Vaccines for immunological defense against traumatic brain injury.

Unlabelled: Traumatic brain injury (TBI) and subsequent neurodegeneration is partially driven by chronic inflammation both locally and systemically. Yet, current clinical intervention strategies do not mitigate inflammation sequalae necessitating the development of innovative approaches to reduce inflammation and minimize deleterious effects of TBI. Herein, a subcutaneous formulation based on polymer of alpha-ketoglutarate (paKG) delivering glycolytic inhibitor PFK15 (PFKFB3 inhibitor, a rate limiting step in glycolysis), alpha-ketoglutarate (to fuel Krebs cycle) and peptide antigen from myelin proteolipid protein (PLP139-151) was utilized as the prophylactic immunosuppressive formulation in a mouse model of TBI.

Crystallinity of covalent organic frameworks controls immune responses.

Biomaterials can act as pro- or anti-inflammatory agents. However, effects of biomaterials crystallinity on immune responses are poorly understood. We demonstrate that the adjuvant-like behaviour of covalent organic framework (COF) biomaterial is dependent on its crystallinity.

Comprehensive proteomic analysis of the differential expression of 62 proteins following intracortical microelectrode implantation.

Intracortical microelectrodes (IMEs) are devices designed to be implanted into the cerebral cortex for various neuroscience and neuro-engineering applications. A critical feature of IMEs is their ability to detect neural activity from individual neurons. Currently, IMEs are limited by chronic failure, largely considered to be caused by the prolonged neuroinflammatory response to the implanted devices.

Comprehensive Proteomic Analysis of the Differential Expression of 83 Proteins Following Intracortical Microelectrode Implantation.

Intracortical microelectrodes (IMEs) are devices designed to be implanted into the cerebral cortex for various neuroscience and neuro-engineering applications. A critical feature of these devices is their ability to detect neural activity from individual neurons. Currently, IMEs are limited by chronic failure, largely considered to be caused by the prolonged neuroinflammatory response to the implanted devices.

Bacteria Invade the Brain Following Sterile Intracortical Microelectrode Implantation.

Brain-machine interface performance is largely affected by the neuroinflammatory responses resulting in large part from blood-brain barrier (BBB) damage following intracortical microelectrode implantation. Recent findings strongly suggest that certain gut bacterial constituents penetrate the BBB and are resident in various brain regions of rodents and humans, both in health and disease. Therefore, we hypothesized that damage to the BBB caused by microelectrode implantation could amplify dysregulation of the microbiome-gut-brain axis.

Inverse-Vaccines for Rheumatoid Arthritis Re-establish Metabolic and Immunological Homeostasis in Joint Tissues.

Rheumatoid arthritis (RA) causes immunological and metabolic imbalances in tissue, exacerbating inflammation in affected joints. Changes in immunological and metabolic tissue homeostasis at different stages of RA are not well understood. Herein, the changes in the immunological and metabolic profiles in different stages in collagen induced arthritis (CIA), namely, early, intermediate, and late stage is examined.

Engineered Tumor-Immune Microenvironment On A Chip to Study T Cell-Macrophage Interaction in Breast Cancer Progression.

Evolving knowledge about the tumor-immune microenvironment (TIME) is driving innovation in designing novel therapies against hard-to-treat breast cancer. Targeting the immune components of TIME has emerged as a promising approach for cancer therapy. While recent immunotherapies aim at restoring antitumor immunity, counteracting tumor escape remains challenging.

Employing Feature Selection Algorithms to Determine the Immune State of Mice Model of Rheumatoid Arthritis.

The immune response is a dynamic process by which the body determines whether an antigen is self or nonself. The state of this dynamic process is defined by the relative balance and population of inflammatory and regulatory actors which comprise this decision making process. The goal of immunotherapy as applied to, e.

Exponentially decreasing exposure of antigen generates anti-inflammatory T-cell responses.

Rheumatoid Arthritis (RA) is a chronic debilitating disease characterized by auto-immune reaction towards self-antigen such as collagen type II. In this study, we investigated the impact of exponentially decreasing levels of antigen exposure on pro-inflammatory T cell responses in the collagen-induced arthritis (CIA) mouse model. Using a controlled delivery experimental approach, we manipulated the collagen type II (CII) antigen concentration presented to the immune system.

Rescue of dendritic cells from glycolysis inhibition improves cancer immunotherapy in mice.

Inhibition of glycolysis in immune cells and cancer cells diminishes their activity, and thus combining immunotherapies with glycolytic inhibitors is challenging. Herein, a strategy is presented where glycolysis is inhibited in cancer cells using PFK15 (inhibitor of PFKFB3, rate-limiting step in glycolysis), while simultaneously glycolysis and function is rescued in DCs by delivery of fructose-1,6-biphosphate (F16BP, one-step downstream of PFKFB3). To demonstrate the feasibility of this strategy, vaccine formulations are generated using calcium-phosphate chemistry, that incorporate F16BP, poly(IC) as adjuvant, and phosphorylated-TRP2 peptide antigen and tested in challenging and established YUMM1.

Characterization of 2 Novel Phosphodiesterase 2 Inhibitors Hcyb1 and PF-05180999 on Depression- and Anxiety-Like Behavior.

Background: Phosphodiesterase 2A (PDE2A) represents a novel target for new therapies addressing psychiatric disorders. To date, the development of PDE2A inhibitors suitable for human clinical evaluation has been hampered by the poor brain accessibility and metabolic stability of the available compounds.

Methods: Corticosterone (CORT)-induced neuronal cell lesion and restraint stress mouse model were used to measure the neuroprotective effect in cells and antidepressant-like behavior in mice.

Succinate based polymers drive immunometabolism in dendritic cells to generate cancer immunotherapy.

Boosting the metabolism of immune cells while restricting cancer cell metabolism is challenging. Herein, we report that using biomaterials for the controlled delivery of succinate metabolite to phagocytic immune cells activates them and modulates their metabolism in the presence of metabolic inhibitors. In young immunocompetent mice, polymeric microparticles, with succinate incorporated in the backbone, induced strong pro-inflammatory anti-melanoma responses.

Vaccines prevent reinduction of rheumatoid arthritis symptoms in collagen-induced arthritis mouse model.

Metabolic reprogramming of immune cells modulates their function and reduces the severity of autoimmune diseases. However, the long-term effects of the metabolically reprogrammed cells, specifically in the case of immune flare-ups, need to be examined. Herein, a re-induction rheumatoid arthritis (RA) mouse model was developed by injecting T-cells from RA mice into drug-treated mice to recapitulate the effects of T-cell-mediated inflammation and mimic immune flare-ups.

Alpha-ketoglutaric acid based polymeric particles for cutaneous wound healing.

Metabolites are not only involved in energy pathways but can also act as signaling molecules. Herein, we demonstrate that polyesters of alpha-ketoglutararte (paKG) can be generated by reacting aKG with aliphatic diols of different lengths, which release aKG in a sustained manner. paKG polymer-based microparticles generated via emulsion-evaporation technique lead to faster keratinocyte wound closures in a scratch assay test.

Immune response differences in degradable and non-degradable alloy implants.

Alloy based implants have made a great impact in the clinic and in preclinical research. Immune responses are one of the major causes of failure of these implants in the clinic. Although the immune responses toward non-degradable alloy implants are well documented, there is a poor understanding of the immune responses against degradable alloy implants.

Biomaterial mediated simultaneous delivery of spermine and alpha ketoglutarate modulate metabolism and innate immune cell phenotype in sepsis mouse models.

Although different metabolic pathways have been associated with distinct macrophage phenotypes, the field of utilizing metabolites to modulate macrophage phenotype is in a nascent stage. In this report, we developed microparticles based on polymerization of alpha-ketoglutarate (a Krebs cycle metabolite), with or without encapsulation of spermine (a polyamine metabolite), to modulate cell phenotype that are critical for resolution of inflammation. Poly (alpha-ketoglutarate) microparticles encapsulated and released spermine (spermine (encap)paKG MPs) in vitro, which was accelerated in an acidic environment.

In silico identification and synthesis of a multi-drug loaded MOF for treating tuberculosis.

Conventional drug delivery systems have been applied to a myriad of active ingredients but may be difficult to tailor for a given drug. Herein, we put forth a new strategy, which designs and selects the drug delivery material by considering the properties of encapsulated drugs (even multiple drugs, simultaneously). Specifically, through an in-silico screening process of 5109 MOFs using grand canonical Monte Carlo simulations, a customized MOF (referred as BIO-MOF-100) was selected and experimentally verified to be biologically stable, and capable of loading 3 anti-Tuberculosis drugs Rifampicin+Isoniazid+Pyrazinamide at 10% + 28% + 23% wt/wt (total > 50% by weight).

Short term, low dose alpha-ketoglutarate based polymeric nanoparticles with methotrexate reverse rheumatoid arthritis symptoms in mice and modulate T helper cell responses.

Activated effector T cells induce pro-inflammatory responses in rheumatoid arthritis (RA) which then lead to inflammation of the joints. In this report, we demonstrate that polymeric nanoparticles with alpha keto-glutarate (aKG) in their polymer backbone (termed as paKG NPs) modulate T cell responses and . Impressively, a low dose of only three administrations of methotrexate, a clinically and chronically administered drug for RA, in conjunction with two doses of paKG NPs, reversed arthritis symptoms in collagen-induced arthritis (CIA) mice.

Drug delivery for metabolism targeted cancer immunotherapy.

Drug delivery vehicles have made a great impact on cancer immunotherapies in clinics and pre-clinical research. Notably, the science of delivery of cancer vaccines and immunotherapeutics, modulating immune cell functions has inspired development of several successful companies and clinical products. Interestingly, these drug delivery modalities not only modulate the function of immune cells (often quantified at the mRNA and protein levels), but also modulate the metabolism of these cells.

Oral drug delivery for immunoengineering.

The systemic pharmacotherapeutic efficacy of immunomodulatory drugs is heavily influenced by its route of administration. A few common routes for the systemic delivery of immunotherapeutics are intravenous, intraperitoneal, and intramuscular injections. However, the development of novel biomaterials, in adjunct to current progress in immunoengineering, is providing an exciting area of interest for oral drug delivery for systemic targeting.

Inhibition of glycolysis in the presence of antigen generates suppressive antigen-specific responses and restrains rheumatoid arthritis in mice.

Dendritic cells (DCs) rely on glycolysis for their energy needs to induce pro-inflammatory antigen-specific immune responses. Therefore, inhibiting DC glycolysis, while presenting the self-antigen, may prevent pro-inflammatory antigen-specific immune responses. Previously we demonstrated that microparticles with alpha-ketoglutarate (aKG) in the polymer backbone (paKG MPs) were able to generate anti-inflammatory DCs by sustained delivery of the aKG metabolite, and by modulating energy metabolism of DCs.

GRAS-microparticle microarrays identify dendritic cell tolerogenic marker-inducing formulations.

Microarrays, miniaturized platforms used for high-content studies, provide potential advantages over traditional investigation in terms of time, cost, and parallel analyses. Recently, microarrays have been leveraged to investigate immune cell biology by providing a platform with which to systematically investigate the effects of various agents on a wide variety of cellular processes, including those giving rise to immune regulation for application toward curtailing autoimmunity. A specific embodiment incorporates dendritic cells cultured on microarrays containing biodegradable microparticles.

Instruction of Immunometabolism by Adipose Tissue: Implications for Cancer Progression.

Disruption of metabolic homeostasis at the organismal level can cause metabolic syndrome associated with obesity. The role of adipose tissue in cancer has been investigated over the last several decades with many studies implicating obesity as a risk factor for the development of cancer. Adipose tissue contains a diverse array of immune cell populations that promote metabolic homeostasis through a tightly controlled balance of pro- and anti-inflammatory signals.