Search PubMed⌕ Search

Biomedical subjects

R M Blaese

Publications and source records attributed to R M Blaese.

At least 145 records · Page 8Linked to original sources
PubMed1983

Reversal of infectious mononucleosis-associated suppressor T cell activity by D-mannose.

Epstein-Barr virus-induced infectious mononucleosis (IM) is associated with the activation of suppressor T lymphocytes that profoundly inhibit immunoglobulin (Ig) production in vitro. We have examined the nature of signals operating in the interaction between IM suppressor T cells and their targets, and explored the possibility that a lectin-like receptor molecule and its specific sugar might provide specificity to this interaction. When D-mannose or some of its derivatives, including alpha-methyl-D-mannoside, mannose-6-phosphate, and mannan, were added to suppressed cultures containing IM T lymphocytes and pokeweed mitogen (PWM)-stimulated normal mononuclear cells, a significant enhancement of Ig production was observed. These sugars had little or no effect on Ig production by the PWM-stimulated responder cells alone and thus the enhanced Ig production could be attributed to the reversal of suppression in the co-cultures by these sugars. This was further confirmed by the observation that the sugars were effective only if present during the first 24 h of culture, a time when IM suppressor T cells exert their principal effect. The effect of sugars on Ig production by suppressed cultures was similar to that achieved by decreasing by about fourfold the number of IM T cells in culture. The effect of the sugars is unlikely to represent a form of nonspecific toxicity, since inhibited cultures become responders in the presence of the sugar. Furthermore, toxicity restricted to the suppressor T cells is unlikely, since preincubation of the T cells with the sugars did not reduce their subsequent ability to suppress in secondary indicator cultures. In addition, there was no correlation between the effect of the sugars on T cell proliferation and their effect on T cell-mediated suppression. The reversal of suppression by sugars was dose dependent and demonstrated stereo-specificity in that L-mannose was without effect while D-mannose reversed suppression. These data indicate that D-mannose and some of its derivatives consistently reverse suppression of Ig production by IM T cells and strongly suggest a role for saccharides as critical components in the cellular receptors involved in certain physiologic immune cell interactions.

Acute Disease↗
PubMed1983

Induction of cytotoxic effector activity in the HL-60 promyelocytic cell line by incubation with phorbol myristate acetate: a model system of human spontaneous monocyte-mediated cytotoxicity.

In an attempt to develop a constant and reproducible in vitro system for a detailed analysis of cytotoxic effector mechanisms of nonimmune mononuclear phagocytes, the HL-60 promyelocytic cell line was studied for its cytotoxic action on chicken erythrocyte target cells. HL-60 cells cultured in complete medium were found to be noncytotoxic for chicken erythrocytes in an 18-hr 51Cr-release assay. These cells have been shown to acquire several characteristics of mature macrophages upon incubation with phorbol myristate acetate (PMA), and when PMA was included in the medium during the assay, the HL-60 cells became strongly cytotoxic to the target cells in the absence of exogenous antibody, lectin, or serum complement. Freshly isolated peripheral blood monocytes also became cytotoxic in the presence of PMA, whereas peripheral blood lymphocytes and the U937 histiocytic cell line did not. Detectable target lysis was observed between 4 and 8 hr after HL-60 stimulation with PMA, and HL-60 cells prestimulated with PMA for 24 hr retained their cytotoxic activity following washing and assay in PMA-free medium. Cytotoxic HL-60 cells developed after exposure to 10(-6) to 10(-9) M PMA, and significant target cell lysis occurred at effector:target cell ratios as low as 0.5:1. The PMA-induced HL-60-mediated cytotoxic response was markedly inhibited by blockers of protein synthesis, inhibition of microfilament function, and depletion of cellular superoxide and hydrogen peroxide. Interestingly, cytotoxicity of HL-60 cells for chicken erythrocyte targets was modulated by the direct addition of certain simple saccharides to the assay in a fashion similar to that observed with spontaneously cytotoxic mononuclear cells from several vertebrate and invertebrate species. Thus, the cytolytic effector function induced in HL-60 cells by incubation with PMA presents a useful model for the study of cellular cytotoxic mechanisms as well as the mechanisms utilized by nonimmune cells in the recognition of non-self.

Animals↗
PubMed1983

Limiting dilution analysis of Epstein-Barr virus-induced immunoglobulin production by human B cells.

The Epstein-Barr virus (EBV) is a herpes virus that has the capacity to infect human B cells and to induce them to secrete immunoglobulin (Ig). In the current experiments, Poisson analysis of limiting dilution cultures has been used to study the activation of human peripheral B cells by the B95-8 strain of EBV. Under the culture conditions used, 0.2-1% of peripheral blood B cells were activated by EBV to secrete IgM or IgG. In addition, when multiple replicate cultures containing limited numbers of B cells were tested for IgM and for IgG production, the precursors for IgM and IgG segregated independently; thus, individual B cell precursors matured into cells secreting IgM or IgG but not both classes of Ig. Additional experiments using limiting dilutions of EBV were undertaken to study the viral requirements for B cell activation. These studies indicated that B cell activation by EBV to produce Ig was consistent with a "one-hit" model and inconsistent with a "two-hit" model. Taken together, these results indicate that infection by one EBV virion is sufficient to induce a precursor peripheral blood B cell to secrete Ig and that only one isotype of Ig is then secreted.

Antibody Formation↗
PubMed1983

The proportion of TA, TG, and TM cells in various immunodeficiency and autoimmune disorders.

Patients with various immunodeficiency and autoimmune disorders were examined for the proportions of T cells bearing Fc-IgA, Fc-IgG, and Fc-IgM receptors. These disorders included common variable immunodeficiency, systemic lupus erythematosus, ataxia-telangiectasia, selective IgA deficiency, and the Wiskott-Aldrich syndrome. Abnormal proportions (higher or lower than an interval containing 95% of our normal values) of Fc-IgA receptor-bearing T cells (TA) were found in common variable immunodeficiency, systemic lupus erythematous, ataxia-telangiectasia, and selective IgA deficiency. However, the proportion of T cells bearing Fc receptors did not correlate with their functional activity in in vitro immunoglobulin production assays.

Ataxia Telangiectasia↗
PubMed1982

Cooperative interaction of factor B and other complement components with mononuclear cells in the antibody-independent lysis of xenogeneic erythrocytes.

Synergistic cytotoxicity is a term used to describe a cytotoxic system in which xenogeneic erythrocyte target cells are lysed in the presence of nonimmune human mononuclear effector cells and antibody-depleted normal human serum. Neither the mononuclear cells nor the serum alone are cytolytic to the target erythrocytes. Previous studies have shown that the serum activity is not immunoglobulin and is heat-labile, suggesting a similarity to serum complement. In this report, sera deficient in various complement components as well as highly purified single complement components were tested with whole mononuclear cell populations and purified monocytes and lymphocytes to further characterize this cytotoxicity system. Whole mononuclear cell populations failed to mediate target cell lysis in sera deficient in C5 or factor B. However, C3-deficient serum, even in the presence of anti-C3 antibody, supported synergistic cytotoxicity normally. Purified lymphocytes were also normally cytotoxic in C3-deficient serum but failed to lyse targets in sera deficient in C5, C7, C8, or depleted of factor B. Purified monocytes failed to lyse the target cells only in factor B-depleted serum and could lyse the target cells in serum-free medium when purified factor B alone was added. Monocyte-mediated cytotoxicity induced by factor B was inhibited 73-100% by adding lymphocytes back to the purified monocytes. Thus, both lymphocytes and monocytes can serve as effector cells in this form of cytotoxicity but require cooperative interaction with different sets of complement components. In addition, lymphocytes can modulate the monocyte-mediated form of target cell lysis associated with factor B.

Animals↗
PubMed1982

Interferon-mediated inhibition of human polyclonal immunoglobulin synthesis.

Human lymphoblastoid IFN suppressed human polyclonal Ig synthesis in a dose-related manner, with 71% mean inhibition of antibody production found when 1000 units of IFN were added to the cultures. This suppression was demonstrated to be mediated by an electrophoretically pure preparation of IFN. Furthermore, IFN inhibition of both the T-dependent and the T-independent polyclonal activators was not the result of direct cellular cytotoxicity. IFN-mediated suppression of human polyclonal Ig production does not result from induction of T suppressor cells, and in a T helper cell-independent system this inhibition appears to result from either a direct action on the B cells or an indirect effect via monocytes.

Antibody Formation↗
PubMed1982

T cell-mediated immunoregulation of Epstein Barr virus- (EBV) induced B lymphocyte activation in EBV-seropositive and EBV-seronegative individuals.

Infection with Epstein Barr virus (EBV) is accompanied by seroconversion and life-long persistence of the virus in B lymphocytes. During acute EBV-induced infectious mononucleosis, suppressor T cells become activated, which may provide an additional mechanism of host defense against the causative agent. When cultures of lymphocytes from normal adults seropositive for EBV were stimulated with the B95-8 strain of EBV, purified B cells produced increasingly higher numbers of immunoglobulin- (Ig) secreting cells, whereas in co-cultures of autologous B and T cells a profound suppressor T cell activity inhibited further B cell activation after 10 to 12 days in culture. No such T cell-mediated inhibitory effect was seen in cultures of lymphocytes obtained from normal adults seronegative for EBV, indicating a correlation between the suppressor effect with evidence of prior immunity to this virus. The T cell-mediated suppression in patients with infectious mononucleosis is characterized by an early-acting inhibitory effect on B cell differentiation that is not specific in that all polyclonal B cell activators are inhibited, whereas in EBV-seropositive normal subjects suppression is delayed in time and affects only EBV-activated cultures. These data indicate that after infection with EBV, immunoregulatory T cells are generated that are capable of inhibiting further EBV-induced activation of autologous B cells and thus may provide an additional unique mechanism of host defense against persisting EBV-infected B cells.

Antibody-Producing Cells↗
PubMed1982

Immunosuppressive activity of succinylacetone.

SA, an inhibitor of ALA dehydrase, the second enzyme of the heme biosynthetic pathway, has been shown to exert immunosuppressive activity in several systems. When the Walker 256 tumor was grown subcutaneously in outbred Sprague-Dawley rats, SA prevented rejection of the tumor by the host. Human peripheral blood lymphocyte transformation in response to mitogens and antigens in vitro was markedly impaired by addition of SA to the medium. Addition of hematin to the medium did not reverse the SA-mediated inhibition of transformation. This finding suggests that SA may exert immunosuppressive activity by a mechanism separate from inhibition of heme biosynthesis. Continuous administration of SA to Fisher 344 rats profoundly suppressed hemolytic antibody production after immunization with SRBC. Administration of large doses (equivalent to the highest dose of Sa given to tumor-bearing animals) for a month produced a 20% decrease of hemoglobin concentration, a 12% decrease in hematocrit, and no significant effect on leukocyte or erythrocyte concentration. There were no significant changes in tissue histology, including marrow cellularity.

Animals↗
PubMed1982

Monocyte cytotoxicity: evidence for multiple mechanisms of in vitro erythrocyte target killing. Trypan blue can both inhibit and enhance target lysis.

Four systems of human monocyte-mediated cytotoxicity against chicken erythrocyte targets were studied using a panel of cellular inhibitors. Monocyte synergistic cytotoxicity (MSC), spontaneous monocyte-mediated cytotoxicity (SMMC), antibody-dependent cellular cytotoxicity (ADCC), and mitogen-induced cellular cytotoxicity (MICC) each had a different pattern of inhibition with these agents. Monocyte synergistic cytotoxicity, a system in which monocytes and certain complement components cooperate in the lysis of target cells, was inhibited only by trypan blue, a known inhibitor of lysosomal enzymes and macrophage cytolysis of tumor cells. In marked contrast, spontaneous monocyte-mediated cytotoxicity, a system in which monocytes become spontaneously cytotoxic after a 5- to 10-day incubation in culture, was enhanced by trypan blue, whereas MICC and ADCC were not affected. Agents which deplete cellular hydrogen peroxide and superoxide were most inhibitory for SMMC and had no effect on ADCC, MICC, and MSC. Inhibitors of protein synthesis only blocked MICC, having no effect on the other systems. These data support the hypothesis that monocytes possess multiple mechanisms by which they may inflict damage on erythroid targets, which may depend on oxidative intermediates (SMMC), protein synthesis (MICC), microfilament function (SMMC, MICC, ADCC), in addition to other mechanisms which have not yet been clearly defined (MSC). Trypan blue can thus both inhibit and enhance different forms of monocyte-mediated cytotoxicity. Further studies with this agent revealed that preincubation of cells with trypan blue depleted the ability of the cells to kill by SMMC but not by ADCC or MICC. Such studies suggest that trypan blue, like certain other compounds, has more than one mechanism of action on cellular processes important for the mediation of cytotoxicity.

Animals↗
PubMed1981

Defective EBV-specific suppressor T-cell function in rheumatoid arthritis.

Several lines of evidence, including high antibody titers to Epstein-Barr virus (EBV)-associated antigens and rapid transformation of B cells into lymphoblastoid cells lines, suggest an association between EBV and rheumatoid arthritis. When lymphocytes from normal immune donors were infected with EBV in culture, they produced an exponentially increasing number of immunoglobulin-secreting cells for eight to 10 days. Thereafter, there was a marked late suppression of their response, mediated by immunoregulatory T cells; by 12 days in culture, this suppression averaged 90 per cent. Lymphocytes from 20 EBV-immune patients with rheumatoid arthritis also responded with increasing production of immunoglobulin-secreting cells, but the late suppression expected in immune donors was absent. Tests of several other T-cell functions in these patients gave normal results, suggesting a more restricted defect in suppressor-T cell function relating specifically to EBV. Since EBV persists in host B cells and thus represents a potential stimulus for immunoglobulin production, this persistence, along with a specific regulatory T-cell defect, may contribute to many of the immune abnormalities underlying rheumatoid arthritis.

Adult↗
PubMed1981

Characterization of a soluble suppressor of human B cell immunoglobulin biosynthesis produced by a continuous human suppressor T cell line.

A human suppressor T cell maintained in long-term culture with conditioned medium containing interleukin 2 elaborates a suppressor factor(s) that specifically inhibits human polyclonal B cell immunoglobulin biosynthesis. This soluble immune suppressor supernate of immunoglobulin production (CTC-SISS-B) shares a number of features with the previously described suppressive mediator elaborated by concanavalin A-activated human peripheral T cells (SISS-B) including: (a) the inhibition by a noncytotoxic mechanism, (b) the suppression of immunoglobulin biosynthesis either through direct action on the B cell or indirect action via the monocyte, (c) the loss of inhibition in the presence of the monosaccharide L-rhamnose, (d) the elaboration by cells irradiated with 500 ro 2,000 rad, and (e) molecular weights of 60,000--90,000. Furthermore, the suppression by this mediator appears to be specific for B cell immunoglobulin production in that CTC-SISS B has no effect on T cell proliferation to mitogens, antigens, an allogeneic cells or on T cell-mediated cytotoxicity. These data indicate that one possible mechanism of suppressor T cell inhibition of human immunoglobulin production is via the generation of a lectinlike suppressor lymphokine that interacts with defined saccharide determinants on the cell surface of either the B cell or monocyte.

Animals↗