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J Troppmair

Publications and source records attributed to J Troppmair.

At least 55 records · Page 3Linked to original sources
PubMed1989

An altered v-raf is required in addition to v-myc in J3V1 virus for acceleration of murine plasmacytomagenesis.

We have isolated and molecularly cloned a highly pathogenic virus variant, J3V1, from murine plasmacytomas induced by a combination of pristane and the weakly transforming recombinant retrovirus J3. J3 virus is a derivative of the v-raf/v-myc-carrying J2 virus that was generated by a frameshifting deletion inactivating v-raf in J2. J3V1 contains an additional deletion of 334 base paris in gag, which restores the correct reading frame for v-raf and results in the expression of a p57 gag-raf fusion protein. Reactivation of v-raf in J3 is required for efficient plasmacytoma acceleration in pristane-conditioned BALB/cAn mice.

Amino Acid Sequence↗
PubMed1988

IFN-mediated induction of MHC antigen expression on human keratinocytes and its influence on in vitro alloimmune responses.

The MHC Ag expression on the surface of keratinocytes is altered after treatment with IFN. IFN-gamma induces, as expected, a strong increase in class I MHC Ag expression as well as de novo expression of class II MHC Ag, whereas IFN-alpha 2 only slightly increases class I MHC Ag and does not induce keratinocytes to express class II MHC Ag. We used untreated and IFN-pretreated keratinocytes as stimulators and also as targets to study whether IFN-induced MHC Ag changes would alter the immunogenicity of keratinocytes in alloimmune responses. It was found that class II MHC Ag-carrying keratinocytes were unable to induce the proliferation of resting lymphocytes, but did stimulate T blasts. Untreated keratinocytes were virtually resistant to the lysis by classical CTL but became susceptible after exposure to IFN-gamma, but not IFN-alpha 2 at physiologic doses. These data demonstrate mechanisms by which the release of IFN-gamma might contribute to the development of disease such as the graft vs host disease.

Cell Division↗
PubMed1988

Comparative study of alloimmune reactions induced by leukocyte and platelet transfusions in humans: characteristic changes of activation markers, gamma interferon, and FcR blocking antibody production.

This study was undertaken to define immune responses induced by leukocyte and platelet transfusions. We offer evidence that activation by alloimmunization with intravenously administered "buffy coat" cells results in immune alterations similar to the early rejection episodes following kidney transplantation. Thus, IL-2 and HLA-DR expression increased on PBL 2 and 3 days after antigen exposure and paralleled elevations of IFN-gamma, neopterin, and beta 2 microglobulin levels. No significant changes were detected in the number of T-cell subpopulations. Alloimmunization by purified platelets alone that express only class I MHC antigens failed to induce the above alteration, even after repeated exposure. Repeated alloimmunization with "buffy coat" cells or isolated platelets stimulated a progressive increase up to 100% blocking activity on EA rosette formation. We conclude that the expression of activation markers on PBL and the production of IFN gamma and neopterin reflect the early phase of alloimmune response induced by leukocytes. This type of alloactivation is not a prerequisite for the development of FcR-blocking antibody, which is produced after pure platelet transfusion as well.

Binding, Competitive↗
PubMed1988

Selective induction of mononuclear phagocytes to produce neopterin by interferons.

Interferon-gamma (IFN-gamma) has been shown to be a potent inducer of neopterin secretion by human peripheral blood monocytes/macrophages (1). In this paper, it is shown that other known stimuli of monocytes (e.g., to secrete proteases or to migrate) such as zymosan-activated human serum, lipopolysaccharide, human C3/iC3 and zymosan coated with complement were unable to trigger monocytes/macrophages to release neopterin. Monocytes/macrophages could be stimulated solely by IFN-gamma (25 U/ml) and IFN-alpha at very high concentrations (10,000 U/ml). In the case of human peripheral blood mononuclear cells (PBMNC), basically the same pattern was observed. If however, in the buffer controls PBMNC showed some neopterin release, all stimuli triggered an increase of neopterin secretion: 10,000 U/ml IFN-alpha induced the same amount of secreted neopterin as did 25 U/ml of IFN-gamma. Both caused higher levels of neopterin secretion than ZAS, LPS and C3/iC3. Amongst the supernatants from PBMNC, only those which were obtained from cells activated with IFN-gamma or -alpha stimulated monocytes/macrophages to produce neopterin. Supernatants from lymphocytes activated with zymosan, lipopolysaccharide and interferon did not contain neopterin, nor did the latter induce monocytes/macrophages to generate and secrete neopterin. Antibodies against IFN-gamma inhibited the triggering effect of the supernatants except when generated by IFN-alpha at 10,000 U/ml. These results demonstrate that both interferons, IFN-gamma and IFN-alpha, the latter only at a 400-fold higher concentration, can trigger monocytes/macrophages directly to secrete neopterin. ZAS, LPS and C3/iC3 are weakly effective only on a mixture of lymphocytes and monocytes/macrophages, provided this cell mixture shows already a basic spontaneous neopterin release.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Interferons (IFNs) and tumor necrosis factors (TNFs) in T cell-mediated immune responses against alloantigens. I. Influence on the activation of resting and antigen-primed T cells.

The aim of this study was to investigate the influence that endogenous IFNs released in response to antigenic or viral stimuli has on recognition of alloantigens in MLC. Results indicated that both the magnitude and the kinetics of response can be modified by IFNs. Neutralizing antibodies with specificity for IFN-gamma inhibit early and enhance late proliferative responses in MLC. Addition of physiological concentrations of IFN-gamma enhanced both early and peak proliferation, whereas IFN-alpha markedly inhibited alloantigen-induced lymphocyte proliferation. Further experiments revealed that IFN effects in MLC are not caused by direct interaction with responder cells: pretreatment with IFNs neither failed to alter their subsequent proliferative reactivity, nor did it influence production of IL 2 in MLC. IFN-gamma mainly affected MLC responses by direct interaction with stimulator cells. These influences on hemopoietic and non-hemopoietic stimulator cells were complex and could not simply be explained on the basis of an altered expression of class II MHC antigens. When induced by IFN-gamma to maximally express class II antigens, pbmnc, LCL or homogeneous populations of macrophages showed a marked deficiency to induce primary or secondary proliferative T cell responses. Resting unsensitized or sensitized T cells were not stimulated by class II MHC antigens constitutively expressed or induced by IFN-gamma on cell types other than dendritic cells or LCL. Class II antigens on the former cells were, however, readily recognized by T helper blasts, and this process involved the T4 epitope of the T cell receptor. IFN-gamma treatment also influenced the intrinsic suppressive capacity of macrophages or keratinocytes without involving prostaglandin synthesis or inducing expression of IL 2 receptors on non T cells.

HLA-DR Antigens↗
PubMed1988

Cytokines in the control of beta-2 microglobulin release. I. In vitro studies on various haemopoietic cells.

The role of cytokines in the control of beta-2 microglobulin release from various haemopoietic cells was studied in vitro. Cell types investigated were resting cells or blasts of the T cell, B cell or monocyte-macrophage lineage. Mediators used in these experiments were r-IFN-alpha 2c, r-IFN-gamma, r-TNF-alpha, r-TNF-beta, r-IL1, r-IL2 and r-GM-CSF. Nanogram amounts of some of these mediators strongly affected beta-2 microglobulin release in vitro. r-IFN-gamma, r-IFN-alpha 2c and r-IL2 strongly enhanced and r-TNF-alpha and r-TNF-beta occasionally increased shedding of beta-2 microglobulin. r-IL1 and high concentrations of r-IFN-alpha 2c were inhibitory, whereas r-GM-CSF was ineffective. The impact of antigenic stimulation on beta-2 microglobulin release in mixed lymphocyte culture (MLC) was also studied. Stimulation with alloantigens in MLC greatly enhanced beta-2 microglobulin shedding, and this enhancement could be inhibited by a monoclonal antibody neutralizing human IFN-gamma. Among the various cell types studied, macrophages derived from peripheral blood monocytes were most susceptible to cytokine-induced alterations of beta-2 microglobulin shedding. From these data, we conclude that cytokines not only control the static expression of beta-2 microglobulin on the surface of haemopoietic cells but also largely affect their shedding.

Antigens↗
PubMed1988

Cytokines in the control of beta-2 microglobulin release. II. In vivo studies with recombinant interferons and antigens.

The influence of in vivo application of recombinant interferon-alpha 2c (IFN-alpha 2c) and recombinant interferon-gamma (IFN-gamma) on beta-2 microglobulin levels was studied in eight patients with chronic myelogenous leukaemia or advanced renal cell carcinoma. Data indicated enhanced beta-2 microglobulin biosynthesis in close temporary association with injection of both types of interferons. The influence of in vivo stimulation by allogenic leukocytes and the influence of renal allografts or cytomegalovirus infection on serum beta-2 microglobulin and IFN-gamma levels were also studied. Increased beta-2 microglobulin concentrations were observed again in each of these clinical situations and were closely associated with enhanced endogenous interferon production. From these in vivo data and the in vitro data presented in the preceding publication, (1) we conclude that endogenous interferon levels are crucial for the regulation of beta-2 microglobulin release in vivo.

Antigens↗
PubMed1988

In-vitro and in-vivo studies on the induction of neopterin biosynthesis by cytokines, alloantigens and lipopolysaccharide (LPS).

Recently we presented evidence that cellular immune responses are associated with increased in-vitro and in-vivo excretion of neopterin (Huber et al., 1983) and that, in vitro at least, macrophages and IFN-gamma play a key role in the induction of this phenomenon (Huber et al., 1984). Although this marker is increasingly applied for monitoring of human disease, there is limited knowledge about the mechanism(s) responsible for its increased biosynthesis during inflammatory states. To further elucidate this question we evaluated neopterin and IFN-levels in culture supernatants of human blood cells and in patients' sera. Cells or patients were exposed to a panel of recombinant cytokines, alloantigens or lipopolysaccharide. To investigate indirect stimulation by induction of production of endogenous IFNs, the impact of neutralization of IFNs by addition of specific antibodies was also studied. The data confirm our previous results which identified the monocyte/macrophage as the main producer cell among human blood cells. They further demonstrate that, at least in vitro, IFN-gamma, IFN-alpha and LPS can all stimulate neopterin release independently from each other. Thirdly, they indicate that stimuli such as alloantigens or TNF-alpha can indirectly enhance neopterin release by their capacity to induce production of endogenous IFN-gamma. On the basis of these data we conclude that enhanced neopterin biosynthesis does not necessarily relate to activation of T cells but can also be caused by non-immune stimuli.

B-Lymphocytes↗
PubMed1987

Biosynthesis and metabolism of pterins in peripheral blood mononuclear cells and leukemia lines of man and mouse.

The cellular origin and the control of neopterin release associated with immune stimulation was studied in cell cultures. Using purified human mononuclear cells, the intracellular change in concentrations of GTP and pterins was measured under various kinds of stimulation. Three enzymes involved in tetrahydrobiopterin biosynthesis, i.e. GTP cyclohydrolase I, 6-pyruvoyl tetrahydropterin synthase and sepiapterin reductase, were also determined. Human macrophages stimulated with culture supernatant from activated T-lymphocytes were the main producers of neopterin. In these cells, GTP cyclohydrolase I activity was elevated due to high GTP levels and therefore neopterin accumulated. Human macrophages lack 6-pyruvoyl tetrahydropterin synthase activity. Exogenous tetrahydrobiopterin added to the culture medium of stimulated T cells and macrophages suppressed the elevation of GTP cyclohydrolase I activity and neopterin concentration, but not the elevation of intracellular GTP. Stimulation of macrophages with recombinant human interferon-gamma and neutralization of the effect of T cell supernatants by addition of a monoclonal antibody specific for human interferon-gamma showed that immune interferon induced the alterations in GTP cyclohydrolase I activity and neopterin concentration. In the human macrophage line U-937 and in the leukemia line HL-60, no GTP cyclohydrolase I activity or intracellular pterins were detected, but high levels of GTP. In mouse mononuclear cells, no neopterin was detected, but biopterin and pterin. After stimulation, biopterin was elevated in the same way as neopterin in human mononuclear cells. This is explained by the different regulation of the rate-limiting steps of tetrahydrobiopterin biosynthesis in man and in mouse. These results suggest that neopterin is an unspecific marker for the activation of the cellular immune system.

Alcohol Oxidoreductases↗
PubMed1987

[Neopterin today].

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Acquired Immunodeficiency Syndrome↗
PubMed1987

Studies on the optimal dose and the mode of action of alpha-interferon in the treatment of hairy cell leukemia.

The therapeutic efficacy and side effects of alpha-2c-interferon (IFN-alpha 2c) treatment of hairy cell leukemia were compared between two different dose regimen: 10 patients received maximum tolerable doses of IFN-alpha 2c for 1 year (group A), and 11 patients received minimum doses of IFN-alpha 2c, which induced an optimal biological response (group B). Induction of neopterin excretion was chosen as the marker to define biological response and the dose of IFN-alpha 2c applied was on average only one tenth of that in group A cases. Average time of treatment in group B was 42 weeks. The data indicate that both dose levels are effective in the treatment of advanced hairy cell leukemia but that the low dose regimen is free of toxicity. Laboratory investigations on the mechanism of IFN-mediated remission in HCL further revealed that hairy cells are resistant to lysis by IFN-alpha activated large granular lymphocytes and that improved natural killer function subsequent to IFN-alpha treatment in vivo is primarily due to the disappearance of leukemic hairy cells which dilute the natural killer effector cells. These findings support the view of a direct antitumor activity of IFN-alpha as the main therapeutic principle.

Adult↗
PubMed1986

[Interferon-alpha in the treatment of hematologic neoplasms].

This report aims to review briefly the current status of treatment of haematological malignancies with interferon-alpha (IFN-alpha). Overall hairy cell leukemia and chronic myelogenous leukemia appear to be most sensitive to IFN-alpha. We started to investigate, how interferon exerts its antileukemic activity and in which way interferon therapy can be optimized. Our preliminary results fail to support the view of interferon mediated enhancement of host responses. They rather indicate direct effects of IFN on leukemic cells in vitro. By means of IFN-dependent biological markers (e.g. beta-2-microglobulin, neopterin) clinically effective but atoxic doses of IFN-alpha could be defined for HCL and CML. In final conclusion, the recent studies on the clinical efficacy of IFN-alpha revealed its potent antitumoral effect in hematological malignancies. However, the further proof of the potential benefit of IFN treatment versus conventional therapeutic strategies remains to be elucidated.

Cell Division↗
PubMed1986

Influence of ethylene-2,2'-bis (dithio)bis(ethanol) on certain human in vitro and in vivo lymphocyte functions.

The influence of in vivo or in vitro exposure of human lymphocytes to ADA 202-718 (ethylene-2,2'-bis (dithio) bis (ethanol)) was tested. Evaluated were spontaneous, lectin, or alloantigen-induced proliferation as well as the release of IFN-alpha, gamma and of neopterin. The spontaneous cell mediated lysis (NK lysis) of K 562 tumor targets was also assessed. In vitro exposure to ADA 202-718 slightly enhanced lectin and alloantigen-induced human lymphocyte proliferation. IFN-gamma release was also slightly increased. These parameters were not clearly affected by in vivo treatment with ADA 202-718. In vitro and in vivo-treatment with this drug did not affect spontaneous lymphocyte blastogenesis. Statistically significant effects, however, were seen when NK activity was assessed. Preincubation of either effector or target cells with ADA 202-718 as well as in vivo treatment caused an increase of NK lysis. When these results obtained with human cells were compared with those previously seen in a murine system, immunostimulatory activity of ADA 202-718 was more pronounced in the murine system.

Biopterins↗
PubMed1986

A biological approach to optimize interferon treatment in hairy cell leukemia.

Progress with the clinical application of interferons to neoplastic diseases has been slow and complicated by the need for attention to a new spectrum of therapeutic and toxic effects manifested by the interferons. In this report, we present a new approach to define clinically effective but atoxic doses of interferon-alpha for treatment of hairy cell leukemia. In order to find in vivo biologically active interferon doses, the biochemical marker neopterin was selected as a means to assess a cellular interferon response in vivo. Subcutaneous administration of minimal doses of recombinant interferon-alpha-2 (5-8 X 10(5) U/day), which induced maximum neopterin release in serum and urine, proved to be clinically effective: Eight of nine patients responded to this dose regimen. This response rate was comparable to that of a conventional dose schedule (3 X 10(6) U/sqm/day) which was also applied to nine patients (eight responders). Whereas no difference in the clinical efficacy between the two therapeutic strategies could be established, toxicity was clearly confined to the conventional dose regimen. These preliminary results suggest that at least in hairy cell leukemia the therapeutic dose range of interferon can be separated from the toxic.

Biopterins↗
PubMed1986

Interferon-gamma enhances biosynthesis of pterins in peripheral blood mononuclear cells by induction of GTP-cyclohydrolase I activity.

In a recent publication, evidence was presented that cellular immune responses are associated with increased in vivo and in vitro excretion of neopterin. Our study aimed at investigating the biosynthesis of unconjugated pterins in highly purified human macrophages and T lymphocytes before and during stimulation with supernatants of activated T cells or with recombinant human interferon-gamma (IFN-gamma) by monitoring the following parameters: substrate concentration (GTP, guanosine triphosphate), activity of the enzyme initiating the biosynthesis of pterins (GTP-cyclohydrolase I) and product concentrations of total neopterin, biopterin, and pterin. In contrast to T cells and other tissues, macrophages were unable to produce tetrahydrobiopterin. This was indicated by our failure to detect biopterin and pterin. Instead, products of the first biosynthetic step accumulated, which were measured as total neopterin. We concluded that in macrophages the other enzymes required for biosynthesis of tetrahydrobiopterin are limiting. GTP concentration correlated with GTP cyclohydrolase I activity. An increase in both was induced by IFN-gamma and suppressed by neutralization of T-cell supernatants with monoclonal antibodies having specificity for IFN-gamma. Addition of tetrahydrobiopterin to the culture medium only led to a suppressed increase in GTP cyclohydrolase I activity and neopterin, but not in GTP concentration. Thus, it appears that IFN-gamma selectively stimulates the early steps of pterin biosynthesis in macrophages, thereby leading to accumulation and excretion of dihydroneopterin and neopterin. Although the physiological role of this phenomenon remains obscure, the fact that it seems to reflect endogenous release of IFN-gamma deserves particular attention.

Aminohydrolases↗
PubMed1986

Relationship of interferon-gamma and neopterin levels during stimulation with alloantigens in vivo and in vitro.

We have recently shown that interferon-gamma is capable of activating the key enzyme of pterin biosynthesis in macrophages. This leads to excretion of the stable degradation product neopterin. In this article we present experimental evidence suggesting that stimulation of T cells by alloantigens is associated with release of interferon-gamma--which, in the case of rejection, is locally restricted and not always detectable in the bloodstream. Neopterin induced by this lymphokine, however, readily penetrates tissue barriers and is detectable in the serum. This conclusion is based on two different sets of observations: (1) If supernatants of MLCs are compared with sera from patients with documented acute rejection episodes for their interferon-gamma and neopterin levels, a marked gradient is observed to exist between interferon levels measured in vitro and in vivo; this is not the case for neopterin for which comparable levels were seen. (2) Detection of interferon-gamma in sera of allograft recipients invariably precedes an increase of neopterin; on the other hand, increasing neopterin counts are also seen in the absence of detectable interferon-gamma levels in the serum. It thus appears that although interferon-gamma release during allograft rejection is primarily restricted to the tissue, evaluation of certain metabolites of interferon-dependent metabolic pathways enables definition of its endogenous release. Whereas interferon gamma represents a less reliable marker in the monitoring of rejection episodes, it might offer an additional means to differentiate rejection from systemic infections. Such a discrimination can not be achieved with the neopterin marker.

Acute Disease↗
PubMed1985

Neopterin release in human mixed lymphocyte culture: requirement of HLA-DR disparity.

Recent evidence suggests that immune responses in vivo as well as in vitro are accompanied by release of neopterin [C. H. Huber, et al. (1983) J. Immunol. 130, 1047]. This investigation aimed to elucidate the genetic control of in vitro neopterin release in family mixed lymphocyte culture (MLC) studies. Neopterin levels and responder cell proliferation were assessed in a total of 92 MLCs established from different intrafamilial combinations. Results indicated a strong association between the magnitude of responder cell proliferation and the neopterin levels induced by stimulation with allogeneic cells. This conclusion was based on three findings: first, almost no neopterin release and proliferation was seen in MLCs established between HLA genotypically identical siblings; secondly, very low proliferation and neopterin levels were observed in MLCs between HLA-DR phenotypically identical family members; and thirdly, high neopterin release and strong cellular proliferation were a feature of MLCs established between individuals differing for at least one HLA-DR antigen. We thus conclude that T cell activation subsequent to recognition of HLA-DR disparity represents an essential prerequisite for induction of neopterin release in human MLC.

Biopterins↗