigate the possible effects of cellular immune stimulation on this disorder, groups of female NZB/NZW mice, aged 2, 5, and 7 months, were treated either with the nonspecific immunostimulatory agent Mycobacterium bovis strain BCG or with saline. Mice treated with BCG at ages 5 and 7 months died sooner than age-matched controls, and death was associated with severe glomerulonephritis, suggesting that BCG may have accelerated autoimmunity in these mice. Since BCG is known to stimulate the production of type II (or gamma) interferon, a substance with potent immunoregulatory effects, a second study was carried out to assess the effects of type II interferon on NZB/NZW disease. A greater number of type II interferon-treated mice died by 9 months of age when compared to controls, and the increased death rate was associated with a more rapid development of antinuclear antibodies and histologically confirmed glomerulonephritis. These data, together with a recent report of increases in the level of serum type II interferon in patients with active systemic lupus erythematosus, suggest that type II interferon may play a role in the pathogenesis of autoimmune disease.

Animals↗
PubMed1981

Clearance of sensitized erythrocytes in NZB/NZW mice. Effects of castration and sex hormone treatment.

The clearance of particulate immune complexes consisting of erythrocytes sensitized with IgG or complement was investigated in (NZB x NZW)F1 (B/W) mice. Treatment of castrated B/W mice with androgen or estrogen was able to modulate this clearance. Young (3-month-old) male and female B/W mice cleared IgG-sensitized mouse erythrocytes rapidly, whereas older males (13 months) and females (7 months) showed a marked impairment in their ability to clear these cells. In addition, erythrocytes sensitized with complement in the absence of antibody were cleared within 5 min in young B/W mice. Older mice showed a greater and more rapid clearance rate of these cells. Castrated female B/W mice treated with androgen implants from three weeks of age showed improved clearance of IgG-sensitized erythrocytes at 7 months, whereas estrogen-treated male mice showed delayed clearance. These results suggest an age-dependent defect in the clearance of IgG-sensitized particles, perhaps due to diminished levels of serum complement and/or saturation of Fc receptors. In addition, there is an alteration in the clearance of complement-sensitized erythrocytes which may be related to changes in macrophage activity or enzyme inactivators of C3 and C4. The possible mechanisms responsible for the hormonal modulation of clearance are discussed in relation to the known ability of these hormones to influence autoimmune diseases.

Androgens↗
PubMed1981

Quantitative immunofluorescence microscopy of renal glomeruli from mice exhibiting murine lupus erythematosus.

Pathologic changes in renal glomeruli of mice with systemic murine lupus erythematosus were quantified using microfluorophotometry. Cryostat sections were taken from kidneys of affected mice, stained with fluorescein-conjugated anti-mouse immunoglobulin, and the extent of immune complex glomerulonephritis was determined. A subjective microscopic examination procedure, which has been used previously, was compared with quantitative microfluorophotometry and a close correlation between the results using each of the two methods was found. Since the microfluorometric procedure measures the total fluorescence per glomerulus, subjective microscopy must estimate that same quantity in a linear fashion. The present advance in measuring capability indicates good potential for rapid, quantitative measurements for further studies on systemic lupus erythematosus, and on other tissue sections stained with fluorescent antibodies.

Animals↗
PubMed1981

Natural killing of tumor cells by human peripheral blood cells. Suppression of killing in vitro by tumor-promoting phorbol diesters.

Tumor-promoting phorbol diesters were shown to suppress natural killing in vitro by human peripheral blood mononuclear cells. The inhibitory effect of different phorbol diesters and their analogues correlated with their potency as tumor promoters, the most effective agent being 12-O-tetradecanoylphorbol-13-acetate (TPA). Both peripheral blood cells and targets specifically bound TPA, and natural killing could be inhibited by pretreatment of either cell population with TPA, though this was less effective than direct addition of TPA to the assay. Cells that had been pretreated with TPA released TPA and metabolites of tPA during subsequent incubation in fresh medium. This release of tPA was evidently responsible for the inhibition of natural killing by pretreated target cells; in experiments where labeled and unlabeled target cells were mixed, pretreatment of unlabeled targets with TPA inhibited killing of labeled targets. Suppression of natural killing by TPA was greatly reduced when adherent cells were removed from the peripheral blood cells, suggesting that monocytes mediate suppression. Inhibition of natural killing by TPA provides a model for examining the regulation of natural killing. Suppression of natural killing by phorbol diesters may contribute to their activity as tumor promoters.

Animals↗
PubMed1981

Comparison of different antinucleic acid antibody spectrotypes in spontaneous, induced, and murine lupus.

Sera from patients with systemic lupus erythematosus and from mice spontaneously developing lupus were subjected to isoelectric focusing by a microsucrose gradient method. The spectrotypes of human antibodies to native DNA, denatured DNA, and polyriboadenylic acid (poly A) were compared. Antibodies to native DNA and denatured DNA focused into two regions whose boundaries were pH 5.0-7.0 and pH 8.5-10.0. Antinative DNA antibodies were more homogeneous than antidenatured DNA antibodies. Anti-DNA antibodies in cryoglobulins showed more restriction than those present in serum. There was no relationship between spectrotype and pattern of disease expression. Murine antibodies to native DNA were more heterogeneous than human anti-DNA antibodies. The spectrotypes of antidenatured DNA antibodies from patients with systemic lupus erythematosus or drug induced lupus, or from an immunized rabbit, were similar. Likewise, antibodies to poly A were similar in both human and murine lupus. In contrast to anti-DNA, antibodies to poly A were restricted and focused only in the alkaline range (pH 9.5-10.0). The spectrotype of antipoly A antibodies induced by lipopolysaccharide were comparable but had an additional small band at pH 6.2. Our results suggest unique antibody spectrotypes with varying degrees of restriction for different nucleic acid antigens. Furthermore, spontaneous and induced autoantibodies have similar spectrotypes. Thus, the B cell clones producing antinucleic acid antibodies may be similar whether they are activated spontaneously, following immunization, or as a consequence of polyclonal stimulation.

Animals↗
PubMed1981

Suppression or enhancement of natural killing does not alter tolerance to bovine gamma globulin.

NZB/NZW F1 (B/W) mice have high levels of natural killing (NK), are resistant to the induction of tolerance to bovine gamma globulin (BGG), and spontaneously develop a disease resembling systemic lupus erythematosus. In vivo administration of 89Strontium (89Sr) to B/W mice reduces NK and improves their autoimmune disease. We tested the hypothesis that the high levels of NK exert an immunoregulatory influence and are responsible for the resistance to BGG tolerance. 89Sr was administered at 4 and 8 weeks, and tolerogen was injected at 10 weeks. Despite a marked suppression of NK, 89Sr-treated B/W mice remained resistant to the induction of tolerance. NK was stimulated in weanling B/W male and female mice, and in adult A/J females, by the injection of Poly I . C one day prior to the administration of tolerogen. Poly I . C induced an acute rise in NK but did not inhibit the induction of tolerance. We conclude that natural killer cells are not involved in the regulation of immune tolerance to BGG and, they do not appear to play a role in the resistance to tolerance in adult B/W mice.

Age Factors↗
PubMed1981

Genetic analysis of induction of anti-polyadenylic acid antibodies and xenotropic type-C viruses.

Normal mice can be induced by lipopolysaccharide to produce anti-polyadenylic acid (poly A) antibodies and xenotropic (X-tropic) type-C viruses. To determine whether these traits are genetically linked, high anti-poly A antibody, high virus-producing NZB mice were crossed with low anti-poly A antibody-producing, virus-negative SWR mice. All mice in the F1 generation could be induced by LPS to produce high levels of both anti-poly A antibodies and X-tropic virus. When F1 hybrids were back-crossed to the SWR parent, all offspring were high anti-poly A antibody producers, but one-third of the mice remained virus-negative. These results demonstrate that these two LPS responses of a B lymphocyte are not genetically-linked and the anti-poly A antibody response is multigenic.

Animals↗
PubMed1981

Surface antigens on mouse natural killer cells: use of monoclonal antibodies to inhibit or to enrich cytotoxic activity.

In studies using monoclonal antibodies to cell-surface antigens we have identified 2 new antigens (H11 and 7.2) expressed on mouse NK cells. These are shared with T cells but not B cells. We have also shown that NK cells express T200 but lack detectable ThB or Lyt-1. The T200 and H11 surface molecules were implicated in the mediation or regulation of natural killing; monoclonal antibodies to T200 and H11 inhibited natural killing when added to the cytotoxicity assay but did not interfere with T cell cytotoxicity against the same target. The inhibitory effect of anti-T200 is consistent with recent evidence showing that antibodies to the Ly-5 polymorphic determinant on T200 block natural killing. The H11 determinants is on a different molecule. The absence of Lyt-1 and ThB on NK cells permitted development of a rapid and simple method for separating NK cells from T cells and B cells. Spleen cells incubated with rat monoclonal antibodies to Lyt-1 (on all T cells) and ThB (on all B cells) were 95% removed by adherence to Petri dishes coated with antiserum to rat immunoglobulin. The natural killer activity in the nonadherent population was enriched 16-fold.

Animals↗
PubMed1981

Interleukin 2 deficiency is a common feature of autoimmune mice.

IL 2 production was studied in autoimmune mice to assess the role of this lymphokine in the pathogenesis of murine lupus. Spleen and lymph node cells from autoimmune-susceptible mice show an age-dependent loss in the ability to produce functional IL 2. This defect correlates with disease expression and is most severe in MLR/Mp-Ipr/Ipr mice. MLR/Mp-Ipr/Ipr thymocytes gradually lose responsiveness to IL 2 with age. These results suggest that the immunoregulatory abnormalities of autoimmune mice may be due in part to IL 2 deficiency.

Aging↗