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Biomedical subjects

N Talal

Publications and source records attributed to N Talal.

At least 145 records · Page 8Linked to original sources
PubMed1985

Monoclonal anti-poly(rA) hybridoma antibodies from an autoimmune MRL/MpJ-lpr/lpr mouse.

Three B cell hybridomas were produced by the fusion of spleen cells from a 5 month old MRL/Mp-lpr/lpr mouse with the myeloma cell line, NS-1. By competitive inhibition, all three monoclonal antibodies (MoAb) were specific for poly(rA) and were inhibited to a lesser extent by dDNA, nDNA, poly(rI) and poly(rC). Moreover, the three MoAb were not inhibited by mononucleosides and the nucleotide, ATP. Competitive inhibition, using poly(rA) of defined lengths, showed that the recognition site among the MoAb varied, one demonstrating binding of poly(rA) as small as two bases in length. This study suggests that the spontaneous autoimmune repertoire to poly(rA) is restricted as compared to other monoclonal autoantibodies to nucleic acids, but contains within itself microheterogeneity.

Animals↗
PubMed1985

Ability of isoprinosine to restore interleukin-2 production and T cell proliferation in autoimmune mice.

Autoimmune mice bearing the single autosomal recessive gene 1pr are unable to produce the T cell growth factor, interleukin-2 (IL-2). A physiological consequence of this defect is the inability of T cells from C57B1/6J-lpr/lpr mice to respond to antigen presented by macrophages. In an attempt to reverse these abnormalities, we administered the inosine containing drug isoprinosine. Injection of isoprinosine after antigen immunization restored both antigen presentation and IL-2 production.

Aging↗
PubMed1985

Regulation of T cell proliferation by cloned interferon-alpha mediated by Leu-11b-positive cells.

The autologous T lymphocyte proliferative response (AMLR) induced by a B lymphocyte-enriched non-T, nonadherent cell population (NT, NAC) and by a macrophage-enriched population were both suppressed by the addition of a cloned interferon-alpha (IFN-alpha Con1) directly to the cultures. Preincubation of the stimulating NT, NAC with IFN-alpha Con1 resulted in comparable suppression. In contrast, preincubation of the macrophages with IFN-alpha Con1 resulted in significant augmentation of T cell proliferation. Depletion of Leu-11b-positive cells from the NT, NAC exposed to IFN-alpha Con1 restored the autologous T cell response. Addition of IFN-alpha Con1 activated Leu-11b-positive cells, isolated from the NT, NAC population, was suppressive of the AMLR. Although NK cytotoxicity was irradiation sensitive, suppression of the AMLR by IFN-alpha Con1-activated NT, NAC was resistant, suggesting that different subsets of cells or mechanisms by the same cells may have been responsible. These observations may offer insights into the potential role of cells with the NK phenotype, Leu-11b, and IFN in contributing to immuno-regulatory changes observed in clinical states associated with elevated concentrations of IFN.

Antibodies, Monoclonal↗
PubMed1985

[Regulation of natural killer activity by adherent cells in synovial rheumatoid medium].

The activity of natural killer cells in the synovial fluid, the synovial tissue and the peripheral blood was studied in 23 patients with active rheumatoid arthritis and was found to be significantly lower than that in the blood of 28 controls. This decrease was inversely related to the erythrocyte sedimentation rate. The preincubation of mononuclear cells with indomethacin significantly increased the natural killer activity in the blood of the controls and the patients with rheumatoid arthritis, but did not have any effect in the synovial compartment. The elimination of the adherent cells increased the natural killer activity in the blood of the controls and the patients with rheumatoid arthritis, but decreased this activity in the synovium. The stimulatory effect of synovial macrophages and the suppressor effect of the blood macrophages on the natural killer activity were confirmed when the adherent and non-adherent populations were mixed and these effects were reproduced by using supernatants of total mononuclear cells. The stimulation of the natural killer activity by interleukin 2 and poly-I:C, an interferon inducer, is independent of the macrophages in rheumatoid arthritis. These results suggest a deficient natural killer activity in active rheumatoid arthritis and a difference in the modulation of these natural killer cells by macrophages in rheumatoid synovium and normal or rheumatoid arthritis blood.

Adult↗
PubMed1985

Sex hormones, immune responses, and autoimmune diseases. Mechanisms of sex hormone action.

Immune reactivity is greater in females than in males. In both experimental animals and in man there is a greater preponderance of autoimmune diseases in females, compared with males. Studies in many experimental models have established that the underlying basis for this sex-related susceptibility is the marked effects of sex hormones. Sex hormones influence the onset and severity of immune-mediated pathologic conditions by modulating lymphocytes at all stages of life, prenatal, prepubertal, and postpubertal. However, despite extensive studies, the mechanisms of sex hormone action are not precisely understood. Earlier evidence suggested that the sex hormones acted via the thymus gland. In recent years it has become apparent that sex hormones can also influence the immune system by acting on several nonclassic target sites such as the immune system itself (nonthymic lymphoid organs), the central nervous system, the macrophage-macrocyte system, and the skeletal system. Immunoregulatory T cells appear to be most sensitive to sex hormone action among lymphoid cells. Several mechanisms of action of sex hormones are discussed in this review. The possibility of using sex hormone modulation of immune responses for the treatment of autoimmune disorders is a promising area for future investigation.

Animals↗
PubMed1985

Interleukin-2 in rheumatoid arthritis: production of and response to interleukin-2 in rheumatoid synovial fluid, synovial tissue and peripheral blood.

Several aspects of interleukin-2 (IL-2) generation and function were studied employing mononuclear cells from synovial fluid (SF), synovial tissue (ST) and peripheral blood (PB) of patients with rheumatoid arthritis (RA). Decreased PHA stimulated IL-2 production by lymphocytes from rheumatoid ST, SF (P less than 0.02), and PB (P less than 0.01) was observed when compared to normal blood and SF of patients with gout. The proliferative response of rheumatoid lymphocyte blasts exposed to exogenous IL-2 was also defective (P less than 0.05-0.001). This defect was greater in SF than in rheumatoid PB (P less than 0.05-0.001). In addition to the proliferative response, the effect of IL-2 on interferon-gamma (IFN-gamma) production was also examined. Rheumatoid lymphocytes from both PB and SF produced less IFN-gamma after overnight treatment with IL-2 than did normal PB lymphocytes. This decreased IFN-gamma induction was discordant with the excellent enhancement by IL-2 of natural killer activity. Removal of adherent cells in synovial fluid did not correct this deficit. Abnormalities in the biology of IL-2 and IFN-gamma suggest that impaired T cell function could contribute to the immunopathogenesis of RA.

Adult↗
PubMed1985

Effects of short-term administration of sex hormones on normal and autoimmune mice.

The effects of short-term administration (2 to 4 wk) of sex hormones on the immune system of normal (C57BL/6) and autoimmune (C57BL/6-lpr, C3H/lpr, B/W) strains of mice were investigated. Both estrogen (E2) and testosterone (Te) had significant effects on the numbers of T and B cells as well as on the density of cell surface antigens as demonstrated by flow cytometry. For example, Te depleted Thy-1.2+ thymocytes in normal mice and brought about a shift to lower density cells. Lyt-2+ cells appeared to be the main target cells of hormonal modulation in normal and autoimmune mice. Both sex hormones significantly depleted these cells in the thymus but had differential effects in the peripheral lymphoid organs, particularly in the spleen. In general, E2 depleted Lyt-2+ cells, whereas Te increased or maintained this subpopulation of cells in spleen and lymph nodes. Similarly, the suppressor cell activity and IL 2 production on a per cell basis in E2-treated animals was diminished, whereas Te-treated animals had normal or enhanced activity. The relevance of these findings to differential sex susceptibility in autoimmune diseases is discussed.

Animals↗
PubMed1985

Anti-idiotypic antiserum to monoclonal anti-Sm inhibits the autoantigen-induced proliferative response.

Anti-idiotypic sera were produced in BALB/c mice against three established monoclonal anti-Sm antibodies. Inhibition assays showed that the anti-idiotypic antibodies recognized determinants that were present on all three monoclonal antibodies but not on normal mouse IgG from unimmunized BALB/c mice or myeloma proteins. Normal (+/+) and autoimmune (lpr/lpr) MRL/MpJ or C3H/HeJ mice were immunized with Sm in complete Freund's adjuvant. Immune T cells from the draining lymph nodes proliferated in response to the addition of Sm in vitro. Anti-idiotypic serum added to these cultures inhibited the proliferative response by 50 to 70%, whereas normal BALB/c serum had no effect. This inhibition of proliferation was antigen specific, because the anti-idiotypic serum did not inhibit the T cell proliferative response to an irrelevant antigen, TNP-KLH, or ovalbumin. Kinetic studies showed that the anti-idiotypic serum inhibited an early event in antigen-induced proliferative response, because the addition of serum late in culture did not cause any significant reduction in proliferation. The reduced proliferative response was due to direct action of the anti-idiotypic serum on the Lyt-1+, 2- T cell population.

Animals↗
PubMed1984

Suppression of cellular and humoral immunity to T-dependent antigens by calorie restriction.

Calorie restriction is known to preserve the immunologic function and prolong the life span of autoimmune-susceptible mice. In order to determine the influence of calorie restriction on cellular and humoral immunity, we tested lymphocyte proliferative response and antibody response to T-dependent antigens in C57Bl/6 mice maintained on restricted diets. C57Bl/6 mice fed a low-calorie diet demonstrated a marked reduction in T-dependent-antigen-specific lymphocyte proliferation and antibody response when compared to mice fed ad libitum. The depressed lymphocyte response seen in calorie-restricted animals is attributed to a defect in both the macrophages and T cells in antigen processing, presentation, and/or proliferation.

Animals↗
PubMed1984

Characterization of the defective autologous mixed lymphocyte response in rheumatoid arthritis.

In order to characterize the autologous mixed lymphocyte response (AMLR) in patients with rheumatoid arthritis (RA) and to define the relationship with disease activity, peripheral blood T lymphocytes were stimulated with either a B lymphocyte-enriched (B cells) or a macrophage-enriched (macrophages) population. A significant reduction (P less than 0.01 to P less than 0.001) of T cell proliferation stimulated both by B cells and macrophages was observed in patients with active disease. The B lymphocytes were significantly less stimulatory (P less than 0.02 to P less than 0.001) than macrophages in the patients compared with the controls. In the normal controls, macrophages in higher concentrations were capable of suppressing the B lymphocyte-stimulated AMLR, but macrophages from patients with RA were not excessively suppressive. A significant association (P less than 0.02) was observed between disease activity and the AMLR. Using the B-enriched population, the AMLR proliferative response was significantly associated (P less than 0.001) with the production of interleukin-2. Defects in proliferation could only be partially restored by the addition of interleukin-2. These data indicate that the defective AMLR observed in patients with RA is related to disease activity and is associated with altered cellular interactions among T lymphocytes, macrophages, and the B lymphocyte-enriched population.

Arthritis, Rheumatoid↗
PubMed1984

Interleukin 2 enhances natural killing of normal lymphocytes.

Purified Interleukin 2 (IL-2), free of interferon (IFN), significantly enhanced NK activity of normal human peripheral blood mononuclear cells (PBMC). This enhancing activity was absorbed by IL-2 receptor-bearing cells but was not blocked by antibody to alpha-IFN. IFN in the culture supernatants was greatly increased after stimulation with poly(I:C) plus IL-2. There was less IFN produced by either modulator acting alone. Stimulation of PBMC with IL-2 and/or poly(I:C) increased the proportion of OKM1+ cells and anti-Leu-7+ cells. When cells expressing either surface antigen were specifically lysed to deplete NK, cytotoxic activity could be restored by overnight incubation in IL-2. This result suggests that IL-2 stimulates the development of NK cells from precursors that lack cell surface OKM1 or Leu-7. IL-2 acted directly on large granular lymphocytes and did not require the presence of adherent cells. These results suggest that IL-2 may act synergistically with other IFN inducers and may play an important role in the regulation of NK cells.

Absorption↗
PubMed1984

Interleukin 2 deficiencies in rheumatoid arthritis and systemic lupus erythematosus.

The ability of peripheral blood lymphocytes from patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and Sjogren's syndrome (SS) to produce interleukin 2 (IL-2) and respond to it in-vitro was examined. Phytohemagglutinin-stimulated lymphocytes from over half of the SLE patients exhibited a decreased ability to produce IL-2 while their concanavalin A-generated blast cells responded normally to exogenous IL-2. Lymphocytes from RA patients not only produced less IL-2 than normals (P less than 0.001), but also responded poorly to exogenous IL-2 (P = 0.011). These abnormalities did not correlate with the patient's age, sex, duration of disease, or disease activity. Production of and response to IL-2 was widely varied among patients with SS and not different from controls. The decreased response of RA lymphocytes to IL-2 may result from a smaller number of cell surface IL-2 receptors since IL-2 adsorption to RA cells was lower than to either SLE or normal cells. These data suggest that IL-2-related abnormalities may play a role in the disordered immunoregulation characteristic of RA and perhaps of SLE.

Absorption↗
PubMed1984

Suppression of lymphoproliferation and auto-immunity by elimination of a radiosensitive bone marrow cell in mice bearing the lpr gene.

The autosomal recessive lpr gene (lymphoproliferative) has been bred into several normal strains of mice. Although the time of disease onset may vary, all of these lpr mice develop hypergammaglobulinaemia, antibodies to nucleoproteins, and massive lymphoproliferation. The abnormalities do not appear in their normal congenic counterparts, which lack the lpr gene. We studied the effects of sublethal whole-body X-irradiation (300 rads) on disease features and lymphocyte subpopulations by using flow cytometry. H-2k strains, C3H and MRL/++ and their autoimmune lpr counterparts, were killed at 1, 2, 4, 8 and 24 weeks after irradiation, which was given at 6-8 weeks of age. In the lpr mice, lymphoproliferation, autoimmunity, mortality and number of Ia+ cells were greatly reduced in the irradiated mice compared with nonirradiated controls. Abnormal cytofluorometric patterns seen with lpr thymocytes were corrected by the low-dose irradiation treatment. In addition, lethally irradiated lpr mice reconstituted with syngeneic bone marrow from low-dose irradiated mice exhibited retarded development of autoimmune disease. We conclude that the lymphoid alterations induced by X-irradiation reflect a recovery of immunologic control associated with suppression of autoimmune manifestations.

Animals↗
PubMed1984

Modulation of natural killer cell activity in the rheumatoid joint and peripheral blood.

Natural killer (NK) cell activity and its regulation in synovial fluid (SF), synovial tissue (ST), and peripheral blood (PB) was studied in 23 patients with active rheumatoid arthritis (RA). NK activity was reduced in PB (P less than 0.005), SF (P less than 0.002), and ST of patients with RA compared to the PB of 28 healthy controls. NK activity in SF was inversely correlated with disease activity as measured by erythrocyte sedimentation rate (r = -0.561; P less than 0.02). Poly I:C, an interferon inducer, stimulated NK activity in RA patients' PB and SF and control subjects' PB to similar extents. However, augmentation of NK activity by interleukin-2 was significantly greater in SF than in PB of RA (P less than 0.02). Preincubation of mononuclear cells with indomethacin significantly increased the NK activity of normal and RA PB but had no effect on that of SF. These observations suggest that the NK activity may be reduced in both PB and SF of RA and that functional differences between populations of cells with NK-like activity and/or differences in the control or modulation of NK activity exist between PB and SF.

Adult↗
PubMed1984

Regulation of natural killer cell activity by macrophages in the rheumatoid joint and peripheral blood.

Recently, in another study, we observed that indomethacin, a prostaglandin synthetase inhibitor, significantly increased NK activity in both normal and rheumatoid arthritis (RA) peripheral blood (PB) but not in RA synovial fluid (SF). Because macrophages are a major source of prostaglandins, we examined the effect of macrophage-enriched adherent cells (AC) on NK activity as measured by a 3-hr Cr-release assay with K 562 cells. The removal of AC resulted in increased (p less than 0.01) NK activity in both normal and RA PB. In contrast, the removal of AC from RA SF resulted in a significant decrease (p less than 0.001) of NK activity. By using only nonadherent cells (NAC), NK activity in RA SF and synovial tissue (ST) was significantly reduced when compared to autologous RA PB (p less than 0.001). Enhancement of NK activity of SF NAC by both poly I:C and IL 2 was not dependent on AC. Mixing experiments demonstrated that the addition of synovial AC for 16 hr increased NK activity of synovial NAC to a level similar to that of unseparated mononuclear cells, whereas autologous PB AC suppressed NK activity of PB NAC. PB AC, when added to SF NAC, also increased NK activity. Supernatants from synovial mononuclear cells were stimulatory of synovial NAC NK activity, whereas normal PB mononuclear supernatants were suppressive. These observations document 1) a significant reduction of NAC-mediated NK activity in the rheumatoid joint as compared to PB from the same patient, and 2) that AC modulate NK activity differently in the rheumatoid joint as compared to RA or normal PB.

Adult↗