Lack of functional TCR-epitope interaction is associated with herpes zoster through reduced downstream T cell activation.

The role of T cell receptor (TCR) diversity in infectious disease susceptibility is not well understood. We use a systems immunology approach on three cohorts of herpes zoster (HZ) patients and controls to investigate whether TCR diversity against varicella-zoster virus (VZV) influences the risk of HZ. We show that CD4 T cell TCR diversity against VZV glycoprotein E (gE) and immediate early 63 protein (IE63) after 1-week culture is more restricted in HZ patients.

Efficient and Non-genotoxic RNA-Based Engineering of Human T Cells Using Tumor-Specific T Cell Receptors With Minimal TCR Mispairing.

Genetic engineering of T cells with tumor specific T-cell receptors (TCR) is a promising strategy to redirect their specificity against cancer cells in adoptive T cell therapy protocols. Most studies are exploiting integrating retro- or lentiviral vectors to permanently introduce the therapeutic TCR, which can pose serious safety issues when treatment-related toxicities would occur. Therefore, we developed a versatile, non-genotoxic transfection method for human unstimulated CD8 T cells.

Mutant superoxide dismutase aggregates from human spinal cord transmit amyotrophic lateral sclerosis.

Motor neurons containing aggregates of superoxide dismutase 1 (SOD1) are hallmarks of amyotrophic lateral sclerosis (ALS) caused by mutations in the gene encoding SOD1. We have previously reported that two strains of mutant human (h) SOD1 aggregates (denoted A and B) can arise in hSOD1-transgenic models for ALS and that inoculation of such aggregates into the lumbar spinal cord of mice results in rostrally spreading, templated hSOD1 aggregation and premature fatal ALS-like disease. Here, we explored whether mutant hSOD1 aggregates with prion-like properties also exist in human ALS.

A versatile T cell-based assay to assess therapeutic antigen-specific PD-1-targeted approaches.

Blockade of programmed cell death protein 1 (PD-1) immune checkpoint receptor signaling is an established standard treatment for many types of cancer and indications are expanding. Successful clinical trials using monoclonal antibodies targeting PD-1 signaling have boosted preclinical research, encouraging development of novel therapeutics. Standardized assays to evaluate their bioactivity, however, remain restricted.

Dendritic Cells and Programmed Death-1 Blockade: A Joint Venture to Combat Cancer.

Two decades of clinical cancer research with dendritic cell (DC)-based vaccination have proved that this type of personalized medicine is safe and has the capacity to improve survival, but monotherapy is unlikely to cure the cancer. Designed to empower the patient's antitumor immunity, huge research efforts are set to improve the efficacy of next-generation DC vaccines and to find synergistic combinations with existing cancer therapies. Immune checkpoint approaches, aiming to breach immune suppression and evasion to reinforce antitumor immunity, have been a revelation in the immunotherapy field.

Shuttling Tolerogenic Dendritic Cells across the Blood-Brain Barrier the Introduction of C-C Chemokine Receptor 5 Expression Using Messenger RNA Electroporation.

The use of tolerance-inducing dendritic cells (tolDCs) has been proven to be safe and well tolerated in the treatment of autoimmune diseases. Nevertheless, several challenges remain, including finding ways to facilitate the migration of cell therapeutic products to lymph nodes, and the site of inflammation. In the treatment of neuroinflammatory diseases, such as multiple sclerosis (MS), the blood-brain barrier (BBB) represents a major obstacle to the delivery of therapeutic agents to the inflamed central nervous system (CNS).

Poly(I:C) primes primary human glioblastoma cells for an immune response invigorated by PD-L1 blockade.

Prognosis of glioblastoma remains dismal, underscoring the need for novel therapies. Immunotherapy is generating promising results, but requires combination strategies to unlock its full potential. We investigated the immunomodulatory capacities of poly(I:C) on primary human glioblastoma cells and its combinatorial potential with programmed death ligand (PD-L) blockade.

Increased herpes zoster risk associated with poor HLA-A immediate early 62 protein (IE62) affinity.

Around 30% of individuals will develop herpes zoster (HZ), caused by the varicella zoster virus (VZV), during their life. While several risk factors for HZ, such as immunosuppressive therapy, are well known, the genetic and molecular components that determine the risk of otherwise healthy individuals to develop HZ are still poorly understood. We created a computational model for the Human Leukocyte Antigen (HLA-A, -B, and -C) presentation capacity of peptides derived from the VZV Immediate Early 62 (IE62) protein.

Production of Monosugars from Lignocellulosic Biomass in Molten Salt Hydrates: Process Design and Techno-Economic Analysis.

ZnCl hydrate, the main molten salt used in biomass conversion, combined with low concentration HCl is an excellent solvent for the dissolution and hydrolysis of the carbohydrates present in lignocellulosic biomass. The most recalcitrant carbohydrate, cellulose, is dissolved in a residence time less than 1 h under mild conditions without significant degradation. This technology is referred to as BIOeCON-solvent technology.

Interleukin-15 stimulates natural killer cell-mediated killing of both human pancreatic cancer and stellate cells.

Pancreatic ductal adenocarcinoma (PDAC) is the 4 leading cause of cancer-related death in Western countries with a 5-year survival rate below 5%. One of the hallmarks of this cancer is the strong desmoplastic reaction within the tumor microenvironment (TME), orchestrated by activated pancreatic stellate cells (PSC). This results in a functional and mechanical shield which causes resistance to conventional therapies.

Phosphorus and nitrogen co-limitation of forest ground vegetation under elevated anthropogenic nitrogen deposition.

Plant growth in northern forest ecosystems is considered to be primarily nitrogen limited. Nitrogen deposition is predicted to change this towards co-limitation/limitation by other nutrients (e.g.

Monocyte-Derived Dendritic Cells with Silenced PD-1 Ligands and Transpresenting Interleukin-15 Stimulate Strong Tumor-Reactive T-cell Expansion.

Although allogeneic stem cell transplantation (allo-SCT) can elicit graft-versus-tumor (GVT) immunity, patients often relapse due to residual tumor cells. As essential orchestrators of the immune system, vaccination with dendritic cells (DC) is an appealing strategy to boost the GVT response. Nevertheless, durable clinical responses after DC vaccination are still limited, stressing the need to improve current DC vaccines.

Desirable cytolytic immune effector cell recruitment by interleukin-15 dendritic cells.

Success of dendritic cell (DC) therapy in treating malignancies is depending on the DC capacity to attract immune effector cells, considering their reciprocal crosstalk is partially regulated by cell-contact-dependent mechanisms. Although critical for therapeutic efficacy, immune cell recruitment is a largely overlooked aspect regarding optimization of DC vaccination. In this paper we have made a head-to-head comparison of interleukin (IL)-15-cultured DCs and conventional IL-4-cultured DCs with regard to their proficiency in the recruitment of (innate) immune effector cells.

IL-15 receptor alpha as the magic wand to boost the success of IL-15 antitumor therapies: The upswing of IL-15 transpresentation.

Interleukin (IL)-15 as a stand-alone therapy can activate the antitumor functions of immune effector cells resulting in significant tumor regression. Interestingly, combining IL-15 with the α-moiety of its receptor (IL-15Rα), also called IL-15 transpresentation, increases the in vivo half-life of IL-15 and enhances binding of IL-15 with cells expressing the IL-15Rβγ, such as NK cells and CD8 T cells. These features enlarge the signal transmission of IL-15, resulting in improved proliferation and antitumor activities of both NK cells and CD8 T cells, eventually leading to enhanced killing of tumor cells.

Interleukin-15 enhances the proliferation, stimulatory phenotype, and antitumor effector functions of human gamma delta T cells.

Background: Adoptive immunotherapy is gaining momentum to fight malignancies, whereby γδ T cells have received recent attention as an alternative cell source as to natural killer cells and αβ T cells. The advent of γδ T cells is largely due to their ability to recognize and target tumor cells using both innate characteristic and T cell receptor (TCR)-mediated mechanisms, their capacity to enhance the generation of antigen-specific T cell responses, and their potential to be used in an autologous or allogeneic setting.

Methods: In this study, we explored the beneficial effect of the immunostimulatory cytokine interleukin (IL)-15 on purified γδ T cells and its use as a stimulatory signal in the ex vivo expansion of γδ T cells for adoptive transfer.

The tumor-associated antigen RHAMM (HMMR/CD168) is expressed by monocyte-derived dendritic cells and presented to T cells.

We formerly demonstrated that vaccination with Wilms' tumor 1 (WT1)-loaded autologous monocyte-derived dendritic cells (mo-DCs) can be a well-tolerated effective treatment in acute myeloid leukemia (AML) patients. Here, we investigated whether we could introduce the receptor for hyaluronic acid-mediated motility (RHAMM/HMMR/CD168), another clinically relevant tumor-associated antigen, into these mo-DCs through mRNA electroporation and elicit RHAMM-specific immune responses. While RHAMM mRNA electroporation significantly increased RHAMM protein expression by mo-DCs, our data indicate that classical mo-DCs already express and present RHAMM at sufficient levels to activate RHAMM-specific T cells, regardless of electroporation.

Two superoxide dismutase prion strains transmit amyotrophic lateral sclerosis-like disease.

Amyotrophic lateral sclerosis (ALS) is an adult-onset degeneration of motor neurons that is commonly caused by mutations in the gene encoding superoxide dismutase 1 (SOD1). Both patients and Tg mice expressing mutant human SOD1 (hSOD1) develop aggregates of unknown importance. In Tg mice, 2 different strains of hSOD1 aggregates (denoted A and B) can arise; however, the role of these aggregates in disease pathogenesis has not been fully characterized.

Comparison of carbon balances between continuous-cover and clear-cut forestry in Sweden.

Continuous-cover forestry (CCF) has been recognized for the production of multiple ecosystem services, and is seen as an alternative to clear-cut forestry (CF). Despite the increasing interest, it is still not well described how CCF would affect the carbon balance and the resulting climate benefit from the forest in relation to CF. This study compares carbon balances of CF and CCF, applied as two alternative land-use strategies for a heterogeneous Norway spruce (Picea abies) stand.

Replacing monocultures with mixed-species stands: Ecosystem service implications of two production forest alternatives in Sweden.

Whereas there is evidence that mixed-species approaches to production forestry in general can provide positive outcomes relative to monocultures, it is less clear to what extent multiple benefits can be derived from specific mixed-species alternatives. To provide such insights requires evaluations of an encompassing suite of ecosystem services, biodiversity, and forest management considerations provided by specific mixtures and monocultures within a region. Here, we conduct such an assessment in Sweden by contrasting even-aged Norway spruce (Picea abies)-dominated stands, with mixed-species stands of spruce and birch (Betula pendula or B.

Socio-ecological implications of modifying rotation lengths in forestry.

The rotation length is a key component of even-aged forest management systems. Using Fennoscandian forestry as a case, we review the socio-ecological implications of modifying rotation lengths relative to current practice by evaluating effects on a range of ecosystem services and on biodiversity conservation. The effects of shortening rotations on provisioning services are expected to be mostly negative to neutral (e.

Transpresentation of interleukin-15 by IL-15/IL-15Rα mRNA-engineered human dendritic cells boosts antitumoral natural killer cell activity.

In cancer immunotherapy, the use of dendritic cell (DC)-based vaccination strategies can improve overall survival, but until now durable clinical responses remain scarce. To date, DC vaccines are designed primarily to induce effective T-cell responses, ignoring the antitumor activity potential of natural killer (NK) cells. Aiming to further improve current DC vaccination outcome, we engineered monocyte-derived DC to produce interleukin (IL)-15 and/or IL-15 receptor alpha (IL-15Rα) using mRNA electroporation.

Interleukin-15 Dendritic Cells Harness NK Cell Cytotoxic Effector Function in a Contact- and IL-15-Dependent Manner.

The contribution of natural killer (NK) cells to the treatment efficacy of dendritic cell (DC)-based cancer vaccines is being increasingly recognized. Much current efforts to optimize this form of immunotherapy are therefore geared towards harnessing the NK cell-stimulatory ability of DCs. In this study, we investigated whether generation of human monocyte-derived DCs with interleukin (IL)-15 followed by activation with a Toll-like receptor stimulus endows these DCs, commonly referred to as "IL-15 DCs", with the capacity to stimulate NK cells.

Engineering monocyte-derived dendritic cells to secrete interferon-α enhances their ability to promote adaptive and innate anti-tumor immune effector functions.

Dendritic cell (DC) vaccination has demonstrated potential in clinical trials as a new effective cancer treatment, but objective and durable clinical responses are confined to a minority of patients. Interferon (IFN)-α, a type-I IFN, can bolster anti-tumor immunity by restoring or increasing the function of DCs, T cells and natural killer (NK) cells. Moreover, type-I IFN signaling on DCs was found to be essential in mice for tumor rejection by the innate and adaptive immune system.

Structural and kinetic analysis of protein-aggregate strains in vivo using binary epitope mapping.

Despite considerable progress in uncovering the molecular details of protein aggregation in vitro, the cause and mechanism of protein-aggregation disease remain poorly understood. One reason is that the amount of pathological aggregates in neural tissue is exceedingly low, precluding examination by conventional approaches. We present here a method for determination of the structure and quantity of aggregates in small tissue samples, circumventing the above problem.

Interleukin-15: new kid on the block for antitumor combination therapy.

Interleukin (IL)-15 is one of the most promising molecules to be used in antitumor immune therapy, as it is able to stimulate the main killer cells of both the innate and adaptive immune system. Although this cytokine can be used as a stand-alone immunotherapeutic agent, IL-15 will probably be most efficient in combination with other strategies to overcome high tumor burden, immune suppression of the tumor microenvironment and/or the short half-life of IL-15. In this review, we will discuss the combination strategies with IL-15 that have been tested to date in different animal tumor models, which include chemotherapy, other immunostimulatory cytokines, targeted therapy, adoptive cell transfer and gene therapy.