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PubMed1999

De-regulation of GRP stress protein expression in human breast cancer cell lines.

The stress-inducible glucose regulated proteins (GRPs), a class of calcium-binding molecular chaperones localized in the endoplasmic reticulum, have been implicated in the development of tumorigenicity, drug resistance, and cytotoxic immunology. This study investigates the expression pattern of GRP94 and GRP78 in a panel of breast carcinoma cell lines, as compared to two independently derived normal human breast epithelial cell lines. Here we report that a 3- to 5-fold increase in the basal level of the GRP94 protein was observed in all five breast carcinoma cell lines examined. The increase was independent of either the p53 or estrogen receptor status of the breast carcinomas. In carcinoma cells deprived of glucose, mimicking the conditions in poorly vascularized solid tumors, up to 9-fold induction of GRP94 was observed relative to the basal level expressed in a normal breast epithelial cell line. Interestingly, while the majority of the breast cancer cell lines can respond to tunicamycin- and thapsigargin-induced stress by increasing the steady state levels of grp94 and grp78 transcripts, the induction at the GRP protein level is variable and does not always correspond with the transcript level. Further, we discovered that one of the human breast carcinoma cell lines, MCF-7, has specifically lost its ability to respond to tunicamycin stress.

Adenocarcinoma↗
PubMed1998

Human myeloma cell apoptosis induced by interferon-alpha.

Although there have been reports regarding the clinical effectiveness of IFN alpha in the treatment of myeloma patients during this decade, its biological effects on human myeloma cells have still not been clarified. Recently, apoptosis has been considered as one of the most important mechanisms in the programmed cell death of malignant tumour cells induced by chemotherapeutic agents or cytotoxic immunological defence in malignancy-carrying hosts. Among the several pathways which function to induce apoptosis, Fas and the Fas ligand system have been thought to play an important role in inducing tumour-cell apoptosis, particularly in immunological prevention. In this study we investigated myeloma cell apoptosis induced by IFN alpha using five human myeloma cell lines which were established without any additional supplementation of IL-6. In addition, the mRNA expression levels of apoptosis-related genes employing the reverse transcriptase-polymerase chain reaction (RT-PCR) were also analysed with the KMS-12-PE cell line, which was the most sensitive of the five cell lines in terms of apoptosis induced by IFN alpha. Based on the results, it was determined that IFN alpha induced myeloma cell apoptosis in a dose-dependent manner, but the sensitivity to IFN alpha in the cell lines examined varied and one cell line revealed growth stimulation by IFN alpha. In addition, the apoptosis induced by IFN alpha did not seem to be mediated by the Fas/Fas ligand pathway. Finally, the IL-6, IL-6R, IRF1 and IRF2 genes were up-regulated in KMS-12-PE cells cultured with IFN alpha. Therefore these genes may play an important role during apoptosis induced by IFN alpha.

Antineoplastic Agents↗
PubMed2004

Statins: novel additions to the dermatologic arsenal?

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), atorvastatin, cerivastatin, fluvastatin, pravastatin, lovastatin and simvastatin, reduce atherogenesis and cardiovascular morbidity. Besides, there is growing evidence that statins have immunomodulatory activities. Statins downregulate the expression of adhesion molecules, intercellular adhesion molecule-1 (ICAM-1), monocyte chemotactic protein-1 (MAC-1) and lymphocyte function-associated antigen-1 (LFA-1), on leucocytes and endothelial cells and, through binding to LFA-1, interfere with ICAM-1-LFA-1 interaction, which is crucial for activation of lymphocytes by antigen-presenting cells, ingress of leucocytes into the inflammation sites and immunologic cytotoxicity. Statins inhibit the inducible expression of major histocompatibility complex class II in several cell types including macrophages and downregulate the expression of T-helper-1 (Th1) chemokine receptors on T cells, leading further to inhibition of activation of lymphocytes and their infiltration into the inflammation sites. Statins block the induction of inducible nitric oxide synthase and the expression of several proinflammatory cytokines such as tumour necrosis factor-alpha and interferon-gamma in macrophages and possess antioxidant effects. These agents inhibit the proliferation of immunocytes and the activation of natural killer cells. Regarding the above facts and in view of their safety and inexpensiveness, statins may prove invaluable in the treatment of a multiplicity of dermatologic disorders, especially those characterized by ingress of activated leucocytes into the skin, such as alopecia areata, vitiligo, lichen planus, subacute cutaneous lupus erythematosus, erythema multiforme, psoriasis, bullous pemphigoid, systemic sclerosis, mycosis fungoides, toxic epidermal necrolysis and Behcet's disease.

Humans↗
PubMed1994

Viral infection and the pathogenesis of dilated cardiomyopathy.

Long-term follow-up studies of patients with suspected viral myocarditis reveal progression to dilated cardiomyopathy (DCM) in a significant number of cases. Thus, an underlying viral etiology has been hypothesized in the pathogenesis of ongoing heart disease that leads to DCM. Recent application of molecular biology in clinical diagnosis has strengthened this hypothesis. By use of probe hybridization and polymerase chain reaction, enteroviral RNA has been detected in the myocardium of patients at all stages of the disease process: myocarditis, chronic heart disease, and DCM. Experimental murine models of enterovirus-induced heart disease provide a framework for examining the pathogenic mechanisms. Viral cytotoxicity, immunological responses, viral RNA persistence, and spasm of the coronary microvasculature are all implicated in the ongoing disease process. Abnormal cardiac function and heart failure are attributed to the pathological changes that occur.

Animals↗
PubMed2006

T-cell activation: A queuing theory analysis at low agonist density.

We analyze a simple linear triggering model of the T-cell receptor (TCR) within the framework of queuing theory, in which TCRs enter the queue upon full activation and exit by downregulation. We fit our model to four experimentally characterized threshold activation criteria and analyze their specificity and sensitivity: the initial calcium spike, cytotoxicity, immunological synapse formation, and cytokine secretion. Specificity characteristics improve as the time window for detection increases, saturating for time periods on the timescale of downregulation; thus, the calcium spike (30 s) has low specificity but a sensitivity to single-peptide MHC ligands, while the cytokine threshold (1 h) can distinguish ligands with a 30% variation in the complex lifetime. However, a robustness analysis shows that these properties are degraded when the queue parameters are subject to variation-for example, under stochasticity in the ligand number in the cell-cell interface and population variation in the cellular threshold. A time integration of the queue over a period of hours is shown to be able to control parameter noise efficiently for realistic parameter values when integrated over sufficiently long time periods (hours), the discrimination characteristics being determined by the TCR signal cascade kinetics (a kinetic proofreading scheme). Therefore, through a combination of thresholds and signal integration, a T cell can be responsive to low ligand density and specific to agonist quality. We suggest that multiple threshold mechanisms are employed to establish the conditions for efficient signal integration, i.e., coordinate the formation of a stable contact interface.

Animals↗
PubMed2000

Comparative analysis of paracrine immunotherapy in experimental brain tumors.

OBJECT: Local delivery of cytokines has been shown to have a potent antitumor activity against a wide range of malignant brain tumors. In this study, the authors examined the efficacy of treating central nervous system (CNS) tumors by transfecting poorly immunogenic B16/F10 melanoma cells with interleukin (IL)-2, IL-4, or granulocytemacrophage-colony stimulating factor (GM-CSF) gene, and using these cells to deliver the cytokine locally at the site of the CNS tumor. The object was to determine which cytokine would possess the greatest antitumor activity and to further elucidate its mechanism of action. METHODS: The transfected B16/F10 cells were irradiated to prevent replication and injected intracranially into C57BL/6 mice (10 mice per group) along with nonirradiated, nontransfected B16/F10 (wild-type) melanoma cells. Sixty percent of mice treated with IL-2 (p < 0.001 compared with control) and 10% treated with IL-4 (median survival = 31 days, p < 0.001 compared with control) were long term survivors (> 120 days). The median survival for animals treated with GM-CSF was 22 days with no long term survivors (p = 0.01 compared with control). Control animals that received only wild-type cells had a median survival of 18 days (range 15-20 days). Histopathological examination of brains from animals killed at different times showed minimal infiltration of tumor cells in the IL-2 group, moderate infiltration of tumor cells in the IL-4 group, and gross tumor invasion and tissue necrosis in the GM-CSF group. Animals treated with IL-2 showed a strong CD8 T cell-mediated response, whereas IL-4 evoked a prominent eosinophilic infiltrate in the area of the tumor. CONCLUSIONS: High levels of locally expressed IL-2 rather than IL-4 or GM-CSF stimulate a strong immunological cytotoxic antitumor response that leads to significant prolongation of survival in mice challenged with B16/F10 intracranial melanoma tumor cells. Consequently, IL-2 may be a superior candidate for use in paracrine immunotherapy.

Animals↗
PubMed2000

[Suppressive effects of lanoconazole on arthus phenomenon in vivo and on production and functions of TNF in vitro].

The anti-inflammatory effect of lanoconazole (LCZ) was investigated in vivo and in vitro. The effect of LCZ was evaluated on the inflammatory reactions elicited by intradermal injection of ovalbumin to ovalbumin-immunized rabbits, as an Arthus phenomenon. A one or two % cream preparation of LCZ was topically applied on the lesion daily after challenging injection until the inflamation had diminished. By macroscopic observation and measuring the diameter of edema, erythema, hemorrhage and necrosis, the effects of LCZ on the reactions were compared with the reactions of the sites administered withcream vehicle as reference agent. Two % LCZ showed an anti-hemorrhagic effect. The in vitro effect of LCZ on production and functions of an inflammatory cytokine, TNF was also examined. LCZ suppressed the production of TNF by murine peritoneal macrophages at 20 micro g/ml and the adhesion of neutrophils at 100 micro g/ml. Moreover, LCZ significantly suppressed the growth inhibitory activity of TNF against L929 fibroblasts at 0.5 micro g/ml. A very low concentration of LCZ might protect the fibroblasts from immunological cytotoxicity in vivo. These findings suggest that LCZ has a suppressive activity to inflammatory responses and this suppressive action may be due to its protective activity to cells like fibroblasts.

Animals↗
PubMedDate not supplied

[Interferon--properties and action].

The role played by interferon in human organism is described, with particular reference to its immunomodulatory effects. The classification of interferons, and the mode of its synthesis in cells infected by viruses are presented. The molecular bases of interferon action as a protein inhibiting virus development and the role of gamma interferon in human immunity are discussed.

Adjuvants, Immunologic↗
PubMed1981

[Immunologic protection against Epstein-Barr virus induced oncogenesis: cooperative effect of lymphocytes, antibodies and interferon in healthy individuals (author's transl)].

Immunologic cytotoxicity against lymphocytes transformed or infected by Epstein-Barr virus (EBV) was mainly studied in an autologous in vitro system by 51Cr release assay and EBV-determined nuclear antigen (EBV)-specific trypan blue exclusion method. The following results were obtained. 1. The EBV-transformed or EBV-infected lymphocytes were killed with high frequency, when they were incubated with autologous lymphocytes in the presence of EBV-positive autologous serum. Exposure to lymphocytes alone or to EBV-positive serum alone was not effective. 2. The cytotoxic reaction was directed against cells positive for EBV-induced membrane antigen complex (MA) but not against MA-negative transformed cells. 3. These data indicated that the present cytotoxic reaction represents antibody-dependent cellular cytotoxicity (ADCC). 4. Such ADCC, however, does not seem to function effectively in patients with systemic lupus erythematosus. (SLE). 5. A very small amount of interferon (5 IU/ml) was found to enhance ADCC activity. Interferon alone, however, was not cytotoxic enough, even though a much larger dose was given. Neither lymphocyte-interferon nor antibody-interferon mixture was effective. 6. Thus, the cooperation of lymphocytes, EBV antibodies and interferon is considered to be a major role in the protection against EBV-induced oncogenesis in seropositive healthy individuals.

Adult↗
PubMed1989

[The natural cytotoxicity system in patients with multiple sclerosis: clinico-immunological parallels].

The cytotoxic activity of natural killer (NK) cells against target cells K-562 was studied in patients with multiple sclerosis (MS). NK activity was increased in patients with remitting course of the disease, its duration of 6 to 10 years and 1 to 3 degree of neurologic defect. The immunocorrective therapy reduced the NK activity in some patients of any group. The authors discuss the possible role of natural cytotoxic system in the pathogenesis of autoimmunization in MS, and the value of NK population assessment for singling out a group of patients that would beneficially respond to immunocorrective therapy.

Adolescent↗
PubMed1975

[The lymphocyte cytotoxicity test in tumor immunology (author's transl)].

The cytotoxic action of lymphocytes on cancer cells in vitro indicates sensitization of the patient against his own tumor. The technical difficulities of this test and possibilities of standardization and simplifying the procedure are discussed. Critical steps are isolation of lymphocytes and culturing target cells without loosing their specific antigenic structure. The need for specificity controls both for lymphocytes and tumor cells is emphasized. Labelling tumor cells with isotopes represents a major improvement in evaluating the result. The role of thymus- and bone marrow-dependent lymphocytes as well as blocking factors in the serum of tumor patients can be analyzed in the cytotoxic assay. A better understanding of these mechanisms may facilitate a therapeutic approach by manipulating the interaction of tumor cells and host.

Animals↗
PubMed1990

Failure of infiltrating precursor cytotoxic T cells to acquire direct cytotoxic function in immunologically privileged sites.

Minor H incompatible P815 tumor cells inoculated into the anterior chamber (AC) of the eyes of BALB/c mice grow progressively, revealing this to be an immunologically privileged site. By contrast, a similar inoculation of tumor cells is rapidly rejected from nonprivileged ocular sites (subconjunctiva). Mice with progressively growing AC-tumors and those that reject their ocular subconjunctiva tumors both have expanded clones of tumor-specific cytotoxic precursor cells (pTc) in their spleens and cervical lymph nodes. In an effort to determine why the expanded pool of primed pTc is unable to effect rejection of AC intraocular tumors, we have examined the susceptibility of the tumor cells growing within the immunologically privileged AC to lysis by cytotoxic T cells and the cytotoxic function of tumor-infiltrating lymphocytes. P815 tumor cells extracted from intraocular tumors and P815 cells maintained in routine tissue culture are equally susceptible to lysis when exposed in vitro to fully differentiated, DBA/2-specific cytotoxic T cells. Thus, progressively growing tumor cells within the AC are not insensitive to immune-mediated lysis by cytotoxic T cells. We have been able to harvest significant numbers of DBA/2-specific pTc from these same intraocular tumors. When the tumor-infiltrating lymphocytes are driven in vitro with exogenous IL-2, they acquire the capacity to lyse specifically P815 tumor cells. However, no evidence of fully cytotoxic, tumor-specific T cells was found among lymphocytes harvested from intraocular tumors, i.e., when the harvested cells were tested immediately for cytolytic activity. Inasmuch as we have reported that directly cytotoxic T cells are present during tumor rejection at nonimmunologically privileged ocular sites, such as the subconjunctival space, we conclude that progressive growth of P815 tumor cells within the anterior chamber is due in part to a failure of infiltrating pTc to differentiate in situ into fully functional cytotoxic effector cells.

Animals↗
PubMed1985

[Relations of tumor-specific cytotoxicity to nonspecific immunological parameters and to clinical course in various surgical cancer patients].

Human malignant cells, obtained from surgical specimens or pleuro-peritoneal exudate in 105 cases, were cultivated. Tumor-specific immunity was estimated by cytotoxicity assay using mixed autologous lymphocyte-tumor cell culture in 27 cases (40 times in all). Relations of the observed specific immunity to various nonspecific immunological parameters and to clinical responses to immunotherapy were examined. Positive reaction was observed in 14 examinations. Eight of 25 digestive tract cancers and 6 of 15 other cancers were positive. Cytotoxic activity was significantly higher in the group of favorable clinical response than in the group of progressive disease. In the group of positive cytotoxicity, incidence of clinical response was significantly higher than in the group of negative cytotoxicity. A significant positive correlation was found between cytotoxicity and T cell ratio. Incidence of positive cytotoxicity tended to be higher in the cases of single OK-432 administration (6/11). Incidence of clinical response was higher in the cases of combined OK-432 and PSK administration group (4/14). In the positive cytotoxicity group, 3 examinations showed progressive disease and 5 showed no change. It has been suggested that a higher incidence of favorable clinical response is to be expected in case of positive cytotoxicity, if some therapy will be combined with the conventional immunotherapy.

Adjuvants, Immunologic↗