WFS1 gene as a putative biomarker for development of post-traumatic syndrome in an animal model.

Post-traumatic stress disorder (PTSD) is an anxiety disorder that may develop after the experiencing or witnessing of a life-threatening event. PTSD is defined by the coexistence of three clusters of symptoms: re-experiencing, avoidance and hyperarousal, which persist for at least 1 month in survivors of the event (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition). Using an established model of PTSD, we addressed the well-accepted clinical finding that only a minority (about 20%) of the individuals exposed to a traumatic event develop PTSD. Moreover, we followed individual rat behavior for up to a month, and then treated the PTSD-like animals with citalopram. Our data demonstrate high face (20% of rats exposed to a reminder of the stressor develop symptoms characteristic of PTSD) and predictive (response to citalopram) validities. Based on these validities we identified alterations in the Wolframin gene in the CA1 and amygdala regions, specifically in exposed PTSD-like rats, which were normalized after treatment with citalopram. We suggest the Wolframin gene as a putative biomarker for PTSD. Since Wolframin gene undergoes alternative splicing and has polymorphism in the population, it may serve a future marker for identification of the vulnerable population exposed to a traumatic event.

The immunomodulator AS101 restores T(H1) type of response suppressed by Babesia rodhaini in BALB/c mice.

The immunomodulator AS101 has been previously shown to confer protection upon BALB/c mice infected with the intraerythrocytic parasite Babesia rodhaini (B. rodhaini). The present study focuses on the effect of AS101 administration on the acute phase of babesial infection where T helper cell subset patterns-TH1/TH2-were assessed in heavily infected mice. Secretion of cytokines of the TH1 subset (IL-2, IFN-gamma, IL-12) and of the TH2 subset (IL-10, IL-4) as well as TGF-beta was measured following the administration of AS101 2 weeks before parasite infection. Our results demonstrate that the parasites suppress IL-2 protein and IL-12 mRNA and that AS101 upregulates their secretion: IL-2, 8 u/ml vs 34 u/ml, respectively; IFN-gamma protein, 2370 pg/ml vs 4777 pg/ml, respectively. Conversely, babesial infection results in the upregulation of IL-10 and IL-4 proteins and TGF-beta transcripts, whereas AS101 downregulates their production: IL-10, 1800 pg/ml vs 360 pg/ml, respectively; IL-4, 58.3 pg/ml vs 24.5 pg/ml, respectively. A possible escape mechanism induced by B. rodhaini is suggested, starting with IL-10 inhibition of macrophage activities leading to a suppression of the TH1 response and of IL-2 in particular. It is therefore possible that AS101 may protect infected mice by activating cellular-mediated immunity and concurrently balancing the TH subset responses. It is suggested that AS101 may be effective as an antiparasitic drug.

Beta-amyloid peptide induces tumor necrosis factor-alpha and nitric oxide production in murine macrophage cultures.

We investigated the effect of beta-amyloid peptide (betaA) on the activation of the murine-derived monocyte/macrophage J774 cell-line. BetaA induced tumor necrotic factor-alpha (TNF alpha) in these cells in a dose-dependent manner. Incubation of cells with betaA slightly increased nitric oxide (NO) production, an effect that was significantly enhanced by the addition of interferon-gamma (IFN gamma). Substitution of betaA4 with TFN alpha and incubation of the cultures with IFN gamma resulted in significant NO production, although this was lower than that obtained in the presence of the peptide. Incubation of cultures with a monoclonal antibody (mAb) against TNF alpha abrogated NO production. Our results suggest that betaA4-induced TNF alpha production is a crucial event in the activation of peripheral macrophages.

T lymphocyte subpopulations and activation markers correlate with severity of Alzheimer's disease.

In this study we investigated immune-associated antigens of peripheral lymphocytes from patients with Alzheimer's disease (AD). The patients were divided into two groups--mild and moderately severe--according to severity of disease stage, and their lymphocytes were compared to those of elderly controls. In the mild stage of the disease we observed a slight increase in the HLA-DR marker (9.5 +/- 2.4% vs 6.5 +/- 1.1%; P = 0.06), but no changes in the CD4, CD8, and interleukin-2 receptor (IL-2R) markers. In the moderately severe stage, we observed a significant increase in the HLA-DR (18.5 +/- 2.7%) and CD4 markers (55.2 +/- 3.5% vs 43.5 +/- 2.1%, P < 0.01), and a slight decrease in the CD8 subset (19.5 +/- 1.4% vs 22.3 +/- 1.3%, P = 0.05). In the same group, following stimulation with the mitogen PHA, we observed a marked reduction in IL-2R expression (30.9 +/- 4.7% vs 41.1 +/- 2.7%, P = 0.05) and in the proliferative ability of lymphocytes (21131 +/- 4676 cpm vs 47909 +/- 1107 cpm, P < 0.04). However, mitogen-induced IL-2 secretion levels from the same lymphocytes were significantly elevated (17.4 +/- 4.8 U/ml vs 8.6 +/- 4.3 U/ml, P < 0.01). Marked changes in immunological parameters in the moderately severe group support the hypothesis of a peripheral immune reaction in AD which may be correlated with the clinical stage of the disease.

IL-2 and IL-6 secretion in dementia: correlation with type and severity of disease.

The production of interleukin-2 (IL-2) and interleukin-6 (IL-6) by peripheral blood mononuclear cells (MNC) was assessed in patients with Alzheimer's disease (AD) who were subdivided into two groups--mild and moderately-severe--according to the severity of the disease, probable vascular dementia (VaD) patients and elderly control subjects. No differences in IL-2 secretion were found between mild AD patients and controls. However, there was a significant increase in IL-2 production both in the moderately-severe AD group and in the VaD group. IL-6 levels in AD patients of both groups were similar and significantly higher than those of VaD and controls. Our results suggest that increased levels of IL-2-production correlate with severity of the dementia, whereas increased levels of IL-6 production seem to be related to AD and thus may play a role in AD pathogenesis.

Modification of cytokine secretion following mild emotional stimuli.

In the present study, changes in the cytokine system (IL-1 beta, IL-2, IL-3, IL-6 and TNF alpha) were assessed following exposure to mild mood induction (negative and positive) in humans. An increase in secretion of TNF alpha, a decrease in that of IL-2 and of IL-3 with no change in IL-1 beta and in IL-6 secretion levels, was observed in response to mild negative emotional changes. A reversed cytokine secretion profile was found following positive mood changes, suggesting the hypothalamic-pituitary-adrenal axis and the autonomic nervous system, as possible mediators underlying these effects, specific to the nature of the emotion.

Correlation of cytokine secretion by mononuclear cells of Alzheimer patients and their disease stage.

Cytokine secretion by human mononuclear cells (MNC) was investigated in age-matched controls and in patients with Alzheimer's disease (AD). AD patients were divided into two study groups: 'mild' and 'moderately severe'. A significant increase in interleukin-2 (IL-2) and gamma interferon (IFN-gamma) secretion was found in AD patients in the moderately severe stage of the disease, whereas in the mild stage of the disease there was a significant decrease in interleukin-3 activity (IL-3) and tumor necrosis factor (TNF) levels. No significant differences were found in the level of production of interleukin-1 (IL-1 beta). Our results demonstrate the existence of defective immune functions in AD patients which are correlated with the clinical condition of these patients.

Elevated interleukin-6 secretion levels by mononuclear cells of Alzheimer's patients.

It has been suggested in recent research that interleukin-1 (IL-1) and interleukin-6 (IL-6) play a role in the pathogenesis of Alzheimer's disease (AD). Production of IL-1, by lipopolysaccharide (LPS)-stimulated monocytes, and IL-6, by phytohaemagglutinin (PHA)-stimulated mononuclear cells, was assessed in patients with AD divided into two groups--mild and moderately severe--according to severity of disease, and elderly controls. No differences in IL-1 production were found among AD patients and controls. However, significant elevation in IL-6 secretion levels was observed in both the mild and moderately severe AD patients. Our results suggest that peripheral IL-6 secretion levels may be responsible for acute-phase proteins observed in the serum of AD patients.

Decreased IL-3 production by peripheral blood mononuclear cells in patients with multiple sclerosis.

The production of interleukin-3 by peripheral blood mononuclear cells (MNC) was assessed in patients with relapsing multiple sclerosis (MS) in both the active and the stable state, and in healthy controls. IL-3 levels were compared to levels of production of interleukin-2 (IL-2), tumor necrosis factor (TNF) and gamma-interferon (gamma-IFN). No significant differences in IL-3 levels were observed between stable-state patients and controls. When levels of cytokine production of patients in the inactive phase were compared to those of the same patients during relapse a significant decrease in IL-3 levels was observed, as opposed to significant increases in gamma-IFN and TNF levels, and an increase, though a non-significant, in IL-2 levels. The functional significance of lowered IL-3 production is unknown. However, the findings support the hypothesis of a highly complex interaction of overlapping regulatory influences within the cytokine network which parallels MS disease activity.

The immunomodulator AS101 administered orally as a chemoprotective and radioprotective agent.

AS101 [ammonium-trichloro (0,0' dioxyethylene)tellurate] is a new immunomodulator shown previously to stimulate the production of various cytokines in vitro and in vivo, and to have minimal toxicity. In the present study we explore the possibility of oral administration of AS101 to mice via cannulation in lieu of interperitoneal or intravenous administration reported to date. Our studies show that oral administration of AS101 at a dose ranging between 50 and 100 micrograms/mouse promotes hemopoietic regeneration after treatment with sublethal doses of cyclophosphamide (CYP) and protects mice from the lethal effects of this compound. In addition, AS101 administered orally confers a strong radioprotective effect upon mice when given before irradiation.

Synergism between AS101 and PMA in lymphokine production.

AS101 [ammonium trichloro (dioxyethylene-o-o') tellurate] has been reported to stimulate normal mouse and human lymphoid cells to proliferate and to produce lymphokines such as interleukin-2 (IL-2) and colony-stimulating factor (CSF), regulators of lymphopoiesis and myelopoiesis. In this study, we demonstrate that the IL-2 secretion and cell proliferation of both human and mouse lymphocytes, and the production of CSF by mouse spleen cells, was significantly enhanced by the synergistic effect of AS101 and phorbol myristate acetate (PMA). AS101-induced activation was found to be very sensitive to inhibition by EGTA, the Ca2+ channel blocker, nifedipine, and cyclosporin A (CsA), an agent which selectively suppresses Ca2(+)-activated steps in this process. Our results suggest that AS101 may efficiently trigger the Ca2+ signal required to initiate lymphocyte activation, but that the enhancement observed when cells are stimulated with both AS101 and PMA may be due to the generation of a second signal, probably the activation of protein kinase C (PKC). A more thorough understanding of the mechanism of action of the immunomodulator AS101, presently under clinical trials on cancer and AIDS patients, is highly relevant to the assessment of its optimal application.

The biological activity and immunotherapeutic properties of AS-101, a synthetic organotellurium compound.

AS-101 (ammonium trichloro[dioxoethylene-O,O'-]tellurate) is a newly developed synthetic compound with immunomodulating properties and minimal toxicity. We evaluated the effects of AS-101 on various parameters of the activation and function of immunocompetent cells. AS-101 induced IL-2 receptor expression, IL-2 production and proliferation by human and mouse lymphocytes in vitro and enhanced the production colony-stimulating factor (CSF) by mouse spleen cells. In vivo treatment of Balb/c mice with AS-101 caused a significantly increased production of IL-2 and CSF in vitro in the presence of mitogen. When administered systemically to mice, AS-101 mediated antitumor effects in vivo. These results suggest that AS-101 is an active biological response modifier, which might have potential use in the treatment of conditions such as malignancy, AIDS and some types of immune deficiency.

A new immunomodulating compound (AS-101) with potential therapeutic application.

There has been interest in the potential of synthetic compounds to modify immune responses by imitation of cytokine action. Direct administration of interleukin 2 (IL-2) in conjunction with adoptive transfer of lymphokine activated killer cells has been used in the treatment of cancer, but there are toxic effects resulting from the high doses of IL-2 required. We have developed a new synthetic compound, ammonium tri-chloro(dioxoethylene-O,O'-)tellurate (AS-101), which has immunomodulating properties and minimal toxicity. The effects of AS-101 on the activation and function of immunocompetent cells have been assessed. We have found that AS-101 induces proliferation and IL-2 production by human lymphocytes in vitro, and enhances the production of IL-2 and colony-stimulating factor by mouse spleen cells. Splenocytes of BALB/c mice injected with AS-101 increased production of IL-2 and CSF in vitro in the presence of mitogen. Mononuclear cells of normal donors acquired responsiveness to recombinant IL-2 and bound monoclonal antibody to IL-2 receptor after incubation with AS-101. Splenocytes of mice treated in vivo with AS-101 expressed high levels of IL-2 receptor. The stimulation of lymphocytes by AS-101 apparently involves an increase in intracellular free calcium. AS-101 administered systemically to mice mediated antitumour effects which could be attributable to its immunomodulatory properties. In addition, AS-101 could directly enhance the ratio of OKT4 to OKT8-positive cells in cultured mononuclear cells from AIDS (acquired immune deficiency syndrome) patients. These results indicate that AS-101 is potentially useful in the treatment of clinical conditions involving immunosuppression.