Dendritic Cells are preferentially targeted among hematolymphocytes by Modified Vaccinia Virus Ankara and play a key role in the induction of virus-specific T cell responses in vivo

<p>Abstract</p> <p>Background</p> <p>Modified Vaccinia Ankara (MVA) is a highly attenuated strain of vaccinia virus (VV) that has lost approximately 15% of the VV genome, along with the ability to replicate in most mammalian cells. It has demonstrated impressive safety and immunogenicity profile in both preclinical and clinical studies, and is being actively explored as a promising vaccine vector for a number of infectious diseases and malignancies. However, little is known about how MVA interacts with the host immune system constituents, especially dendritic cells (DCs), to induce strong immune responses despite its inability to replicate in vivo. Using <it>in vitro </it>and <it>in vivo </it>murine models, we systematically investigated the susceptibility of murine DCs to MVA infection, and the immunological consequences of the infection.</p> <p>Results</p> <p>Our data demonstrate that MVA preferentially infects professional antigen presenting cells, especially DCs, among all the subsets of hematolymphoid cells. In contrast to the reported blockage of DC maturation and function upon VV infection, DCs infected by MVA undergo phenotypic maturation and produce innate cytokine IFN-α within 18 h of infection. Substantial apoptosis of MVA-infected DCs occurs after 12 h following infection and the apoptotic DCs are readily phagocytosed by uninfected DCs. Using MHC class I – deficient mice, we showed that both direct and cross-presentation of viral Ags are likely to be involved in generating viral-specific CD8⁺T cell responses. Finally, DC depletion abrogated the T cell activation <it>in vivo</it>.</p> <p>Conclusion</p> <p>We present the first <it>in vivo </it>evidence that among hematolymphoid cells, DCs are the most susceptible targets for MVA infection, and DC-mediated Ag presentation is required for the induction of MVA-specific immune responses. These results provide important information concerning the mechanisms by which strong immune responses are elicited to MVA-encoded antigens and may inform efforts to further improve the immunogenicity of this already promising vaccine vector.</p

Self-Calibration of Precision XY<em>θ_z</em> Metrology Stages

This chapter studies the on-axis calibration for precision XYθz metrology stages and presents a holistic XYθz self-calibration approach. The proposed approach uses an artifact plate, specially designed with XY grid mark lines and angular mark lines, as a tool to be measured by the XYθz metrology stages. In detail, the artifact plate is placed on the uncalibrated XYθz metrology stages in four measurement postures or views. Then, the measurement error can be modeled as the construction of XYθz systematic measurement error (i.e. stage error), artifact error, misalignment error, and random measurement noise. With a new property proposed, redundance of the XYθz stage error is obtained, while the misalignment errors of all measurement views are determined by rigid mathematical processing. Resultantly, a least square-based XYθz self-calibration law is synthesized for final determination of the stage error. Computer simulation is conducted, and the calculation results validate that the proposed scheme can accurately realize the stage error even under the existence of various random measurement noise. Finally, the designed artifact plate is developed and illustrated for explanation of a standard XYθz self-calibration procedure to meet practical industrial requirements

Nanoporous Zeolite Thin Film-Based Fiber Intrinsic Fabry-Perot Interferometric Sensor for Detection of Dissolved Organics in Water

A fiber optic intrinsic Fabry-Perot interferometric (IFPI) chemical sensor was developed by fine-polishing a thin layer of polycrystalline nanoporous MFI zeolite synthesized on the cleaved endface of a single mode fiber. The sensor operated by monitoring the optical thickness changes of the zeolite thin film caused by the adsorption of organic molecules into the zeolite channels. The optical thickness of the zeolite thin film was measured by white light interferometry. Using methanol, 2-propanol, and toluene as the model chemicals, it was demonstrated that the zeolite IPFI sensor could detect dissolved organics in water with high sensitivity

Overexpression of IL-1α in Skin Differentially Modulates the Immune Response to Scarification with Vaccinia Virus

Transepidermal inoculation of vaccinia virus (VV), or scarification, has been used effectively for the induction of specific and long-lasting immunity to smallpox and is superior to other routes of immunization. Scarification of individuals with atopic skin disease or immune deficiency, however, can lead to persistent viral replication and result in significant morbidity and mortality. These effects of scarification presumably reflect the unique immunological properties of skin and the immune cells resident in, or recruited to, the site of inoculation. To explore these phenomena, we utilized transgenic mice engineered to overexpress IL-1α, a critical mediator of cutaneous inflammation, in the epidermis. Following scarification with VV, both transgenic and wild-type mice develop local pox. At high doses of VV, IL-1α transgenic mice recruited immune cells to the inoculation site more rapidly and demonstrated enhanced T-cell and humoral immune responses. At limiting doses, however, IL-1α transgenic mice could effectively control virus replication without formation of pox lesions or activation of a memory response. This study suggests that IL-1 might be useful as an adjuvant to enhance antiviral immunity and promote safer vaccination strategies; however, understanding the balance of IL-1 effects on innate and adaptive immune functions will be critical to achieve optimal results

Disruption of TNFα/TNFR1 function in resident skin cells impairs host immune response against cutaneous vaccinia virus infection

One strategy adopted by vaccinia virus (VV) to evade the host immune system is to encode homologs of TNF receptors (TNFR) that block TNFα function. The response to VV skin infection under conditions of TNFα deficiency, however, has not been reported. We found that TNFR1−/− mice developed larger primary lesions, numerous satellite lesions and higher skin virus levels after VV scarification. Following their recovery, these TNFR1−/− mice were fully protected against challenge with a lethal intranasal dose of VV, suggesting these mice developed an effective memory immune response. A functional systemic immune response of TNFR1−/− mice was further demonstrated by enhanced production of VV-specific IFNγ and VV-specific CD8+ T cells in spleens and draining lymph nodes. Interestingly, bone marrow (BM) reconstitution studies using WT BM in TNFR1−/− host mice, but not TNFR1−/− BM in WT host mice, reproduced the original results seen in TNFR1−/− mice, indicating that TNFR1 deficiency in resident skin cells, rather than hematopoietic cells, accounts for the impaired cutaneous immune response. Our data suggest that lack of TNFR1 leads to a skin-specific immune deficiency and that resident skin cells play a crucial role in mediating an optimal immune defense to VV cutaneous infection via TNFα/TNFR1 signaling

A Global Learning Algorithm for a RBF Network

This article presents a new learning algorithm for the construction and training of a RBFneural network. The algorithm is based on a global mechanism of parameter learning using a maximum likelihood classification approach. The resulting neurons in the RBF network partitions a multidimensional pattern space into a set of maximum-size hyper-ellipsoid subspaces in terms of the statistical distributions of the training samples. An important feature of the algorithm is that the learning process includes both the tasks of discovering a suitable network structure and of determining the connection weights. The entire network and its parameters are thought of evolved gradually in the learning process

A Multiple Hyper-ellipsoidal Subclass Model for an Evolutionary Classifier

A pattern classification scheme in which the classifier is able to grow and evolve during the operation process is presented. The evolutionary property of the classifier is made possible by modeling the pattern vectors in multiple hyper-ellipsoidal subclass distributions. Learning of the classifier takes place at the subclass levels only. This property allows the classifier to retain its previously learned patterns while accepting and learning new pattern classes. The classifier is suitable to operate in dynamical environments where continuous updating of the pattern class distributions is needed

Comparative investigation on magnetic capture selectivity between single wires and a real matrix

High gradient magnetic separation (HGMS) achieves the effective separation to fine weakly magnetic minerals through a magnetic matrix. In practice, the matrix is made of numerous magnetic wires, so that an insight into the magnetic capture characteristics of single wires to magnetic minerals would provide a basic foundation for the optimum design and choice of real matrix. The magnetic capture selectivity of cylindrical and rectangular single wires in concentrating ilmenite minerals were investigated through a cyclic pulsating HGMS separator with its key operating parameters (magnetic induction, feed velocity and pulsating frequency) varied, and their capture selectivity characteristics were parallelly compared with that of a real 3.0 mm cylindrical matrix. It was found that the cylindrical single wires have superior capture selectivity to the rectangular one; and, the single wires and the real matrix have basically the same capture trend with changes in the key operating parameters, but the single wires have a much higher capture selectivity than that of real matrix. Keywords: High gradient magnetic separation, Capture selectivity, Single wires, Real matrix, Ilmenit