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Biomedical subjects

R S Geha

Publications and source records attributed to R S Geha.

At least 235 records · Page 13Linked to original sources
PubMed1984

Role of interleukin 1 in antigen-specific T cell proliferation.

The role of interleukin 1 (IL 1) in human antigen-specific T cell proliferation was examined. Nylon wool-purified T cells proliferated in the presence of autologous monocytes (Mo.) pulsed for 18 h with tetanus toxoid (TT) antigen (Mo.TT). Irradiation of Mo.TT with ultraviolet (UV) light (72 J/m2) abolished their capacity to support T cell proliferation and drastically reduced their capacity to secrete IL 1 after stimulation with Staphylococcus albus. The defect in antigen presentation induced by UV irradiation of Mo.TT was reversed in a dose-dependent manner by the addition of two different preparations containing human interleukin 1 (IL 1). The first preparation consisted of supernatants of Mo. stimulated with Con A for 18 hr and in which Con A activity was blocked by alpha-D-methyl-mannoside (Mo.-Con A-Sup). The second preparation consisted of human IL 1 partially purified from supernatants of human peripheral blood mononuclear cells stimulated with S. albus. This IL 1 copurified with human leukocyte pyrogen (LP) and was termed IL 1/LP. Both IL 1-containing preparations enhanced the response of C57BL/6 mouse thymocytes to phytohemagglutinin. A rabbit antibody to human IL 1/LP inhibited the capacity of T cells to proliferate in response to Mo.TT and inhibited the capacity of Mo.-Con A-Sup to reconstitute the T cell response to UV-irradiated Mo.TT. IL 1/LP was not necessary for T cells to recognize the immunogenic moiety presented by Mo., because monolayers of UV-irradiated Mo.TT were equivalent to monolayers of unirradiated MO.TT in their capacity to adsorb TT-reactive T cells specifically. Furthermore, the addition of rabbit antibody to IL 1/LP did not interfere with the capacity of UV-irradiated Mo.TT to adsorb TT-reactive T cells. The results obtained in this study indicate that IL 1 is involved in optimal antigen-driven proliferation of human T lymphocytes.

Adult↗
PubMed1984

Idiotypic determinants on human T cells and modulation of human T cell responses by anti-idiotypic antibodies.

The role of idiotypic anti-idiotypic interactions in the regulation of the human T cell response to tetanus toxoid (TT) antigen was examined in three subjects. Rabbit anti-idiotypic (anti-Id) antisera were raised against IgG (Fab')2 anti-TT obtained 7 to 10 days after booster immunization with TT. F(ab')2 fragments of rabbit-anti-Id IgG were used in conjunction with fluorescein-conjugated goat anti-rabbit Ig in an indirect immunofluorescence assay to determine the frequency of Id-positive cells in T cell-enriched preparations. This frequency was 24, 29, and 38 per 10,000, respectively, in the three subjects studied. Significant contribution of contaminating B cell to fluorescence-staining was ruled out by capping experiments using goat anti-human Ig (GAHIG) and by double staining experiments using rhodamine-conjugated GAHIG. Absorption of anti-Id antisera with Epstein Barr virus (EBV)-transformed B cell lines from the IgG (Fab')2 anti-TT donor, but not with EBV-B cell lines from unrelated donors, removed their reactivity with the T cells. Rabbit anti-Id IgG caused minimal proliferation (two-threefold) of T cells and had no effect on T cell proliferation in response to TT antigen when added to the cultures. Preincubation of T cells for 48 hr with rabbit anti-Id IgG (Fab')2, but not with preimmune rabbit IgG (Fab')2, resulted in the generation of antigen-specific suppressor cells that inhibited T cell proliferation in response to TT, but not in response to diphtheria toxoid (DT). These cells also inhibited the synthesis of IgG anti-TT in response to in vitro stimulation with TT antigen, but not the synthesis of IgG anti-DT in response to DT antigen. Adsorption of T cells over plates coated with rabbit anti-Id IgG (Fab')2 enhanced the proliferative response of the T cells to TT, but not to DT antigen, and enhanced the helper activity of the T cells for the in vitro synthesis of IgG anti-TT but not of IgG anti-DT antibodies. These results suggest that idiotypic-anti-idiotypic interactions play a role in the human T cell response to antigen.

Absorption↗
PubMed1984

Mechanisms of the failure of resting B cells to present tetanus toxoid antigen to T cells.

The present study examines the failure of resting B cells to present tetanus toxoid (TT) antigen to T cells. A hybrid antibody directed against TT and against human IgM was prepared from immunosorbent-purified rabbit anti-TT and rabbit anti-human IgM. Peripheral blood B cells were prepared by double rosetting with sheep red cells and were depleted of monocytes by double adherence over plastic plates and by passage over a Sephadex G-10 column followed by treatment with OKM1 and complement. B cells were preincubated with medium or with hybrid antibody (60 micrograms/ml) for 1 hr at 4 degrees C, washed, irradiated (2500 R), and tested for their capacity to present TT to an autologous TT-specific T cell clone. B cells coated with the hybrid antibody took up equivalent amounts of 125I-TT as monocytes or EBV-B cells and they internalized fluorescein-labeled TT. In contrast, in the absence of hybrid antibody B cells took up negligible amounts of TT antigen. However, B cells preincubated with the hybrid antibody failed to induce proliferation of autologous TT-specific T cell clones in response to TT. This was not corrected by the addition of partially purified human interleukin I. EBV-B cells sequentially pulsed with hybrid antibody and then with TT for 1 hr at 4 degrees C were equivalent in their capacity to induce T cell proliferation to EBV-B cells presenting soluble TT to the T cells. In contrast EBV-B cells pulsed with TT alone at 4 degrees C failed to take up and present TT. Thus the failure of hybrid antibody-coated resting B cells to present TT reflects an intrinsic inability of the resting B cells to present antigen. Monolayers of hybrid antibody-coated B cells pulsed with TT were prepared on anti-human Fab-coated dishes and were compared with monolayers of TT-pulsed monocytes for their capacity to adsorb TT-specific autologous T cells. In contrast to TT-pulsed monocytes, TT-pulsed hybrid antibody-coated B cells completely failed to bind TT-specific T cells. These results suggest that in addition to their poor antigen uptake resting B cells are incapable of processing antigen and generating the immunogenic moiety recognized by the T cells.

Animals↗
PubMed1983

Evaluation of clinical data in childhood asthma. Application of a computer file system.

A computer file system was used in our pediatric allergy clinic to assess the value of chest roentgenograms and hemoglobin determinations used in the examination of patients and to correlate exposure to pets and forced hot air with the severity of asthma. Among 889 children with asthma, 20.7% had abnormal chest roentgenographic findings, excluding hyperinflation and peribronchial thickening, and 0.7% had abnormal hemoglobin values. Environmental exposure to pets or forced hot air was not associated with increased severity of asthma, as assessed by five measures of outcome: number of medications administered, requirement for corticosteroids, frequency of clinic visits, frequency of emergency room visits, and frequency of hospitalizations.

Adolescent↗
PubMed1983

Characterization of the mononuclear cell infiltrate in atopic dermatitis using monoclonal antibodies.

Tissue sections from involved and uninvolved skin of nine patients with atopic dermatitis (AD) were investigated by light microscopy, electron microscopy, and an immunoperoxidase method using monoclonal antibodies to cell-surface antigens. Acute lesions were characterized by spongiotic epidermis, with increased numbers of infiltrating mononuclear cells consisting predominantly of lymphocytes. Perivascular dermal infiltrates consisted of lymphocytes and a few monocytes-macrophages. Capillary endothelial cells were not enlarged. In chronic lesions the epidermis was hyperplastic, with virtually no cellular infiltrate. The perivascular dermal infiltrates consisted primarily of monocytes-macrophages intermixed with lymphocytes. Capillary lumens were narrowed by enlarged endothelial cells. The majority of the infiltrating lymphocytes in all skin biopsy specimens from AD patients were stained with anti-T3, anti-Leu-1, anti-T4, and anti-Leu-3 antibodies, suggesting that most of the infiltrating lymphocytes were T cells possessing the helper/inducer phenotype. In contrast, a smaller number of infiltrating cells reacted with anti-T8 or anti-Leu-2 antibodies, which define the suppressor/cytotoxic T cell population. Langerhans cells, as defined by reactivity with anti-T6 monoclonal antibody, were increased in the diseased skin of AD patients. The presence of increased numbers of Langerhans cells and T cells of the helper/inducer phenotype may reflect increased antigen processing in the diseased skin of patients. In addition, the smaller number of T8+ cells infiltrating into the skin suggests that the depression of circulating T8+ cells observed in the majority of patients with AD is not due to the selective migration of these T8+ cells into the skin.

Antibodies, Monoclonal↗
PubMed1983

EBV transformed B cell lines present to antigen specific T cell clones determinants different from those recognized by antibody in an HLA-DR linked restricted fashion.

Human B cells nonspecifically activated by Epstein Barr virus (EBV) can present tetanus toxoid (TT) antigen to TT specific helper T cell lines and T cell clones. Presentation of TT antigen by EBV-B cells did not require the presence of TT specific B cells and did not involve B cell surface immunoglobulins. Immunosorbent purified antibody to TT added in great excess to EBV-B cells pulsed with TT for 18 hr did not inhibit the capacity of the EBV-B cells to present TT antigen. Furthermore, EBV-B cells induced proliferation in T cells in the presence of urea denatured TT which contained less than 1% TT reactive with serum anti TT antibody. Studies of TT presentation by a panel of EBV-B cells obtained from HLA typed donors indicated that T cell recognition of TT presented by EBV-B cells was MHC restricted by products of the HLA-D region and some of which differed from serologically defined HLA-DR. These results indicate that the immunogenic moiety presented by EBV activated human B cells consists of antigenic determinants, which differ from those recognized by serum antibody, and of HLA-DR linked MHC determinants. This moiety is similar to that presented by monocytes. The implications of these findings for the amplification of the immune response by activated B cells are discussed.

Antibody Specificity↗
PubMed1983

Regulation of immunoglobulin E antibody synthesis in man by antiidiotypic antibodies.

The effect of rabbit antiidiotypic antibody raised against human IgG F(ab')2 anti-tetanus toxoid (TT) antibodies on the in vitro synthesis of TT-specific IgE antibody by peripheral blood lymphocytes (PBL) was examined in three subjects. Two of these subjects were allergic twins whose sera persistently contained IgE anti-TT antibodies. The third subject was a nonallergic individual who had a slightly elevated serum IgE (250 IU/ml) and who exhibited a transient serum IgE anti-TT response after booster immunization with TT. After appropriate absorptions rabbit anti-idiotype (Id) IgG reacted with anti-TT antibodies of both IgG and IgE isotypes in an idiotype- and antigen-specific fashion. PBL and B cells from the three subjects studied spontaneously synthesized TT-specific IgE in culture. In all three cases, adsorption of B cells over plastic plates coated with anti-Id before culture specifically decreased the synthesis of IgE antibodies to TT but did not affect the synthesis of IgE antibodies to ragweed antigen E by PBL from the twin allergic subjects. Addition of anti-Id to cultures of PBL from all three subjects specifically inhibited the synthesis of TT-specific IgE. This inhibition was shown to be exerted both at the level of the B cells and via the generation of antigen-specific suppressor T cells from radiosensitive precursors. The present results indicate that the synthesis of antigen-specific IgE in man is subject to regulation by idiotypic anti-idiotypic interactions that can involve both B and T lymphocytes.

Antibodies, Anti-Idiotypic↗
PubMed1983

Regulation of human immunoglobulin E synthesis in acute graft versus host disease.

Immunoglobulin (Ig) E synthesis was studied in vitro in eight patients who had received transplants of allogeneic bone marrow. Seven of these patients developed acute graft vs. host disease (GVHD) and elevated serum IgE levels, whereas the eighth did not. In vitro synthesis of IgE, but not of IgG, was elevated in cultures of lymphocytes obtained during acute GVHD (17,923 +/- 14,607 pg/10(6) cells) but not in cultures of lymphocytes obtained after resolution of the acute GVHD when the serum IgE had returned to normal (106 +/- 31 pg/10(6) cells). In contrast, lymphocytes from the patient with no acute GVHD, like normal lymphocytes, failed to synthesize IgE in vitro. The increased in vitro IgE synthesis in acute GVHD was suppressed by normal allogeneic lymphocytes and by autologous lymphocytes obtained after the resolution of the acute GVHD, but not by allogeneic lymphocytes obtained from patients undergoing acute GVHD. The deficiency in functional IgE-specific suppressor cells in acute GVHD occurred in the face of normal or increased percentages of circulating T8+ cells, which in normal subjects contain the IgE-specific suppressor cells. In two patients studied, there was evidence of activated IgE-specific, circulating helper T cells. T cells from these two patients, but not normal T cells, secreted spontaneously upon culture in vitro a factor that induced IgE, but not IgG, synthesis by normal B cells. Finally, a survey of 21 bone marrow transplant recipients revealed that acute GVHD was a necessary requirement for the development of elevated serum IgE levels in recipients of bone marrow transplants. These results suggest that acute GVHD is accompanied by an imbalance in IgE-specific immunoregulatory T cells consisting of activated helper T cells and deficient suppressor cells.

Acute Disease↗
PubMed1983

Major histocompatibility restriction of antigen recognition by T cells in a recipient of haplotype mismatched human bone marrow transplantation.

Immune T cells proliferate in response to antigen that is recognized in association with self-Ia determinants. T cells from a patient with severe combined immunodeficiency that has been successfully reconstituted with haplotype-mismatched, maternal bone marrow were studied in an attempt to understand the development of Ia restriction of antigen recognition in man. All the patient's T cells were of maternal origin as determined by HLA typing. The patient received a series of three immunizations with tetanus toxoid (TT) antigen between the 6th and 14th week posttransplant. TT-specific T cell lines were established from the patient's peripheral blood at 6 and 8 mo posttransplantation and were maintained in culture in the presence of irradiated monocytes from the patient, TT antigen, and interleukin-2. HLA typing of the two T cell lines revealed them to be exclusively of donor origin. Both T cell lines could proliferate to TT in the presence of monocytes derived from either the patient's mother or father. In contrast, a TT-specific T cell line obtained from the patient's mother proliferated to TT in the presence of autologous monocytes, but not in the presence of monocytes derived from the patient's father. Studies using monocytes from a panel of HLA-typed donors indicated that the patient's T cell lines proliferated to TT in the presence of monocytes that expressed the paternal DR antigen (HLA-DR4) inherited by the patient but not in the presence of monocytes that expressed the paternal DR antigen (HLA-DR1) not inherited by the patient or in the presence of monocytes bearing irrelevant DR antigens. Monocytes that expressed either one of the two maternal DR antigens (HLA-DR3 and DR5) could support the proliferation of the patient's T cell lines in response to TT antigen. HLA typing of the patient's monocytes at 6 mo post-transplant revealed only recipient HLA-DR antigens (HLA-DR3 and DR4). At 12 mo posttransplant, the patient's monocytes expressed recipient HLA-DR antigens as well as the non-shared HLA-DR5 antigen of donor origin. The results of the present study indicate that T cells of human bone marrow chimera recognized antigen in the context of Ia determinants of recipient origin. The apparent recognition of antigen by the chimera's T cells in the context of donor Ia determinants that were not shared with the recipient is discussed.

Antigens, Bacterial↗
PubMed1983

Impairment of the autologous mixed lymphocyte reaction in atopic dermatitis.

The T cell proliferative response to autologous non-T cells is termed the autologous mixed lymphocyte reaction (AMLR). Recent studies have suggested that the AMLR represents an inducer circuit for the activation of T8+ suppressor/cytotoxic effector cells. Since atopic dermatitis (AD) patients are deficient in T8+ cytolytic T cell function, we investigated the AMLR in AD. When sheep erythrocytes were used to separate T cells from non-T cells, the AMLR was found to be significantly decreased (P less than 0.001) in AD patients (n = 11; delta cpm = 1,550 +/- 393) when compared with normal control subjects (n = 13; delta cpm = 25,819 +/- 4,609). To exclude the possibility that these results were an artifact of the sheep erythrocyte separation, T cells were also separated on a fluorescence-activated cell sorter after treatment of peripheral blood lymphocytes with the OKT3 monoclonal antibody. AD T cells separated by the latter method were also found to have a significantly reduced AMLR response when compared with similarly treated normal T cells. Co-culture studies using cells from AD patients and their HLA identical siblings indicated that the defect resided at the responder T cell level rather than at the stimulator non-T cell level. Co-culture studies revealed no evidence for excessive suppressor cell activity resulting in the decreased AMLR. However, enumeration of T cells reactive with the monoclonal antibody T29, which recognizes a subset of T cells proliferating in the AMLR, demonstrated that AD patients (n = 8; % T29 = 2.5 +/- 0.7) had a significantly decreased (P less than 0.001) number of circulating T29+ T cells when compared with normal controls (n = 8; % T29 = 10.4 +/- 0.8). These studies suggest that a deficiency of T4+ T29+ cells contributes to the deficient AMLR in AD and possibly underlies the abnormalities of T8+ effector cells present in this disease.

Adolescent↗
PubMed1983

Cellular basis of defective cell-mediated lympholysis in atopic dermatitis.

Peripheral blood lymphocytes (PBL) from patients with atopic dermatitis (A.D.) were examined for their capacity to generate cytotoxic T lymphocytes (CTL) during mixed lymphocyte cultures (MLC). Cell-mediated lympholysis (CML) activity, but not proliferative response during MLC, was significantly decreased (p less than 0.01) in patients with A.D. (n = 19) compared with normal controls (n = 19) or patients with other skin diseases (n = 14). Regression analysis revealed a significant correlation (p less than 0.001) between CML activity and the percentage of circulating T8+ suppressor/cytotoxic T cells. Deficient CML activity in A.D. patients, however, was not corrected when isolated autologous T4+ and T8+ cells were recombined at a normal ratio (2:1) of T4+ to T8+ cells. Examination of CML activity in co-cultures of isolated T4+ and T8+ cells obtained from two A.D. patients and their respective HLA-identical healthy siblings indicated that the defect in CML resided in both the helper/inducer T4+ cells and the effector T8+ cells. The defective cytotoxic T cell function reported in the present study may account for the increased susceptibility of patients with A.D. to develop severe viral infections.

Adolescent↗
PubMed1983

Immunoregulatory T cell abnormalities in mucocutaneous lymph node syndrome.

We recently demonstrated that during the acute phase of mucocutaneous lymph node syndrome (MCLS)3 there was a significant reduction in circulating T8+ suppressor/cytotoxic T cells and an increased number of Ia/Dr-bearing T4+ T cells, which suggests the presence of circulating activated helper T cells (1). Furthermore, the vast majority of patients with acute MCLS had a significantly elevated number of circulating B cells spontaneously secreting IgG and IgM. In the present study, the possible role of the immunoregulatory T cell abnormalities in the polyclonal B cell activation was investigated by assaying the ability of T cells and T cell factors from patients with acute MCLS to induce immunoglobulin production by normal B lymphocytes. We also examined the capacity of normal T cells to suppress immunoglobulin production by activated B cells from patients with acute MCLS.

Antibody-Producing Cells↗
PubMed1983

Induction of human IgE synthesis by a factor derived from T cells of patients with hyper-IgE states.

The requirements for the induction of IgE synthesis in normal B cells were studied. In contrast to peripheral blood lymphocytes (PBL) from allergic subjects, normal PBL failed to synthesize IgE spontaneously in vitro. Pokeweed mitogen (PWM) and Epstein Barr virus (EBV) failed to induce IgE synthesis in normal PBL and in tonsil lymphocytes. In the case of PWM, this failure was not overcome by prior removal of T8+ cells, which were shown previously to contain IgE-specific suppressor cells. In the case of EBV, the failure to induce IgE synthesis was not overcome by prior removal of sheep rosette-forming cells. Supernatants of T cells derived from three groups of patients with elevated serum IgE (hyper-IgE syndrome, atopic dermatitis, and acute graft-vs-host disease) induced significant IgE synthesis in cultures of normal B cells without causing an increase in IgE synthesis. In contrast, supernatants of normal T cells failed to induce IgE synthesis. Release of the IgE isotype-specific helper factor was inhibited by cycloheximide and tunicamycin, and its activity was destroyed by treatment with trypsin and neuraminidase. These results indicate that whereas classical polyclonal B cell activators (PWM, EBV) fail to induce IgE synthesis by normal B cells, IgE synthesis is readily induced by an IgE-specific helper factor released by T cells from patients with hyper-IgE states.

B-Lymphocytes↗
PubMed1983

Identification of circulating maternal T and B lymphocytes in uncomplicated severe combined immunodeficiency by HLA typing of subpopulations of T cells separated by the fluorescence-activated cell sorter and of Epstein Barr virus-derived B cell lines.

Circulating maternal T cells were sought in a child with severe combined immunodeficiency (SCID) and no evidence of acute graft-vs-host disease, but who had small numbers (9 to 11%) of circulating T3-positive cells. HLA typing of unfractionated peripheral blood lymphocytes (PBL) and of isolated E rosette-forming cells (37 to 44% of PBL) failed to reveal the presence of maternal lymphocytes. T3-positive cells isolated by the fluorescence-activated cell sorter, however, expressed exclusively maternal HLA antigens. A lymphoblastoid B cell line established by infecting the patient's PBL with Epstein Barr virus then expressed exclusively maternal HLA antigens. The presence of maternal T and B cells in uncomplicated SCID may be more common than thought previously and calls for a careful assessment of the origin of any mature T cells that are present in affected infants. In addition, the presence of maternal cells in SCID may complicate the infant's therapy.

B-Lymphocytes↗