Wanda Stankiewicz

Immunomodulatory Properties of Thalidomide Analogs: Pomalidomide and Lenalidomide, Experimental and Therapeutic Applications

Thalidomide has a broad spectrum of anti-cancer activity. Antitumor activity of thalidomide may be related to a number of known properties, including anti-tumor necrosis factor (TNF)-α and T-cell costimulatory and antiangiogenic activities. The therapeutic potential of thalidomide provided motivation to develop more effective derivatives with considerably reduced toxicity. Thalidomides immunomodulatory (IMiDs) analogs (lenalidomide, CC-5013; CC-4047, ACTIMID) represent a novel class of compounds with numerous effects on the immune system. Some of these analogs are thought to mediate the anticancer and anti-inflammatory effects observed in humans. Thalidomide is currently approved for the treatment of dermal reaction to leprosy and is currently in phase III trials for multiple myeloma (MM). IMiDs inhibit the cytokines tumor necrosis factor-α (TNF-α), interleukins (IL) 1β, 6, 12, and granulocyte macrophage-colony stimulating factor (GM-CSF). The repression of the tumor necrosis factor-a (TNF-α) expression is the crucial factor of many of the anti-inflammatory properties of thalidomide. The mechanisms underlying many of the anti-inflammatory properties of thalidomide, including its ability to co-stimulate T cells, still remain unclear. Some recent patent are also summarized in this review.

Changes in antioxidant capacity of blood due to mutual action of electromagnetic field (1800 MHz) and opioid drug (tramadol) in animal model of persistent inflammatory state.

BACKGROUND The biological effects and health implications of electromagnetic field (EMF) associated with cellular mobile telephones and related wireless systems and devices have become a focus of international scientific interest and world-wide public concern. It has also been proved that EMF influences the production of reactive oxygen species (ROS) in different tissues. METHODS Experiments were performed in healthy rats and in rats with persistent inflammatory state induced by Complete Freunds Adjuvant (CFA) injection, which was given 24 h before EMF exposure and drug application. Rats were injected with CFA or the same volume of paraffin oil into the plantar surface of the left hind paw. Animals were exposed to the far-field range of an antenna at 1800 MHz with the additional modulation which was identical to that generated by mobile phone GSM 1800. Rats were given 15 min exposure, or were sham-exposed with no voltage applied to the field generator in control groups. Immediately before EMF exposure, rats were injected intraperitoneally with tramadol in the 20 mg/kg dose or vehicle in the 1 ml/kg volume. RESULTS Our study revealed that single EMF exposure in 1800 MHz frequency significantly reduced antioxidant capacity both in healthy animals and those with paw inflammation. A certain synergic mode of action between applied electromagnetic fields and administered tramadol in rats treated with CFA was observed. CONCLUSIONS The aim of the study was to examine the possible, parallel/combined effects of electromagnetic radiation, artificially induced inflammation and a centrally-acting synthetic opioid analgesic drug, tramadol, (used in the treatment of severe pain) on the antioxidant capacity of blood of rats. The antioxidant capacity of blood of healthy rats was higher than that of rats which received only tramadol and were exposed to electromagnetic fields.

Interactions of orphanin FQ/nociceptin (OFQ/N) system with immune system factors and hypothalamic-pituitary-adrenal (HPA) axis.

BACKGROUND Brain-immune system interactions and neurohormonal changes which are induced by psychophysiological factors are growing areas of scientific interest. Central (CNS) and autonomic nervous-endocrine-immune system pathways are connected with a number of behavioral and physiological factors which may be linked to disease susceptibility and progression. METHODS In this paper, influence of orphanin FQ/nociceptin receptor (OFQ/N) on the hypothalamic-pituitary-adrenal (HPA) axis and their influence on the immunological system was reviewed. CONCLUSIONS The neuroendocrine system, in particular the hypothalamic-pituitary-adrenal (HPA) axis, is closely connected with the cytokines. HPA axis activation by cytokines, via the release of glucocorticoids has, in turn, been found to play a critical role in restraining and shaping immune responses. Investigation of the OFQ/N system and G-proteins suggests a role for this receptor as a down-regulator of cytokine, chemokine and chemokine receptor expression.

Fas/FasL Pathway Participates in Regulation of Antiviral and Inflammatory Response during Mousepox Infection of Lungs

Fas receptor-Fas ligand (FasL) signalling is involved in apoptosis of immune cells as well as of the virus infected target cells but increasing evidence accumulates on Fas as a mediator of apoptosis-independent processes such as induction of activating and proinflammatory signals. In this study, we examined the role of Fas/FasL pathway in inflammatory and antiviral response in lungs using a mousepox model applied to C57BL6/J, B6. MRL-Faslpr/J, and B6Smn.C3-Faslgld/J mice. Ectromelia virus (ECTV) infection of Fas- and FasL-deficient mice led to increased virus titers in lungs and decreased migration of IFN-γ expressing NK cells, CD4+ T cells, CD8+ T cells, and decreased IL-15 expression. The lungs of ECTV-infected Fas- and FasL-deficient mice showed significant inflammation during later phases of infection accompanied by decreased expression of anti-inflammatory IL-10 and TGF-β1 cytokines and disturbances in CXCL1 and CXCL9 expression. Experiments in vitro demonstrated that ECTV-infected cultures of epithelial cells, but not macrophages, upregulate Fas and FasL and are susceptible to Fas-induced apoptosis. Our study demonstrates that Fas/FasL pathway during ECTV infection of the lungs plays an important role in controlling local inflammatory response and mounting of antiviral response.

Role of Fas/FasL signaling in regulation of anti-viral response during HSV-2 vaginal infection in mice

Fas receptor-Fas ligand (FasL) signaling is involved in apoptosis of virus-infected cells but increasing evidence accumulates on Fas receptor as a mediator of apoptosis-independent processes such as induction of activating and pro-inflammatory signals. In this study, we examined the role of Fas/FasL pathway in regulation of anti-viral response to genital HSV-2 infection using a murine model of HSV-2 infection applied to C57BL6/J, B6. MRL-Faslpr/J and B6Smn.C3-Faslgld/J mice. HSV-2 infection of Fas- and FasL-deficient mice led to decreased migration of IFN-γ expressing NK cells and CD4+ T cells, but not of γδ T cells, into the vaginal tissue. The vaginal tissues of HSV-2 infected Fas- and FasL-deficient mice showed increased production of IL-10, followed by low expression of the early CD69 activation marker on CD4+ and CD8+ T cells and increased numbers of regulatory T cells (Tregs). Experiments in co-cultures of CD4+ T cells and bone marrow derived dendritic cells showed that lack of bilateral Fas-FasL signaling led to expansion of Tregs and increased production of IL-10 and TGF-β1. Our results demonstrate that Fas/FasL can regulate development of tolerogenic dendritic cells and expansion of Tregs early during HSV-2 infection, which further influences effective anti-viral response.

Hepatitis and the polyglandular autoimmune syndrome, type 1

Autoimmune polyglandular syndrome, type 1 (APS-1) is a rare syndrome. Here we present a case report of a 24-year-old female patient who complained of progressive weakness. While autoimmune hepatitis was diagnosed, no improvement of biochemical parameters was obtained after immunosuppressive treatment. Hypoparathyroidism and adrenocortical failure were identified. Her health status clearly improved once proper control of the calcium-phosphate metabolism was obtained and after the administration of substitution hydrocortisone doses, leading to full normalization of biochemical liver tests. The reported case illustrates a rare form of APS-1 failure, in which the diagnosed autoimmune hepatitis was only the first symptom.

Influence of electromagnetic field (1800 MHz) on lipid peroxidation in brain, blood, liver and kidney in rats

OBJECTIVES The aim of this study is the evaluation of the influence of repeated (5 times for 15 min) exposure to electromagnetic field (EMF) of 1800 MHz frequency on tissue lipid peroxidation (LPO) both in normal and inflammatory state, combined with analgesic treatment. MATERIAL AND METHODS The concentration of malondialdehyde (MDA) as the end-product of the lipid peroxidation (LPO) was estimated in blood, liver, kidneys, and brain of Wistar rats, both healthy and those with complete Freunds adjuvant (CFA)-induced persistent paw inflammation. RESULTS The slightly elevated levels of the MDA in blood, kidney, and brain were observed among healthy rats in electromagnetic field (EMF)-exposed groups, treated with tramadol (TRAM/EMF and exposed to the EMF). The malondialdehyde remained at the same level in the liver in all investigated groups: the control group (CON), the exposed group (EMF), treated with tramadol (TRAM) as well as exposed to and treated with tramadol (TRAM/EMF). In the group of animals treated with the complete Freunds adjuvant (CFA) we also observed slightly increased values of the MDA in the case of the control group (CON) and the exposed groups (EMF and TRAM/EMF). The MDA values concerning kidneys remained at the same levels in the control, exposed, and not-exposed group treated with tramadol. Results for healthy rats and animals with inflammation did not differ significantly. CONCLUSIONS The electromagnetic field exposure (EMF), applied in the repeated manner together with opioid drug tramadol (TRAM), slightly enhanced lipid peroxidation level in brain, blood, and kidneys.

The Effect of Anti-Inflammatory and Antimicrobial Herbal Remedy PADMA 28 on Immunological Angiogenesis and Granulocytes Activity in Mice

PADMA 28 is a herbal multicompound remedy that originates from traditional Tibetan medicine and possesses anti-inflammatory, antioxidant, antimicrobial, angioprotecting, and wound healing properties. The aim of the present study was to evaluate the influence of this remedy on immunological angiogenesis and granulocytes metabolic activity in Balb/c mice. Mice were fed daily, for seven days, with 5.8 mg of PADMA (calculated from recommended human daily dose) or 0.085 mg (dose in the range of active doses of other herbal extracts studied by us previously). Results. Highly significant increase of newly formed blood vessels number in ex vivo cutaneous lymphocyte-induced angiogenesis test (LIA) after grafting of Balb/c splenocytes from both dosage groups to F1 hybrids (Balb/c × C3H); increase of blood lymphocytes and granulocytes number only in mice fed with lower dose of remedy; and significant suppression of metabolic activity (chemiluminescence test) of blood granulocytes in mice fed with higher dose of PADMA. Conclusion. PADMA 28 behaves as a good stimulator of physiological angiogenesis, but for this purpose it should be used in substantially lower doses than recommended by producers for avoiding the deterioration of granulocyte function.

Inhibitory Effect of Herbal Remedy PERVIVO and Anti-Inflammatory Drug Sulindac on L-1 Sarcoma Tumor Growth and Tumor Angiogenesis in Balb/c Mice

Anticancer activity of many herbs was observed for hundreds of years. They act as modifiers of biologic response, and their effectiveness may be increased by combining multiple herbal extracts . PERVIVO, traditional digestive herbal remedy, contains some of them, and we previously described its antiangiogenic activity. Numerous studies documented anticancer effects of nonsteroidal anti-inflammatory drugs. We were the first to show that sulindac and its metabolites inhibit angiogenesis. In the present paper the combined in vivo effect of multicomponent herbal remedy PERVIVO and nonsteroidal anti-inflammatory drug sulindac on tumor growth, tumor angiogenesis, and tumor volume in Balb/c mice was studied. These effects were checked after grafting cells collected from syngeneic sarcoma L-1 tumors into mice skin. The strongest inhibitory effect was observed in experimental groups treated with PERVIVO and sulindac together. The results of our investigation showed that combined effect of examined drugs may be the best way to get the strongest antiangiogenic and antitumor effect.

Involvement of Fas/FasL pathway in the murine model of atopic dermatitis

Objective and designThe aim of this study was to elucidate the role of apoptosis mediated through Fas/FasL pathway using the mouse model of atopic dermatitis (AD).Materials and treatment AD was induced by epicutaneous application of ovalbumin (OVA) in wild-type C57BL/6, B6. MRL-Faslpr/J (Fas−) and B6Smn.C3-Faslgld/J (FasL−) mouse strains.MethodsSkin samples were subjected to staining for Fas/FasL expression, M30 epitope and assessment of inflammatory response via immunohistochemical staining. Cytokine and chemokine production was assessed by real-time PCR.ResultsIn comparison to wild-type mice, OVA sensitization of Fas- and FasL-deficient mice led to increased epidermal and dermal thickness, collagen deposition and local inflammation consisting of macrophages, neutrophils and CD4+ T cells. Fas- and FasL-deficient mice showed increased total counts of regulatory T cells (Tregs) and IgE levels in blood as well as increased expression of IL-1β, IL-4, IL-5, IL-13 and TGF-1β mRNA in comparison to wild-type mice. On the other hand, expression of CXCL9 and CXCL10, IL-17 mRNAs in the skin samples in Fas- and FasL-deficient mice was decreased.ConclusionsOur results show that lack of the Fas-induced apoptosis leads to exacerbation of AD characteristics such as Th2 inflammation and dermal thickening. Therefore, Fas receptor can play an important role in AD pathogenesis by controlling development of the local inflammation.