Microglia activation is associated with IFN-α induced depressive-like behavior.

Inflammatory immune activation has been frequently associated with the development of major depression. This association was confirmed in patients receiving long-term treatment with pro-inflammatory interferon-α (IFN-α). Microglia, the resident immune cells in the brain, might serve as an important interface in this immune system-to-brain communication. The aim of the present study was to investigate the role of microglia in an IFN-α mouse model of immune-mediated depression. Male BALB/c mice were treated with daily injections of IFN-α for two weeks. Depressive-like behavior was analyzed in the forced swim and tail suspension test. Activation of microglia was measured by flow cytometry. Pro-inflammatory M1 type (MHC-II, CD40, CD54, CD80, CD86, CCR7), anti-inflammatory M2 type (CD206, CD200R), and maturation markers (CD11c, CCR7) were tested, as well as the chemokine receptor CCR2. IFN-α led to a significant increase in depressive-like behavior and expression of the pro-inflammatory surface markers MHC-II, CD86, and CD54, indicating M1 polarization. Because IFN-α-treated mice showed great individual variance in the behavioral response to IFN-α, they were further divided into vulnerable and non-vulnerable subgroups. Only IFN-α vulnerable mice (characterized by their development of depressive-like behavior in response to IFN-α) showed an increased expression of MHC-II and CD86, while CD54 was similarly enhanced in both subgroups. Thus, IFN-α-induced activation of microglia was specifically associated with depressive-like behavior.

Schizophrenia associated sensory gating deficits develop after adolescent microglia activation.

Maternal infection during pregnancy is a well-established risk factor for schizophrenia in the adult offspring. Consistently, prenatal Poly(I:C) treatment in mice has been validated to model behavioral and neurodevelopmental abnormalities associated with schizophrenia. By using the Poly(I:C) BALB/c mouse model, we investigated the functional profile of microglia by flow cytometry in relation to progressive behavioral changes from adolescence to adulthood. Prenatal Poly(I:C) treatment induced the expected sensory gating deficits (pre-pulse inhibition (PPI) of the acoustic startle response) in 100day-old adult offspring, but only in female not in male descendants. No PPI-deficits were present in 30day-old adolescent mice. Sensory gating deficits in adult females were preceded by a strong M1-type microglia polarization pattern during puberty as determined by flow cytometric analysis of multiple pro- and anti-inflammatory surface markers. Microglia activation in females did not persist until adulthood and was absent in behaviorally unaffected male descendants. Further, the specific activation pattern of microglia was not mirrored by a similar activation of peripheral immune cells. We conclude that prenatal Poly(I:C) treatment induces post pubertal deficits in sensory gating which are specifically preceded by a pro-inflammatory activation pattern of microglia during puberty.

Soluble Intracellular Adhesion Molecule-1 in Patients with Unipolar or Bipolar Affective Disorders: Results from a Pilot Trial.

BACKGROUND: Immunological and vascular markers may play a role in the pathophysiology of mood disorders and mood changes. AIM: To test whether the cell adhesion molecule soluble intracellular adhesion molecule-1 (sICAM-1) may serve as a biomarker for patients with unipolar or bipolar affective disorders when compared to a healthy control group, and whether sICAM-1 blood levels change during different mood states. METHODS: sICAM-1 serum concentrations were compared between 20 healthy controls and 48 patients with affective disorders (unipolar, bipolar II and bipolar I disorder) during different mood states (euthymic mood state, depression or mania). RESULTS: When compared to healthy controls, patients with affective disorders had significantly higher sICAM-1 levels during the euthymic state (p = 0.015). Differences became more pronounced during depression (p = 0.013). When unipolar and bipolar patients were analyzed separately, unipolar patients significantly differed from controls during the euthymic and depressive mood state, while bipolar II patients showed a trend towards higher sICAM-1 levels during depression. Patients with bipolar I disorders had significantly higher sICAM-1 levels during manic states when compared to controls (p = 0.007). CONCLUSIONS: sICAM-1 elevation in unipolar and bipolar patients, independent of mood changes, might support the hypothesis of chronic immune activation and endothelial dysfunction in patients with affective disorders.

Escitalopram for the prevention of peginterferon-α2a-associated depression in hepatitis C virus-infected patients without previous psychiatric disease: a randomized trial.

BACKGROUND: Depression is a major complication during treatment of chronic hepatitis C virus (HCV) infection with interferon-α (IFN-α). It is unclear whether antidepressants can prevent IFN-induced depression in patients without psychiatric risk factors. OBJECTIVE: To examine whether preemptive antidepressant treatment with escitalopram can decrease the incidence or severity of depression associated with pegylated IFN-α in HCV-infected patients without a history of psychiatric disorders. DESIGN: Randomized, multicenter, double-blind, prospective, placebo-controlled, parallel-group trial. (ClinicalTrials.gov registration number: NCT00136318) SETTING: 10 university and 11 academic hospitals in Germany. PATIENTS: 181 HCV-infected patients with no history of psychiatric disorders enrolled between August 2004 and December 2008. INTERVENTION: Escitalopram, 10 mg/d (n = 90), or placebo (n = 91) administered 2 weeks before and for 24 to 48 weeks during antiviral therapy. MEASUREMENTS: The primary end point was the incidence of depression, defined as a Montgomery-Asberg Depression Rating Scale (MADRS) score of 13 or higher. Secondary end points were time to depression, incidence of major depression according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, quality of life, sustained virologic response, tolerability, and safety. RESULTS: 32% (95% CI, 21% to 43%) of the patients in the escitalopram group developed a MADRS score of 13 or higher compared with 59% (CI, 48% to 69%) in the placebo group (absolute difference, 27 percentage points [CI, 12 to 42 percentage points]; P < 0.001). Major depression was diagnosed in 8% of the patients in the escitalopram group and 19% in the placebo group (absolute risk difference, 11 percentage points [CI, 5 to 15 percentage points]; P = 0.031). Tolerability and safety parameters did not differ between the groups. In the escitalopram group, 56% (CI, 46% to 66%) of patients achieved a sustained virologic response compared with 46% (CI, 37% to 57%) in the placebo group (P = 0.21). LIMITATIONS: Results might not be generalizable to patients with previous psychiatric disease. Some patients withdrew or developed temporary elevated MADRS scores after randomization but before the study medication was started. CONCLUSION: Prophylactic antidepressant treatment with escitalopram was effective in reducing the incidence and severity of IFN-associated depression in HCV-infected patients without previous psychiatric disease. PRIMARY FUNDING SOURCE: Roche Pharma and Lundbeck.

Hepatitis C infection, antiviral treatment and mental health: a European expert consensus statement.

Mental health problems frequently occur in chronic infection with the hepatitis C virus (HCV) and during antiviral treatment with pegylated interferon-alpha (PegIFNα) and ribavirin. Depression is one of the most important complications during antiviral treatment of chronic hepatitis C infection. However, an increased prevalence of depression, fatigue, and cognitive disturbances has also been reported in untreated HCV-positive patients. Patients with psychiatric disorders or drug addiction also have an increased risk of HCV infection. Furthermore, because of possible drug-drug interactions, new antivirals administered together with PegIFNα and ribavirin may complicate psychiatric side effect management, even if no specific psychiatric adverse events are known so far for these new drugs. The European liver patient's organization (ELPA) organised a European expert conference to review the literature and develop expert recommendations for the management of mental health problems in HCV infected patients. This paper results from the output of the 2011 EASL meeting and subsequent dialogue with patient groups and relevant experts in Europe. It summarises the current knowledge of HCV infection and the brain; prevalence, course, and neurobiology of IFN-α associated psychiatric side effects; possible risk factors for IFN-α associated depression and suicide attempts; psychiatric management of HCV infected patients before and during antiviral treatment; prevention of IFN- α associated psychiatric side effects; and psychiatric aspects of the new antivirals. The summarised current knowledge about mental health changes before and during antiviral treatment should improve interdisciplinary management of HCV infected patients.

Characterization of immunostimulatory components of orf virus (parapoxvirus ovis).

Inactivated orf virus (ORFV, parapoxvirus ovis) induces antiviral activity in animal models of acute and chronic viral infections and exerts strong effects on human immune cells. ORFV activates antigen presenting cells (APC) via CD14 and, probably, Toll-like receptor signalling, and triggers the release of IFN-γ that has been identified as the key mediator of the antiviral activity. After delineating virus proteins as being the most likely active constituent, we aimed to characterize the ORFV proteins responsible for the therapeutic effect. By using a vaccinia virus/ORFV expression library we identified several multi-gene DNA fragments with strong immunomodulatory activity. Together these fragments contain 27 ORFs. The encoded proteins are related to virion structure and transcription but are otherwise unrelated. Two proteins were separately expressed and purified, and demonstrated immunostimulatory activity. Gene expression profiles induced by ORFV and the identified fragments were investigated by microarray analysis. Interestingly, all active fragments induced a similar gene-expression pattern, differing only in quantitative aspects. Obviously, several proteins of ORFV activate similar cellular pathways, modulating APC to generate a strong T-helper 1-dominated immune response. This was balanced by additional induction of immune dampening mechanisms, suggesting regulatory differences compared to single cytokine therapies. We conclude that ORFV may have the potential to enrich the armamentarium of antiviral therapies.

Influence of gender on cytokine induced depression and treatment: Gender aspects of IFN-α-induced depression.

BACKGROUND: Cytokine treatment with Interferon-alpha (IFN-α) represents a clinical model of immune associated depression, but it remains unclear if it is of the same entity as major depressive disorder (MDD). The study focuses on possible gender differences in IFN-α induced depression and effects of a pre-emptive antidepressant treatment. METHODS: Data from 181 patients with chronic hepatitis C infection (cHC) without history of mental illnesses undergoing treatment with IFN-α 2a and ribavirin were re-analyzed for gender effects. Patients with a pre-emptive antidepressant therapy with Escitalopram (n = 90, verum group) to prevent IFN-induced depression were compared to patients who received placebo (n = 91). Depressive symptoms before and during HCV-treatment were assessed using the Montgomery-Asberg Depression Rating Scale (MADRS), Beck's Depression Inventory (BDI) and the Hamilton Anxiety Rating Scale. RESULTS: We found significant differences regarding the incidence and severity of depressive symptoms between men and women for patients without antidepressant pre-treatment (placebo group). Significantly more women without pre-emptive antidepressant therapy suffered from clinically relevant depression (MADRS values ≥ 13, p = 0.041) and self-rated depressive symptoms (BDI ≥ 17, p = 0.024). Antidepressant pre-treatment showed comparable effects regarding the reduction of incidence and severity of depression in both women and men. CONCLUSIONS: Compared to MDD, IFN-alpha-induced depression in patients with cHC is also characterized by gender differences with an increased risk for women but no gender difference regarding the effects of an antidepressant pre-treatment is found. Our data strengthens the hypothesis that Interferon-induced depression serves as a clinical model for immune related depressive disorders.

Dose-dependent development of depressive symptoms during adjuvant interferon-{alpha} treatment of patients with malignant melanoma.

BACKGROUND: Adjuvant IFN-α treatment for patients with malignant melanoma is often complicated by depression. The influence of dosage, however, is unknown. OBJECTIVE: The authors sought to elucidate this dosage effect. METHOD: Using the Zung Self-Rating Depression Scale and the German Bf-S Self-Rating (Affectivity) Scale, the authors prospectively compared the frequency and severity of IFN-α-induced depressive symptoms between a group of 29 patients receiving low-dose and 17 patients getting high-dose induction therapy for 4 weeks. RESULTS: Patients receiving high-dose induction treatment had significantly higher depression scores after 4 weeks, and significantly more patients in the high-dose group developed depression. CONCLUSION: The authors concluded that frequency and severity of IFN-α-associated depression during melanoma treatment are dose-dependent.

Causes for spontaneous abortion: what the bugs 'gut' to do with it?

Spontaneous miscarriage is the most common adverse pregnancy outcome in humans and occurs in 15-20% of all recognized pregnancies. High psychosocial stress perception has long been recognized as a threat to pregnancy maintenance and accumulating evidence supports that stress affects maternal adaptation to pregnancy and subsequently impedes fetomaternal tolerance. This review strongly focuses on the role of microbial products within the stress-induced signalling cascade, linking the disequilibrium of the endogenous microflora to immune activation and pregnancy loss. The stress signalling cascade utilizes the presence of lipopolysaccharide (LPS), which acts as a danger signal via Toll like receptor 4. Physiologically, the intestinal microflora provides a source for endogenous LPS, i.e. during the stress response, and psychosocial stress challenge in mice enhances the gastrointestinal permeability and bacterial uptake from the gut. Clearly, these novel insights not only deepen our understanding of mechanisms involved in the stress response cascade, but also initiate a renaissance of therapeutic intervention strategies, aiming to modulate the intestinal flora by probiotic bacteria. In turn, intestinal barrier function may be enhanced and mediators of immune tolerance may be restored, i.e. in the context of reproduction.

Three cases of successful tryptophan add-on or monotherapy of hepatitis C and IFNalpha-associated mood disorders.

BACKGROUND: Interferon-alpha (IFN(alpha))-associated mood disorder is a major complication of treatment for chronic hepatitis C. METHOD: The authors report on three patients infected with chronic hepatitis C showing severe depressive symptoms during or after IFN(alpha) treatment. Because patients had lowered tryptophan blood levels and did not response to antidepressants, they received tryptophan up to a dosage of 1,000 mg/day as mono- or add-on treatment. RESULTS: Tryptophan, used as augmentation or monotherapeutic treatment, led to a significant improvement of depressive symptoms in all three patients. CONCLUSION: A tryptophan deficit seems to be involved in the pathophysiology of persistent mood changes during and after IFN(alpha) treatment.

Inactivated Orf-virus shows disease modifying antiviral activity in a guinea pig model of genital herpesvirus infection.

BACKGROUND: Inactivated Orf virus (iORFV) has been used as a preventative as well as a therapeutic immunomodulator in veterinary medicine in different species. iORFV elicits strong effects on cytokine secretion in mice and human immune cells leading to an auto-regulated loop of initial up-regulation of inflammatory and Th1-related cytokines followed by Th2-related cytokines that attenuate immunopathology. The therapeutic potential of iORFV has been recognized in several models for difficult-to-treat disease areas such as chronic viral diseases, liver fibrosis or various forms of cancer. METHODS: Guinea pigs were infected with Human Herpesvirus (HSV)-2 strain MS and treated with iORFV, Acyclovir (ACV) or placebo, respectively. Clinical score of herpes lesions and viral shedding was assessed over a period of 40 days. In addition, viral DNA in dorsal root ganglia was quantified at the end of the study. RESULTS: Disease symptoms were minimal or absent in iORFV-treated guinea pigs but tended to be severe in animals treated with either ACV or placebo. The cumulated disease score was significantly reduced in iORFV-treated but not in ACV- or placebo-treated guinea pigs. In addition, treatment with iORFV, but not ACV or placebo, led to significant reduction of viral DNA load in dorsal root ganglia. CONCLUSION: iORFV effectively suppressed recurrences in guinea pigs experimentally infected with HSV. iORFV did not only reduce recurrent disease episodes but was, compared with ACV, more effective in reducing latency as measured by viral DNA detected in dorsal root ganglia of infected animals.

Interleukin-4 is a participant in the regulation of depressive-like behavior.

Inflammatory immune activation has been frequently associated with the development of major depression. Microglia might serve as an important interface in this immune system-to-brain communication. Interleukin-4, the major Th2 type cytokine, might be protective against depression due to its ability to counter-regulate inflammation and to inhibit serotonin transporter activity. By using an Interferon-α mouse model, we show that a decreased IL-4 responsiveness of microglia was specifically related to the development of depressive-like behavior. IL-4 deficient mice in a BALB/cJ background showed a considerable increase of depressive-like behavior in the forced swim (FST) and tail suspension test (TST) and reduced avoidance behavior in an active avoidance task. Prior conditioning with unescapable foot shocks further decreased avoidance behavior (learned helplessness) but to a similar level as in the wild type strain. IFN-α treatment was not able to further enhance the already increased level of depressive-like behavior in the FST and TST. Thus, IL-4 seems to be a critical participant in the regulation of depressive-like behavior in an untreated baseline condition. Increase of depressive-like behavior during inflammation in wild-type mice might be mediated to some extent by a reduction of IL-4 signaling.

Emotional Contagion is not Altered in Mice Prenatally Exposed to Poly (I:C) on Gestational Day 9.

Prenatal immune activation has been associated with increased risk of developing schizophrenia. The polyinosinic-polycytidylic acid (Poly(I:C)) mouse model replicates some of the endophenotype characteristic of this disorder but the social deficits observed in schizophrenia patients have not been well studied in this model. Therefore we aimed to investigate social behavior, in particular emotional contagion for pain, in this mouse model. We injected pregnant mouse dams with Poly(I:C) or saline (control) on gestation day 9 (GD9) and we evaluated their offspring in the pre-pulse inhibition (PPI) test at age 50-55 days old to confirm the reliability of our model. Mice were then evaluated in an emotional contagion test immediately followed by the light/dark test to explore post-test anxiety-like behavior at 10 weeks of age. In the emotional contagion test, an observer (prenatally exposed to Poly(I:C) or to saline) witnessed a familiar wild-type (WT) mouse (demonstrator) receiving electric foot shocks. Our results replicate the sensory gating impairments in the Poly(I:C) offspring but we only observed minor group differences in the social tasks. One of the differences we found was that demonstrators deposited fewer feces in the presence of control observers than of observers prenatally exposed to Poly(I:C), which we suggest could be due to the observers' behavior. We discuss the findings in the context of age, sex and day of prenatal injection, suggesting that Poly(I:C) on GD9 may be a valuable tool to assess other symptoms or symptom clusters of schizophrenia but perhaps not comprising the social domain.

Flow cytometric characterization of microglia in the offspring of PolyI:C treated mice.

The neuropathology of schizophrenia has been reported to be closely associated with microglial activation. In a previous study, using the prenatal PolyI:C schizophrenia animal model, we showed an increase in cell numbers and a reduction in microglial branching in 30-day-old PolyI:C descendants, which suggests that there is microglial activation during adolescence. To provide more information about the activation state, we aimed to examine the expression levels of Iba1, which was reported to be up-regulated in activated microglia. We used a flow cytometric approach and investigated CD11b and CD45, two additional markers for the identification of microglial cells. We demonstrated that intracellular staining against Iba1 can be used as a reliable flow cytometric method for identification of microglial cells. Prenatal PolyI:C treatment had long-term effects on CD11b and CD45 expression. It also resulted in a trend towards increased Iba1 expression. Imbalance in CD11b, CD45, and Iba1 expression might contribute to impaired synaptic surveillance and enhanced activation/inflammatory activity of microglia in adult offspring.

Emotional contagion in mice: the role of familiarity.

Empathy is a complex emotional process that involves sharing an emotional state with another organism. The extent to which nonhuman animals are capable of empathizing with others is still far from clear, partly due to a lack of empirical work in this domain, but also due to definitional confusion of empathy with emotional contagion and other related terms. In this study, an observer mouse witnessed a familiar cagemate or an unfamiliar non-cagemate receiving electric foot shocks in an experiment that consisted of three periods: baseline (no shocks), test (shocks) and recovery (no shocks). Freezing behavior in the observer was significantly increased in the cagemate, as opposed to the non-cagemate condition during the test period, but not during baseline or recovery, emphasizing the role of familiarity in empathy-like processes. In agreement with this, we also found a correlation that approached significance between the total number of fecal droppings of the observers, as an indication of distress, and those of the demonstrator in the cagemate, but not in the non-cagemate, condition. While the freezing behavior of the demonstrators increased with time, reaching a maximum at the recovery period, the observers froze the most during the test period while the demonstrators were receiving the electric foot shocks. The observation that the freezing response of the observers ceased when the shocks in the adjacent compartment stopped could be due to a decrease in saliency of the demonstrators' behavioral response. Finally, the presence of a cagemate, as compared to a stranger, possibly reduced the demonstrator's pain-induced behavior, suggesting an ameliorating effect of familiarity on stress responses.

A Preliminary Study on the Relationship between Platelet Serotonin Transporter Functionality, Depression, and Fatigue in Patients with Untreated Chronic Hepatitis C.

Objective and Methods. Although the interaction between fatigue and depression in patients with chronic hepatitis C infection (HCV) has been recognized, the biological correlates of this observation have yet to be reported. We addressed this issue by examining serotonin transporter- (SERT-) driven [(14)C]-serotonin uptake rate (SUR) and serotonin content in platelets of 65 untreated HCV patients and 65 healthy control subjects (HCS). All patients completed report questionnaires for fatigue, depression, and general psychopathology. Structured interviews were conducted by a board-certified psychiatrist. Results. Whereas 36 of the patients experienced fatigue of moderate-to-severe intensity, only 16 reported symptoms of depression (BDI score > 10). Mean SUR in patients with depressive symptoms was significantly higher relative to the HCS, corresponding to a large Cohen's effect size of d = 1.45 (95% CI = 0.66-1.83). Patients who rated their fatigue to have a marked impact on mood and activity displayed a moderate relationship between the BDI score and SUR (n = 18, r = 0.563, P = 0.015), which becomes stronger after controlling for age, gender, and thrombocytopenia (r part = 0.710, P = 0.003). In the univariate analysis, high fatigue interference score, thrombocytopenia, and high SUR were all significant predictors of depression. Conclusions. High SERT activity could be implicated in the expression of depressive symptoms especially in a subgroup of HCV patients who are feeling fatigue as markedly distressing.

Effects of complete vagotomy and blockage of cell adhesion molecules on interferon-α induced behavioral changes in mice.

OBJECTIVES: Sickness behavior and chronic immune diseases are frequently associated with depressive symptomatology. In addition, immune activation by single cytokine therapies, such as treatment of malignancies and hepatitis C with interferon-alpha (IFN-α) often induces significant changes in emotional reactivity and affect. However, underlying pathogenic mechanisms of cytokine-induced brain dysfunction largely remain unknown. METHODS: We presently demonstrate the induction of anxiety- and depressive-like behavior in male BALB/c mice after prolonged treatment with murine IFN-α for up to four weeks. Subsequently, neural and cellular communication routes between the immune system and the brain were examined. RESULTS: IFN-α induced anxious and depressive-like behavior in a light dark, open field, tail suspension, and novel object paradigm with a maximum effect after two weeks of treatment. Effect sizes of IFN-α varied between variables from 23 to 41%. Behavioral deficits were not prevented by complete vagotomy, or by blocking leukocyte function-associated-1 (LFA-1)/intercellular adhesion molecule-1 (ICAM-1) and activated leukocyte cellular adhesion molecule (ALCAM)-mediated cellular adhesion events, which are both involved in immune cell entry to the brain. CONCLUSIONS: We demonstrate emergence of anxiety- and depressive-like behavior in a mouse model of sustained IFN-α application allowing investigation of its pathogenic mechanisms, which is of clinical importance. We failed to demonstrate a critical effect for the vagus nerve or adhesion molecules, but current experiments do not allow excluding the vagus nerve as an afferent communication route. Future studies are needed to unveil if both pathways can be completely excluded in the etiology of behavioral deficits induced by IFN-α.

Neutralization of LPS or blockage of TLR4 signaling prevents stress-triggered fetal loss in murine pregnancy.

Maternal stress can cause loss of both histocompatible (syngeneic) and histoincompatible (semiallogeneic) embryos in pregnant mice. Stress increases abortogenic Th1 cytokines and reduces levels of anti-abortogenic Th2 cytokines, progesterone levels, and T regulatory cell activity. While physiological levels of interferon-γ promote vascular remodeling at the feto-maternal interface, an overshooting Th1 cytokine response requires a Toll-like receptor (TLR)-mediated "danger signal" such as lipopolysaccharide (LPS). Interestingly, stress can enhance permeability of mucosal membranes to entry of bacterial products and promote transmucosal migration of commensal bacteria. We hypothesized that bacterial component such as LPS may provide the danger signal through which stress triggers maternal immune activation, subsequently resulting in fetal rejection. Blocking the TLR4 receptor for LPS or neutralization of LPS using bactericidal permeability increasing protein abrogate fetal loss due to sonic stress challenge in DBA/2J-mated CBA/J mice. These treatments prevented stress-triggered immune responses in the decidua, upregulated Treg cells, and reduced the frequency of mature dendritic cells in uterine-draining lymph nodes but not in the uterus. Interestingly, anti-TLR4 treatment only partly ameliorated stress-induced endocrine responses, such as increased hypothalamic corticotropin releasing hormone and vasopressin mRNA expression but not decrease of serum progesterone. Galectin-1 knock-out mice were more susceptible to stress-triggered complete implantation failure rather than fetal loss, which was also abolished by LPS neutralization. Insights provided in this paper shed new light on the mechanisms by which stress affects pregnancy outcome and introduce microbial-derived LPS as a mediator within the cascade of stress-triggered immune and endocrine events during pregnancy.

Microglial activation in a neuroinflammational animal model of schizophrenia--a pilot study.

Inflammatory and immunological processes interfering with brain development are discussed as one cause of schizophrenia. Various signs of overactivation of the immune system were often found in this disease. Based on post-mortem analysis showing an increased number of activated microglial cells in patients with schizophrenia, it can be hypothesized that these cells contribute to disease pathogenesis and may actively be involved in gray matter loss observed in such patients. In the present study, PolyI:C incubation of pregnant dams was used as animal model of schizophrenia, and the number and shape of microglia were assessed in the offspring in the early phase of this disease, using fluorescence immunostaining (Iba1). Descendants of mice exposed to PolyI:C at embryonic day 9 showed higher number of microglial cells in the hippocampus and striatum, but not in the frontal cortex at postnatal day 30, which is similarly to adolescence in man, as compared to those exposed to saline. Furthermore, offspring microglia from PolyI:C treated mothers were morphologically characterized by a reduced arborization indicative for a status of higher activation compared to the offspring microglia from vehicle treated mice. This study supports the hypothesis that maternal infection during embryogenesis contributes to microglial activation in the offspring, which may therefore represent a contributing factor to the pathogenesis of schizophrenia and underlines the need for new pharmacological treatment options in this regard.

Inactivated orf virus (Parapoxvirus ovis) induces antitumoral activity in transplantable tumor models.

Orf virus (ORFV, Parapoxvirus ovis) possesses strong immunomodulating activity including the induction of interferon gamma (IFN-γ) and interleukin-12 (IL-12) expression. Antiviral effects have been described which appeared to be facilitated by an ORFV-induced Type 1 helper T-cell (Th1-type) immune response. In this study, we investigated the potential antitumoral activity of inactivated ORFV in transplantable tumor models. We show that parenteral administration of inactivated ORFV mediates antitumor effects in various models including the murine syngenic B16 F10 melanoma and MDA-MB-231 human breast cancer xenograft. Inhibition of natural killer (NK) and NKT cell activity through administration of an anti-mouse NK-1.1 antibody led to a reduction of ORFV-mediated antitumoral effects. However, residual antitumoral activity was observed. This observation was confirmed in MDA-MB-231 tumor-bearing NOD/LtSz-scid/j mice which not only lack functional T and B lymphocytes but, in addition, have virtually no cells positive for the NK 1.1 cell surface marker. Thus, administration of inactivated ORFV induced inhibitory effects on the growth of transplantable tumors even under conditions of severe immunosuppression.