Natural Immunity (Nat Immun)
Covers current research relating to all aspects of tumor biology. Discontinued in 1998.
Journal Impact: 0.43*
Journal impact history
|2016 Journal impact||Available summer 2017|
|2000 Journal impact||0.43|
|Website||Natural Immunity website|
|Material type||Periodical, Internet resource|
|Document type||Journal / Magazine / Newspaper, Internet Resource|
Publications in this journal
Article: Andrei Sulica, MD, 1938-2000.
- [Show abstract] [Hide abstract] ABSTRACT: The possibility of natural cancer therapy has been recently suggested by advances in the knowledge of tumor immunobiology. Either cytokines such as IL-2, or neurohormones, such as the pineal indole melatonin (MLT), may activate anticancer immunity. In addition, immunomodulating substances have also been isolated from plants, particularly from Aloe vera. Preliminary clinical studies had already shown that MLT may induce some benefits in untreatable metastatic solid tumor patients, whereas, for the time being, no clinical trial has been performed with aloe products. We have carried out a clinical study to evaluate whether the concomitant administration of aloe may enhance the therapeutic results of MLT in patients with advanced solid tumors for whom no effective standard anticancer therapies are available. The study included 50 patients suffering from lung cancer, gastrointestinal tract tumors, breast cancer or brain glioblastoma, who were treated with MLT alone (20 mg/day orally in the dark period) or MLT plus A. vera tincture (1 ml twice/day). A partial response (PR) was achieved in 2/24 patients treated with MLT plus aloe and in none of the patients treated with MLT alone. Stable disease (SD) was achieved in 12/24 and in 7/26 patients treated with MLT plus aloe or MLT alone, respectively. Therefore, the percentage of nonprogressing patients (PR + SD) was significantly higher in the group treated with MLT plus aloe than in the MLT gorup (14/24 vs. 7/26, p < 0.05). The percent 1-year survival was significantly higher in patients treated with MLT plus aloe (9/24 vs. 4/26, p < 0.05). Both treatments were well tolerated. This preliminary study would suggest that natural cancer therapy with MLT plus A. vera extracts may produce some therapeutic benefits, at least in terms of stabilization of disease and survival, in patients with advanced solid tumors, for whom no other standard effective therapy is available.
- [Show abstract] [Hide abstract] ABSTRACT: Porcine NK cells are small to medium-size lymphocytes having a variety of functions that may include the regulation of immune response. Thus frequency and function of NK cells were examined in generations 6 and 8 (G6, G8) of pigs selectively bred for high (H) and low (L) antibody and cell-mediated immune response (CMIR). Using the monoclonal antibody 5C6 as a pan NK phenotype marker and target cell binding and lysis as assays of function, it was found that H and L immune response pigs had high and low NK cell frequency, respectively, at G6 and G8. Function of NK cells differed by line, with the control (unselected) pigs being higher (with respect to target cell binding) or similar (with respect to lytic activity) to H which were higher than the L line pigs. Frequency of NK cells after primary immunization was in significant negative correlation with antibody after secondary immunization with hen egg white lysozyme (HEWL). Therefore, simultaneous selection for antibody and CMIR altered the frequency and function of NK cells in pigs with C > or = H > L.
- [Show abstract] [Hide abstract] ABSTRACT: The present study aimed to quantitatively analyze the effects of thyroxin on natural killer (NK) cells in the bone marrow and spleen of older adult (6 months) mice of both sexes. Five intraperitoneal injections of thyroxin were administered over 10 days in an attempt to stimulate the virtually negligible levels of NK cells in these older mice. Immunoperoxidase labeling of an NK cell surface marker, together with a tetrachrome hematologic counterstain, permitted morphological microscopic identification of mature NK cells, distinct from all other hemopoietic and immune (lymphoid) cells in the spleen and bone marrow. The results revealed that in spite of similar total cell content in both the spleen and bone marrow in both sexes at this age, there were significant, gender-based differences in NK cells and various other hemopoietic and immune cells. NK cells in the 6-month-old female mice are significantly more abundant than those of males at this age. Granulocytes in females were also significantly more numerous in both the spleen and bone marrow than in males. By contrast, monocytes and nucleated erythroid cells were significantly more numerous in males of this age. In both sexes, at this postbreeding age, the immunostimulant, thyroxin, had the common effect of significantly elevating the levels of NK cells. Our results underline the need for considering the two basic parameters of age and gender, as potentially confounding variables, prior to therapeutic administration of thyroxin, and possibly a host of hormones, cytokines and other regulators of hemopoietic and immune phenomena.
- [Show abstract] [Hide abstract] ABSTRACT: Interferon-gamma and interferon inducers such as polyinosinic-polycytidylic acid (poly I:C) promote natural-killer (NK)-cell-mediated killing of a wide range of tumor cells both in vitro and in vivo. The aim of the present work was to administer poly I:C to irradiated, leukemic mice, both before and after syngeneic bone marrow transplant with the intent of boosting the host's natural immunity in the critical peritransplant period. Briefly, DBA/2 mice were injected with Friend-virus-induced erythroleukemia cells. After 5 days of tumor growth, some mice received daily injections of poly I:C for the next 4 days while control, leukemic mice received the saline vehicle only. All mice were then irradiated (450 R x 2 at 4-hour intervals) and transplanted 1 day following irradiation with bone marrow from age- and sex-matched, normal DBA/2 donor mice. After transplant, daily injections of poly I:C (or vehicle) continued for 8 more days. On day 9 after transplant, treated and control mice were killed, and the total cellularity, total numbers of lymphoid cells, the total numbers of NK cells (identified by the presence of an immuno-labelled, specific cell surface marker) were obtained from both the spleen and the bone marrow. Other identically treated mice subjected, however, to several additional rounds of poly I:C treatment were sampled 3 and 6 months after irradiation and bone marrow transplant. The results indicated that (a) poly I:C administered in the peritransplant period (before and after transplant) significantly increases the absolute numbers of NK cells in both the bone marrow and spleen of the transplanted host at all time intervals studied, (b) no erythroleukemic tumor cells were found, even as late as 6 months after transplant in the poly-I:C-treated hosts in spite of the fact that poly I:C treatment in this group had been terminated more than 2 months prior to tissue sampling, and (c) survival was significantly improved by pre- and posttransplant treatment with poly I:C.
- [Show abstract] [Hide abstract] ABSTRACT: We have previously reported that the priming of thioglycollate-elicited peritoneal macrophages (PMphi), as a representative population of mononuclear phagocytes (MNP), by macrophage-colony-stimulating factor (M-CSF or CSF-1) rendered these cells more susceptible to secondary stimulation by extracellular matrix (ECM) proteins, in particular fibronectin (FN), and that at least two beta1 integrins, VLA 4 (alpha4beta1 or CD49d) and VLA 5 (alpha5beta1 or CD49e), regulate IL-6 gene expression when PMphi come into contact with FN. In this report, we focused our attention on resident PMphi, as a more mature/differentiated MNP subpopulation. By using granulocyte-macrophage colony-stimulating factor (GM-CSF)- and IL-6-knockout (null) mice, we demonstrated that the cooperative effect between CSF-1 and FN in IL-6 release was a result of a sequential stimulation of the GM-CSF, but not the TNF-alpha, gene via interaction with VLA 5. We also showed that regardless of the presence or absence of CSF-1 or FN, IL-6 inhibits GM-CSF and TNF-alpha gene expression in an autocrine manner. The observed effects were specific because CSF-1 enhanced VLA 5 expression and blocking FN-treated resident PMphi in vitro with VLA 5 monoclonal antibodies inhibited the IL-6 response. We found that treatment of resident PMphi with the protein kinase C inhibitor, staurosporine, and the activator, phorbol myristate acetate (PMA), resulted in marked modulation of either FN- or FN/CSF-1-induced cytokine release. An increased level of VLA 5 expression was observed in PMA-treated resident PMphi. We concluded that in inflammatory processes, CSF-1 drives a number of pathways involved in the regulation of the expression of several genes and renders MNP highly susceptible to stimulation by ECM proteins that transform the MNP into secretory inflammatory cells.
- [Show abstract] [Hide abstract] ABSTRACT: Porcine NK cells are small to medium lymphocytes which are lytic for tumours and virally infected cells when co-cultured for long periods ( approximately 16 h). The frequency and function of NK cells were examined in generation 8 of pigs genetically selected for high (H), low (L), and control (C) antibody (Ab) and cell-mediated immune response (CMIR). The NK phenotype was identified using a pan-species NK-specific murine monoclonal antibody (5C6) and both binding and lysis of the NK target, K562. Vaccination with modified live transmissible gastroenteritis virus (TGEV) had no effect on blood leucocyte NK cell frequency. In interactions with K562 targets, NK cells of H and C pigs responded similarly in frequency of conjugate formation and lytic activity, while L pigs had very little or no response. Therefore, in pigs selected for high Ab and CMIR, there was no correlated enhancement of NK-cell-related traits following vaccination with TGEV, while selection for low immune response was associated with reduced NK response in pigs. This may suggest that low immune response can reflect reduced contribution of NK cells in pigs.
- [Show abstract] [Hide abstract] ABSTRACT: This paper outlines research that has led to the concept of the inevitable participation of the immune system in an organism's chemical homeostasis. This function of the immune system is tentatively named the 'immune mechanism of the chemical homeostasis' (IMCH). It is based on the theory of a permanent physiological synthesis of antibodies to endogenous biologically active substances. Minimal accumulation of biologically active substances as a result of the influence of different factors specifically activates the immune system in order to maintain its chemical homeostasis. The concept suggests the necessity of widening the notion of the range of the immune system's censorial functions. The concept explains the preexistence of immunocompetent cells preadapted to biologically active substances and autoantibodies specific to them; the natural clonality of the B lymphocyte pool; the polyclonal lymphocyte activation triggered by mitogens, foreign proteins, erythrocytes, and microbes, and tolerance to drugs.
- [Show abstract] [Hide abstract] ABSTRACT: The CD95 (APO-1/Fas)-Fas ligand (FasL) system is an important mediator of antitumor T cell cytotoxicity. The aim of the current study was to assess its significance in human cancer. Malignant effusions were selected as an environment allowing direct cell-to-cell contact in a fluid phase. Malignant pleural effusions collected from 23 patients with metastatic carcinoma of the bronchus, ovary, stomach or breast were examined by means of flow cytometry. The expression ofFas and FasL, probed with the appropriate antibodies, apoptosis of tumor cells and the characteristics of tumor-associated lymphocytes (TAL) were determined by TUNEL reaction in malignant and nonmalignant (control) effusions. All malignant cells had partially or completely lost the expression of CD95 and expressed an elevated level of FasL. In contrast, TAL obtained from malignant pleural effusions demonstrated a marked decrease in the expression of surface FasL and an increase in surface-bound Fas. The percentage of apoptotic malignant cells was significantly decreased, as compared to TAL and lymphocytes from nonmalignant pleural effusions. There were also differences in the expression of Fas and FasL among mononuclear cells from malignant and nonmalignant pleural effusions. The ability of TAL from malignant pleural effusions to induce apoptosis of K562 cells was diminished, as compared to peripheral blood lymphocytes. Taken together, these data suggest that tumor cells in the microenvironment of malignant pleural effusions can evade immune attack by downregulation of the CD95 receptor and by killing lymphocytes through the expression of FasL. These results confirm earlier reports which showed that lymphocytes from a tumor microenvironment appear to have a depressed cytotoxic action.
- [Show abstract] [Hide abstract] ABSTRACT: The present investigation was carried out to study the effect of tumor growth on the spleen of an aged host. Dalton's lymphoma (DL), a spontaneous T cell lymphoma, was grown in mice of different age groups classified as young, adult or old on the basis of their reproductive status. Splenocytes obtained from normal and tumor-bearing young, adult and old mice were checked for an in vitro blastogenic response to concanavalin A (Con A), colony-forming ability and apoptosis. There was an enhanced apoptosis of splenocytes and a concomitant inhibition of splenocyte blastogenesis and their responsiveness to the mitogenic stimulus of Con A in aged mice. The counts of granulocyte macrophage- and macrophage-colony forming units were significantly enhanced in the spleen of tumor-bearing adult mice. It is proposed that the DL-growth-dependent increase in the size of the spleen in adult mice is due to an increased blastogenesis of splenocytes, which, however, may not be applicable in the case of old tumor-bearing mice. The role of splenic macrophages in the regulation of the functions of the spleen by macrophage-derived NO is shown.
- [Show abstract] [Hide abstract] ABSTRACT: The immunomodulatory substance, VaQuFrF (an aqueous extract of Viscum album L. of the oak tree) is used as an adjuvant and as monotherapy in the treatment of cancer and AIDS. After subcutaneous injection, there is a local inflammatory reaction at the injection site and systemic elevation of activated lymphocytes. The immunomodulatory effect of VaQuFrF in the first 24 h after subcutaneous injection on blood leukocyte and lymphocyte subpopulation was investigated. Because a significant natural circadian variation of these cellular parameters exist, the influence was studied in regard to this. In two groups of healthy volunteers, one group receiving VaQuFrF, the following parameters were measured every 2-3 h over a period of 24 h: leukocytes, band form, segmented and eosinophilic granulocytes, monocytes, total lymphocytes and CD4-, CD8-, CD3/25- and CD8/38-positive lymphocytes in count and percentage. In regard to the natural circadian variation 24 h after injection of VaQuFrF, a statistically significant fall in the absolute numbers and percentage of CD3/ 25- and CD8/38-positive lymphocytes was observed. Also, monocytes in percent and absolute numbers show a transient fall 6-9 h, lymphocytes only in absolute and CD4-positive lymphocytes only in percentage 2 h after injection. The results demonstrate that there is increased extravasation of (activated) lymphocytes and monocytes after subcutaneous injection of 1 mg VaQuFrF.
- [Show abstract] [Hide abstract] ABSTRACT: The CD95/CD95L (Fas/Fas ligand) receptor/ligand system plays an important role in regulation of cell survival and induction of a programmed cell death. It is also involved in regulation of effector phase of T and NK cell cytotoxicity, establishment of immune privilege sites, and tumor escape from immune recognition. In this study, we assessed expression of CD95L in tumors obtained from patients with neuroblastoma (NB) and in established NB cell lines. We measured the presence of intratumoral T cell infiltrates and T cell survival in tumor tissue samples. High levels of apoptosis were observed in tumor-associated lymphocytes as well as in Jurkat T cells cocultured with NB cells in vitro. T cell death was reduced after treatment of NB cells (in vitro) with antibody to FAS ligand (FasL). Overall, our data suggest that NB-induced apoptosis of Fas-sensitive Jurkat T cells is mediated by functional FasL expressed on NB and Fas/FasL interaction may be responsible for the elimination of T cells in the NB microenvironment.
- [Show abstract] [Hide abstract] ABSTRACT: The role of Ikaros in early stages of natural killer (NK) cell differentiation was investigated using an in vitro system that promotes proliferation and differentiation of NK cell precursors into mature NK1.1+ cells. Day 14.5 fetal liver cells from mice, either homozygous for Ikaros Null or dominant negative (DN) mutations, had severe 55- to 79-fold reductions in functional NK cell precursors. Although there was no statistically significant difference between values for +/+ and +/- Null mice, the mean precursor frequency for DN mutant (+/-) mice was significantly above that for DN -/- mice and below that for DN +/+ mice. The NK activity values for cells generated from the NK cell precursors followed the same respective relationships found for NK cell precursor frequencies. These data suggest that the deficiency of mature NK cells in Ikaros mutant mice is related to lack of functional precursors.
- [Show abstract] [Hide abstract] ABSTRACT: In an attempt to understand the basis of lowered natural killer (NK) and T cell functions in unaffected members from cancer families, we investigated cytotoxic T lymphocyte function (CD3-directed lysis) and the ability of the lymphocytes to respond to cytokines such as IL-2, IFN-alpha and IL-12. We observed lower CD3-mediated cytotoxic activity in these individuals supported by significantly lower numbers of circulating CD3+ lymphocytes. The cytokine treatment studies revealed impaired response to IFN-alpha and IL-12 in unaffected members and breast cancer patients. The observations presented herein not only reinforce our earlier finding that lower NK and T lymphocyte function may be a feature of cancer families, but also suggest that such impaired responses may be one of the factors contributing to lower cytotoxic potential of the circulating lymphocytes.
- [Show abstract] [Hide abstract] ABSTRACT: In addition to IL-2, IL-12 would constitute one of the most promising cytokines in the treatment of human neoplasms. IL-2 has been proven to induce in vitro and in vivo several evident changes in the secretion of cytokines and various other immunoinflammatory substances. In contrast, very little data are available about the immune effects of IL-12 in humans. The present study was carried out to investigate the in vivo immunoinflammatory effects of IL-12 by analyzing the secretions of neopterin, soluble IL-2 receptor (SIL-2R), tumor necrosis factor alpha (TNF), IL-2 and IL-6 in relation to the neuroendocrine function of the pineal gland, which is one of the most important organs involved in neuroimmunomodulation. Pineal endocrine function was investigated by evaluating the whole daily urinary excretion of the main catabolite of its hormone melatonin, 6-sulfatoxymelatonin (6-MTS). The study was performed on metastatic renal cell cancer patients. Each course of IL-12 consisted of 1.25 microg/ kg b.w. subcutaneously in the morning once a week for 3 consecutive weeks. The study evaluated 10 IL-12 courses. Mean serum levels of neopterin, SIL-2R and TNF significantly increased in response to IL-12, whereas no significant change occurred in IL-6 and IL-2 mean concentrations. Finally, 6-MTS urinary excretion was significantly reduced by IL-12 injection, particularly during the dark phase of the day. This preliminary study would suggest that IL-12 may induce important changes in the in vivo immunoinflammatory response. Moreover, IL-12 administration would suppress pineal endocrine activity, thus confirming its previously suggested involvement in the neuroimmunomodulatory processes. Because of the fundamental role of the pineal gland in neuroimmunomodulation, IL-12-induced immune variations could depend at least in part on its action at central neuroendocrine sites.
- [Show abstract] [Hide abstract] ABSTRACT: Iscador, an aqueous extract of Viscum album L., has been used for more than 80 years as an anticancer drug. Due to its immunomodulatory potential, since the onset of the AIDS epidemic it has also been applied in the treatment of HIV-positive and AIDS patients in the form of the preparation V. album QuFrF (VaQuFrF; Labor Hiscia, Arlesheim, Switzerland). In in vitro investigations, incubation of peripheral blood mononuclear cells with V. album L. extracts resulted in stimulation of lymphocyte activity with increased gene expression and release of various cytokines and also of interferon gamma (IFN-gamma). In the latent phase, HIV positives exhibit only slightly elevated IFN-gamma concentrations in serum in comparison with HIV negatives, but in the acute phase of AIDS, there is an increase in levels of IFN-gamma. As the assay of cytokine levels in serum is a simple method of measuring immune system reactions, the aim of this trial was to determine whether increases in serum IFN-gamma levels in HIV positives and HIV negatives can be detected using this method after repeated injections of VaQuFrF. Five healthy subjects and 13 HIV-positive patients were investigated. IFN-gamma concentrations in serum were assayed using an ELISA test kit (ELISA test; ENDOGEN, Cambridge, Mass., USA). No drug-related elevation of serum IFN-gamma was observed at any time point during the trial. It can thus be concluded that this method is not suitable for direct investigation of the immunomodulatory effects of VaQuFrF in vivo.
- [Show abstract] [Hide abstract] ABSTRACT: The aim of this study was to determine whether treatment of patients with immune thrombocytopenic purpura (ITP) with intravenous immunoglobulin (IVIg) is associated with a modification in the antiplatelet glycoprotein (GP) antibodies (Abs). Fourteen patients with ITP (11 females and 3 males, mean age 36.6 years, range 18-72) received one to four IVIg treatment courses. The preparation used was ISIVEN that was given in a dose of 2 g/kg body weight in a 5-day schedule and in monthly intervals. Levels of IgG, IgM and IgA isotypes of Abs to GPs IIb/IIIa and Ib/IX were measured before the treatment, and before and after each treatment course. Two patients did not respond to IVIg, 6 had a temporary response, 5 had a sustained response and 1 patient responded well to the treatment but was lost to follow-up. The patients had a high prevalence of serum Abs directed against GPs IIb/IIIa and Ib/IX before the treatment, and the mean IgG isotype levels of both Abs increased after each treatment course, and decreased again before the following course began. Whenever high Ab levels of either isotype (> 10 U/ml) were detected before the treatment, they were significantly decreased before the last treatment course. The elevated levels of IgG Abs to IIb/IIIa and Ib/IX after every course are probably a result of displacement of these Abs from Fc receptors by the IVIg, rather than of exogenous infusion of these Abs contained within the IVIg, whereas the decrease in high Ab levels after a few treatment courses results from the immunomodulatory effects of IVIg: suppression of Ab formation, and the presence of anti-idiotypes.
Article: Andrei Sulica, MD, 1938–2000
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