Biological Modulation of the Treg:Teff Ratio: From Immunosuppression to Immunoactivation

T cell-mediated immunomodulation can be, in simple terms, defined as altering the normal Treg:Teff ratio. Immunosuppression skews the net Treg:Teff ratio toward the ‘tolerogenic’ Treg component, while immunoactivation skews the response toward the ‘proinflammatory’ Teff component. In the treatment of autoimmune diseases, achieving an immunosuppressive state is a desirable goal in order to prevent ongoing injury by activated Teff cells. In contrast, an innate, or induced, immunosuppressive state can be deleterious and prevent pathogen-induced disease while allow for the progression of cancer. Indeed, a current goal of cancer therapy is attenuating an existing endogenous immunosuppressive state that prevents effective T cell-mediated immunorecognition of cancer cells. Thus, the biological modulation of the Treg:Teff ratio provides a unique approach for treating both autoimmune diseases and cancers. Using a biomanufacturing system, miRNA-enriched immunotherapeutic has been generated that either induce (TA1) or overcome (IA1) an immunosuppressive state. As will be shown, these therapeutics show efficacy both in vitro and in vivo in the prevention of autoimmune Type 1 diabetes and in enhancing the ability of resting immune cells to recognize and inhibit cancer cell growth. The successful development of these cost-effective, and easily biomanufactured, secretome-based therapeutics may prove useful in treating both autoimmune diseases and cancer

Modulating the T Lymphocyte Immune Response via Secretome Produced miRNA: From Tolerance Induction to the Enhancement of the Anticancer Response

T cells are key mediators of graft tolerance/rejection, development of autoimmunity, and the anticancer response. Consequently, differentially modifying the T cell response is a major therapeutic target. Most immunomodulatory approaches have focused on cytotoxic agents, cytokine modulation, monoclonal antibodies, mitogen activation, adoptive cell therapies (including CAR-T cells). However, these approaches do not persistently reorient the systemic immune response thus necessitating continual therapy. Previous murine studies from our laboratory demonstrated that the adoptive transfer of polymer-grafted (PEGylated) allogeneic leukocytes resulted in the induction of a persistent and systemic tolerogenic state. Further analyses demonstrated that miRNA isolated from the secretome of polymer-modified or control allogeneic responses effectively induced either a tolerogenic (TA1 miRNA) or proinflammatory (IA1 miRNA) response both in vitro and in vivo that was both systemic and persistent. In a murine Type 1 diabetes autoimmune model, the tolerogenic TA1 therapeutic effectively attenuated the disease process via the systemic upregulation of regulatory T cells while simultaneously downregulating T effector cells. In contrast, the proinflammatory IA1 therapeutic enhanced the anticancer efficacy of naïve PBMC by increasing inflammatory T cells and decreasing regulatory T cells. The successful development of this secretome miRNA approach may prove useful treating both autoimmune diseases and cancer

Immunocamouflaged RBC for Alloimmunized Patients

While ABO/Rh(D) red blood cells (RBC)-matched transfusions are generally considered as safe, a significant risk of alloimmunization to non-A/B blood group antigens exists; especially in chronically transfused patients. Indeed, alloimmunization to non-A/B antigens can be so severe that RBC transfusion can no longer be safely administered without the risk of a potentially deadly immune haemolytic reaction. Currently, no satisfactory solutions exist either to prevent blood group alloimmunization or to cost-effectively treat patients with severe alloimmunization. To address this problem, we have pioneered the immunocamouflage of donor RBC. The immunocamouflaged (stealth) RBC is manufactured by the covalent grafting of biologically safe polymers to RBC membrane proteins. As a result of the grafted polymer, non-A/B blood group antigens are biophysically and immunologically masked. Of particular interest is the immunocamouflage of the Rh(D) antigen which could be used to improve blood inventory and transfusion safety. The polymer-modified RBCs are morphologically normal and, in mice, exhibit normal in vivo survival at immunoprotective grafting concentration. In this chapter, we explore both the biophysical and immunological consequences of the grafted polymers, explore the conditions in which they might be appropriately used, and describe the technology necessary to manufacture functional transfusable units of these cells within the clinical setting

Versatile gold-silver-PB nanojujubes for multi-modal detection and photo-responsive elimination against bacteria

Bacterial infections have become a serious threat to global public health. Nanomaterials have shown promise in the development of bacterial biosensing and antibiotic-free antibacterial modalities, but single-component materials are often less functional and difficult to achieve dual bacterial detection and killing. Herein, we report a novel strategy based on the effective integration of multi-modal bacterial detection and elimination, by constructing the versatile gold-silver-Prussian blue nanojujubes (GSP NJs) via a facile template etching method. Such incorporation of multi-components involves the utilization of cores of gold nanobipyramids with strong surface-enhanced Raman scattering (SERS) activity, the shells of Prussian blue as both an efficient bio-silent SERS label and an active peroxidase-mimic, and functionalization of polyvinyl pyrrolidone and vancomycin, respectively endowing them with good colloidal dispersibility and specificity against S. aureus. The GSP NJs show operational convenience in the SERS detection and excellent peroxidase-like activity for the sensitive colorimetric detection. Meanwhile, they exhibit robust near-infrared photothermal/photodynamic effects, and the photo-promoted Ag+ ions release, ultimately achieving a high antibacterial efficiency over 99.9% in 5 min. The NJs can also effectively eliminate complex biofilms. The work provides new insights into the design of multifunctional core-shell nanostructures for the integrated bacterial detection and therapy

Enhancing the anti-cancer T cell response via a biomanufactured, acellular, pro-inflammatory, secretome-based immunotherapeutic

Pro-inflammatory responses play an important role in controlling the development and progression of cancer. Contrary to the radiotherapy/chemotherapy that cause off-target bystander injuries, immunotherapies activate the patient’s immune responses for cancer elimination. Consequent to the critical role T lymphocytes play in the anti-cancer response, substantial pharmacologic efforts have been made to activate the endogenous T cell response. Unfortunately, many of these approaches have shown noteworthy toxicity due to their pan T cell activation. In contrast, the less robust T cell alloresponse has demonstrated a synergistic effect on the anti-cancer response but poses an inherent risk of Graft versus Host Disease. To overcome this risk, an acellular, allorecognition-derived, secretome-based, inflammatory agent (IA1) has been developed. To assess IA1’s immunomodulatory activity, T cell proliferation and differentiation were determined in vitro. The acellular effectors of the secretome were soluble and exosome-encapsulated microRNA and, due to the conserved nature of microRNA, demonstrated cross-species efficacy. The proliferation induced by IA1 was approximately 50% that of the allogeneic response and dramatically less than that induced by mitogen/mitogen-like stimulations suggesting that bystander cell injury, relative to these agents, could be substantially reduced. IA1 exerted no direct leukocyte toxicity but induced a significant proliferation of resting CD3⁺ (CD4⁺ and CD8⁺) T cells and skewed the response towards a pro-inflammatory state as evidenced by an increased ratio of effector versus regulatory T cells. In assessing the in vitro efficacy of IA1-activated leukocytes on cancer cell proliferation, we showed that IA1-treatment of resting leukocytes resulted in an enhanced anti-proliferative effect on cancer cells relative to untreated or sham-treated donor-matched leukocytes. The inhibition of HeLa cell proliferation by IA1-activated leukocytes was noted by ~12 hours versus 4-5 days for resting cells. Importantly, no toxicity of IA1-activated leukocytes to non-cancerous cells was noticed. A second biomanufactured therapeutic (IA2; produced using HeLa cells) surprisingly demonstrated broad direct toxicities to cancer cells but was less effective than IA1 in inducing a leukocyte-mediated response. Successful development of this secretome therapeutic approach may prove useful in enhancing the endogenous immune response to cancer, and consequent to enhanced immunosurveillance, in reducing the metastatic potential of existing cancers.Medicine, Faculty ofPathology and Laboratory Medicine, Department ofGraduat

Recent progress in preparation process of ionic polymer-metal composites

10.1016/j.rinp.2021.104800Results in Physics2910480

Integrating bottom-up building stock model with logistics networks to support the site selection of circular construction hub

The circular construction hub is a logistics point for the storage, processing, and distribution of secondary construction materials. However, its site selection is dampened by the lack of detailed spatial information on material flows. In this study, the quantities and the spatial distribution of material flows are projected using a bottom-up building stock model. The material flows are integrated with logistics networks to assess the environmental impact of transporting materials between the building stock and the circular construction hub. The model is demonstrated on the building stock of Leiden, a municipality in the Netherlands. The results show that the location of future construction and demolition activities has a major impact on transportation carbon emissions. As construction decreases and demolition increases, the relative share of transportation carbon emissions from recycling will increase. The comparison between the two candidate sites for the circular construction hub is made to select the site with lower total transportation carbon emissions. By considering the evolution of building stock, the model can help urban planners make a more comprehensive decision on the location of the circular construction hub.</p

Fabrication and Actuation of Cu-Ionic Polymer Metal Composite

In this study, Cu-Ionic polymer metal composites (Cu-IPMC) were fabricated using the electroless plating method. The properties of Cu-IPMC in terms of morphology, water loss rate, adhesive force, surface resistance, displacements, and tip forces were evaluated under direct current voltage. In order to understand the relationship between lengths and actuation properties, we developed two static models of displacements and tip forces. The deposited Cu layer is uniform and smooth and contains about 90% by weight of copper, according to the energy-dispersive X-ray spectroscopy (EDS) analysis data obtained. The electrodes adhere well (level of 5B) on the membrane, to ensure a better conductivity and improve the actuation performance. The penetration depth of needle-like electrodes can reach up to around 70 &mu;m, and the structure shows concise without complex branches, to speed up the actuation. Overall the maximum displacement increased as the voltage increased. The applied voltage for the maximum force output is 8&ndash;9 V. The root mean square error (RMSE) and determination coefficient (DC) of the displacement and force models are 1.66 and 1.23, 0.96 and 0.86, respectively

Electroless copper deposition and interface characteristics of ionic electroactive polymer

10.1016/j.jmrt.2021.01.062Journal of Materials Research and Technology11849-85

Use of Social Media for the Detection and Analysis of Infectious Diseases in China

Social media activity has become an important component of daily life for many people. Messages from Twitter (US) and Weibo (China) have shown their potential as important data sources for detecting and analyzing infectious diseases. Such emerging and dynamic new data sources allow us to predict how infectious diseases develop and evolve both spatially and temporally. We report the dynamics of dengue fever in China using messages from Weibo. We first extract and construct a list of keywords related to dengue fever in order to analyze how frequently these words appear in Weibo messages based on the Latent Dirichlet Allocation (LDA). Spatial analysis is then applied to detect how dengue fever cases cluster spatially and spread over time