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Biomedical subjects

H Kirchner

Publications and source records attributed to H Kirchner.

At least 289 records · Page 16Linked to original sources
PubMed1988

Deficiency in interferon production of peripheral blood leukocytes from patients with non-Hodgkin lymphoma.

In search for a rationale for the use of interferons (IFNs) in treatment of non-Hodgkin lymphoma (NHL), we have investigated the IFN system of 13 patients with low-grade NHL, 15 patients with high-grade NHL, and 20 patients with chronic lymphocytic leukemia or leukemic immunocytoma (CLL/IC). Production of IFN induced by phytohemagglutinin (PHA), concanavalin A (Con A), pokeweed mitogen (PWM), Corynebacterium parvum, Herpes simplex virus (HSV), Newcastle disease virus (NDV), and interleukin 2 (IL-2) were studied in the peripheral leukocytes from the patients and from 21 control persons by means of a whole blood technique. All three groups of patients with NHL had significantly reduced production upon stimulation by NDV (p ranged between 0.0038 and less than 0.0001) compared to controls. Similarly, C. parvum also induced lower titers of IFN in the leukocytes of patients with non-leukemic NHL (p = 0.0015 for low-grade NHL and p = 0.0038 for high-grade NHL). When stimulated by PHA, the IFN response of all groups of patients was within normal range. With the exception in low-grade NHL, Con A also induced normal titers of IFN in the patients with NHL. The levels of IFN induced by PWM, HSV, and IL-2 were very low and no differences between controls and patients could be found. As NDV and C. parvum induce mainly IFN-alpha and the mitogens PHA and Con A mainly IFN-gamma, our results suggest that there is a deficiency in the IFN-alpha response in the patients with NHL but normal response in IFN-gamma. This deficiency may have implications for the choice of subtypes of IFN in the treatment of NHL.

Adult↗
PubMed1988

Effects of different interferons on the replication of herpes simplex virus in human T lymphocytes.

Human T cells were activated with PHA and after 48 h they were treated with preparations of different human interferons (IFNs). After a further incubation period of 24 h, the cells were washed and infected with herpes simplex virus type 1 (HSV-1). Reduced virus titers were observed in T cells pretreated with IFN-alpha or IFN-beta, whereas IFN-gamma showed no antiviral effects. These findings indicate that IFN-gamma does not exert protection against viral infection in this system. We investigated the synthesis of HSV-coded early and late proteins in T cells pretreated with IFN-alpha and IFN-beta. Immunofluorescence studies revealed inhibition of expression of the immediate early alpha-protein ICP 4. Induction of DNA-polymerase, a viral beta-protein, was inhibited both by IFN-alpha and IFN-beta in a dose-dependent manner. As suggested by SDS-polyacrylamide gel electrophoresis, other viral beta- and gamma-proteins of HSV were inhibited by IFN-alpha and IFN-beta as well.

Cell Division↗
PubMed1988

Pharmacokinetics of recombinant murine interferon-gamma in mice.

Administration of interferon-gamma (IFN-gamma) provides a new approach to the treatment of tumors and viral and microbial infections. The aim of this study was to evaluate the pharmacokinetics of recombinant murine IFN-gamma (rMuIFN-gamma) in the mouse system as a model for future investigations of the therapeutical effect of IFN-gamma. After a bolus injection of 2 x 10(4) LU/mouse by the intravenous (i.v.) route, a biphasical elimination pattern of the antiviral activity from the serum was detected in female and male C57BL/6 and CBA/2 mice with a beta half-life time of 19-32 min. After intramuscular (i.m.) and subcutaneous (s.c.) injection of rIFN-gamma, antiviral activity in serum could be detected from 30 to 270 min after the bolus application. There was a plateau in the activity from 65 to 135 min after s.c. and from 84 to 143 min after i.m. injection. Both kinetics fit with a pharmacokinetic model of biphasical elimination with an entrance compartment.

Animals↗
PubMed1988

Antiviral activity of tumour necrosis factor. Synergism with interferons and induction of oligo-2',5'-adenylate synthetase.

Tumour necrosis factor (TNF) induces antiviral activity in HEp-2 cells. Virus yield reduction assays with vesicular stomatitis virus as challenging virus demonstrated that the antiviral state was more pronounced in confluent cultures under low serum conditions. A significant enhancement of the antiviral state was obtained by combining TNF with low concentrations of either interferon (IFN)-beta 1 or IFN-gamma. The reduction in virus yield was significantly higher than that expected from summation of the independent antiviral activities of either substance alone, i.e. TNF and IFN acted synergistically as antiviral agents. Synergism of TNF with IFN-beta or IFN-gamma appeared to be mediated by different pathways, since different requirements for pretreatment and different effects on oligo-2',5'-adenylate synthetase (2-5AS) induction were observed. Induction of 2-5AS by TNF could be shown to be an indirect event that was sensitive to an antiserum against natural IFN-beta 1.

2',5'-Oligoadenylate Synthetase↗
PubMed1988

Decreased production of interferon in whole blood cultures derived from patients with psoriasis.

Patients suffering from psoriasis show many alterations with respect to their immune system as documented by in vitro test systems. In the present study we investigated the in vitro production of interferons (IFN) of leukocytes from psoriatic patients to stimulation with a variety of IFN inducers. Furthermore, the lymphoproliferative responses were tested. Whole blood cultures of 30 psoriatic patients showing moderate to severe disease activity and 21 cultures from healthy controls were stimulated with the mitogens PHA, ConA, and PWM, with PPD and Tetanus Antigen as IFN gamma inducers and with C. parvum, PolyI-PolyC, and Herpes simplex virus as inducers of IFN alpha. Interferon activity was tested in the supernatant of 48-h cultures by using an antiviral assay. Lymphoproliferation was assayed in 5-d cultures in parallel. Psoriatic patients showed a significantly decreased IFN production to all the stimuli tested. There were no significant differences in the lymphoproliferative responses; only the response to PWM was slightly decreased. The decreased IFN production by leukocytes from psoriatic patients seems to be very remarkable since increased susceptibility to infections is not generally known in these patients.

Cells, Cultured↗
PubMed1988

Production of gamma interferon in Mls disparate interactions.

The murine T-cell clone E11 isolated from a primary H-2k histocompatible one-way mixed lymphocyte culture of B10.BR anti C3H/Tif spleen cells was used to study multidirectional interactions in strong stimulatory Mls disparate responses. Several parameters have recently been studied, and proliferation of T cells upon stimulation by macrophages or B cells of Mls-disparate stimulator cells, induction of differentiation of B cells of stimulator strains but inhibition of their macrophage differentiation, and the inhibition by E11 T cells of the production of a mitogenic mediator by Mls-disparate spleen cells have been found. As shown in this paper, these phenomena can be explained by an Mlsa, d, e specific induction of gamma-interferon (IFN-gamma) production in the responder B10.BR (Mlsb) E11 T cells. It is suggested that IFN-gamma, as a regulator of feedback mechanisms plays a critical role in Mls disparate T-cell stimulation.

Animals↗
PubMed1988

Increased production of interferon gamma and tumor necrosis factor precedes clinical manifestation in multiple sclerosis: do cytokines trigger off exacerbations?

We have carried out a longitudinal study of interferon (IFN) and tumor necrosis factor (TNF) using a whole-blood mitogen stimulation assay in 20 multiple sclerosis (MS) patients and in a healthy control group. We set up individual profiles and the results were quite constant for each individual, both in healthy donors and in the patients in remission. Before exacerbations, however, we found an increase of IFN-gamma and TNF production preceding clinical symptoms by a maximum of 2 weeks. In benign cases, the increase disappeared rapidly, even before the appearance of symptoms, whereas we found sequelae whenever the increase persisted during weeks. In chronic progressive patients, we frequently found intervening increases. It may be that IFN-gamma and TNF trigger off exacerbations at a very early stage and that these cytokines may also play a role in maintaining disease in chronic progressive and invalidating forms.

Adult↗
PubMed1988

Induction of antinuclear antibodies in patients with rheumatoid arthritis receiving treatment with human recombinant interferon gamma.

Of six patients with rheumatoid arthritis (RA) treated with human recombinant interferon gamma for two to eight months, three developed antinuclear antibodies (ANAs). This was accompanied by a simultaneous clinical exacerbation of the disease activity. In this study both anti-inflammatory and immunostimulatory effects of human recombinant interferon gamma in patients with RA were observed.

Adult↗
PubMed1988

[Therapy of Hodgkin's lymphomas. Results of the German Hodgkin's Disease Study Group].

Between July 1983 and May 1987 143 untreated patients with Hodgkin's lymphoma in stages I-IIIA with risk factors qualified for the HD1 protocol, and 230 patients in stages IIIB/IV qualified for HD3. Patients in HD1 received a combined chemo-radiotherapy (2 x COPP + ABVD + 20 Gy EF vs. 40 Gy EF). Patients in HD3 received induction chemotherapy (3 x COPP + ABVD) and were randomized into consolidation by radiotherapy (20 Gy IF) vs. chemotherapy (1 x COPP + ABVD). In HD1, 73 of 89 evaluable patients (82%) achieved a complete remission. The survival of patients in stages I-IIIA with risk factors treated according to HD1 is as good as the survival of patients in stages I and II without risk factors. In HD3, 86 of 137 patients (63%) achieved complete remission after induction chemotherapy with 3 x COPP + ABVD. This is significantly better than the 31% complete remission rate observed in a pilot study with COPP alone (p less than 0.01). Including salvage therapy (radiotherapy in case of persisting nodal disease; chemotherapy with 4 x CEVD in case of persisting disseminated disease), a total of 76% complete remissions in stages IIIB/IVAB were achieved. An ESR greater than 80 mm/h was the most significant single risk factor in stages IIIB/IV for induction of CR and freedom from progression.

Adolescent↗
PubMed1988

[Interferons and their effects].

The interferon system is an integral part of the defense system of the body, mediating a large variety of biologic effects. Presently, three groups of interferons (IFN) are known: IFN alpha, IFN beta and IFN gamma. IFN alpha and IFN beta show homology on the nucleotide level of about 40-50%, and both IFNs bind to a common receptor. IFN alpha and IFN beta are produced after induction by leukocytes and fibroblasts. IFN gamma is, by definition, not only an interferon but also a lymphokine, since it is a product exclusively of lymphocytes. There is no homology on the nucleotide level between IFN gamma and IFN alpha/beta. Furthermore, the receptor of IFN gamma is different from the receptor of IFN alpha/beta. IFNs are defined by their antiviral activity directed against a large number of different viruses. The target of IFN is the cell rather than the virus itself. Through binding on the cell surface and subsequent activation of specific genes IFNs induce an antiviral state which makes cells less permissive for virus replication. The antiviral state consists of various antiviral mechanisms. Among the non-antiviral effects of IFNs are the effects on cellular components of the immune system. Thus, one has postulated a role for interferons as immunoregulatory molecules. Interferons augment the expression of MHC-genes of which IFN alpha/beta only affect the molecules of class I, whereas IFN gamma affects both the molecules of class I and class II. Moreover, all IFNs increase the activity of macrophages and NK cells. Possibly the activation of components of the immune system is in part responsible for the antitumor effects of interferon.(ABSTRACT TRUNCATED AT 250 WORDS)

Humans↗
PubMed1988

Contamination of a monoclonal antibody with LDH-virus causes interferon induction.

Interferon induction occurred unexpectedly during an in vivo study using a mouse monoclonal antibody. The interferon was typed alpha/beta and the titer reached a maximum at 24 hours in contrast with other inducers. Similar results were obtained with a virus pool derived from the antibody and with a LDV reference strain. MAP-testing of the monoclonal antibody revealed contamination with lactate dehydrogenase virus (LDV). The production of IFN seems to be controlled genetically. This experimental error demonstrates the importance of an appropriate quality control of biological materials.

Animals↗
PubMed1988

Decrease of natural killer cell activity and monokine production in peripheral blood of patients treated with recombinant tumor necrosis factor.

Tumor necrosis factor (TNF), a protein predominantly produced by activated macrophages/monocytes, is presently available in recombinant, purified form for clinical trials. Intensive studies in many laboratories have shown that besides the tumorcytotoxic effects, TNF acts on a large array of different cells and has potent immunomodulatory activities. In a clinical phase I study, some immunologic functional parameters of blood cells from patients who received 24-hour infusions of recombinant human TNF (rhTNF) were analyzed. Natural killer (NK) cell activity, TNF production, interleukin-1 (IL-1) production and mitogen-induced proliferation were measured either in whole blood samples or in cultures of peripheral mononuclear leukocytes of the patients directly before and after rhTNF infusion. NK cell activity, TNF and IL-1 production capacity and proliferative responses to concanavalin A (Con A) were significantly reduced after rhTNF application. We conclude from these observations that rhTNF in vivo acts directly or indirectly on NK cells and monocytes by either inactivating their functional capacity or by absorbing the relevant cells to the endothelial cell layer, thus removing them from circulation.

Adult↗
PubMed1988

Recombinant human granulocyte-macrophage colony stimulating factor (rh GM-CSF) after bone marrow transplantation.

Bone marrow transplantation improves the chances of survival in a variety of hematological malignancies. However, infectious complications during the post-transplant phase contribute significantly to morbidity and mortality. To reduce the duration of granulocytopenia, which is approximately 20 days after BMT, in this study patients with ALL, relapsed or high-grade NHL, relapsed or refractory HD, or Neuroblastoma stage III/IV, were given rh GM-CSF to assess the effects on hematological and immunological reconstitution after conditioning therapy and BMT. The results of 9 patients are presented. After autologous BMT and subsequent rh GM-CSF therapy, a peripheral blood neutrophil count of 500/microliters was reached within 8-12 days, i.e., between 7 and 10 days earlier than would have been expected without rh GM-CSF. Furthermore, it appeared that rh GM-CSF was useful in case of insufficient bone marrow regeneration post autologous transplant. The influence of rh GM-CSF after allogeneic BMT is not yet clear. Further studies will be necessary to evaluate the potential of this promising new drug after BMT.

Adult↗
PubMed1987

Activation of cytotoxic activity in cultures of bone marrow-derived macrophages by indomethacin.

Indomethacin was tested for its ability to augment the cytotoxic capacity of cultured bone marrow-derived macrophages (M phi) against P815 and YAC-1 tumor cells. M phi were obtained from the bone marrow of C57BL/6 mice precultured for 10-14 days and were virtually 100 percent pure. By addition of indomethacin these cells were activated to kill tumor cells in a 4-h and 18-h Cr-release assay. Since indomethacin is a potent inhibitor of the cyclooxygenase system, M phi were treated with prostaglandin E2. This treatment partially reversed indomethacin-induced cytotoxicity. Addition of other cyclooxygenase inhibitors such as acetyl-salicylic-acid, diclofenac or carprofen also induced cytotoxicity in bone marrow-derived M phi. In all experiments we failed to detect any production of interferon. Addition of anti-interferon did not alter the cytolytic capacities demonstrating that endogenously induced interferon was not relevant in this mechanism. Our data show that cyclooxygenase inhibitors induce cytolytic activity of murine M phi not only against a M phi target but also against YAC-1 cells usually considered to be targets for natural killer cells.

Animals↗
PubMed1987

Reversal of defective lymphoproliferation in postoperative patients with colon cancer.

To establish a method for evaluation of immunological parameters in small blood samples, a whole blood technique was developed for the estimation of mitogen- or antigen-induced proliferation. Studies regarding cellular immunity in patients with colon cancer were done with 108 patients in all tumor stages, aged 32 to 80 years. They were studied before surgery and 10 days after operation. A group of 35 patients were further tested 3 months after surgical treatment. In patients with colon cancer the proliferative responses of peripheral blood lymphocytes to mitogens were significantly lower in comparison to healthy controls. These results were found when the response to concanavalin A, phytohemagglutinin, OKT 3, and pokeweed mitogen were analyzed preoperatively and 10 days postoperatively. There was no relation to the stage of disease. The marked reduction of mitogen responses was followed by a gradual return toward normal values 3 months after surgical resection of neoplastic growth in 80% of the patients. Our studies indicate that the defects were largely restored when testing was performed 3 months after operation. Using this result, it will be possible to perform long-term studies in order to establish if there is a correlation between the return to normal immune reactivity and the survival of individual patients.

Adult↗
PubMed1987

Production of interferon and lymphoproliferative response in whole blood cultures derived from patients with atopic dermatitis.

Enhanced susceptibility to viral infections has been reported repeatedly in atopic dermatitis (AD). A difference in the capacity to produce interferons (IFN) in response to viral antigens may be the cause. In the present study we investigated the in vitro IFN production of leukocytes from AD patients in response to different stimuli. Furthermore, the lymphoproliferative responses were tested. The patients showed moderate to severe disease activity. Whole blood cultures of 25 AD patients and 21 healthy nonatopic controls were stimulated with the mitogens phytohemagglutinin (PHA), concanavalin A (ConA), and pokeweed mitogen (PWM), with tuberculin derivative (PPD) and tetanus antigen as IFN-gamma inducers, and with C. parvum, poly I-poly C, and herpes simplex virus (HSV) as inducers of IFN-a. Lymphoproliferation was assayed in 5-day cultures in parallel. In AD no significant difference of the IFN production was found in comparison with the controls with any stimuli tested. The lymphoproliferative response of leukocytes of patients with AD was significantly decreased upon stimulation with PHA, Con A, PWM, and PPD. We suggest that in AD the described susceptibility to viral infections is not due to an altered capability of leukocytes to generate IFN.

Antigens↗
PubMed1987

Role of interferon in persistent infection of macrophages with herpes simplex virus.

Splenic macrophage cultures from C57BL/6 mice resistant to infection with herpes simplex virus (HSV) in vivo survived HSV infection in vitro. In contrast, macrophages from HSV-susceptible DBA/2 mice were completely lysed by the virus. During prolonged culturing, macrophages from C57BL/6 mice continued to produce infectious virus, indicating establishment of a persistent infection. At this time, interferon (IFN) was undetectable. However, as shown directly by the addition of an anti-IFN serum and indirectly by an increased activity of (2'-5')oligoadenylate synthetase, IFN was involved in the maintenance of the persistent infection. During the acute phase of virus infection, viral DNA replication was identical in macrophages from resistant or susceptible mice. Later, viral DNA content and the number of cells expressing HSV antigens decreased in macrophages from C57BL/6 mice. However, single cells remained to express viral proteins and to produce infectious particles. The results show that macrophages can be persistently infected with HSV due to their genetically controlled properties.

2',5'-Oligoadenylate Synthetase↗