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Biomedical subjects

C Huber

Publications and source records attributed to C Huber.

At least 163 records · Page 9Linked to original sources
PubMed1996

Phase I trial of inhaled natural interleukin 2 for treatment of pulmonary malignancy: toxicity, pharmacokinetics, and biological effects.

Safety, local and systemic immunomodulation, and tumor response to treatment with aerosolized natural interleukin 2 (nIL-2) applied five times a day were studied in a Phase I trial in 16 patients with pulmonary malignancies refractory to conventional therapy. The toxicity of inhaled nIL-2 was different from that observed after systemic administration. Reversible airway irritation causing a nonproductive cough represented the dose-limiting toxicity. Mild to moderate reduction of the vital capacity and forced expiratory volume (FEV1) with minor effects on relative FEV1, peak expiratory flow, airway resistance, and PaO2 was experienced by individual patients. In 14 patients suffering from pulmonary metastases due to renal cell cancer, one durable complete response, one partial response, and one mixed response were observed. Inhalation of nIL-2 aerosol resulted in a dose-dependent expansion of pulmonary immunocompetent cells in bronchoalveolar lavage fluid. Posttreatment bronchoalveolar lavage showed an activated lymphocyte phenotype with increased HLA-DR expression. The only systemic biological effect detectable in peripheral blood was a marked increase of soluble interleukin 2 receptor serum levels. We conclude that treatment with aerosolized nIL-2 is an effective means for site-specific immunomodulation and deserves further investigation for the treatment of malignant and inflammatory lung disease.

Administration, Inhalation↗
PubMed1996

Reduced membrane major histocompatibility complex class I density and stability in a subset of human renal cell carcinomas with low TAP and LMP expression.

Suppression of MHC class I expression is thought to allow tumor cells to escape immune surveillance mediated by CD8(+) CTLs. For stable MHC class I surface expression, multiple protein interactions are required for efficient assembly of MHC class I heavy chain and beta 2-microglobulin with endogenous peptides. Peptide processing and transport into the endoplasmic reticulum involves the genes of the transporters associated with antigen processing, TAP-1 and TAP-2, and the two components of the proteasome complex, the low molecular weight proteins LMP-2 and LMP-7. We selected human renal cell carcinoma (RCC) cells derived from a tumor that is thought to be controlled by host immunity to study the MHC class I antigen presentation machinery. Eleven RCC lines established from primary tumors were investigated for the mRNA and protein expression of MHC class I, TAP, and LMP genes. In addition, membrane stability of MHC class I was determined by incubation of the RCC cell lines at low temperature and in the presence of exogenous HLA-binding peptides. Our results revealed the existence of two different phenotypes of RCC cell lines. Group I displayed temperature-stable MHC class I surface expression associated with high, and in most cases coordinated, expression of MHC class I heavy and light chain, TAP and LMP transcripts, and proteins. Group II demonstrated a marked MHC class I instability at 37 degreesC associated with low but coordinated expression of the respective transcripts and proteins. MHC class I membrane expression of group II, but not of group I RCC cells, could be stabilized by incubation with specific MHC class I binding peptides. These results suggest an important role of the genes of the antigen presentation machinery in stable and efficient MHC class I surface expression of RCC cells. However, it has still to be defined whether deficient antigen processing is one of the mechanisms of RCC cells to escape the surveillance of the immune system.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Role of accessory cells in cytokine production by T cells in chronic B-cell lymphocytic leukemia.

We investigated the production of cytokines by highly purified T helper cells from B-cell chronic lymphocytic leukemia (B-CLL) patients stimulated by different activation pathways, and we studied the influence of various accessory cell populations on the pattern of the secretion of cytokines, including interleukin (IL)-2, IL-4, interferon-gamma (IFN-gamma), and IL-10. Neither a qualitative nor a quantitative difference in cytokine production and proliferative capacity was observed in CLL-derived purified T cells compared with normal individuals, when T cells were stimulated by different pathways, including CD3, CD2, and costimulation with CD28. Addition of autologous accessory cells (aAC), however, dramatically influenced the cytokine pattern of normal versus B-CLL-derived T cells. CLL cells as aAC caused a marked increase of IL-2, whereas IFN-gamma was only slightly induced and IL-4 was not influenced. In contrast, in normal individuals addition of aAC, which predominantly consisted of monocytes, resulted in a significant increase of IFN-gamma and a reduction of IL-4 secretion. IL-2 production was inhibited by higher concentrations of aAC. The increased stimulation of IL-2 production by CLL cells was not specific to the leukemic cell population, as purified B cells from normal individuals had the same effect. On the other hand, purified monocytes from CLL patients and controls both induced IFN-gamma production and inhibited IL-4 secretion. After antigen-specific stimulation with tetanus toxoid, cytokine secretion was influenced by the type of aAC in a similar pattern. We conclude that T helper cells derived from patients with B-CLL are intrinsically normal and that the predominance of B cells as accessory cells in CLL significantly alters the immune function of T helper cells in vitro.

Antigen-Presenting Cells↗
PubMed1995

Overexpression of annexin V in cystic fibrosis epithelial cells from fetal trachea.

In this report, we investigated the expression of annexins I, II, V, and VI by Northern and Western blot analysis in four cell lines isolated from human fetal tracheae. Two cell lines were obtained from normal fetuses and the two others from fetuses with cystic fibrosis (CF). One CF fetus was heterozygous for the S549N and N1303K substitutions, whereas the other was homozygous for the delta F508 deletion. We found that the four annexins are always coexpressed. The expression of annexins I, II, and VI was the same in the four cell lines. In contrast, that of annexin V was significantly higher in CF than in normal cells. These observations demonstrate that annexins I, II, V, and VI are independently regulated in tracheal epithelial cell lines. Moreover, they suggest that the overexpressed annexin V, a Ca2+ channel, might profoundly modify Ca2+ transport across the membranes of CF cells.

Actins↗
PubMed1995

Biotherapy of chronic myelogenous leukemia.

The aim of this review is to summarize the current knowledge on the clinical results of biotherapy of chronic myelogenous leukemia (CML) and potential mechanisms of the antitumor action of interferon alpha. IFN alpha treatment induces hematologic and cytogenetic remissions in patients with chronic phase CML. In addition, the duration of the chronic phase is prolonged by IFN alpha resulting in a significant survival benefit. In two randomized clinical trials this survival benefit was demonstrated in all chronic phase CML patients independent of their risk scores. Moreover, IFN treatment also delays the onset of clinical relapse after allogeneic bone marrow transplantation. The critical mechanisms of IFN action have not yet been identified. Both direct and indirect antiproliferative mechanisms have been described. In particular, differential regulation of growth promoting and growth inhibiting cytokines represents an attractive hypothetical mechanism of IFN action. Nevertheless, no leukemia specific IFN activities explaining cytogenetic remissions and/or delay of disease progression have been identified. Further research on that field are required to further improve biological CML therapies.

Humans↗
PubMed1995

Cytokines in the pathophysiology and treatment of chronic B-cell malignancies. A review.

Chronic B-cell malignancies are characterized by accumulation of transformed B cells of low proliferative index in lymphatic and extralymphatic tissues. Cytokines do not appear to play a role in the primary step of transformation. However, proliferation as well as inhibition of apoptosis of malignant B cells can readily be explained by cytokine effects. Clinical trials of interferons (IFN) and interleukin-2 alone or in combination have been performed in patients with hairy cell leukemia (HCL), CLL, and low- and intermediate-grade non-Hodgkin's lymphoma. While IFN alpha became standard therapy of HCL, responses in other entities were variable, ranging from 0 to 70% in selected populations. Combination of IFN and cytotoxic chemotherapy in general revealed no additional benefit as compared to chemotherapy alone. Perspectives for future clinical testing of cytokines in low-grade B-cell lymphomas are discussed.

B-Lymphocytes↗
PubMed1995

Plasma levels of IL-1, TNF alpha, IL-6, IL-8, G-CSF, and IL1-RA during febrile neutropenia: results of a prospective study in patients undergoing chemotherapy for acute myelogenous leukemia.

Plasma levels of IL-1, IL-6, IL-8, IL1-RA, TNF alpha, and G-CSF were prospectively studied during 23 chemotherapy cycles of 20 patients suffering from acute myelogenous leukemia. Increased plasma levels of IL-6, IL-8, and G-CSF were observed in patients with febrile neutropenia and/or major infection. Plasma levels of IL-6, IL-1, TNF alpha and IL-1-RA measured 1 day before and 1 day after the onset of febrile episodes did not accurately predict the development of major infection. In contrast, IL-8 plasma levels were significantly higher in those patients who subsequently developed major infection. The question whether IL-8 plasma levels identify high risk or low risk patients with sufficient specificity and sensitivity has to be answered in large scale clinical trials.

Adolescent↗
PubMed1995

Tc-99m MAA lung perfusion scintigraphy performed before and after pulmonary embolectomy for saddle-type pulmonary embolism.

A 58-year-old man had shortness of breath, hypotension, and decreased partial pressure of oxygen (PO2) on the eighteenth day after undergoing craniotomy for a meningioma. Tc-99m MAA pulmonary perfusion scintigraphy showed little perfusion to the right lung and left lower lung and multiple perfusion defects in the left upper lung. Although the results of concurrent chest radiography were negative for pulmonary infiltrates, pulmonary angiography demonstrated a saddle-type embolism. The patient underwent emergency pulmonary artery embolectomy to remove blood clots and organized thromboemboli from the main pulmonary artery and the right and left pulmonary arteries. The patient's postoperative course was uneventful, and a second Tc-99m MAA lung perfusion scan demonstrated marked improvement in lung perfusion.

Embolectomy↗
PubMed1995

Adjuvant polychemotherapy of nonorgan-confined bladder cancer after radical cystectomy revisited: long-term results of a controlled prospective study and further clinical experience.

A total of 83 patients with nonorgan-confined bladder cancer with or without lymph node metastases (tumor stages pT3b, pT4a and/or pN1, pN2) was evaluated in November 1993 for relapse-free and overall survival. All patients underwent radical cystectomy between 1987 and 1991, 38 underwent adjuvant polychemotherapy with methotrexate, vinblastine and cisplatin plus doxorubicin (M-VAC) or epirubicin (M-VEC). Of the 83 patients 49 had entered a prospective randomized trial comparing adjuvant to no adjuvant treatment. The protocol was activated in May 1987. Patient recruitment was concluded in December 1990 because an interim analysis of the 49 randomized patients revealed a significant prognostic advantage in favor of the 26 patients randomized to the chemotherapy group compared to 23 in the control group (p = 0.0015, log-rank test for relapse-free survival curves). Preliminary data were published in 1992. Of the 26 patients randomized for adjuvant chemotherapy 18 were treated with M-VAC or M-VEC, 7 refused chemotherapy before or during cycle 1 and 1 received chemotherapy without cisplatin because of impaired renal function. The update of patient followup obtained in November 1993 continues to demonstrate a significant improvement in progression-free survival in favor of patients randomized for adjuvant chemotherapy (p = 0.0005). Followup of patients living free of disease ranged from 38 to 78 months. In a second analysis of actual treatment, the total collective of 83 patients treated from 1987 to 1991 was reviewed: 38 who had actually undergone adjuvant M-VAC/M-VEC (18 during the prospective trial and 20 in 1991 as the routinely recommended therapy) were compared with 45 without adjuvant M-VAC/M-VEC (7 refused to participate in the adjuvant trial, 8 randomized for but did not undergo adjuvant M-VAC/M-VEC, 23 belonged to the control group of the trial, and 7 underwent cystectomy in 1991 and remained without adjuvant treatment). This analysis again revealed a significant prognostic advantage in favor of the patients treated with adjuvant M-VAC/M-VEC. We conclude that adjuvant chemotherapy with M-VAC/M-VEC leads to a significant prolongation of relapse-free survival and to an improvement of the definitive cure rates after radical cystectomy for locally advanced transitional cell carcinoma of the bladder.

Adult↗
PubMed1995

Interferon-alpha (IFN-alpha) inhibits granulocyte-macrophage colony-stimulating factor (GM-CSF) expression at the post-transcriptional level in murine bone marrow stromal cells.

Recently it has been shown that IFN-alpha inhibits expression of GM-CSF in adherent cells of human long-term bone marrow cultures (LTBMC) stimulated with interleukin-1 (IL-1), tumour necrosis factor-alpha (TNF-alpha) or endotoxin. The murine bone marrow stromal cell line +/+(-1).LDA11 was used to further define regulatory mechanisms of IFN-alpha inhibition on GM-CSF expression. This cell line originated from a murine Dexter type culture and exhibits a preadipocytic phenotype. As in human LTBMC, we could demonstrate a inhibitory effect of IFN-alpha co-incubation on GM-CSF activity in serum-free supernatants of +/+(-1).LDA11 stromal cell cultures stimulated with IL-1 or TNF-alpha or the combination of IL-1 plus TNF-alpha. IFN-alpha inhibitory effect on GM-CSF expression was shown to be dose dependent with minimal response at 10 U/ml and maximal inhibition at a dose of 500 U/ml. Northern blot analysis confirmed these data at the mRNA level. Reprobing of Northern blots for interleukin-6 (IL-6) mRNA showed increased expression after IFN-alpha incubation, demonstrating specific and differential regulatory effects of IFN-alpha on cytokine production in bone marrow stromal cells. Inhibition of GM-CSF mRNA by IFN-alpha was time dependent, starting at about 90-120 min post-treatment. Cycloheximide (CHX) incubation abolished the inhibitory effect of IFN-alpha on GM-CSF expression, suggesting the requirement of a labile protein. Reporter gene studies were used in order to evaluate the effect of IFN-alpha incubation on GM-CSF mRNA transcription in stromal cells. For this purpose, GM-CSF promoter fragments were subcloned into a luciferase expression vector. Neither constitutive nor TNF-alpha stimulated GM-CSF transcription was inhibited by IFN-alpha coincubation. On the other hand, actinomycin-D chase experiments revealed a reduced GM-CSF mRNA stability after IFN-alpha incubation. The induction of a RNAase, possibly a 2-5A-dependent RNAase, by IFN-alpha may be a possible cause for the increased GM-CSF mRNA decay. These results show a regulatory role for IFN-alpha in the bone marrow microenvironment possibly involved in the myelosuppressive effect of IFN-alpha therapy or viral infections.

Animals↗
PubMed1995

Effect of interleukin-3 pretreatment on granulocyte/macrophage colony-stimulating factor induced mobilization of circulating haemopoietic progenitor cells.

Recombinant human colony stimulating factors (CSFs) as single agents are increasingly used for mobilizing peripheral blood progenitor cells (PBPCs) for stem cell transplantation. We have shown in rhesus monkeys that interleukin-3 (IL-3) pretreatment markedly potentiated the increase in PBPC numbers of subsequent administration of granulocyte/macrophage-CSF (GM-CSF). Here we studied the effect of IL-3 pretreatment on GM-CSF-induced mobilization of PB progenitors in patients who were potential candidates for autologous stem cell transplantation (n = 16). Patients were treated with GM-CSF at a dose of 5 micrograms/kg/d for 5 d and after a treatment free interval received another cycle of GM-CSF immediately following pretreatment with IL-3 at different doses and duration: 2.5 micrograms/kg/d (n = 4), 5 micrograms/kg/d (n = 3) and 10 micrograms/kg/d (n = 3) for 3 d, 5 micrograms/kg/d for 7 d (n = 4) and 5 micrograms/kg/d for 14 d (n = 2), respectively. Only 7 d pretreatment with IL-3 showed consistent effects. Although IL-3 did not mobilize by itself, pretreatment with 5 micrograms/kg/d of IL-3 for 7 d significantly potentiated GM-CSF-induced mobilization of PB CFU-GM numbers, leading to a mean increase in PB CFU-GM numbers over baseline by 18.5 +/- 5.2 (SEM) fold by IL-3/GM-CSF as compared to a 4.7 +/- 1.7-fold increase by GM-CSF alone. A significant enhancement by the 7 d IL-3 pretreatment was also observed for erythroid (BFU-E) and multipotential progenitor cells (CFU-mix) which were 3.3 +/- 1.3- and 3.4 +/- 0.9-fold, respectively, mobilized by GM-CSF alone, as compared to 8.5 +/- 2.3- and 19.2 +/- 3.4-fold, respectively, by the IL-3/GM-CSF combination. Our results suggest that 7 d pretreatment with IL-3 may be a useful mean to augment mobilization of circulating progenitors by more lineage-restricted CSFs. These findings may be important for the design of mobilization strategies that use growth factors without preceding chemotherapy.

Adolescent↗
PubMed1995

Treatment of choroidal neovascularization in age-related macular degeneration with interferon alpha-2a: a short term, nonrandomized pilot study.

A total of 11 patients exhibiting in 11 eyes a subfoveal or juxtafoveal choroidal neovascular membrane due to age-related macular degeneration (AMD) were treated with interferon alpha-2a (Roferon) according to a protocol that was designed for an independent, randomized, open-label pilot study to evaluate the efficacy and safety of this therapy. However, none of the patients agreed to be randomized and all elected to be treated. The average follow-up period after treatment was 8.2 months. In 6 of 7 eyes with classic choroidal neovascularization the membrane increased in size during and after treatment. Of these 6 eyes, 5 lost more than 6 lines of visual acuity. In 2 of 4 eyes with occult neovascularization the lesion enlarged. In the other 2 eyes the lesion became atrophic in 1 case and remained stable in size in the other. Visual acuity decreased by 3-9 lines in 3 eyes with occult neovascularization. Of the 11 patients, 2 discontinued interferon treatment after 8 weeks because of severe adverse reactions. From the data collected thus far in this study and in the majority of published series, we conclude that interferon alpha-2a in the dose range of 3-6 million IU given three times weekly over 8-12 weeks is neither effective nor safe for the treatment of subfoveal neovascularization in AMD.

Aged↗
PubMed1995

GM-CSF in a double-blind randomized, placebo controlled trial in therapy of adult patients with de novo acute myeloid leukemia (AML).

We investigated whether GM-CSF given concomitantly with chemotherapy (CT) and thereafter, improves the outcome of adults with de novo AML by increasing the efficacy of CT and reducing infections. CT included Ara-C, daunorubicin and etoposide (DAV) for induction and early consolidation therapy and one cycle with high-dose (patients aged < or = 50 years) or intermediate dose Ara-C (patients aged > 50 years)/daunorubicin for late consolidation therapy. Eight patients were randomized after DAVI to receive either GM-CSF (E. coli, 250 micrograms/m2/day, s.c.) or placebo starting 48 h prior to DAVII and the subsequent courses and given throughout CT until the absolute neutrophil count had recovered to > 500/microliters. The CR rate was 81% in the GM-CSF and 79% in the placebo group (p = 0.57; Fisher's exact test). The probability of relapse-free survival at 41 months after a median follow-up of 35 months was 42% in the GM-CSF and 41% in the placebo group (p = 0.89; log rank test). GM-CSF did not shorten the period of neutropenia < or = 500/microliters, while it prolonged the duration of thrombocytopenia < or = 25,000/microliters. The incidence and severity of infections as well as the non-hematological toxicity were similar in both groups. In summary, in this randomized trial GM-CSF as an adjunct to AML therapy was feasible. For the present GM-CSF does not have a significant effect on treatment outcome.

Adolescent↗
PubMed1995

Differential effect of type I interferons on hematopoietic progenitor cells: failure of interferons to inhibit IL-3-stimulated normal and CML myeloid progenitors.

We observed a differential effect of type I interferons (IFNs) in inhibiting the proliferation of various hematopoietic progenitor cell types. Upon stimulation with interleukin-3 (IL-3), IFN-alpha and IFN-beta failed to inhibit colony formation of myeloid progenitors (day-14 colony-forming units-granulocyte/macrophage [CFU-GM]) obtained from peripheral blood (PB) and bone marrow (BM) of untreated chronic myelogenous leukemia (CML) patients in chronic phase even at IFN doses as high as 10,000 U/mL. In contrast, day-7 CFU-GM stimulated with granulocyte colony-stimulating factor (G-CSF) and burst-forming units-erythroid (BFU-E) were readily inhibited by moderate doses of IFNs. IFN-resistant myeloid progenitor cells were also detected in normal BM but not in normal PB cells. When suboptimal doses of IL-3 were used in clonal progenitor cell assays, day-14 CFU-GM were not protected from the inhibitory action of IFN. The failure of IFN to inhibit immature myeloid progenitors was confirmed in normal and CML cells highly enriched in CD34-expressing cells. Combinations of growth factors were required for sufficient colony formation in these cells, whereas IL-3 alone provided only an inadequate stimulation, which was further inhibited by IFN. In purified CD34+ cells, day-14 CFU-GM were protected from IFN-mediated inhibition only upon stimulation with stem cell factor (SCF) in combination with IL-3 or G-CSF.

Antigens, CD34↗
PubMed1995

Expression of c-fos correlates with IFN-alpha responsiveness in Philadelphia chromosome positive chronic myelogenous leukemia.

This study evaluates (i) constitutive levels of oncogene and p53 transcripts in chronic phase CML patients and (ii) their modulations subsequent to in vivo therapy with rIFN-alpha 2c. Peripheral blood mononuclear cells (pbmc) and bone marrow cells of 26 patients were examined for c-fos, c-myc, p53 and the hybrid bcr/abl mRNA levels. Results indicated that (i) constitutive c-fos transcript levels are significantly higher in patients subsequently responding to IFN-alpha therapy (p < 0.01) and positively correlated with the proportion of lymphocytes (r = 0.6895, p < 0.01) and negatively with the proportion of immature cells (r = -0.568, p < 0.01) contained in the pbmc preparations tested, (ii) constitutive mRNA levels of the hybrid bcr/abl, c-myc and p53 are positively correlated with each other, but failed to relate to disease parameters, and (iii) acute and chronic in vivo exposure to IFN-alpha is accompanied by upregulation of c-fos and downregulation of c-myc mRNA levels in responder patients.

Bone Marrow Cells↗