Allergic Encephalomyelitis Research Articles

Potential Effects of Geraniol on Cancer and Inflammation-Related Diseases: A Review of the Recent Research Findings.

Geraniol (GNL), a natural monoterpene, is found in many essential oils of fruits, vegetables, and herbs, including lavender, citronella, lemongrass, and other medicinal and aromatic plants. GNL is commonly used by the cosmetic and food industries and has shown a wide spectrum of pharmacological activities including anti-inflammatory, anticancer, antimicrobial, antioxidant, and neuroprotective activities. It represents a potential anti-inflammatory agent and a promising cancer chemopreventive agent, as it has been found to be effective against a broad range of cancers, including colon, prostate, breast, lung, skin, kidney, liver, and pancreatic cancer. Moreover, GNL scavenges free radicals and preserves the activity of antioxidant enzymes. In addition, GNL induces apoptosis and cell cycle arrest, modulates multiple molecular targets, including p53 and STAT3, activates caspases, and modulates inflammation via transcriptional regulation. In the present study, different modes of action are described for GNL's activity against cancer and inflammatory diseases. This compound protects various antioxidant enzymes, such as catalase, glutathione-S-transferase, and glutathione peroxidase. Experiments using allergic encephalomyelitis, diabetes, asthma, and carcinogenesis models showed that GNL treatment had beneficial effects with low toxicity. GNL has been shown to be effective in animal models and tumor cell lines, but there have not been any clinical studies carried out for it. The aim of the present review is to provide updated data on the potential effects of GNL on cancer and inflammation, and to enhance our understanding of molecular targets, involved pathways, and the possible use of GNL for clinical studies and therapeutic purposes in the treatment of cancer and inflammation-related diseases.

Chrysin Attenuates VCAM-1 Expression and Monocyte Adhesion in Lipopolysaccharide-Stimulated Brain Endothelial Cells by Preventing NF-κB Signaling.

Adhesion of leukocytes to endothelial cells plays an important role in neuroinflammation. Therefore, suppression of the expression of adhesion molecules in brain endothelial cells may inhibit neuroinflammation. Chrysin (5,7-dihydroxyflavone) is a flavonoid component of propolis, blue passion flowers, and fruits. In the present study, we examined the effects of chrysin on lipopolysaccharide (LPS)-induced expression of vascular cell adhesion molecule-1 (VCAM-1) in mouse cerebral vascular endothelial (bEnd.3) cells. In bEnd.3 cells, LPS increased mRNA expression of VCAM-1 in a time-dependent manner, and chrysin significantly decreased LPS-induced mRNA expression of VCAM-1. Chrysin also reduced VCAM-1 protein expression in a concentration-dependent manner. Furthermore, chrysin blocked adhesion of monocytes to bEnd.3 cells exposed to LPS. Nuclear factor-κB (NF-κB), p38 mitogen-activated protein kinase (MAPK), and c-Jun N-terminal kinase, which are all activated by LPS, were significantly inhibited by chrysin. These results indicate that chrysin inhibits the expression of VCAM-1 in brain endothelial cells by inhibiting NF-κB translocation and MAPK signaling, resulting in the attenuation of leukocyte adhesion to endothelial cells. The anti-inflammatory effects of chrysin suggest a possible therapeutic application of this agent to neurodegenerative diseases, such as multiple sclerosis, septic encephalopathy, and allergic encephalomyelitis.

Cellular and molecular mechanisms of the demyelination in the central nervous system and cell therapy approaches

The review summarizes the current concepts of cell-tissue and molecular features of development of demyelinating processes in the central nervous system related to multiple sclerosis and its animal model – allergic encephalomyelitis. An analysis of recently published studies of this pathology, carried out with light and electron microscopy and immunohistochemical and molecular genetic methods, is given. New methodological approaches to the study of the pathomorhological aspects of demyelinating disorders allowed receiving in-depth understanding of the etiology and mechanisms of demyelination processes in the brain and spinal cord tissues at the cellular level and identifying the ways to develop effective modern methods of pathogenetic treatment of these diseases using cell therapy.

Exposure to PM2.5 causes genetic changes in fetal rat cerebral cortex and hippocampus.

PM2.5 travels along the respiratory tract and enters systemic blood circulation. Studies have shown that PM2.5 increases the incidence of various diseases not only in adults but also in newborn infants. It causes chronic inflammation in pregnant women and retards fetal development. In this study, pregnant rats were exposed to PM2.5 for extended periods of time and it was found that PM2.5 exposure increased immune cells in mother rats. In addition, cytokines and free radicals rapidly accumulated in the amniotic fluid and indirectly affected the fetuses. The authors collected cerebral cortex and hippocampus samples at E18 and analyzed changes of miRNA levels. Expression levels of cortical miR-6315, miR-3588, and miR-466b-5p were upregulated, and positively correlated with the genes Pkn2 (astrocyte migration), Gorab (neuritogenesis), and Mobp (allergic encephalomyelitis). In contrast, PM2.5 decreased expression of miR-338-5p and let-7e-5p, both related to mental development. Further, PM2.5 exposure increased miR-3560 and let-7b-5p in the hippocampus, two proteins that regulate genes Oxct1 and Lin28b that control ketogenesis and glycosylation, and neural cell differentiation, respectively. miR-99b-5p, miR-92b-5p, and miR-99a-5p were decreased, leading to reduced expression of Kbtbd8 and Adam11 which reduced cell mitosis, migration, and differentiation, and inhibited learning abilities and motor coordination of the fetus. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1412-1425, 2017.

Targeting Potassium Channels Kv1.3 and KCa3.1: Routes to Selective Immunomodulators in Autoimmune Disorder Treatment?

The Kv1.3 and KC a 3.1 potassium channels are promising targets for the treatment of autoimmune disorders. Many Kv1.3 and KC a 3.1 blockers have a more favorable adverse event profiles than existing immunosuppressants, suggesting the selectivity of Kv1.3 and KC a 3.1 blockade. The Kv1.3 and KC a 3.1 blockers exert differential effects in different autoimmune diseases. The Kv1.3 inhibitors or gene deletion have been shown to have benefits in multiple sclerosis, type 1 diabetes, rheumatoid arthritis, psoriasis, and rapidly progressive glomerulonephritis. The KC a 3.1 blockers have demonstrated efficacy in human primary biliary cirrhosis and showed protective effects in animal models of severe colitis, allergic encephalomyelitis, inflammatory bowel disease, and multiple sclerosis. The KC a 3.1 blockers are not considered candidates for treatment of multiple sclerosis. The selective immunosuppressive effects of the Kv1.3 and KC a 3.1 blockers are due to the differences in their distribution on autoimmune-related immune cells and tissues and β1 integrin (very late activating antigen)-Kv1.3 channel cross-talk.

Donor Th17 and Th1 Contribute to Chronic Graft-Versus-Host Disease

Abstract 727 Chronic graft-versus-host disease (cGVHD) remains a major cause of late death and morbidity after allogeneic hematopoietic cell transplantation, and the treatment of cGVHD remains challenging. All- trans retinoic acid (ATRA), a potent derivative of vitamin A, can regulate immune responses. Am80, which has biological activity approximately 10 times more potent than that of ATRA by binding to RARα and RARβ, but not RARγ, also reduces the severity and progression of immune disease models, including contact dermatitis, collagen-induced arthritis, allergic encephalomyelitis, and atherosclerosis models. Am80 has been reported to suppress the differentiation of Th17 and Th1 cells. Previously, we demonstrated that the administration of ATRA or Am80, significantly decreased skin fibrosis and alopecia, a dominant feature of cutaneous cGVHD, using a well-characterized experimental model of cGVHD: B10.D2 (H−2d) → BALB/c (H−2d). Flow cytometry analysis of the peripheral lymph nodes (PLNs) on day 16 showed significant reductions in Th1, Th17, and Foxp3+ regulatory T cells (Tregs) in Am80-treated recipients, as compared to controls, whereas no reduction in Th2 cells was observed (Nishimori et al ., 2009 ASH). To further investigate the roles of Th17 cells and other Th subsets (Th1 and Th2) in cGVHD, we first assessed the kinetics of Th cytokines in the B10.D2 (H-2d) → BALB/c (H-2d) model of cGVHD, which reflects the clinical and pathological symptoms of human cGVHD. BALB/c mice were subjected to sublethal irradiation (6.75 Gy) and injected with 8 × 106 T-cell-depleted bone marrow cells and 8 × 106 spleen cells or 2 × 106 CD90+ spleen T cells from B10.D2 mice. In the early phase (day 14) of post bone marrow transplant (BMT), donor T cells produced significantly less IL-17 in the PLNs of recipients in allogeneic BMT than in syngeneic BMT (1.68±0.09% vs. 4.30±0.53%, p <0.01), while in the late phase (day 28) donor T cells that produced IL-17 were increased significantly in allogeneic recipients, compared with syngeneic controls (7.76±0.27% vs. 1.61±0.16%, p < 0.005). Both IL-17−/IFN-γ+ and IL-17/IFN-γ double positive cells (Th17/Th1 cells) were constantly detected more frequently in allogeneic recipients ( p <0.05). Next, we evaluated whether Th17 contributes in a model utilizing IL-17-deficient mice on a B10.D2 background as donor mice; these mice were backcrossed for more than six generations from the original knock-out (KO) mice. Upon transfer of IL-17−/− B10.D2 donor T cells in allogeneic BMT models, skin cGVHD was significantly ameliorated, as compared to recipients of wild-type (WT) T cells, as shown in Figure ( p =0.02). Histopathological examination of the skin showed significantly reduced cGVHD pathology in recipients of IL-17−/− donors (3.17±1.09 vs. 8.50±0.84, p =0.006). Flow cytometry analysis of the PLNs, mesenteric lymph nodes (MLNs), and spleen cells in the early phase (day 14) showed no differences in Th1, Th2, and Tregs, while recipients of IL-17−/− had significantly fewer Th1 ( p <0.05) and Th17/Th1 ( p <0.01) cells on day 35. Furthermore, IFN-γ deficient mice on a B10.D2 background were also backcrossed from the original KO mice and cGVHD was evaluated. BMT from IFN-γ−/− donors significantly improved the clinical cGVHD score, compared with WT donors ( p <0.05). Allogeneic recipients given anti-IFN-γ mAb (500 μg/mouse) on days 0, 5, 10, and 15 post BMT had significantly less severe cGVHD, compared with control antibody recipients ( p <0.05). Taken together, Th17, especially in the late-chronic phase, and Th1 contribute to the development of cGVHD by promoting the production of proinflammatory cytokines. Targeting Th17 and Th1 may be a promising strategy for preventing and treating cGVHD. ![Figure][1] Disclosures: No relevant conflicts of interest to declare. [1]: pending:yes

Donor Th17 and Th1 Contribute to Chronic Graft-Versus-Host Disease

AbstractAbstract 727Chronic graft-versus-host disease (cGVHD) remains a major cause of late death and morbidity after allogeneic hematopoietic cell transplantation, and the treatment of cGVHD remains challenging. All-trans retinoic acid (ATRA), a potent derivative of vitamin A, can regulate immune responses. Am80, which has biological activity approximately 10 times more potent than that of ATRA by binding to RARα and RARβ, but not RARγ, also reduces the severity and progression of immune disease models, including contact dermatitis, collagen-induced arthritis, allergic encephalomyelitis, and atherosclerosis models. Am80 has been reported to suppress the differentiation of Th17 and Th1 cells. Previously, we demonstrated that the administration of ATRA or Am80, significantly decreased skin fibrosis and alopecia, a dominant feature of cutaneous cGVHD, using a well-characterized experimental model of cGVHD: B10.D2 (H−2d) → BALB/c (H−2d). Flow cytometry analysis of the peripheral lymph nodes (PLNs) on day 16 showed significant reductions in Th1, Th17, and Foxp3+ regulatory T cells (Tregs) in Am80-treated recipients, as compared to controls, whereas no reduction in Th2 cells was observed (Nishimori et al., 2009 ASH). To further investigate the roles of Th17 cells and other Th subsets (Th1 and Th2) in cGVHD, we first assessed the kinetics of Th cytokines in the B10.D2 (H-2d) → BALB/c (H-2d) model of cGVHD, which reflects the clinical and pathological symptoms of human cGVHD. BALB/c mice were subjected to sublethal irradiation (6.75 Gy) and injected with 8 × 106 T-cell-depleted bone marrow cells and 8 × 106 spleen cells or 2 × 106 CD90+ spleen T cells from B10.D2 mice. In the early phase (day 14) of post bone marrow transplant (BMT), donor T cells produced significantly less IL-17 in the PLNs of recipients in allogeneic BMT than in syngeneic BMT (1.68±0.09% vs. 4.30±0.53%, p<0.01), while in the late phase (day 28) donor T cells that produced IL-17 were increased significantly in allogeneic recipients, compared with syngeneic controls (7.76±0.27% vs. 1.61±0.16%, p < 0.005). Both IL-17−/IFN-γ+ and IL-17/IFN-γ double positive cells (Th17/Th1 cells) were constantly detected more frequently in allogeneic recipients (p<0.05). Next, we evaluated whether Th17 contributes in a model utilizing IL-17-deficient mice on a B10.D2 background as donor mice; these mice were backcrossed for more than six generations from the original knock-out (KO) mice. Upon transfer of IL-17−/− B10.D2 donor T cells in allogeneic BMT models, skin cGVHD was significantly ameliorated, as compared to recipients of wild-type (WT) T cells, as shown in Figure (p=0.02). Histopathological examination of the skin showed significantly reduced cGVHD pathology in recipients of IL-17−/− donors (3.17±1.09 vs. 8.50±0.84, p=0.006). Flow cytometry analysis of the PLNs, mesenteric lymph nodes (MLNs), and spleen cells in the early phase (day 14) showed no differences in Th1, Th2, and Tregs, while recipients of IL-17−/− had significantly fewer Th1 (p<0.05) and Th17/Th1 (p<0.01) cells on day 35. Furthermore, IFN-γ deficient mice on a B10.D2 background were also backcrossed from the original KO mice and cGVHD was evaluated. BMT from IFN-γ−/− donors significantly improved the clinical cGVHD score, compared with WT donors (p<0.05). Allogeneic recipients given anti-IFN-γ mAb (500 μg/mouse) on days 0, 5, 10, and 15 post BMT had significantly less severe cGVHD, compared with control antibody recipients (p<0.05). Taken together, Th17, especially in the late-chronic phase, and Th1 contribute to the development of cGVHD by promoting the production of proinflammatory cytokines. Targeting Th17 and Th1 may be a promising strategy for preventing and treating cGVHD. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Synthetic Retinoid Am80 Ameliorates Chronic Graft-Versus-Host Disease.

Abstract 4487Chronic graft-versus-host disease (cGVHD) remains a major cause of late death and morbidity after allogeneic hematopoietic cell transplantation, and the treatment of cGVHD remains challenging. All-trans retinoic acid (ATRA), a potent vitamin A derivative, can regulate immune responses. Synthetic retinoid Am80, which shows biological activity approximately 10 times more potent than that of ATRA by binding to RARα and RARβ, but not RARγ, also reduces the severity and progression of immune disease models, including those for contact dermatitis, collagen-induced arthritis, allergic encephalomyelitis, and atherosclerosis. We hypothesized that the administration of ATRA or Am80 could modulate cGVHD. BALB/c (H-2d) mice were subjected to sublethal irradiation and injected with 8 × 106 T-cell-depleted bone marrow cells and 8 × 106 spleen cells from major histocompatibility complex-matched, multiple minor histocompatibility antigen-mismatched B10.D2 (H-2d) mice. Then, the mice were given oral ATRA (200 μg/body), Am80 (1.0 mg/kg body weight), or vehicle daily, beginning from day 0. ATRA slightly decreased the clinical cGVHD score, whereas Am80 significantly reduced the score (Table). When administered daily, Am80 decreased the clinical score beginning from day 21, as in a treatment setting (data not shown). Histopathological examination of the skin showed significantly reduced GVHD pathology in recipients of Am80 (Table). Flow cytometry analysis of the peripheral draining lymph nodes on day 16 showed significant reductions in IFN-γ+, IL-17+, and Foxp3+ cells in Am80-treated recipients compared to controls (Table), whereas no reduction in IL-13+ cells was observed. Cytometric bead arrays and enzyme-linked immunosorbent assays (ELISA) revealed decreased levels of the cytokines IFN-γ, IL-17, TNF-α, and IL-6 in the supernatant of peripheral lymph nodes from Am80-administered recipients (data not shown). Real-time RT-PCR of ears from these recipients on day 21 showed that the administration of Am80 reduced the expression of Foxp3 and TGF-β (Table and data not shown). Therefore, the administration of retinoids ameliorates cGVHD by reducing Th1 and Th17 inflammatory cytokines and the fibrosis factor TGF-β. Thus, treatment with retinoids may be effective for prophylaxis and treatment of cGVHD. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

A complementary La/SSB epitope anchored to Sequential Oligopeptide Carrier regulates the anti‐La/SSB response in immunized animals

Complementary peptide epitopes, derived from complementary RNA sequences, have been used for suppressing the autoimmune response in experimental autoimmune diseases as myasthenia gravis, allergic neuritis and allergic encephalomyelitis. Aiming at contributing to the development of a tool that could regulate the autoantibody production against La/SSB, which is the main target of autoantibodies in Sjogren's syndrome (SS) and systemic lupus erythematosus (SLE), the complementary epitope, cpep349-364, of the minor T/major B cell epitope of La/SSB, pep349-364, was utilized for the induction of neutralizing anti-cpep349-364 antibodies in rabbit immunizations. Complementary peptides were coupled to an artificial carrier, developed in our laboratory, in order to enhance the complementary potency of cpep349-364 and its counterpart. This carrier, named Sequential Oligopeptide Carrier, SOC(n), formed by the repeating tripeptide Lys-Aib-Gly, adopts helical conformation, which allows the anchored peptide epitopes to preserve their initial reactivity such as molecular recognition, antigenicity/immunogenicity. Our study provides proof of evidence of specific interactions between idiotypic (Id)/anti-idiotypic (anti-Id) antibodies generated in immunized animals by the sense epitope (conjugate I) of La/SSB and its complementary counterpart (conjugate II). It was also demonstrated that the Id/anti-Id association is specifically disrupted by adding either the sense epitope (conjugate I) or its complementary counterpart (conjugate II). A mutual neutralization of Id/anti-Id antibodies was observed in vivo, which implies that generation of anti-Id antibodies by immunization with the complementary La/SSB epitope could scavenge the anti-La/SSB response.

Perplexity of monocyte responses to C-reactive protein (CRP)

Thromb Haemost 2008; 99: 461–462 C-reactive protein (CRP), a member of the pentraxin family, is one of the prototypic plasma biomarkers of inflammation (1, 2). The physiological roles of CRP in the innate immune response have, however, remained elusive as it possesses both proand anti-inflammatory actions (1, 2). Inflammation is pivotal in all phases of atherosclerosis from the nascent lesion through progression to the culmination in acute coronary syndromes (3). To date, over two dozen large-scale prospective clinical studies have reported that moderate elevations in base-line CRP levels predict, albeit to varying degrees, future cardiovascular disease and death across all levels of lowdensity lipoprotein (LDL) cholesterol and of the Framingham Risk Score (4, 5). CRP has been implicated inmultiple aspects of atherogenesis and plaque vulnerability; however, whether CRP plays a direct causal role in these events remains controversial (reviewed in [6]). For example, transgenic expression of human CRP in apolipoprotein E-deficient mice has been reported to accelerate atherogenesis (7, 8), to show no effect (9) or even to slow atherosclerosis development (10). In vitro, CRP induces release of proinflammatory interleukins IL-1, IL-6, IL-8 and tumor necrosis factor-α NF (11, 12) from human monocytes; promotes monocye adhesion to endothelial cells through upregulation of endothelial adhesion molecules (13, 14) and enhances phagocytosis of oxidized LDL (6). These observations are consistent with the role of monocytes in the initiation and progression of atherosclerosis (3). However, monocytes may have a more complex role in atherogenesis than previously thought. In this issue of Thrombosis and Haemostasis, Hanriot et al. (15) show that CRP modulates expression of genes known to mediate both proand anti-inflammatory responses. These novel observations raise the intriguing possibility that CRP could activate yet unidentified pathways in human monocytes. Using a custom-made 250 oligonucleotide microarray for screening CRP regulated genes in monocytes isolated from apparently healthy men and women (aged 25 to 35 years), Hanriot et al. detected changes in approximately 10% of the genes represented on the microarray. The authors confirm previous studies on CRP induction of pro-inflammatory cytokine gene expression with the exception of TNF, which was unaffected by CRP, and show increased mRNA expression of monocyte chemotactic protein-1 (MCP-1), Gro-β, the chemokine receptors CCR-8 and CXCR-4, and plasminogen activator inhibitor type 2 (PAI-2). In concert with IL-8,MCP-1 andGro-β facilitatemonocyte recruitment and adhesion to endothelial cells, whereas CCR-8 and CXCR-4 mediate monocyte (and macrophage) chemotaxis. The function of PAI-2 appears to be more complex. PAI-2 promotes fibrin deposition in the arterial wall, thereby contributing to progression of the initial lesion, whereas it may stabilize more advanced plaques by inhibiting activation of matrix metalloproteinases, enzymes overexpressed in human atheromata (3). While the concept of CRP’s anti-inflammatory role is not new (reviewed in [1, 2]), Hanriot et al. also report CRP-induced changes in monocyte gene expression that are consistent with suppression of inflammation. Thus, the authors show that CRP attenuates expression of the monocyte/lymphocyte chemotactic proteins MIP-1α and MIP-1β and α2-macroglobulin, which antagonize the actions of the anti-inflammatory cytokine transforming growth factor-β. Protection of mice overexpressing human CRP from allergic encephalomyelitis is mediated through reduction of MIP-1 (16). The most striking finding is that CRP increases expression of the nuclear receptor liver X receptor-α (LXR-α) and one of its target genes the ATP-binding cassette transporter A1 (ABCA1). ABCA1 promotes reverse cholesterol transport from macrophages in atherosclerotic plaques to high density lipoprotein (HDL) and suppresses genes involved in macrophage inflammatory signaling and apoptosis, thereby inhibiting atherosclerosis (17). CRP induction of LXR-α expression and activation is mediated through the high affinity IgG receptor FcγR1 (CD64) and, to lesser a degree, the low affinity IgG receptor FcγRII (CD32), and involves activation of both p42/44MAPK and phosphatidylinositol 3-kinase signaling pathways. A critical issue whether CRP could effectively facilitate reverse cholesterol transport in monocytes (and macrophages) remains to be elucidated. The complexity of LXR-α responses makes it difficult to extrapolate the beneficial or deleterious effects of a target gene in isolation to human pathology when target genes are likely beingmodulated in concert. For example, an-

Complementary peptide epitopes and anti-idiotypic antibodies in autoimmunity.

Application of complementary B and T cell epitopes in inducing anti-idiotypic and anti-clonotypic antibodies capable of regulating or suppressing the autoimmune responses in experimental autoimmune myasthenia gravis (EAMG), allergic neuritis (EAN) and allergic encephalomyelitis (EAE) has been the stimulus of many research efforts. Studies on the idiotypic/anti-idiotypic network of anti-La/SSB positive sera from patients with Sjogren's Syndrome (SS) and Systemic Lupus Erythematosus (SLE) and on animals immunized with the complementary epitopes are presented.

Poly(ADP-ribose) polymerase inhibitors.

Poly(ADP-ribose) polymerase-1 (PARP-1) is the principal member of the PARP enzyme family consisting of PARP-1 and several recently identified novel poly(ADP-ribosyl)ating enzymes. PARP-1 functions as a DNA damage sensor and signalling molecule. Upon binding to DNA breaks, activated PARP cleaves NAD(+) into nicotinamide and ADP-ribose and polymerizes the latter onto nuclear acceptor proteins including histones, transcription factors and PARP itself. This Poly(ADP-ribosyl)ation contributes to inflammatory signal transduction processes. In addition, oxidative stress-induced overactivation of PARP consumes NAD(+) and consequently ATP, culminating in cell dysfunction or necrosis. Activation of PARP has been implicated in the pathogenesis of stroke, myocardial ischemia, diabetes, diabetes-associated cardiovascular dysfunction, shock, traumatic central nervous system injury, arthritis, colitis, allergic encephalomyelitis and various other forms of inflammation. Therefore, inhibition of PARP by pharmacological agents may prove useful for the therapy of these diseases, as has been shown in preclinical animal models. Moreover, PARP inhibitors may have additional, potential utility as anticancer agents, radiosensitizers and antiviral agents. In the present article we overview the structures and pharmacological actions of various pharmacological classes of compounds which inhibit the catalytic activity of PARP.

Experimental basis of hematopoietic stem cell transplantation for treatment of autoimmune diseases

Experiments with animal models of autoimmune disease provided the rational and stimulus for the current, clinical studies of autologous stem cell transplantation for the treatment of a variety of severe, refractory, autoimmune diseases. The discoveries that led to the recognition of the key role of hematopoietic stem cells and the successful treatment of autoimmune diseases with bone marrow transplants are reviewed. The relevance of spontaneous and induced autoimmune disease models for the development of clinical treatment regimens is discussed. Most of the investigations with autologous stem cell transplantation have been performed with induced autoimmune disorders: in rats with adjuvant arthritis and in rats or mice with experimental, allergic encephalomyelitis, the current model for multiple sclerosis. The main aspects of this translational research were the conditioning regimens and the degree of T cell depletion of the graft as determinants of remission induction and the incidence of relapses. The emerging recommendations are compared with the outcome so far of the clinical studies.

The Therapeutic Potential of Poly(ADP-Ribose) Polymerase Inhibitors

Poly(ADP-ribose) polymerase-1 (PARP-1) is a member of the PARP enzyme family consisting of PARP-1 and several recently identified novel poly(ADP-ribosylating) enzymes. PARP-1 is an abundant nuclear protein functioning as a DNA nick-sensor enzyme. Upon binding to DNA breaks, activated PARP cleaves NAD(+) into nicotinamide and ADP-ribose and polymerizes the latter onto nuclear acceptor proteins including histones, transcription factors, and PARP itself. Poly(ADP-ribosylation) contributes to DNA repair and to the maintenance of genomic stability. On the other hand, oxidative stress-induced overactivation of PARP consumes NAD(+) and consequently ATP, culminating in cell dysfunction or necrosis. This cellular suicide mechanism has been implicated in the pathomechanism of stroke, myocardial ischemia, diabetes, diabetes-associated cardiovascular dysfunction, shock, traumatic central nervous system injury, arthritis, colitis, allergic encephalomyelitis, and various other forms of inflammation. PARP has also been shown to associate with and regulate the function of several transcription factors. Of special interest is the enhancement by PARP of nuclear factor kappa B-mediated transcription, which plays a central role in the expression of inflammatory cytokines, chemokines, adhesion molecules, and inflammatory mediators. Herein we review the double-edged sword roles of PARP in DNA damage signaling and cell death and summarize the underlying mechanisms of the anti-inflammatory effects of PARP inhibitors. Moreover, we discuss the potential use of PARP inhibitors as anticancer agents, radiosensitizers, and antiviral agents.

Molecular Cloning and Characterization of Another Leukotriene B4 Receptor

Molecular Cloning and Characterization of Another Leukotriene B4 Receptor

Effectiveness and risks of total body irradiation for conditioning in the treatment of autoimmune disease with autologous bone marrow transplantation.

The results of experiments with the induced autoimmune diseases adjuvant arthritis and allergic encephalomyelitis in rats, which led to the discovery of the curative effect of autologous bone marrow transplantation following high-dose myeloablative treatment, are reviewed. The rationale is eradication of the autoreactive lymphocytes and memory cells, and the prevention of relapse due to transfer of lymphocytes with the autograft. Comparison of various conditioning regimens in the animal models indicates that a combination conditioning with low-dose total body irradiation (TBI) and high-dose cyclophosphamide is optimal. These findings were the basis for the conditioning currently employed in the treatment of polyarticular juvenile chronic arthritis (JCA) by the teams in Utrecht and Leiden, which consists of cyclophosphamide 50 mg/kg for 4 days, 4 Gy TBI and anti-thymocyte globulin (ATG). The use of TBI for the treatment of non-malignant disease is regarded as undesirable by many physicians in view of the risks, in particular, of growth inhibition in children and the induction of tumours. Experimental and clinical data show that a dose of 4 Gy does not cause significant inhibition of skeletal growth in infants. The risk of excess cancer due to TBI has been well established in quantitative terms and is compared with the expected risk of high-dose cyclophosphamide and the risk associated with the highly immunosuppressive regimens currently used for the treatment of JCA.

Glutamate in CNS disorders as a target for drug development: an update

The authors provide an extensive review of new data related to the role of glutamate in CNS disorders, describing new aspects in glutamate and glutamatergic receptors-NMDA receptors, NR2B-selective antagonists, non-NMDA ionotropic glutamate receptors, N-acetylaspartylglutamate, and glutamate and glycine transporters. New findings in animal models and in human diseases-stroke, traumatic brain injury, Alzheimer's, Parkinson's and Huntington's diseases, tardive dyskinesia, ALS, olivopontcerebellar degeneration, AIDS, allergic encephalomyelitis, epilepsy, anxiety, depression, schizophrenia, liver disease, aminoglycoside antibiotic-induced hearing loss, hemiplegia, chronic pain and drug tolerance and abuse-are presented. Finally, the authors cite the progress achieved in the development of agents that interact with the glutamatergic system: NMDA channel blockers, competitive NMDA receptor antagonists, NR2B-selective antagonists, glutamate release inhibitors, glycineB antagonists, AMPA and kainate receptor antagonists, AMPA receptor-positive modulators and agents that act by modifying endogenous kynurenic acid metabolism.

Neural cells from dogs with spontaneous distemper encephalitis express class II major histocompatibility complex molecules

Expression of class II major histocompatibility complex (MHC) molecules by non-immune cells (e.g., parenchymal cells) leads to the presentation of self-antigens, and may have a role in the pathogenesis of many diseases mediated by autoimmunity. Such diseases, characterized by demyelination of the central nervous system and expression of class II MHC molecules on neural cells, include multiple sclerosis, experimental allergic encephalitis and Theiler's murine encephalomyelitis virus infection. Canine distemper encephalitis probably does not have an autoimmune character, but it shares many similarities with the aforementioned diseases. For this reason, the expression of class II MHC molecules in the brains of dogs with canine distemper encephalitis was investigated immunohistochemically. The results presented here demonstrate that canine microglia and astrocytes "upregulate" class II MHC expression in cases of encephalitis associated with chronic canine distemper.

An ultrastructural analysis of human post-infectious (allergic) encephalomyelitis

An ultrastructural analysis of human post-infectious (allergic) encephalomyelitis

Allergic encephalomyelitis in guinea pigs after intradermal and subcutaneous injection of fragment 114?122 of human basic myelin protein

In guinea pigs EAE can be induced [I, 3, 9-15] by injection of a fragment of basic myelin protein containing tryptophan. The presence and position of tryptophan in the amino acid chain are:decisive for induction of EAR. The important role of glutathione and lysine also is emphasized, although the latter can be replaced by arginine [15]. The view has been expressed [ii] that other amino acid residues of synthetic peptides play an exclusive role, for replacement of any of them leads to loss of the encephalitogenic properties.