Alzheimer's disease patients display neuropathological lesions, including the accumulation of amyloid-beta (Aβ) peptide and neurofibrillary tangles. Although the mechanisms causing the neurodegenerative process are largely unknown, increasing evidence highlights a critical role of immunity in the pathogenesis of Alzheimer's disease. In the present study, we investigated the role of regulatory T cells (Tregs) on Alzheimer's disease progression. First, we explored the effect of Tregs (CD4+CD25+ T cells) and Teffs (CD4+CD25− T cells) in an adoptive transfer model. Systemic transplantation of purified Tregs into 3xTg-AD mice improved cognitive function and reduced deposition of Aβ plaques. In contrast, adoptive transfer of Teffs diminished behavioral function and cytokine production. Next, we transiently depleted Treg population using an anti-CD25 antibody (PC61). Depletion of Tregs for four months resulted in a marked aggravation of the spatial learning deficits of six-month-old 3xTg-AD mice. Additionally, it resulted in decreasing glucose metabolism, as assessed by positron emission tomography (PET) with 18F-2 fluoro-2-deoxy-D-glucose ([F-18] FDG) neuroimaging. Importantly, the deposition of Aβ plaques and microglia/macrophage was increased in the hippocampal CA1 and CA3 regions of the Treg depleted 3xTg-AD compared to the vehicle-treated 3xTg-AD group. Our finding suggested that systemic Treg administration ameliorates disease progression and could be an effective Alzheimer's disease treatment.

Glioblastoma multiforme (GBM) remains an untreatable human brain malignancy. Despite promising preclinical studies using oncolytic herpes simplex virus (oHSV) vectors, efficacy in patients has been limited by inefficient virus replication in tumor cells. This disappointing outcome can be attributed in part to attenuating mutations engineered into these viruses to prevent replication in normal cells. Alternatively, retargeting of fully replication-competent HSV to tumor-associated receptors has the potential to achieve tumor specificity without impairment of oncolytic activity. Here, we report the establishment of an HSV retargeting system that relies on the combination of two engineered viral glycoproteins, gD and gB, to mediate highly efficient HSV infection exclusively through recognition of the abundantly expressed epidermal growth factor receptor (EGFR) on glioblastoma cells. We demonstrate efficacy in vitro and in a heterotopic tumor model in mice. Evidence for systemically administered virus homing to the tumor mass is presented. Treatment of orthotopic primary human GBM xenografts demonstrated prolonged survival with up to 73% of animals showing a complete response as confirmed by magnetic resonance imaging. Our study describes an approach to HSV retargeting that is effective in a glioma model and may be applicable to the treatment of a broad range of tumor types.

Bee venom (BV) is one of the alternative medicines that have been widely used in the treatment of chronic inflammatory diseases. We previously demonstrated that BV induces immune tolerance by increasing the population of regulatory T cells (Tregs) in immune disorders. However, the major component and how it regulates the immune response have not been elucidated. We investigated whether bee venom phospholipase A2 (bvPLA2) exerts protective effects that are mediated via Tregs in OVA‐induced asthma model. bvPLA2 was administered by intraperitoneal injection into control and OVA‐challenged mice. The Treg population, total and differential bronchoalveolar lavage fluid (BALF) cell count, Th2 cytokines, and lung histological features were assessed. Treg depletion was used to determine the involvement of Treg migration and the reduction of asthmatic symptoms. The CD206‐dependence of bvPLA2‐treated suppression of airway inflammation was evaluated in OVA‐challenged CD206‐/‐ mice. The bvPLA2 treatment induced the Tregs and reduced the infiltration of inflammatory cells into the lung in the OVA‐challenged mice. Th2 cytokines in the bronchoalveolar lavage fluid (BALF) were reduced in bvPLA2‐treated mice. Although bvPLA2 suppressed the number of inflammatory cells after OVA challenge, these effects were not observed in Treg‐depleted mice. In addition, we investigated the involvement of CD206 in bvPLA2‐mediated immune tolerance in OVA‐induced asthma model. We observed a significant reduction in the levels of Th2 cytokines and inflammatory cells in the BALF of bvPLA2‐treated OVA‐induced mice but not in bvPLA2‐treated OVA‐induced CD206‐/‐ mice. These results demonstrated that bvPLA2 can mitigate airway inflammation by the induction of Tregs in an OVA‐induced asthma model.

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Endoplasmic reticulum (ER) stress has been implicated in neurodegenerative diseases, but its role in neuropathic pain remains unclear. In this study, we examined the ER stress and the unfolded protein response (UPR) activation in a L5 spinal nerve ligation (SNL)-induced rat neuropathic pain model. SNL-induced neuropathic pain was assessed behaviorally using the CatWalk system, and histologically with microglial activation in the dorsal spinal horn. L5 SNL induced BIP upregulation in the neuron of superficial laminae of dorsal spinal horn. It also increased the level of ATF6 and intracellular localization into the nuclei in the neurons. Moreover, spliced XBP1 was also markedly elevated in the ipsilateral spinal dorsal horn. The PERK-elF2 pathway was activated in astrocytes of the spinal dorsal horn in the SNL model. In addition, electron microscopy revealed the presence of swollen cisternae in the dorsal spinal cord after SNL. Additionally, inhibition of the ATF6 pathway by intrathecal treatment with ATF6 siRNA reduced pain behaviors and BIP expression in the dorsal horn. The results suggest that ER stress might be involved in the induction and maintenance of neuropathic pain. Furthermore, a disturbance in UPR signaling may render the spinal neurons vulnerable to peripheral nerve injury or neuropathic pain stimuli.

Salivary function in mammals may be defective for various reasons, such as aging, Sjogren's syndrome or radiation therapy in head and neck cancer patients. Recently, tissue-specific stem cell therapy has attracted public attention as a next-generation therapeutic reagent. In the present study, we isolated tissue-specific stem cells from the human submandibular salivary gland (hSGSCs). To efficiently isolate and amplify hSGSCs in large amounts, we developed a culture system (lasting 4–5 weeks) without any selection. After five passages, we obtained adherent cells that expressed mesenchymal stem cell surface antigen markers, such as CD44, CD49f, CD90 and CD105, but not the hematopoietic stem cell markers, CD34 and CD45, and that were able to undergo adipogenic, osteogenic and chondrogenic differentiation. In addition, hSGSCs were differentiated into amylase-expressing cells by using a two-step differentiation method. Transplantation of hSGSCs to radiation-damaged rat salivary glands rescued hyposalivation and body weight loss, restored acinar and duct cell structure, and decreased the amount of apoptotic cells. These data suggest that the isolated hSGSCs, which may have characteristics of mesenchymal-like stem cells, could be used as a cell therapy agent for the damaged salivary gland.

Interaction of herpes simplex virus (HSV) glycoprotein D (gD) with specific cellular receptors is essential forHerpes simplex virus (HSV) enters most cells by pH-independent fusion of the virus envelope with the cell surface membrane through a poorly understood cascade of molecular interactions involving multiple viral glycoproteins and cellular receptors. HSV attachment to the cell involves recognition both of cell surface proteoglycans and one or more specific cellular receptors (see references 70 to 72 for reviews). While binding to proteoglycans is not essential for virus entry, it enhances the efficiency of infection (3,27,30,31,41). In cell culture, glycoproteins designated gH/gL, gB, and gD have been shown to be essential for entry (5, 15, 21-23, 32, 33, 35, 43, 62). Deletion of one or more of these essential proteins results in enveloped virus particles that are capable of binding to cells but cannot proceed further into the entry cascade (5,20,22,43,62).Virus attachment to cell surface glycosaminoglycans (GAGs) is mediated by the virion glycoproteins gC and gB (69,70,73) and involves interactions between positively charged sequences on these molecules and negatively charged components of heparan, chondroitin, and dermatan sulfate (3,27,66,73,80,81). A second binding event involves recognition by gD of a cognate cell surface receptor. The target cell must express a receptor for gD (25,51), and gD must bind this receptor to initiate the entry process (23,25,33,43,51,79). While it has recently been shown that HSV type 1 (HSV-1) can enter certain cells through endocytosis, productive infection in these instances also requires a gD receptor (48,55,56,58). Three receptors have been described for HSV-1 gD: (i) herpesvirus entry mediator A (HVEM, or HveA), a member of the tumor necrosis factor alpha receptor family (51), binds gD in vitro (57, 79), and its expression on the surface of nonsusceptible cells is sufficient to mediate viral entry (51, 79). HVEM has a somewhat limited expression pattern in vivo (51).(ii) Nectin-1 or herpesvirus entry mediator C (HveC; also referred to as poliovirus receptor-related protein 1) is a member of the nectin family of adhesion molecules belonging to the immunoglobulin superfamily (25). Nectin-1 is a type I transmembrane glycoprotein (25) with a cytoplasmic C terminus that interacts with the cytoskeleton (64) and an ectodomain comprised of an N-terminal V domain and two C2-like domains. The nectin-1 V domain mediates cell-cell adhesion by homotypic or heterotypic trans interactions with nectin V domains on neighboring cells (63,75). In addition, nectins can form cis homo-oligomers by interactions involving C2-like domains of adjacent molecules (40, 50). Nectin-1 has three isoforms, nectin-1␣ (HveC), nectin-1␤ (HIgR), and nectin-1␥, which are derived from a single primary transcript by alternative splicing (11,25,44). The three isoforms share identical V and C domains but differ in their transmembrane and intracellular domains. All three have the ability to bind gD and mediat...

Atopic dermatitis (AD) is a biphasic inflammatory skin disease that is provoked by epidermal barrier defects, immune dysregulation, and increased skin infections. Previously, we have demonstrated that bvPLA2 evoked immune tolerance by inducing regulatory T cells (Treg), and thus alleviated Th2 dominant allergic asthma in mice. Here, we would like to determine whether treatment with bvPLA2 exacerbates the AD-like allergic inflammations induced by house dust mite extract (DFE) in a murine model. Epidermal thickness, immune cell infiltration, serum immunoglobulin, and cytokines were measured. Ear swelling, skin lesions, and the levels of total serum IgE and Th1/Th2 cytokines were elevated in DFE/DNCB-induced AD mice. Topical application of bvPLA2 elicited significant suppression of the increased AD symptoms, including ear thickness, serum IgE concentration, inflammatory cytokines, and histological changes. Furthermore, bvPLA2 treatment inhibited mast cell infiltration into the ear. On the other hand, Treg cell depletion abolished the anti-atopic effects of bvPLA2, suggesting that the effects of bvPLA2 depend on the existence of Tregs. Taken together, the results revealed that topical exposure to bvPLA2 aggravated atopic skin inflammation, suggesting that bvPLA2 might be a candidate for the treatment of AD.