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Biomedical subjects

H Tilg

Publications and source records attributed to H Tilg.

At least 109 records · Page 6Linked to original sources
PubMed1989

Acute effects of single doses of recombinant interferon-gamma on blood cell counts and lymphocyte subsets in patients with advanced renal cell cancer.

The object of this study was to investigate the effects of different single doses of recombinant interferon-gamma (rIFN-gamma) on white blood cell counts, differential blood counts, and the relative composition of T-cell subsets in the peripheral blood of cancer patients. Sixteen patients suffering from metastasizing renal cell carcinoma received 10, 100, or 500 micrograms of rIFN-gamma three times at weekly intervals. After a therapy-free interval of 2 weeks, the next dose level was applied. The order of dose levels was assigned randomly to each patient. White blood cells, differential blood counts, and the number of Leu1, Leu3, Leu2a, Leu7, and HLA DR+ cells were measured immediately before and at 4, 24, 48, 72, 96, and 168 h after the administration of single doses of rIFN-gamma. Results indicated that white blood cells were transiently removed from the blood circulation after administration of IFN-gamma. Monocytes, HLA DR+ cells, and Leu7+ cells were reduced to below 50% of pretreatment values 4 h after application of the cytokine. CD8+ cells and granulocyte counts declined to approximately 70% of pretreatment values 24 h after IFN therapy. The preferential reduction of CD8+ lymphocytes resulted in a temporary increase of the T4/T8 ratio in these patients.

Adult↗
PubMed1989

Neopterin excretion after liver transplantation and its value in differential diagnosis of complications.

The aim of this study was to investigate patterns and clinical utility of a neopterin marker in liver allograft recipients. Urinary neopterin levels were studied in 59 transplant patients daily until discharge. During the early postoperative period (days +1 to +20) neopterin excretion exhibited a liver-specific pattern that clearly differed from that seen in renal and bone marrow transplant recipients. Neopterin concentrations increased and reached peak values on day +7. The height of this early peak varied in context with complications such as infection or rejection, and was correlated with an unfavorable prognosis. In contrast to the early phase, no liver-specific pattern was observed after day 20. As seen in all other transplant patient populations, values normalized in patients with an uncomplicated course but again increased during infection or rejection episodes. Neopterin levels were particularly high during CMV infection, and their increments were directly related to the severity of CMV disease. The neopterin marker, although not specific, enables discrimination between patients with a complicated and uncomplicated clinical course. High neopterin values early after transplantation are associated with unfavorable prognosis and correlate with an increased risk of developing CMV disease.

Biopterins↗
PubMed1989

[Diagnosis and therapeutic strategies in pneumonia in childhood].

Acute lower respiratory tract infections remain a major cause of morbidity in infants and children. In the majority of patients therapy is complicated by difficulties in securing a specific diagnosis and identification of the causative organism. Treatment is therefore largely based on experiential rather than experimental data. In our study we have tried in 722 patients with pneumonia to correlate the clinical findings with the causative agents. Age and a careful medical history give good clues towards the most probable aetiologic agent. Additional information is gained by the course of the illness. Physical examination, chest X-ray and few limited laboratory tests can also be of help to identify the most likely organism. Once the organism is identified, appropriate antimicrobial agent can be started. It is not only the choice of the antimicrobial substance, but also the choice of the proper total daily dose, dosage interval and mode of administration. By this management we had good results also in elimination of problem organism such as pseudomonas in CF.

Anti-Bacterial Agents↗
PubMed1989

Comparison of clinical efficacy and toxicity of conventional and optimum biological response modifying doses of interferon alpha-2C in the treatment of hairy cell leukemia: a retrospective analysis of 39 patients.

Hairy cell leukemia (HCL) has been shown to be extraordinarily sensitive to treatment with alpha-interferon (IFN). In order to define clinically effective IFN doses associated with minimal toxicity, the therapeutic efficacy and side effects of recombinant IFN-alpha-2C treatment of HCL were compared for two different dose regimens: 18 patients (group A) received conventional doses of recombinant IFN-alpha-2C (2 x 10(6)U/m2) for a median time of 35 weeks (range 26-52 weeks), and 21 patients (group B) received optimum biological response-modifying doses of IFN-alpha-2C (0.2-0.6 x 10(6)U/m2) for a median time of 31 weeks (range 12-52 weeks). Interferon was administered daily subcutaneously for 3 months and then every second or third day. Induction of neopterin excretion was chosen as the marker for definition of biological response. The smallest IFN dose causing maximum in vivo induction of biosynthesis of the GTP-degradation product neopterin was deemed "biologically optimal." Both dose regimens were effective, but the low-dose regimen was almost free of toxicity. Thus, in HCL patients alpha-IFN related toxicity can be separated from its antineoplastic activity. Low doses of alpha-IFN should be considered for treatment of HCL patients who develop toxic side effects and for primary treatment of HCL patients with severe cytopenia.

Adult↗
PubMed1988

Cytomegalovirus infection.

Interest has focused on cytomegalovirus (CMV) infections during recent years for two reasons: First, the number of immunocompromised patients with CMV infections has risen continuously and, secondly, recent advances in basic research have clarified some of the mechanisms of persistent and recurrent CMV infection. Three different clinical pictures can arise with CMV infection. In healthy individuals most of the CMV infections are not clinically apparent. In immunocompromised patients CMV causes a wide spectrum of diseases and is one of the predominant causes of death in AIDS patients and bone marrow transplant recipients. The most important problem for public health associated with CMV are connatal and perinatal CMV infections. Progress has been made with treatment of CMV infection in immunocompromised patients with inhibitors of viral replication.

Acquired Immunodeficiency Syndrome↗
PubMed1988

Enhanced serum levels of beta-2-microglobulin, neopterin, and interferon-gamma in patients treated with recombinant tumor necrosis factor-alpha.

The effect of different doses of recombinant human tumor necrosis factor-alpha (rTNF-alpha) on serum levels of neopterin, beta-2-microglobulin and interferon-gamma (IFN-gamma) was investigated in tumor patients. Twelve patients with advanced malignant disease were treated and received single doses of either 1, 10, or 100 micrograms/m2 rTNF-alpha on days 0 and 7. Neopterin, beta-2-microglobulin and IFN-gamma serum levels were measured from day -2 to day 12 of the study. Application of rTNF-alpha leads to a marked and dose-dependent increase of neopterin and beta-2-microglobulin levels; no rTNF-alpha-dependent changes were observed after 1 microgram/m2, and maximum increments were seen in patients receiving 100 micrograms/m2. Serum levels of both parameters peaked after 2 days and returned to baseline values within 1 week. IFN-gamma levels were also elevated after application of rTNF-alpha. We failed, however, to demonstrate a clear correlation between the serum levels of IFN-gamma, beta-2-microglobulin, and neopterin because of the wide range of pre- and posttreatment levels of IFN-gamma. We conclude that neopterin and beta-2-microglobulin represent useful markers for monitoring biological response to treatment with rTNF-alpha.

Adult↗
PubMed1988

Serum colony stimulating factors in patients undergoing bone marrow transplantation: enhancing effect of recombinant human GM-CSF.

Sera from 11 patients undergoing autologous or allogeneic BMT were tested for their content of megakaryocytic, granulocytic and erythrocytic colony stimulating factors. During the first week after BMT, all patients sera revealed a low/inadequate production of granulocytic, erythrocytic and megakaryocytic colony-stimulating activity (defined as the number of colonies per plate induced by 30% test serum from monocyte and T-lymphocyte depleted bone marrow cells). Thereafter an increase of colony-stimulating activity for all cell lineages tested was observed with peak levels between days 8 to 14 after BMT. The peak level was followed by a decline of colony stimulating activity, which shows an inverse correlation to basal blood leukocyte counts suggesting an adequate counter-regulation during this period. The GM colonies grown in the presence of patient serum were found to consist largely of neutrophilic granulocytes with only single monocytic colony, but without eosinophilic colony formation, suggesting that granulopoietic colony formation during this period is mediated predominantly by G-CSF and not by GM-CSF. All patients undergoing autologous BMT revealed a low/inadequate endogenous CSF production. rh GM-CSF addition in vitro was able to compensate from the impaired endogenous granulopoietic CSA in all patients and resulted in a constant augmentation of granulopoietic colony formation. The percentage of eosinophilic colony formation showed an inverse correlation to endogenous CSF production also suggesting that G-CSF is secreted during this period. In contrast to the granulopoietic colony formation, erythropoietic and megakaryopoietic colony formation was not enhanced by GM-CSF addition in vitro and even showed a slight reduction in some experiments. Our results suggest the treatment with recombinant GM-CSF might be beneficial for a faster reconstitution of granulo-monocytopoiesis after BMT, that rh GM-CSF therapy should be started immediately after bone marrow transplantation and that G-CSF is the main factor secreted in allogeneic bone marrow transplantations in the regeneration period.

Bone Marrow Transplantation↗
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↗
PubMed1988

Comparison of serum neopterin levels and urinary neopterin excretion in renal allograft recipients.

Determination of serum and urinary neopterin levels was performed daily in 30 patients undergoing kidney transplantation for treatment of end-stage renal failure. Neopterin serum levels were determined by RIA and urinary excretion by HPLC. In parallel, the same samples were tested for creatinine content. Results indicated a strong correlation between the clearance of neopterin and creatinine. This correlation was independent of the extent of functional impairment as well as of the different causes of renal insufficiency. As a consequence, a strong relationship between serum and urinary neopterin levels was only obtained when values were corrected for different renal function by dividing them by the creatinine levels. It thus appears that major attention has to be paid to the functional state of the kidney when studying neopterin serum and/or urine values. It also appears that under these prerequisites both methods of detection as well as both sample sources yield comparable results.

Adult↗
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

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↗
PubMed1985

Evaluation of spontaneous lymphocyte proliferation by single cell autoradiography in human allograft recipients.

Spontaneous lymphocyte proliferation was studied in 22 patients receiving cadaveric renal transplants before and at various times after grafting. Prophylactic immunosuppression consisted of CyA and prednisone. Spontaneous lymphocyte proliferation was evaluated in a total of 500 single cell autoradiographs after short term in vitro incubation with [3H]TdR. In 13 patients without clinical problems a transitory increase of lymphocyte labeling indices to approximately five times the pretransplant levels was observed. The failure to detect such increments in two patients receiving optimally matched grafts suggested that this early proliferative lymphocyte peak might be caused by in vivo recognition of major histocompatibility antigens. Much higher labeling indices were detected in close temporary association with acute cellular rejection (4 cases), severe infections and withdrawal of CyA (3 cases) and venous thrombosis (1 case). Only moderately elevated numbers of spontaneously proliferating lymphocytes were seen in one patient with a reversible vascular rejection episode. It appears that assessment of spontaneous lymphocyte proliferation is capable of discriminating on a quantitative level between patients with and without clinical problems such as acute cellular rejection and infection.

Adolescent↗
PubMed1985

[Results of a phase II study on the treatment of hairy cell leukemias with various doses of alpha-2-recombinant interferon].

Hairy-cell leukemia has been shown to be extraordinary sensitive to treatment with alpha-interferon. In order to define clinically effective interferon doses associated with minimal toxicity two different dose regimens were applied in this clinical trial: firstly, a conventional dose schedule, and secondly, a biologically defined dose regimen. For dose finding in the latter group, neopterin, a GTP degradation product produced by macrophages under control of interferon, was chosen. Six patients (Group A) received conventional doses of recombinant interferon--alpha-2 (rIFN-alpha-2) 3 X 10(6) U/sqm/daily by the subcutaneous route. Five patients (Group B) were treated with the minimal dose of rIFN-alpha-2 which had previously been shown to induce maximum neopterin levels in urine. Already interferon doses in the range of 3 to 5 X 10(5) U/sqm2/daily administered subcutaneously proved to be sufficient for triggering maximum neopterin excretion in the urine. After six months of interferon treatment all patients were evaluable. At this time both doses regimens proved to be effective in terms of their anti-leukemic activity, but differed significantly in toxicity, which was only seen in Group A patients.

Adult↗