Robust Adaptive LCMV Beamformer Based On An Iterative Suboptimal Solution

The main drawback of closed-form solution of linearly constrained minimum variance (CF-LCMV) beamformer is the dilemma of acquiring long observation time for stable covariance matrix estimates and short observation time to track dynamic behavior of targets, leading to poor performance including low signal-noise-ratio (SNR), low jammer-to-noise ratios (JNRs) and small number of snapshots. Additionally, CF-LCMV suffers from heavy computational burden which mainly comes from two matrix inverse operations for computing the optimal weight vector. In this paper, we derive a low-complexity Robust Adaptive LCMV beamformer based on an Iterative Suboptimal solution (RAIS-LCMV) using conjugate gradient (CG) optimization method. The merit of our proposed method is threefold. Firstly, RAIS-LCMV beamformer can reduce the complexity of CF-LCMV remarkably. Secondly, RAIS-LCMV beamformer can adjust output adaptively based on measurement and its convergence speed is comparable. Finally, RAIS-LCMV algorithm has robust performance against low SNR, JNRs, and small number of snapshots. Simulation results demonstrate the superiority of our proposed algorithms

Blockade but not overexpression of the junctional adhesion molecule C influences virus-induced type 1 diabetes in mice

Type 1 diabetes (T1D) results from the autoimmune destruction of insulin-producing beta-cells in the pancreas. Recruitment of inflammatory cells is prerequisite to beta-cell-injury. The junctional adhesion molecule (JAM) family proteins JAM-B and JAM–C are involved in polarized leukocyte transendothelial migration and are expressed by vascular endothelial cells of peripheral tissue and high endothelial venules in lympoid organs. Blocking of JAM-C efficiently attenuated cerulean-induced pancreatitis, rheumatoid arthritis or inflammation induced by ischemia and reperfusion in mice. In order to investigate the influence of JAM-C on trafficking and transmigration of antigen-specific, autoaggressive T-cells, we used transgenic mice that express a protein of the lymphocytic choriomeningitis virus (LCMV) as a target autoantigen in the β-cells of the islets of Langerhans under the rat insulin promoter (RIP). Such RIP-LCMV mice turn diabetic after infection with LCMV. We found that upon LCMV-infection JAM-C protein was upregulated around the islets in RIP-LCMV mice. JAM-C expression correlated with islet infiltration and functional beta-cell impairment. Blockade with a neutralizing anti-JAM-C antibody reduced the T1D incidence. However, JAM-C overexpression on endothelial cells did not accelerate diabetes in the RIP-LCMV model. In summary, our data suggest that JAM-C might be involved in the final steps of trafficking and transmigration of antigen-specific autoaggressive T-cells to the islets of Langerhans

Chronic viral infection promotes sustained Th1-derived immunoregulatory IL-10 via BLIMP-1

During the course of many chronic viral infections, the antiviral T cell response becomes attenuated through a process that is regulated in part by the host. While elevated expression of the immunosuppressive cytokine IL-10 is involved in the suppression of viral-specific T cell responses, the relevant cellular sources of IL-10, as well as the pathways responsible for IL-10 induction, remain unclear. In this study, we traced IL-10 production over the course of chronic lymphocytic choriomeningitis virus (LCMV) infection in an IL-10 reporter mouse line. Using this model, we demonstrated that virus-specific T cells with reduced inflammatory function, particularly Th1 cells, display elevated and sustained IL-10 expression during chronic LCMV infection. Furthermore, ablation of IL-10 from the T cell compartment partially restored T cell function and reduced viral loads in LCMV-infected animals. We found that viral persistence is needed for sustained IL-10 production by Th1 cells and that the transcription factor BLIMP-1 is required for IL-10 expression by Th1 cells. Restimulation of Th1 cells from LCMV-infected mice promoted BLIMP-1 and subsequent IL-10 expression, suggesting that constant antigen exposure likely induces the BLIMP-1/IL-10 pathway during chronic viral infection. Together, these data indicate that effector T cells self-limit their responsiveness during persistent viral infection via an IL-10-dependent negative feedback loop.This work was supported by an Australian NHMRC Overseas Biomedical Postdoctoral Fellowship (to I.A. Parish); a Yale School of Medicine Brown-Coxe Postdoctoral Fellowship (to I.A. Parish); the Alexander von Humboldt Foundation (SKA2010, to P.A. Lang); a CIHR grant (to P.S. Ohashi); and by the Howard Hughes Medical Institute and NIH grant RO1AI074699 (to S.M. Kaech). P.S. Ohashi holds a Canada Research Chair in Autoimmunity and Tumor immunity

PD-1 signaling promotes control of chronic viral infection by restricting type-I-interferon-mediated tissue damage

Immune responses are essential for pathogen elimination but also cause tissue damage, leading to disease or death. However, it is unclear how the host immune system balances control of infection and protection from the collateral tissue damage. Here, we show that PD-1-mediated restriction of immune responses is essential for durable control of chronic LCMV infection in mice. In contrast to responses in the chronic phase, PD-1 blockade in the subacute phase of infection paradoxically results in viral persistence. This effect is associated with damage to lymphoid architecture and subsequently decreases adaptive immune responses. Moreover, this tissue damage is type I interferon dependent, as sequential blockade of the interferon receptor and PD-1 pathways prevents immunopathology and enhances control of infection. We conclude that PD-1-mediated suppression is required as an immunoregulatory mechanism for sustained responses to chronic viral infection by antagonizing type-I interferon-dependent immunopathology

Cure of chronic viral infection and virus-induced type 1 diabetes by neutralizing antibodies

The use of neutralizing antibodies is one of the most successful methods to interfere with receptor–ligand interactions in vivo. In particular blockade of soluble inflammatory mediators or their corresponding cellular receptors was proven an effective way to regulate inflammation and/or prevent its negative consequences. However, one problem that comes along with an effective neutralization of inflammatory mediators is the general systemic immunomodulatory effect. It is, therefore, important to design a treatment regimen in a way to strike at the right place and at the right time in order to achieve maximal effects with minimal duration of immunosuppression or hyperactivation. In this review, we reflect on two examples of how short time administration of such neutralizing antibodies can block two distinct inflammatory consequences of viral infection. First, we review recent findings that blockade of IL-10/IL-10R interaction can resolve chronic viral infection and second, we reflect on how neutralization of the chemokine CXCL10 can abrogate virus-induced type 1 diabetes

Efficient calculation of sensor utility and sensor removal in wireless sensor networks for adaptive signal estimation and beamforming

Wireless sensor networks are often deployed over a large area of interest and therefore the quality of the sensor signals may vary significantly across the different sensors. In this case, it is useful to have a measure for the importance or the so-called "utility" of each sensor, e.g., for sensor subset selection, resource allocation or topology selection. In this paper, we consider the efficient calculation of sensor utility measures for four different signal estimation or beamforming algorithms in an adaptive context. We use the definition of sensor utility as the increase in cost (e.g., mean-squared error) when the sensor is removed from the estimation procedure. Since each possible sensor removal corresponds to a new estimation problem (involving less sensors), calculating the sensor utilities would require a continuous updating of different signal estimators (where is the number of sensors), increasing computational complexity and memory usage by a factor. However, we derive formulas to efficiently calculate all sensor utilities with hardly any increase in memory usage and computational complexity compared to the signal estimation algorithm already in place. When applied in adaptive signal estimation algorithms, this allows for on-line tracking of all the sensor utilities at almost no additional cost. Furthermore, we derive efficient formulas for sensor removal, i.e., for updating the signal estimator coefficients when a sensor is removed, e.g., due to a failure in the wireless link or when its utility is too low. We provide a complexity evaluation of the derived formulas, and demonstrate the significant reduction in computational complexity compared to straightforward implementations

Gene therapy of malignant glioma with retroviral vectors and tumor-infiltrating progenitor cells

Gene therapy as a therapeutic strategy in the treatment of human gliomas is limited by the efficacy of gene transfer and intratumoral distribution of viral vectors. The major goals of this study were to enhance the gene transfer to glioma cells in vivo by using lentiviral vectors and to improve intratumoral distribution by selecting migratory progenitor cells that could function as packaging cells for the viral vectors. Therefore, the final goal was to establish tumor infiltrating packaging cells that release viral vectors within glioma in vivo. Lentiviral vectors were chosen to deliver genes into glioma cells. In contrast to currently used retroviral vectors, they transduce quiescent as well as mitotic cells. This is of major importance as within a defined treatment window, the majority of tumor cells are not mitotically active. However, lentiviral vectors can also infect normal brain cells. To define vectors with a specific tropism for glioma cells, lentiviral vectors pseudotyped with two different glycoproteins were used. Vectors pseudotyped with glycoproteins of the lymphocytic choriomeningitis virus (LCMV-GP) mediated efficient and specific transduction of rat glioma cells in vitro and in vivo, whereas vectors pseudotyped with the glycoproteins of the vesicular stomatatitis virus (VSV-G) preferentially transduced normal brain cells [Miletic et al., 2004]. Bone marrow derived progenitor cells were isolated to establish the tumor-infiltrating cells (BM-TICs) that could also serve as packaging cells. BM-TICs have a high passaging capacity in vitro, which is necessary for genetic modification and large scale production in the clinic. They were also found to show specific migration towards and into malignant glioma in vivo. In a therapeutic approach using BM-TICs stably expressing a suicide gene, an efficient therapeutic effect was demonstrated. The modified cells were also detected in vivo by non-invasive positron emission tomography (PET) and therapeutic outcome was followed-up by imaging methods and correlated with histopathology [Miletic et al., 2007]. To test packaging capabilities of BMTICs, the cells were modified with packaging constructs for retroviral LCMV-GP pseudotypes (BM-TIPCs). BM-TIPCs continuously produced retroviral vector particles for several weeks. Upon injection into experimental rat glioma, these cells migrated and were widely distributed within the tumor. Furthermore, released vector particles transduced glioma cells in solid as well as border areas [Fischer, Miletic et al., 2007]. In conclusion, the presented packaging system is highly attractive for future therapeutic applications in human glioblastoma especially in conjunction with an imaging-guided approach

Alloreactive cytotoxic T lymphocytes generated in the presence of viral- derived peptides show exquisite peptide and MHC specificity

The nature of alloreactivity to MHC molecules has been enigmatic, primarily because of the observation that allogeneic responses are considerably stronger than syngeneic responses. To better determine the specificity potential of allogeneic responses, we have generated alloreactive CTL specific for exogenous, viral-derived peptide ligands. This approach allowed us to critically evaluate both the peptide- and MHC-specificity of these alloreactive T cells. Exploiting the accessibility of the H-2Ld class I molecule for exogenous peptide ligands, alloreactive CTL were generated that are specific for either murine cytomegalovirus (MCMV) or lymphocytic choriomeningitis virus (LCMV) peptides bound by Ld alloantigens. Peptide specificity was initially observed in bulk cultures of alloreactive CTL only when tested on peptide-sensitized T2.Ld target cells that have defective presentation of endogenous peptides. Subsequent cloning of bulk alloreactive CTL lines generated to MCMV yielded CTL clones that had exquisitely specific MCMV peptide recognition requirement. All of the MCMV/Ld alloreactive CTL clones were also exquisitely MHC-specific in that none of the CTL clones lysed targets expressing MCMV/Lq complexes, even though Lq differs from Ld by only six amino acid residues and Lq also binds the MCMV peptide. This observation clearly demonstrates that alloreactive CTL are capable of the same degree of specificity for target cell recognition as are syngeneic CTL in MHC-restricted responses