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Biomedical subjects

R S Geha

Publications and source records attributed to R S Geha.

At least 217 records · Page 12Linked to original sources
PubMed1985

Differential requirements of B cells from normal and allergic subjects for the induction of IgE synthesis by an alloreactive T cell clone.

Human T cell helper/inducer clones were used to induce IgE synthesis in B cells from both allergic and nonallergic donors. An alloreactive T cell clone, activated by recognition of specific HLA-DR antigens, stimulated peripheral blood B cells from both allergic and nonallergic donors to synthesize IgE antibody. B cells of allergic donors differed from those of nonallergic donors in their requirements for induction of IgE synthesis. Induction of IgE synthesis in B cells from nonallergic individuals occurred only under conditions of cognate interaction, in which the B cells expressed the alloantigen recognized by the T cells. In contrast, IgE synthesis in B cells from allergic donors occurred under conditions of cognate interaction with T cells as well as bystander conditions where the B cells did not express the alloantigen recognized by the T cell clones and where the T cell clones were stimulated by third-party monocytes bearing the relevant alloantigens. Furthermore, bystander stimulation of IgE synthesis in allergic donors occurred in the presence of tetanus toxoid (TT) antigen-specific T cell clones activated by the appropriate TT-pulsed monocytes. In contrast to the differing requirements of B cells from normal vs. allergic subjects for the induction of IgE synthesis, these B cells did not differ in their requirements for the induction of IgG synthesis. IgG synthesis was induced in all B cells under conditions of cognate interaction with the T cells as well as under conditions of bystander stimulation. These results suggest that cognate T-B cell interactions may be important in the development of IgE immune responses in the normal host.

Adult↗
PubMed1985

Acquired C1-inhibitor deficiency associated with antiidiotypic antibody to monoclonal immunoglobulins.

The syndrome of acquired angioedema and C1-inhibitor deficiency is associated with B-cell lymphoproliferative disease. It is characterized by accelerated consumption of C1q and C1 inhibitor in vivo and by low levels of serum C2 and C4. Four patients with B-cell malignant diseases (IgA myeloma, macroglobulinemia, chronic lymphocytic leukemia, and B-cell lymphoma, respectively) and acquired C1-inhibitor deficiency were found to have circulating antiidiotypic antibodies to the monoclonal immunoglobulin expressed on the surface of their B cells (three patients) or in the cytoplasm of their bone-marrow cells (one patient). Two of the four patients had circulating M components, and their antiidiotypic antibodies reacted with the M components. In three patients studied the percentage of B cells bearing C1q was 18, 24, and 35 per cent, as compared with 2.3 +/- 1.7 per cent (mean +/- S.D.) in six normal controls. These results suggest that an interaction between the idiotype of monoclonal immunoglobulins and antiidiotypic antibodies causes increased consumption of C1q and C1 inhibitor in patients with acquired angioedema and C1-inhibitor deficiency. We propose that the subsequent activation of the early components of complement leads to increased vascular permeability and to angioedema and that these patients have a disease caused by antiidiotypic antibodies.

Aged↗
PubMed1985

HLA-DR-4-associated alloreactivity of an HLA-DR-3-restricted human tetanus toxoid-specific T cell clone: inhibition of both reactivities by an alloantiserum.

We present here the first report of a human helper/inducer T cell clone (F6) that specifically recognizes tetanus toxoid (TT) in the context of self-major histocompatibility complex (MHC) determinant(s) (HLA-DR3), and in addition recognizes a specific but unrelated MHC determinant(s) in the absence of conventional antigen. Extensive subcloning insured that the cells were progeny of a single cell. Furthermore, removal of the cells proliferating to the alloantigen with bromodeoxyuridine and light removed cells responding to both TT plus self-MHC and to the stimulating alloantigen, again indicating that F6 was the progeny of a single cell. The alloantigen recognized by this TT-specific clone appears to be closely linked to HLA-DR4 since cells from 13 of 14 HLA-DR4+ donors stimulated F6. An antiserum which recognizes HLA-DR4, when added to cultures, blocked the alloreactivity of F6, and in addition blocked its proliferation to TT plus HLA-DR3. Absorption of this antiserum with HLA-DR4+ cells or with TT-pulsed HLA-DR3+ cells removed its capacity to inhibit the proliferation of F6. These results suggest that the antigen recognition unit on F6 is stimulated both by allodeterminants expressed on HLA-DR4 cells and by TT plus HLA-DR3. These moieties cross-react at the T cell recognition level as well as at the antibody level.

Clone Cells↗
PubMed1985

Role of Ia antigens and interleukin 1 in T-cell proliferation to phytohemagglutinin.

Highly purified human T cells were obtained by a four-step purification procedure which included: removal of plastic adherent cells, rosetting with sheep red cells, passage over nylon-wool columns, and treatment with mouse monoclonal antibodies to human Ia antigens and complement. The resulting T cells did not proliferate to phytohemagglutinin (PHA). Purified human interleukin 1 (IL-1) could not substitute for accessory cells in supporting a PHA response. Reconstitution with as little as 0.03% adherent cells resulted in a proliferative response to PHA. T-Cell proliferation to PHA was supported by monocytes, by Ia+ Epstein-Barr virus-transformed lymphoblastoid B-cells lines, and by Ia- cultured human dermal fibroblasts but not by Ia-containing liposomes. Addition of anti-Ia antibodies to monocyte-containing cultures did not inhibit the T-cell proliferative response to PHA. These results suggest that Ia antigen expression by accessory cells is neither necessary nor sufficient to support T-cell proliferation to PHA and that IL-1 is not sufficient to support the proliferation of T cells to PHA.

B-Lymphocytes↗
PubMed1985

Serum sickness triggered by anaphylaxis: a complication of immunotherapy.

An 8-year-old boy developed anaphylaxis after receiving his maintenance dose of immunotherapy and proceeded to display the signs and symptoms of serum sickness. These consisted of fever, arthralgia, arthritis, urticaria followed by a hemorrhagic palpable rash, edema, lymphadenopathy, splenomegaly, abdominal pain, proteinuria, and neurologic manifestations consistent with vascular compromise of the posterior cerebral circulation. A skin biopsy specimen revealed perivascular infiltrates of lymphocytes and few polymorphonuclear neutrophils. The timing of events in this patient suggests that immunotherapy initiated a chain of events beginning with anaphylaxis and leading to serum sickness. It is hypothesized that the enhanced vascular permeability that accompanied the anaphylaxis allowed immune complexes that may have preexisted in the circulation to deposit in the blood vessels of the patient. These complexes may or may not have been related to the immunotherapy itself. Because antihistamines are known to prevent the induction of serum sickness, early and aggressive treatment of anaphylaxis during immunotherapy may prevent the occurrence of immune complex disease.

Anaphylaxis↗
PubMed1985

Regulation of human IgE synthesis.

The capacity to mount an IgE antibody response to antigen differentiates normal from allergic individuals. The frequent association of high serum IgE with T cell immunodeficiencies suggest a role for T cells in the regulation of human IgE. Peripheral blood lymphocytes (PBL) from allergic individuals spontaneously secrete IgE in vitro whereas normal PBL do not. Unlike the situation with other isotypes the polyclonal B-cell activators, pokeweed mitogen, and Epstein-Barr virus, do not induce IgE synthesis in normal B cells. However, normal B cells synthesize IgE when cultured with T cell clones that recognize determinants expressed by the B cells. B cells from allergic subjects but not from normal subjects are induced to secrete IgE via a bystander effect when cultured with T cell clones which are stimulated by antigenic determinants not expressed by the B cells. T cells with Fc receptors for IgE can be isolated from patients with hyper IgE syndrome and maintained as long term continuous T cell lines or T-T hybridomas. These cells secrete IgE binding factors which enhance IgE synthesis by preactivated IgE bearing B cells from allergic subjects but not resting B cells from normal donors. The phenotype of these Fc R+ IgE-potentiating T cell lines are predominantly T3+T4+Ia+. IgE binding factors have been isolated from normal serum and selectively suppress IgE synthesis. In contrast IgE binding factors isolated from patients with hyper IgE syndrome contain IgE-potentiating activity as well as IgE suppressor activity. These results suggest that in allergic individuals IgE B cells are activated by T cells and their antibody secretion is modulated by IgE binding factors.

Animals↗
PubMed1985

Secretion of IgE-specific potentiating factors by human Fc epsilon R+ T cell lines.

In the present study, Fc epsilon R+ and Fc epsilon R- T cells were isolated from patients with the hyper-IgE syndrome and maintained in long-term cultures with interleukin 2. Supernatants from the Fc epsilon R+ but not from the Fc epsilon R- T cell lines enhanced IgE but not IgG synthesis in B cells derived from patients with allergic rhinitis. There was, however, no induction of IgE synthesis in B cells from nonatopic donors. The IgE-potentiating factors bound to IgE-Sepharose but not to IgG-Sepharose. The target B cells for these IgE binding factors appear to be preactivated IgE-bearing B cells.

B-Lymphocytes↗
PubMed1985

A human T cell lymphoma secreting an immunoglobulin E specific helper factor.

An 8-yr-old nonallergic girl with non-Hodgkin's lymphoma had markedly elevated serum IgE at presentation (greater than 10,000 IU/ml), negative skin tests to a battery of 24 common allergens, and no evidence of parasitic infestation. Serum levels of IgG, IgA, and IgM were normal. Remission after cytotoxic chemotherapy was accompanied by a marked reduction in serum IgE levels (to less than 200 IU/ml) with no change in the level of serum IgG, IgM, or IgA. Recurrence of the lymphoma 7 mo after remission was accompanied by an isotype specific rise in serum IgE (to 3,850 IU/ml). Isoelectric focusing revealed that the IgE was polyclonal. Phenotypic analysis of the lymphoma obtained during relapse revealed all (greater than 98%) cells to be T3+, T4+, and T8+. Incubation of lymphoma cells with human myeloma IgE followed by immunosorbent purified fluorescein tagged goat anti-human IgE (anti-IgE PS-adsorbed over IgE ADZ) stained 25% of the cells. In contrast, less than 1% of the cells were stained after incubation with human IgG followed by fluorescein conjugated goat anti-human IgE. Supernatants from lymphoma cells (5 X 10(6)/ml, 48 h) enhanced IgE production in B cells derived from four patients with allergic rhinitis (mean +/- SD picograms per milliliter of net IgE 930 +/- 320 in unstimulated cultures versus 2,450 +/- 650 in cultures stimulated with lymphoma supernatants; P less than 0.01) but did not induce IgE synthesis in B cells from two normal subjects that synthesized no IgE spontaneously. Lymphoma supernatants failed to enhance IgG synthesis by B cells of both allergic and nonallergic subjects. These results indicate that a T cell lymphoma comprised of cells bearing Fc receptors for IgE with a phenotype characteristic of immature T cells (i.e., T3+, T4+, T8+) exhibited IgE specific helper function. This lymphoma may represent the monoclonal expansion of a subpopulation of IgE specific helper T cells.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1985

Human dermal fibroblasts present tetanus toxoid antigen to antigen-specific T cell clones.

Cultured human dermal fibroblasts treated with immune interferon express HLA-DR antigens. We report here that DR-positive fibroblasts present tetanus toxoid (TT) to autologous TT-specific monoclonal helper T cells vigorously depleted of monocytes by passage over Sephadex G10 columns followed by treatment with the monoclonal antibodies (mAb) OKM1 and Leu M1 plus complement. The extent of T cell proliferation in response to TT presented by DR-positive fibroblasts was similar to that elicited using monocytes as antigen-presenting cells. The proliferative response was TT dependent, antigen specific, depended upon DR expression by fibroblasts, appeared MHC restricted, and was completely blocked by mouse mAb to HLA-DR but not by mAb to HLA-A,B, or DQ. DR-positive fibroblasts pulsed with TT were similarly effective in antigen presentation. In summary, immune interferon-stimulated human dermal fibroblasts can substitute for classical antigen-presenting cells in antigen-specific proliferative responses. Since fibroblasts are a ubiquitous cell type in the body, they may play a significant role in the immunobiology of the host.

Antibodies, Monoclonal↗
PubMed1985

Regulation of IgE synthesis in man.

It is clear that T cells play a role in the regulation of IgE synthesis. This is in part mediated via the secretion of IgE binding factors which home on the IgE B cells and deliver either enhancing signals prompting the B cell to differentiate into secreting more IgE antibody or suppressor signals which shut off antibody production. A balance between these two signals will determine the magnitude of the IgE antibody response. The presence of IgE suppressor factor in normal serum and the presence of IgE helper factors in serum and in supernatants of cell lines from individuals with high IgE will allow us to better understand the mechanism of IgE regulation and devise more rational strategies for treatment of allergic diseases. Initial encouraging clinical results have been obtained with administration of normal serum and suppression of IgE synthesis. With the advent of hybridoma techniques and DNA recombinant technology, one should be able to isolate these factors in sufficient quantity, and test them safely in clinical situations.

B-Lymphocytes↗
PubMed1985

Antigen presentation by EBV-B cells to resting and activated T cells: role of interleukin 1.

We have previously demonstrated that Epstein Barr virus-transformed human B lymphocytes (EBV-B cells) present antigen to activated T cells (lines and clones) in a MHC-restricted manner. In the present study, using EBV-nonimmune donors, we demonstrate that EBV-B cells are unable to trigger tetanus toxoid (TT) antigen-specific proliferation in autologous highly purified resting T cells. EBV-B cells from these same individuals were able to present TT to autologous TT-specific activated T cell blasts (Tbl). The inability of EBV-B cells to present TT to resting T cells was not caused by defective antigen processing by EBV-B cells. Thus, paraformaldehyde treatment of antigen-pulsed EBV-B cells did not impair their ability to trigger proliferation of antigen-specific Tbl, and EBV-B cells pulsed with antigen in the presence of autologous TT-specific T cell blasts did not present antigen to resting T cells. Furthermore, antigen-specific proliferation of resting T cells triggered by monocytes was enhanced rather than suppressed by EBV-B cells. The addition of partially purified human IL 1 allowed EBV-B cells to present TT antigen to resting T cells, suggesting that failure to secrete IL 1 contributed to the failure of EBV-B cells to present antigen. IL 1 could not be detected in supernatants of EBV-B cells stimulated with Staphylococcus epidermidis, concanavalin A, and TT antigen in the presence or absence of up to 5% autologous T cells. The differential capacity of EBV-B cells to present antigen to resting T cells vs activated T cells correlated with the T cell requirement for IL 1, because a rabbit antibody to human IL 1 inhibited the monocyte-supported proliferation of resting T cells but not that of activated T cells. These results suggest that the inability of EBV-B cells to present antigen to resting T cells is related to their inability to secrete detectable IL 1.

Adult↗
PubMed1985

Mechanisms of human T cell response to mitogens: IL 2 induces IL 2 receptor expression and proliferation but not IL 2 synthesis in PHA-stimulated T cells.

Human peripheral blood T cells were purified by a four-step procedure which included depletion of plastic-adherent cells, rosetting with sheep red blood cells, nylon wool passage, and treatment with mouse monoclonal antibodies to human Ia antigens plus complement. The purified T cells completely failed to proliferate to phytohemagglutinin (PHA). Bacterially derived recombinant human interleukin 2 (IL 2) reconstituted the proliferative response of resting T cells to PHA. The optimal concentration of IL 2 required was 100 to 200 U/ml. IL 2 alone caused no T cell proliferation. Both PHA and IL 2 needed to be present together for the proliferation of T cells to occur. Incubation of T cells with either PHA or IL 2 alone for up to 18 hr, followed by washing, then by the addition of the reciprocal reagent, resulted in no T cell proliferation. Expression of IL 2 receptors and of Ia antigens, as assessed by indirect immunofluorescent staining, revealed that both PHA and IL 2 needed to be present for Tac and Ia antigen expression by T cells. T cells incubated with PHA and IL 2 for 18 to 42 hr acquired responsiveness to IL 2. These T cells remained absolutely dependent on IL 2 for proliferation to occur. In contrast to T cells stimulated with PHA in the presence of monocytes, T cells stimulated with PHA and IL 2 released no detectable IL 2. The failure of IL 2 secretion was not caused by down-regulation of IL 2 production by IL 2 itself, because the addition of IL 2 to cultures of T cells stimulated with PHA in the presence of monocytes did not interfere with IL 2 production. These results indicate that IL 2 is a sufficient signal to induce the expression of its receptor in PHA-stimulated T cells and subsequent proliferation but is not sufficient to cause endogenous IL 2 release.

Cells, Cultured↗
PubMed1984

Analysis of antigen uptake and presentation by Epstein-Barr virus-transformed human lymphoblastoid B cells.

Epstein-Barr virus-transformed human B cells (EBV-B cells), but not resting B cells or B cells activated by T cell-derived factors, have been shown to support the proliferation of tetanus toxoid (TT)-specific autologous T cell clones in response to TT antigen. The accessory cell function of EBV-B cells was compared to that of monocytes with regard to antigen uptake and processing. After an 18-h incubation period with 125I-labeled TT, the amount of radioactivity associated with the cells (approximately 50 ng/10(7) cells) and the percentage of cells containing radiolabeled material (approximately 50%) were equivalent for EBV-B cells and monocytes. Like with monocytes, EBV-B cells pulsed with TT for 18 h or more were equivalent in their capacity to induce T cell proliferation to EBV-B cells to which soluble TT was added for the duration of the culture period. The requirements for antigen uptake and presentation to T cells were similar for both EBV-B cells and monocytes. Both processes were energy dependent, inhibited by cold (4 degrees C), 2-deoxyglucose, and azide, and both required no de novo protein synthesis as they were not affected by pretreatment of the cells with the irreversible protein inhibitor pactamycin . Trypsin treatment of antigen-pulsed EBV-B cells and monocytes followed by fixation for 1 min in 0.03% paraformaldehyde completely abolished the capacity of both cell types to induce T cell proliferation. In both EBV-B cells and monocytes, antigen presentation, but not antigen uptake, was inhibited by the addition of the lysosomotropic agent chloroquine during the antigen-pulse period suggesting that the mechanisms of antigen processing are similar for both cell types. Vacuoles positive for acid phosphatase with an electron microscopic structure similar to that of lysosomes were found in EBV-B cells but not in resting B cells or B cells activated by T cell-derived factors. The present observations indicate that EBV-B cells take up antigen and process it in a fashion similar to monocytes. The presence of lysosomes appears to correlate with the capacity of B cells to present antigen.

Azides↗
PubMed1984

Production of IgE-potentiating factor in man by T cell lines bearing Fc receptors for IgE.

The regulation of human IgE production in vitro by soluble T cell factors was examined. T cells were isolated from the peripheral blood of 2 patients with the hyper-IgE syndrome on the basis of their expression of Fc receptors for human IgE (Fc epsilon R). The T cells were incubated with human myeloma IgE (10 micrograms/ml), washed, reacted with immunosorbent-purified goat anti-human IgE conjugated with fluorescein isothiocyanate, and then separated into Fc epsilon R+ and Fc epsilon R- T cells on the fluorescence-activated cell sorter. Fc epsilon R+ T cells and Fc epsilon R- T cells were propagated in culture using supernatants of phytohemagglutinin-stimulated peripheral blood mononuclear cells (PBMC) and irradiated autologous PBMC. Supernatants of Fc epsilon R+ T cell lines but not of Fc epsilon R- T cell lines selectively enhanced IgE synthesis in cultures of B cells obtained from patients with allergic rhinitis but not from normal nonallergic subjects. The surface phenotype of the Fc epsilon R+ T cell line was predominantly T3+, T4+, Ia+ with few (15%) T8+ cells. Two T cell clones were grown from the Fc epsilon R+ T cell line by limiting dilution (0.3 cells/well). These clones possessed the T4+ helper/inducer phenotype and secreted IgE-enhancing factor(s). The IgE-enhancing factor(s) which had affinity for insolubilized human IgE was sensitive to treatment with trypsin and neuraminidase, and had as its target an IgE-bearing B cell. These results suggest that a subset of human T cells bearing an Fc epsilon R secretes an IgE-binding glycoprotein which selectively enhances IgE synthesis by IgE-bearing B cells.

Adult↗
PubMed1984

IgE-specific suppressor factors in normal human serum.

The effect of normal human serum on in vitro IgE production was studied in an attempt to determine whether IgE-specific suppressor factors are present in the circulation of nonallergic individuals. Sera from 10 nonatopic donors (serum IgE less than 20 I.U./ml) were filtered through Diaflo CF50A membranes (cutoff point 50,000 D) and various dilutions of the IgE-free serum filtrates (less than 150 pg/ml of IgE) were examined for their ability to suppress spontaneous in vitro IgE synthesis by peripheral blood mononuclear cells (PBMC) from patients with hyper-IgE states. Serum filtrates from all 10 nonatopic donors tested suppressed IgE synthesis (mean suppression = 70 +/- 4%). IgE suppression was isotype specific because addition of the serum filtrates to pokeweed mitogen-stimulated normal PBMC or to spontaneously activated B cells from patients with active systemic lupus erythematosus did not suppress IgG or IgM production. The IgE suppressor activity was destroyed by treatment with trypsin but not with neuraminidase or exposure to heat. Substantial suppressor activity bound to IgE-Sepharose but not to a control IgG-Sepharose column. Further evaluation of the IgE-binding serum IgE suppressor factor(s) revealed a marked affinity for peanut agglutinin-Sepharose but minimal binding to lentil lectin-Sepharose. These results suggest that human serum from nonatopic donors contain low molecular weight IgE-binding factors which selectively suppress IgE production but not IgG production. Characterization of ths IgE-binding suppressor factor(s) reveals physicochemical features similar to those previously described for rat T-cell-derived IgE-binding factors with IgE suppressive activity.

Drug Stability↗
PubMed1984

Human IgE.

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Antigen-Antibody Complex↗
PubMed1984

Immunodeficiency with defective T-cell response to interleukin 1.

Normal proliferation of T cells in vitro requires production of and response to the lymphokine interleukin 2 (IL-2). Optimal IL-2 production by T cells is dependent on the monokine interleukin 1 (IL-1). A 10-year-old male with recurrent infections and failure to thrive was evaluated for possible defects in the production and response to IL-1 and IL-2. The patient had normal levels of serum immunoglobulins and a normal distribution of circulating T-cell subsets. However, the in vitro proliferative response of his peripheral blood mononuclear cells (PBMC) to phytohemagglutinin was depressed (40% of normal) and the response of his PBMC to antigens was absent. Delayed hypersensitivity skin tests and in vitro response to tetanus toxoid remained absent despite repeated immunizations. Monocyte function in this patient was normal as judged by the following criteria: normal expression of Ia antigens (77% +), normal IL-1 production, and normal capacity to present tetanus toxoid to a maternal T-cell line specific for tetanus toxoid antigen. The abnormal phytohemagglutinin response of the patient's PBMC was corrected by the addition of exogenous IL-2. IL-2 production by the patient's phytohemagglutin-stimulated PBMC was severely deficient but was corrected by the addition of phorbol 12-myristate 13-acetate, suggesting a defective response to IL-1. T-cell blasts derived from a normal subject but not T-cell blasts derived from the patient absorbed out IL-1 activity from a preparation of purified human IL-1. These results indicate that the patient's T-cell deficiency was due to a defective T-cell response to IL-1 and suggest that IL-1 plays an important role in the in vivo immune response.

Cells, Cultured↗