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Biomedical subjects

C Huber

Publications and source records attributed to C Huber.

At least 307 records · Page 17Linked to original sources
PubMed1987

Characterization of an interferon-resistant mutant of the human breast cancer cell line BT-20.

The human breast cancer cells BT-20 were treated for 18 months in the continuous presence of interferon-gamma (HuIFN-gamma; 500 U/ml). These cells have become completely resistant to HuIFN-gamma and interestingly also to IFN-alpha 2. However, the expression of HLA-DR and the regulation of cell adhesion to tissue culture plastic remained partially under the domain of HuIFN-gamma. A reduced number of IFN-gamma binding sites in comparison to the wild-type cells were observed on the IFN-resistant BT-20 cells.

Breast Neoplasms↗
PubMed1987

Selective reduction of donor-specific cytotoxic T lymphocyte precursors in patients with a well-functioning kidney allograft.

We have recently developed a sensitive limiting dilution (LD) culture system to measure human alloreactive cytotoxic T lymphocyte precursors (CTL-p) in a given lymphoid cell population. We have now used this system to determine frequencies of donor HLA antigen-inducible CTL-p in the peripheral blood of human allograft recipients at various stages after transplantation. All patients (1 pancreas recipient and 9 kidney recipients) were on continuous cyclosporine treatment throughout the study. We report that, in patients with a well-functioning kidney graft (6/9), the number of donor-reactive CTL-p among peripheral blood lymphocytes decreased within 3-8 months after transplantation--in some cases (2/6) more than 10-fold. In contrast, frequencies of CTL-p with specificity for third-part HLA antigens remained largely unaltered in these patients. Furthermore, no decrease of donor-reactive CTL-p frequencies was seen in 3 of 4 patients showing clinical symptoms of graft rejection. These results indicate that functional clonal deletion of antigraft-reactive CTL-p may contribute to the state of graft tolerance in certain patients with a well-functioning kidney allograft.

Cells, Cultured↗
PubMed1987

Rapid reappearance of large granular lymphocytes (LGL) with concomitant reconstitution of natural killer (NK) activity after human bone marrow transplantation (BMT).

The frequency of large granular lymphocytes and their relationship to functional NK-activity as assessed by the capacity to lyse the K562 tumour target was analysed in five allogenic and two autologous human bone marrow transplant recipients. Date revealed: almost identical disappearance and reconstitution of both parameters further indicating that LGL represent effector cells of spontaneous lysis of K562 targets; a long-lasting suppression of the absolute numbers per ml of blood of both LGL and functional NK activity which we believe was not the consequence of reconstitution with immature effector cells but rather reflected immunosuppressive therapy; LGL exhibits the fastest reappearance rate subsequent to total body irradiation of all populations of circulating leucocytes.

Antigens, Surface↗
PubMed1987

[Retrospective study of the reasons for admission and the principal causes of mortality in the pediatric service of the Port-Gentil General Hospital of (Gabon), June 1985-May 1986].

A retrospective study of 534 bed-rests permitted us to specify the reasons of admissions and mortality in the hospital service of pediatrics, Port-Gentil, Gabon, from June 1985 to May 1986: a high mortality rate (7.5%) with, specially, diarrheas (46%) and proteinocaloric malnutrition (19%). The other reasons of mortality are constituted by infections and neonatal diseases. Priority in public health seems to be child welfare (vaccinations, primary health care in the whole province of Ogoue, health certificates...).

Cause of Death↗
PubMed1987

[Acute petroleum poisoning in infants in Gabon].

Acute intoxications with petroleum are frequent in children: we have seen 36 cases in a year in the General Hospital, Port-Gentil (Gabon), service of pediatrics. Pulmonary lesions are aggravated by vomitus; radiological signs appear after half an hour, interest the right side and are characterized by an interstitial syndrome. Evolution is always good with antibiotherapy. Prevention consists in health education.

Accident Prevention↗
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

Alpha-interferon induces remission in hairy cell leukemia without enhancement of natural killing.

The number of large granular lymphocytes (LGL) and the capacity of peripheral blood mononuclear cells (PBMC) to lyse K 562 target cells in a natural killer (NK)-like fashion was evaluated in seven hairy cell leukemia (HCL) patients undergoing treatment with recombinant interferon-alpha-2 (rIFN-alpha-2). In HCL patients, whose peripheral blood showed high numbers (greater than or equal to 15 X 10(3)/microliters) of leukemic cells the number of LGL and their capacity to lyse K 562 tumor target cells were very low prior to treatment but increased significantly (p less than 0.05) following interferon (IFN) therapy. In patients with low numbers of hairy cells (HC) in their peripheral blood, both these parameters were higher and remained largely unaffected throughout IFN treatment. In vitro, HC proved to be completely insensitive to natural killing when tested against unstimulated and IFN-activated LGL from healthy donors. These results fail to support the concept of IFN-mediated enhancement of host antitumor actions, responsible for the favourable clinical results in HCL.

Adult↗
PubMed1986

Abnormal expansions of granular lymphocytes: reactive lymphocytosis or chronic leukemia? Case report and literature review.

A case of chronic lymphoproliferative disorder is presented, wherein a morphologically homogeneous population of lymphoid cells displayed properties similar to those described for large granular lymphocytes (LGL). Besides their LGL-like phenotype (VEP 13+, OKM 1+, OKT 10+ Fc-IgG-receptor+, OKT 3-), the proliferating cells were cytotoxic to NK targets as well as to antibody-coated target cells. Clinically, our patient presented low-grade lymphocytosis, splenomegaly, neutropenia, hyperimmunoglobulinemia and recurrent infections. Based upon this and 32 similar cases reported in the literature, we conclude that lympho-proliferative disorders involving GL encompass a variety of clinical entities, ranging from reactive GL lymphocytoses to overt lymphocytic malignancies.

Adult↗
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

Treatment of hairy-cell leukemia with recombinant alpha 2-interferon.

Eleven patients with hairy-cell leukemia (eight with progressive and three with non-progressive disease) were treated with low dose recombinant human alpha 2-interferon. After a 3-month treatment period, nine patients showed an improvement and one patient a partial remission. By then, transfusions were not required any more and serious infections were no longer encountered. Four patients were further treated: three for a total period of 9 months and one for 6 months; all of them reached a partial or complete remission. The treatment was equally effective in patients with both progressive and non-progressive disease. Previous absence of response to splenectomy did not preclude a positive effect of IFN therapy. In two patients, IFN dose reduction was necessary due to unremitting flu-like symptoms.

Humans↗
PubMed1986

Exogenous IL2 partially reverts CML non-reactivity acquired during prophylactic immunosuppression with cyclosporin A of human allograft recipients.

Proliferative and cytolytic lymphocyte responses and the influence of exogenous interleukin 2 (IL2) on cell-mediated lympholysis (CML) reactivity were evaluated in 12 allograft recipients. Responses were induced by mitogenic lectins or by donor and third-party cells. Patients were tested immediately before transplantation (Tx) and one and three months after grafting. Prophylactic immunosuppression consisted of Cyclosporin A (CyA) and low-dose prednisone (P). Analysis of post transplant cells revealed a reduced overall proliferative T cell responsiveness induced by both alloantigens and mitogenic lectins. No evidence for donor-specific reduction of MLC responses was seen. Overall CML reactivity of post-Tx lymphocytes was also impaired. This was accompanied by donor-specific CML non-reactivity in six of seven patients with quiescent grafts. In these patients, the cytolytic potential against donor cells could be restored when maximal T cell help via exogenous IL2 was provided.

Adult↗
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↗
PubMed1986

Use of donor-specific T-cell lines for monitoring of human allograft recipients. I. Demonstration of IgG binding to autologous TCL.

Donor-specific and highly cytotoxic T-cell lines (TCL) as well as lectin-induced TCL were established from pretransplant lymphocytes of 6 cadaveric renal allograft recipients. These TCL were used in the 125I-staphylococcus protein A assay to detect IgG antibodies in pre- and posttransplant sera of these patients preferentially binding to autologous donor-specific TCL. Such antibodies were detected in pretransplant sera from 4 of these 6 allograft recipients. Antibody levels in these 4 patients and in 1 additional case who became positive after transplantation further increased during acute cellular rejection episodes. They disappeared after successful treatment but remained elevated until transplantectomy for treatment of irreversible rejection in 1 case. IgG antibodies binding to autologous lectin-induced TCL were detected in only 1 patient and exhibited a pattern clearly different from those binding to donor-reactive TCL. Although attempts to define the antigenic specificity of the autoantibodies binding to donor-specific TCL by genetical and biochemical means has remained unsuccessful so far, the demonstration of their relationship to in vivo expansion of donor-reactive immune cells deserves further attention.

Adult↗