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Biomedical subjects

K Welte

Publications and source records attributed to K Welte.

At least 181 records · Page 10Linked to original sources
PubMed1985

Prostaglandin E2 acts at two distinct pathways of T lymphocyte activation: inhibition of interleukin 2 production and down-regulation of transferrin receptor expression.

The mechanism by which prostaglandin E2 (PGE2) inhibits human T lymphocyte activation and proliferation was studied. We analyzed the effect of physiologic concentrations of PGE2 on interleukin 2 (IL 2) production, expression of IL 2 receptor (Tac antigen), and expression of the transferrin receptor after in vitro activation with phytohemagglutinin. PGE2 inhibited T lymphocyte proliferation by 80 to 90% of control values. This was associated with a similar degree of inhibition of IL 2 production while the expression of IL 2 receptor was not affected. This was in marked contrast to the expression of the transferrin receptor, which was inhibited 65% after 72 hr of in vitro activation. The addition of exogenous, purified IL 2 reconstituted lymphocyte proliferation to 50% of control values, but had no effect on transferrin receptor expression. Because PGE2 is known to increase the intracellular concentration of 3',5' cyclic adenosine monophosphate (cAMP), we investigated the effect of another adenylate cyclase activator, i.e., isoproterenol, as well as the effect of extracellular administration of the cAMP derivative dibutyryl cAMP (dBcAMP) on IL 2 production, Tac antigen expression, and transferrin receptor expression. It was demonstrated that isoproterenol, as well as dBcAMP, inhibited transferrin receptor expression on PHA-activated T lymphocytes to the same extent as PGE2, and exogenous IL 2 could not counteract the down-regulation of the receptor expression. In contrast, neither isoproterenol nor dBcAMP had any significant effect on IL 2 receptor expression. Prostaglandin F2 alpha (PGF2 alpha), which has been reported to elevate intracellular cyclic GMP levels, had no effect on lymphocyte activation and proliferation, and did not counteract the PGE2-induced depression in IL 2 production. In contrast to its effect on peripheral blood lymphocytes, PGE2 had no effect on transferrin receptor expression or cell proliferation by IL 2-dependent T cell clones and IL 2-independent T cell lines. These studies demonstrate that PGE2 exerts its inhibitory effects on T cell activation and proliferation via two distinct pathways: inhibition of IL 2 production and inhibition of transferrin receptor expression. The transferrin receptor inhibition is mediated via the cAMP pathway and is IL 2-independent.

Antigens, Surface↗
PubMed1985

Constitutive production of leukemia differentiation, colony-stimulating, erythroid burst-promoting, and pluripoietic factors by a human hepatoma cell line: characterization of the leukemia differentiation factor.

Conditioned medium (CM) obtained from a human hepatoma cell line, SK-HEP-1, contains colony-stimulating factors (CSFs) active on murine and human bone marrow-derived granulocyte and macrophage colony-forming units (CFU-GM) and a factor capable of inducing granulocyte-macrophage differentiation (GM-DF) of murine myelomonocytic leukemic cells WEHI-3B(D+) and human promyelocytic leukemic cells HL-60 when assayed in semisolid agar cultures. The human active granulocyte-macrophage colony-stimulating factor (GM-CSF) for day 7 CFU-GM and the GM-DF for WEHI-3B(D+) and for HL-60 are not separable by acrylamide agarose column chromatography, eluting at an apparent molecular weight between 20,000 and 35,000 daltons, or by isoelectric focusing (isoelectric point, pH 5.4). In addition, SK-HEP-1 CM contains erythroid burst-promoting activity (BPA) and a factor that promotes the growth of human mixed colonies. SK-HEP-1 cells, which grow as an adherent monolayer, appear not to be endothelial or monocytic in origin since by immunofluorescent staining they are negative for Ia (HLA-DR), monocyte antigen 1 and 2, lysozyme, and factor VIII-related antigen. Positive immunofluorescent staining for keratin and fibronectin suggests the possibility that SK-HEP-1 is an epithelial cell line. Constitutive production of GM-DF as well as other hematopoietic activities including GM-CSF, erythroid BPA, and an activity that promotes the growth of human mixed colony progenitors by a human epithelial tumor cell line, SK-HEP-1, suggests that this cell line is a valuable resource for both large-scale production of these factors and the cloning of the gene(s) that code for these regulators.

Animals↗
PubMed1985

Interleukin 2: a review.

Interleukin 2 (IL 2) is a central mediator of the growth and functional activity of B- and T-cells, and cytotoxic cells, including Natural Killer and Lymphokine Activated Killer cells. Significant defects in the production of, and response to, IL 2 have been described in a variety of congenital and acquired immunodeficiency states. IL 2 has demonstrated major anti-tumor activity in animal models. The biochemistry and molecular biology of IL 2 and its gene are reviewed, along with data regarding the IL 2 receptor, normal T-cell activation, abnormalities in IL 2 production and response in immunodeficiency states and leukemia, and initial explorations of IL 2 in the treatment of human cancer.

Acquired Immunodeficiency Syndrome↗
PubMed1985

Differential effect of anti-beta 2-microglobulin on IL 2 production and IL 2 receptor expression in the primary mixed lymphocyte culture reaction.

The mechanism of inhibition of the proliferative response in primary mixed lymphocyte culture (1 degree MLC) by antibodies to beta 2-microglobulin (beta 2m) was investigated. It is demonstrated that anti-beta 2m antibodies inhibit the production of interleukin 2 (IL 2). In contrast, the expression of IL 2 receptor is not affected by anti-beta 2m. The addition of purified exogenous IL 2 to the antibody-treated 1 degree MLC can completely restore the proliferative response, indicating that anti-beta 2m does not interfere with IL 2 binding to its receptor. Similarly, anti-beta 2m does not interfere with the capacity of IL 2-dependent T cell lines or T cell clones to respond to exogenous IL 2. The inhibition of cell proliferation and IL 2 production by anti-beta 2m is maximal when the antibody is added at the beginning of 1 degree MLC culture, and no effect of anti-beta 2m is seen when added after 3 days of culture. Anti-beta 2m has no effect on mitogen-induced cell proliferation and IL 2 production. Anti-beta 2m acts on the responder cell population, as demonstrated in experiments in which responder cells or stimulator cells are treated separately with the antibody. The expression of HLA-class II antigens (i.e., HLA-DR and DQ (DC) on the T cells activated on 1 degree MLC is not affected by anti-beta 2m. These studies indicate that the HLA-beta 2m class I antigen complex plays a role in T lymphocyte activation via release of IL 2, and suggest the existence of different mechanisms for activation of IL 2 producers and IL 2 responders in 1 degree MLC.

Antibodies, Monoclonal↗
PubMed1985

Lymphokine-activated killer cells are generated before classical cytotoxic T lymphocytes after bone marrow transplantation in mice.

Lymphokine-activated killer (LAK) cells are demonstrable within 2 wk after syngeneic or allogeneic (H-2-compatible) bone marrow transplantation in mice. Classical cytotoxic T lymphocytes (CTL) are not active until at least 4 wk after transplant. Both LAK cells and CTL bear the Thy-1 marker and do not possess the murine natural killer cell marker asialo GM.

Animals↗
PubMed1985

OKT3 monoclonal antibody induces production of colony-stimulating factor(s) for granulocytes and macrophages in cultures of human T lymphocytes and adherent cells.

OKT3 monoclonal antibody (mab) recognizes a membrane antigen associated with the T cell antigen recognition receptor, and is known to be mitogenic and to induce lymphokine production. Our studies demonstrate the ability of OKT3 mab to induce from cultures of human T lymphocytes supplemented with adherent cells the production of colony-stimulating factor(s) for granulocytes and macrophages (GM-CSF) and interferon-gamma (IFN-gamma), an inhibitor of clonal growth of hematopoietic progenitor cells. As has been shown for the mitogenic and IFN-gamma-inducing activity of OKT3 mab, the induction of GM-CSF release in cultures of T cells is strictly dependent on the presence of adherent cells. However, the concentrations of OKT3 mab required for optimal GM-CSF production (50 ng/ml) were found to be 80-fold higher than those sufficient for maximal IFN-gamma production, proliferation, and interleukin 2 production. IFN-gamma activity induced by OKT3 mab partially inhibited colony and cluster formation from progenitor cells of granulocytes and macrophages in vitro. Therefore, neutralization of the IFN-gamma by monoclonal anti-human-IFN-gamma antibody before assay of conditioned medium in bone marrow cultures significantly enhanced the detection of GM-CSF. Kinetic studies demonstrated maximal cumulative GM-CSF production in response to optimal OKT3 mab concentrations on days 4 through 6 in cultures of T cells supplemented with 15% adherent cells. Highly enriched OKT4+ and OKT8+ T cell subsets co-cultured with adherent cells in the presence of OKT3 mab both produced GM-CSF and IFN-gamma and showed similar dose-response curves to OKT3 mab. The requirement for the presence of adherent cells could not be overcome by the addition of purified interleukin 1 or macrophage supernatants. Studies using irreversible inhibitors of DNA (mitomycin C) or protein biosynthesis (emetine-HCl) revealed the necessity of intact DNA synthesis and translation in mononuclear cells to produce GM-CSF in response to OKT3 mab. Loss of GM-CSF production was observed when either adherent cells or T lymphocytes were treated with emetine before co-culture with untreated cells of the other population in the presence of OKT3 mab. In contrast, mitomycin C reduced GM-CSF production significantly when T cells, but not adherent cells, were pretreated. These results suggest that T lymphocytes and adherent cells closely cooperate in the production of GM-CSF induced by OKT3 mab.

Antibiotics, Antineoplastic↗
PubMed1984

Interleukin 2 regulates the expression of Tac antigen on peripheral blood T lymphocytes.

We investigated the effect of OKT3 antibody and interleukin 2 (IL-2) on Tac antigen expression and the proliferation of human peripheral blood mononuclear leukocytes. OKT3 monoclonal antibody at low, nonmitogenic concentrations (25 pg/ml) or IL-2 alone at optimal concentrations (20 U/ml) did not induce IL-2 receptor expression, as measured by Tac antibody or by T cell proliferation. However, costimulation with these concentrations of OKT3 antibody and IL-2 led to Tac antigen expression and T cell proliferation. These data suggest that the T cells are activated in two steps: OKT3 antibody at 25 pg/ml does not induce Tac antigen expression, but preactivates T cells to become responsive to IL-2. The addition of exogenous IL-2 then leads to expression of the IL-2 receptor, as recognized by Tac antibody, and to subsequent proliferation.

Antibodies, Monoclonal↗
PubMed1984

Activation of human macrophages. Comparison of other cytokines with interferon-gamma.

Cytokines affecting mononuclear phagocytes were screened for activation of human macrophages to secrete H2O2 and kill toxoplasmas. In contrast to recombinant interferon-gamma (rIFN gamma), the following factors, tested in partially or highly purified form and over a wide range of concentrations, did not augment these functions: native interferon-alpha (nIFN alpha), rIFN alpha A, rIFN alpha D, rIFN beta, colony stimulating factor (type 1) (CSF-1), CSF for granulocytes and macrophages (GM-CSF), pluripotent CSF (p-CSF), tumor necrosis factor (TNF), native interleukin 2 (nIL-2), and rIL-2. Partially purified migration inhibitory factor (MIF) enhanced H2O2-releasing capacity submaximally without inducing antitoxoplasma activity, and warrants further study.

Biological Products↗
PubMed1984

Interleukin-2 correction of defective in vitro T-cell mitogenesis in patients with common varied immunodeficiency.

We studied the ability of phytohemagglutinin (PHA) and two anti-T-cell monoclonal antibodies, OKT3 and Pan T2, to induce interleukin-2 (IL2) production and proliferation in peripheral blood lymphocytes (PBL) from 14 patients with combined varied immunodeficiency (CVI). The median values of endogenous IL2 produced by mitogen-stimulated PBL was significantly lower in patients than controls irrespective of the mitogen used. The patients, taken as a group, had a significantly decreased in vitro PBL response to mitogen stimulation when compared to controls. With the addition of a highly purified human IL2 preparation, the proliferative response in the majority of patients was significantly improved with all mitogens. Three patient groups could be distinguished: Group A (3/14) had full restoration of proliferative response with the addition of IL2, Group B (5/14) had partial restoration, and Group C (6/14) had no significant response. The monoclonal antibody, Pan T2, recognized a T-cell proliferative defect in 5 of 14 patients which neither PHA nor OKT3 recognized. This was not significantly corrected by the addition of IL2. This T-cell proliferative defect correlated with the lack of B-cell proliferation and immunoglobulin production in response to B-cell mitogens in three-fourths of the patients assayed. These data show that CVI patients are a heterogeneous group but have in common a decreased in vitro production of IL2 resulting in a proliferative defect which is correctable at least in part, in vitro, in the majority by the addition of purified IL2.

Adolescent↗
PubMed1984

Generation of nonspecific murine cytotoxic T cells in vitro by purified human interleukin 2.

Murine spleen cells developed into nonspecific cytotoxic cells within 72 hr of culture in the presence of highly purified sources of human interleukin 2. In whole spleen cell cultures, human interleukin 2 generated effector cells which were Thy 1.2+, Lyt 2.2+, resistant to gamma irradiation (1000 R), and capable of lysing both H-2 compatible and incompatible targets. The effector cells generated in this manner were not restricted to classical natural killer cell-sensitive targets. If thymus-derived cells (T cells) were depleted from the spleen cell population before culture with human interleukin 2, the effector cells generated were enriched in effectors capable of lysing natural killer cell-sensitive targets. Interferon was not produced in interleukin 2-stimulated spleen cell cultures. In addition, heterologous antibody to murine gamma-interferon did not abrogate the generation of cytotoxic cells by human interleukin 2. These and additional data suggest that human interleukin 2 is capable of stimulating gamma-irradiation-sensitive Thy 1.2+ cell(s) capable of lysing a variety of target cells regardless of inherent sensitivities to classical natural killer cells. Thy 1.2- cells were also stimulated by human interleukin 2 and lysed only natural killer cell-sensitive targets. Human interleukin 2 caused some Thy 1.2- cells to become susceptible to lysis by anti-Thy 1.2 serum and complement.

Animals↗
PubMed1984

Characterization of interleukin 2 (IL-2)-dependent cytotoxic T-cell clones. V. Transfer of resistance to allografts and tumor grafts requires exogenous IL-2.

The adoptive transfer of resistance to tumor grafts with cloned interleukin 2 (IL-2)-dependent cytotoxic T-cell lines was examined. Two clones were used: clone CTLL-A2 which recognizes H-2Dd determinants and clone CTLL-R5 which recognizes a unique cell surface antigen of BALB/c leukemia RL male 1. Systemic transfer of resistance with these clones was accomplished only when exogenous (rat or human) IL-2 was administered at the same time. Intraperitoneal injection of CTLL-A2 cells accelerated rejection of sarcoma Meth A (H-2Dd), but not ascites sarcoma BP8 (H-2k) or leukemia EL4 (H-2b) inoculated subcutaneously into C57BL/6 mice. CTLL-R5 cells were examined in local (Winn tests) as well as systemic transfer experiments. When mixed with leukemia cells before subcutaneous injection, they suppressed the growth of leukemia RL male 1 without exogenous IL-2. When injected intraperitoneally, CTLL-R5 cells inhibited the growth of subcutaneous grafts of leukemia RL male 1 only when exogenous IL-2 was administered at the same time. CTLL-R5 did not inhibit the growth of other radiation-induced BALB/c leukemias.

Animals↗
PubMed1984

Autologous and allogeneic mixed-lymphocyte responses following thermal injury in man: the immunomodulatory effects of interleukin 1, interleukin 2, and a prostaglandin inhibitor, WY-18251.

A group of 30 burn patients with 36-87% total body surface area (TBSA) burns was studied at 24-48 hr postburn. These included studies of (1) autologous and allogeneic mixed-lymphocyte reactions (MLR); (2) the immunoregulatory influence of mitomycin C-treated T cells, non-T cells, and unfractionated peripheral blood lymphocytes (PBL) on allogeneic MLR; and (3) correlation between the proportions of T-cell subsets defined with monoclonal antibodies (OKT4 and OKT8) and autologous MLR. Studies concerning adherent cell production of thromboxane, prostaglandin E2, and prostaglandin F2a and the immunomodulatory effects of Interleukin 1 (IL-1), Interleukin 2 (IL-2), and a prostaglandin inhibitor, WY-18251, on autologous MLR are presented. The autologous mixed-lymphocyte reaction was depressed in 60% of the burn patients tested. This depressed response correlated closely to the extent of third-degree injury (P less than 0.025) and to TBSA injury greater than 60% (P less than 0.025). A linear correlation was observed between the depression in autologous MLR and a decrease in both the percentage of OKT4+ T cells and the OKT4+/OKT8+ ratio. The response of T cells from burn patients in allogeneic MLR was normal. Age, sex, TBSA of the burn, and size of second-degree burn did not correlate with the abnormalities observed in MLR. Mitomycin C-treated mononuclear cells, purified T cells, or non-T cells from burned patients did not demonstrate any suppressive influence on MLR in normals. Monocyte number and arachidonic acid metabolism were investigated. In addition to increased numbers of monocytes following thermal injury, adherent cells produced increased quantities of thromboxane, prostaglandin E2, and prostaglandin F2a. The effects of Interleukin 1, Interleukin 2, and a prostaglandin inhibitor, WY-18251, were studied in autologous MLR (AMLR) of burned and normal patients. Interleukin 1 and WY-18251 did not induce any significant changes in proliferation in burned patients or normal controls. When compared to cultures without exogenous IL-2, an increase in AMLR was observed following the addition of IL-2 to burn patient cultures at Day 6 and Day 7 of culture. Although the addition of IL-2 did increase proliferation in AMLR of normal controls at Day 6 and Day 7, the enhancement observed for the burn patient cultures represented a restoration to the level of normal control cultures without IL-2. A dose-dependent increase in AMLR was observed in T cells isolated from normal and burned patients in the presence of purified Interleukin 2.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed1984

Rescue of anti-influenza A virus cytotoxic T-lymphocyte responses in chemotherapy-suppressed mice.

The administration of cyclophosphamide (50 to 100 mg/kg) at 48 to 72 h before removal of murine lung or spleen mononuclear cells for culture rendered DBA/2 mice incapable of generating an effective cytotoxic T-lymphocyte response to influenza A virus-infected cells. The cytotoxic T-lymphocyte precursor frequency to influenza A virus in lung and spleen cells from cyclophosphamide-treated mice was significantly decreased when compared with that of normal littermate controls. The low cytotoxic T-lymphocyte activity in the lungs and spleens of cyclophosphamide-treated mice could be partially restored in vitro by human interleukin 2.

Animals↗
PubMed1984

Induction of T cell aggregation by antibody to a 16kd human leukocyte surface antigen.

We describe studies of a human leukocyte antigen, termed Leu-13, that is defined by a mouse monoclonal antibody that reacts with T and B lymphocytes. Optimal staining of T cells requires a much higher concentration of alpha Leu-13 (greater than or equal to 200 micrograms/ml) than alpha Leu-4 (6 micrograms/ml). However, the fluorescence intensity of T cells labeled with alpha Leu-13, washed and kept at 4 degrees C for different periods, does not diminish more rapidly than the fluorescence of T cells stained with alpha Leu-4 and treated the same way. These results indicate that the novel binding pattern of alpha Leu-13 is not due to weak affinity. Immunoprecipitation and SDS-PAGE analysis indicates that alpha Leu-13 precipitates a major 16-kilodalton (16kd) band and a minor 26kd component from Nonidet P-40-solubilized membrane of normal T cells that are surface-labeled with 125I. The similar sizes of the 16kd to 26kd (Leu-13) and 22kd to 28kd (Leu-4) molecules prompted us to compare the capacity of alpha Leu-13 and alpha Leu-4 to trigger T cell functions, and to co-modulate and co-precipitate the T cell antigen receptor. Unlike alpha Leu-4, alpha Leu-13 does not trigger T cell proliferation or augment NK activity, but inhibits the mitogenic effect of alpha Leu-4/T3 antibodies. alpha Leu-13 also induces T cells to clump into large aggregates after 16 hr of culture at 37 degrees C, but not at 4 degrees C. T cell aggregation is triggered by concentrations of alpha Leu-13 as low as 12.5 ng/ml. At this concentration, alpha Leu-13 is not detectable on the surface of T cells by indirect immunofluorescence analysis in a FACS. On leukemic T cells, alpha Leu-4 was found to co-modulate and co-precipitate a 38kd to 44kd dimer having apparent idiotypic determinants, whereas alpha Leu-13 did not. The possible significance of these findings to immune regulation by T cells is discussed.

Animals↗
PubMed1984

Treatment of immunodeficiency with interleukin-2: initial exploration.

Fifteen patients with acquired immunodeficiency syndrome (AIDS), lymphoma and immunodeficiency, or severe combined immunodeficiency were treated with highly purified interleukin-2 (IL-2) prepared from human lymphocytes. All patients showed a defect in mitogen-induced T cell proliferation which was partially corrected when IL-2 was added in vitro. IL-2 was administered subcutaneously by daily injection or continuous infusion. The maximum daily dose was 20,000 U/m2, the maximum total dose 855,000 U/m2, and the maximum period of treatment 77 days. An increase in the platelet count was seen in one patient with AIDS, a decrease in the serum level of a monoclonal immunoglobulin in another patient with AIDS, and a minor tumor response in a patient with diffuse histiocytic lymphoma. As no toxicity was observed, further study of IL-2 in the treatment of human immunodeficiency is indicated.

Acquired Immunodeficiency Syndrome↗