Immuno

Immunoglobulin-like transcript 4 (ILT4) is an immunosuppressive molecule predominantly expressed on myeloid cells. Recent studies combining ILT4 suppression with programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) blockade have shown promising signs of activity in immune checkpoint inhibitor refractory patients. We theorized that coupling ILT4 and PD-1/PD-L1 blockade in a bispecific antibody (bsAb) may provide greater immune activating properties than combining the individual mAbs due to enhanced bridging of APCs to T cells. To test this approach, we developed CDX-585, a tetravalent ILT4xPD-1 IgG1-scFv bsAb from novel PD-1 and ILT-4 mAbs. CDX-585 is a potent antagonist of both PD-1 and ILT4. CDX-585 promotes M1 macrophage polarization and enhances pro-inflammatory cytokine secretion in response to lipopolysaccharide or CD40 agonist mAb treatment. In mixed lymphocyte reaction (MLR) assays, CDX-585 is more potent than the combination of parental antibodies. In a humanized NCG mouse SK-MEL-5 tumor model, CDX-585 exhibits greater antitumor activity than the combination of parental mAbs. A pilot study of CDX-585 in cynomolgus macaques confirmed a mAb-like pharmacokinetic profile without noted toxicities. These studies demonstrate that CDX-585 effectively combines ILT4 and the PD-1 blockade into one molecule that is more potent than the combination of the parental antibodies, providing the rationale to advance this bsAb into clinical studies. Full article

Osteoarthritis (OA) is the most common degenerative joint disease that causes chronic pain and disability. Different innate immune components, including macrophages, T cells, and neutrophils, participate in OA pathophysiology. Neutrophils are the most abundant circulating leukocytes with multiple specialized functions contributing to innate and adaptive immune functions. Although neutrophils produce proinflammatory cytokines and chemokines, reactive oxygen species (ROS), matrix-degrading enzymes, and neutrophil extracellular traps (NET) that promote joint degradation as the first recruit cells in an inflamed joint, these cells also play an important role in joint repair by regulating the immune response, releasing anti-inflammatory factors, and activating certain protective genes. In this review, various aspects of neutrophil biology, their role in inflammation and its association with OA, and possible therapeutic approaches to target neutrophils for the treatment of OA are described. Since neutrophils play a complex role in the pathophysiology of osteoarthritis, contributing to joint degradation as well as joint repair, targeting these cells is likely to pave the way for a potential therapeutic approach for the management of OA. Future studies are needed to investigate the use of targeted therapies to modulate neutrophil function and identify their subpopulations that are associated with osteoarthritis progression or response to treatment. Full article

Chemotherapy-refractive multiple myeloma (MM) is serious and life-threatening, and better treatments are urgently needed. BCMA is a prominent marker on the cell surface of MM cells, rendering it an accepted target for antibody therapy. Considering that MM is a liquid tumor and immunotherapy has enjoyed success against leukemia, we devise an approach designed to enhance NK cell activity against MM. Ordinarily, NK cells function to naturally survey the body and eliminate malignant cells. Our platform approach is designed to enhance NK function. A tri-specific immune-engaging TriKE is manufactured, consisting of a camelid nanobody VHH antibody fragment recognizing CD16 expressed on NK cells and an scFv antibody fragment specifically recognizing BCMA. These two fragments are crosslinked by the human cytokine interleukin-15 (IL-15) known to have prominent activating effects on NK cells. The molecule, when tested by flow cytometry, shows activation of NK cells in their numbers and activity. Additionally, the molecule demonstrates anti-cancer effects in an in vivo xenograft model of human MM. We believe that the drug will have the capability of enhancing NK cells at the site of the immune synapse, i.e., the effector:target cell interface, and this will promote cancer remissions. Full article

In terms of the global burden of disease, helminthiasis is the most common infectious disease in the world. In response to the disease, the human host develops an immunological response that occurs predominantly through the action of T helper 2 (Th2) cells and the interleukins IL-4, IL-5 and IL-13. However, other types of Th cells, such as Th9, are also involved in the defense against helminths, with the IL-9 produced by these cells promoting the induction of mastocytosis and the increased production of IgG1 and IgE, in addition to the increase in intestinal contractility that promotes the expulsion of worms. Together, IL-9 and IL-10, which is also produced by Th9, induce a type 2 inflammatory response characterized by the coordinated actions of innate lymphoid cells, mast cells, basophils and other cells that work together toward a single objective: the reduction of the parasitic burden. This review presents the latest findings on Th9 effector mechanisms in helminthic infections. Full article

The 19th century saw the development of vaccines, which were biological preparations designed to enhance immunity against specific diseases. Edible vaccines function by stimulating both systemic and mucosal immune responses against foreign pathogens, and they may potentially protect the host from autoimmunity. The mucosal surfaces provide a convenient and rapid route for delivering therapeutic small molecules. This is due to their large surface areas and easy administration. The effectiveness of mucosal immunization relies on the fact that mucous membranes represent the body’s largest immunogenic organ. Within this interface, there is a well-organized lymphatic structure known as MALT (mucosa-associated lymphoid tissue), which includes both T and B cells and encompasses the adaptive arms of the immune system. Oral vaccines specifically stimulate immune responses in the gut-associated lymphoid tissue (GALT), which consists of lymph nodes, Payer’s patches (where B cells make up about 75% of the population and T cells account for approximately 20%), and isolated lymphoid follicles within the gastrointestinal tract (GIT). However, a significant challenge in developing vaccines is the rapid degradation of antigens within the harsh environment of the digestive tract, which hampers effective protein delivery to the GIT. In light of recent proteomic analysis revealing strong up-regulation of the tryptophan catabolic enzyme indoleamine 2, 3-dioxygenase (IDO1) in DCs inoculated with the Cholera toxin B-subunit-Insulin fusion protein vaccine (CTB-INS), we are interested in investigating the effects of transgene integration into a selected plant cell as an edible vaccine. Full article

Breast cancer is the most commonly diagnosed cancer in women and is a leading cause of cancer death in women worldwide. Despite the available treatment options, such as surgery, chemotherapy, radiotherapy, endocrine therapy and molecular targeted therapy, breast cancer treatment remains a challenge. The advent of immunotherapy has revolutionized the treatment of breast cancer as it utilizes the host’s immune system to directly target tumor cells. In this literature review, we aim to summarize the recent advancements made in using immunotherapy for treating breast cancer patients. We discuss the different types of existing immunotherapies for breast cancer, including targeted therapy using monoclonal antibodies against breast cancer specific antigens and the use of immune checkpoint inhibitors to elicit an immune response against cancer cells. Finally, we consider the development of breast cancer vaccines that train the immune system to specifically recognize cancer cells and the future perspectives of immunotherapy for breast cancer. Full article

Inflammation is considered a natural reaction of the immune system that can be caused by several factors such as pathogens, chemical substances, and damaged cells. Since the classical era, therapeutic substances have been made from medicinal plants. According to recent studies, nanotechnology provides a fresh approach to maintaining the standard quality, distribution, and bioactivity of therapeutic compounds. This review emphasizes the anti-inflammatory effects of green, synthetic, plant-based nanoparticles and nanoemulsions. A reduction of the dosage of anti-inflammatory medications and an improved therapeutic impact is highly desirable with an efficient drug delivery method. Along with the discussion of nanotechnology of medicinal plant-based anti-inflammatory effects, this review also offers a perspective view of the use of nanoparticles and nanoemulsions in inflammatory diseases in the future. Full article

Pandemics in the last two centuries have been initiated by causal pathogens that include Severe Acute Coronavirus 2 (SARS-CoV-2) and Influenza (e.g., the H1N1 pandemic of 2009). The latter is considered to have initiated two prior pandemics in 1918 and 1977, known as the “Spanish Flu” and “Russian Flu”, respectively. Here, we discuss other emerging infections that could be potential public health threats. These include Henipaviruses, which are members of the family Paramyxoviridae that infect bats and other mammals. Paramyxoviridae also include Parainfluenza and Mumps viruses (Rubulavirus) but also Respiratory Syncytial virus (RSV) (Pneumovirus). Additionally included is the Measles virus, recorded for the first time in writing in 1657 (Morbillivirus). In humans and animals, these may cause encephalitis or respiratory diseases. Recently, two more highly pathogenic class 4 viral pathogens emerged. These were named Hendra Henipavirus (HeV) and Nipah Henipavirus (NiV). Nipah virus is a negative-sense single-stranded ribonucleic acid ((−) ssRNA) virus within the family Paramyxoviridae. There are currently no known therapeutics or treatment regimens licensed as effective in humans, with development ongoing. Nipah virus is a lethal emerging zoonotic disease that has been neglected since its characterization in 1999 until recently. Nipah virus infection occurs predominantly in isolated regions of Malaysia, Bangladesh, and India in small outbreaks. Factors that affect animal–human disease transmission include viral mutation, direct contact, amplifying reservoirs, food, close contact, and host cell mutations. There are different strains of Nipah virus, and small outbreaks in humans limit known research and surveillance on this pathogen. The small size of outbreaks in rural areas is suggestive of low transmission. Person-to-person transmission may occur. The role that zoonotic (animal–human) or host immune system cellular factors perform therefore requires analysis. Mortality estimates for NiV infection range from 38–100% (averaging 58.2% in early 2019). It is therefore critical to outline treatments and prevention for NiV disease in future research. The final stages of the disease severely affect key organ systems, particularly the central nervous system and brain. Therefore, here we clarify the pathogenesis, biochemical mechanisms, and all research in context with known immune cell proteins and genetic factors. Full article

The production of pro-inflammatory and anti-inflammatory cytokines, as well as adipocyte differentiation and fat accumulation in the 3T3-L1 mouse embryo fibroblast cell line and the human monocytic cell line THP-1 were measured to determine the anti-inflammatory and antiadipogenic effects of ethanolic extracts of verjuice (unripe grape juice (Vitis vinifera L.)), Salvia officinalis L., and Alchemilla vulgaris L. On both cell lines, the three extracts had much greater cytostatic effects than cytotoxic effects. With an IC50 of 505 μg/mL, S. officinalis had the highest cytostatic effect on THP-1-derived macrophages. After treatment with 125 μg/mL, the three extracts dramatically reduced the LPS-induced NO generation in THP-1-derived macrophages from 80 μM to control values after treatment with 125 µg/mL. Furthermore, the extracts reduced the levels of TNF-α and IL-6 production in a dose-dependent manner with the highest effects reached at 250 µg/mL. The production of TNF-α decreased at higher levels compared to IL-6 production. V. vinifera, S. officinalis, and A. vulgaris extracts improved the production levels of IL-10 from 32 pg/mL to 86 pg/mL, 98 pg/mL, and 80 pg/mL at an extract concentration of 125 µg/mL, respectively. The adipocyte differentiation and fat accumulation in 3T3-L1 were decreased to 20% of control values after treatment with plant extracts. Taken together, these results suggest that V. vinifera, S. officinalis, and A. vulgaris likely exert their anti-obesity effects through cytostatic actions and modulation of pro-inflammatory and anti-inflammatory cytokine production, as well as by reducing adipocyte differentiation and fat accumulation. Full article

Modulation of the immune system has been demonstrated as a powerful approach to treating cancer. Immunotherapies are generally classified as active or passive according to their ability to trigger the immune system. During the last decades, information regarding the relevance of aberrant glycosylation as a major player in tumour biology encouraged expectations for the development of new therapeutic strategies directed at glycans. Several tumour-associated carbohydrate antigens (TACAs) have been identified and validated as suitable immunotherapeutic targets, leading to promising therapeutic developments. It is known that TACAs are poorly immunogenic since they are unable to trigger a proper immune response. Given that they are not presented by major histocompatibility complex (MHC) molecules and that they induce immune tolerance, the development of active immunotherapeutic strategies against TACAs is a real challenge. However, antitumor strategies based on mimetics of TACAs have been developed and show promising results. Active immunotherapies based on TACAs mimicry can currently be grouped into strategies based on the use of mimetic peptides and anti-idiotype (Id) antibodies. In this review, we discussed the scientific basis on which these strategies are based and the available therapeutic options that have shown the best results in preclinical studies and in clinical practice. Full article

COVID-19 has presented itself as a challenging task to medical teams and researchers throughout the world, since the outbreak of SARS-CoV-2 started in the Chinese city of Wuhan. To this day, there are still new variants emerging, and the knowledge about the mechanisms used by the virus to infect cells and perpetuate itself are still not well understood. The scientific community is still trying to catch up with the velocity of new variants and, consequently, the new physiological pathways that appear along with it. It is known that the new coronavirus plays a role in changing many molecular pathways to take control of the infected cells. Many of these pathways are related to control genomic expression of certain genes by epigenetic ways, allowing the virus to modulate immune responses and cytokines production. The let-7 family of microRNAs, for instance, are known to promote increased viral fusion in the target cell through a mechanism involving the transmembrane serine protease 2 (TMPRSS2). It was also demonstrated they are able to increase the inflammatory activity through the NF-κB/IL-6/let-7/LIN-28 axis. In addition, let-7 overexpression led to a reduction in inflammatory cytokines and chemokines expression (IL-6, IL-8 and TNF-α). Interestingly, the cytokines modulated by the let-7 family are related to COVID-19-induced cytokine storm observed in patients undergoing clinical phase three. Thus, let-7 can be considered a novel and attractive biomarker for therapeutic purpose. Based on that, the present study aims to critically analyze the immunopathological mechanisms of the microRNA let-7 in the infection caused by SARS-CoV-2. Full article

COVID-19 is a viral disease that has caused millions of deaths around the world since 2020. Many strategies have been developed to manage patients in critical conditions; however, comprehension of the immune system is a key factor in viral clearance, tissue repairment, and adaptive immunity stimulus. Participation of immunity has been identified as a major factor, along with biomarkers, prediction of clinical outcomes, and antibody production after infection. Immune cells have been proposed not only as a hallmark of severity, but also as a predictor of clinical outcomes, while dynamics of inflammatory molecules can also induce worse consequences for acute patients. For convalescent patients, mild disease was related to higher antibody production, although the factors related to the specific antibodies based on a diversity of antigens were not clear. COVID-19 was explored over time; however, the study of immunological predictors of outcomes is still lacking discussion, especially in convalescent patients. Here, we propose a review using previously published studies to identify immunological markers of COVID-19 outcomes and their relation to antibody production to further contribute to the clinical and laboratorial management of patients. Full article

Since the momentous discovery of X-rays, high-dose radiotherapy (H-XRT) has been a cornerstone for combating cancer. The high-energy electromagnetic waves induce direct damage to tumor-cells’ DNA, thereby halting cell growth and proliferation, and eventually leading to tumor eradication. Furthermore, recent evidence suggests that H-XRT may have immunomodulatory properties which arise from its ability to induce the release of neoantigens, which in turn prime T-cells and contribute to T-cell repertoire diversity. Throughout the years, there have been different treatment modalities introduced as complements to H-XRT that have yielded greater results than monotherapy alone. In this review, we will discuss preclinical and clinical data related to the recently introduced low-dose radiotherapy (L-XRT) modality. We will also explore the justification for combining L-XRT and H-XRT, which became known as the “RadScopal Technique”, as a novel immune adjuvant to treat cancer. In this analysis, we detail and dissect the physiological mechanisms of action of each modality and describe the synergistic amalgamation effect observed on primary and metastatic tumors. Finally, we will explore the impetus for further studies to investigate combinations of the “RadScopal Technique” with various immune-oncology drug candidates. Full article

Mastic oil (MO) is extracted from the resin of the bark of Pistacia lentiscus var. chia, a tree abundantly grown in the Greek island of Chios. Various biological activities, such as antimicrobial, anticancer and antioxidant, have been associated with the dietary intake of MO. However, little is known about MO’s potential anti-inflammatory effects, while some of its main chemical constituents were reported to exert significant anti-inflammatory activity. This study aims to assay the bioactivity of MO on in vitro and in vivo experimental inflammation models, in particular on LPS-stimulated RAW264.7 macrophages, murine primary peritoneal macrophages and a model of zymosan-induced peritonitis in BALB/c mice. The per os administration of MO inhibited the recruitment of macrophages into the peritoneal cavity of zymosan-treated mice, but did not affect neutrophil mobilisation or the levels of IL-6 or TNF-α in the peritoneal fluid. Similarly, IL-6 and TNF-α secretion in primary LPS-stimulated macrophages was not affected by MO, but the levels of phosphoproteins that activate inflammation in macrophages were differentially regulated. Finally, MO and some of its individual constituents reduced nitric oxide (NO), prostaglandin E2 and TNF-α levels in supernatants of LPS-stimulated RAW264.7 cells and inhibited their phagocytosis rate. Our data imply that MO may promote an anti-inflammatory transition in macrophages due to the combined bioactivities of its individual constituents. Thus, as a mixture of various compounds, MO seems to affect multiple molecular mechanisms that are involved in the development of inflammation. Therefore, more research, focusing on MO’s individual constituents and employing various pre-clinical inflammation models that activate different mechanisms, is required for a detailed investigation of the oil’s potential anti-inflammatory activity. Full article

Despite advances in treatment options, the clinical outcomes of pediatric patients with advanced solid tumors have hardly improved in decades, and alternative treatment options are urgently needed. Innovative therapies, such as chimeric antigen receptor (CAR) T cells and oncolytic viruses (OVs), are currently being evaluated in both adults and children with refractory solid tumors. Because pediatric solid tumors are remarkably diverse and biologically different from their adult counterparts, more research is required to develop effective treatment regimens for these patients. Here, we first summarize recent efforts and advances in treatments for pediatric solid tumors. Next, we briefly introduce the principles for CAR T cell therapy and oncolytic virotherapy and clinical trials thereof in pediatric patients. Finally, we discuss the basis for the potential benefits of combining the two approaches in pediatric patients with advanced solid tumors. Full article

Differences in the baseline levels of serum cytokines or in single-nucleotide polymorphisms (SNPs) in cytokine genes may be useful to predict outcomes for patients being treated for metastatic breast cancer. We have measured the plasma levels and characterized individual SNPs for IL-1RA, IL-1β, IL-2, IL-6 and TNFα in 130 patients with metastatic breast cancer treated with high-dose chemotherapy. Patients were treated with high-dose cyclophosphamide (Group 1, 74 patients) or high-dose paclitaxel-containing regimens (Group 2, 56 patients). A high plasma level of IL-1RA and a SNP in the IL-1RA gene indicated a better prognosis for patients in Group 1 (but not Group 2). However, the level of plasma IL-1RA did not correlate with the SNP genotype. A high plasma level of IL-6 or TNFα indicated a poorer outcome for patients in Group 1 although the SNP genotypes for the IL-6 and TNFα SNPs were not associated with differences in outcome. The plasma levels of IL-1β and IL-2 and the genotype of the IL-1β SNPs did not indicate differences in outcome. Although, individually, plasma levels of cytokine or “risk” SNP genotypes may not indicate outcome, in combination there was an increased trend to predict outcome for patients treated with high-dose cyclophosphamide but not high-dose paclitaxel. These results suggest that the immune cytokines may be useful as prognostic biomarkers in the treatment of patients with metastatic breast cancer treated with different types of chemotherapy. Full article

Interceding nutrients have been acquiring increased attention and prominence in the field of healing and deterrence of various disorders. In this light, the present article encompasses several facets of ketogenic diet as an immunomodulator with respect to its expansive clinical applications. Accordingly, several scientific records, models, and case histories, including viral infections, cancer, chronic diseases, e.g., cardiovascular diseases, epilepsy, as well as numerous other neuro-disorders, are assembled, revealing a profound influence of KD in favor of improvement in the patient’s condition. We accentuate possible manifold mechanisms of KD that require further exploration. Full article

In the chronic phase of chikungunya virus (CHIKV) infection, excessive inflammation manifests as incapacitating joint pain and prolonged arthritis. Arthritis resulted from a large influx of infiltrating immune cells driven by pro-inflammatory cytokines and chemokines originating from the toll-like receptor (TLR)-mediated innate antiviral response. This study investigated fisetin’s ability to modulate TLR-mediated antiviral responses against CHIKV in Huh7 cells. The CHIKV inhibitory potential of fisetin was assessed by plaque-forming unit assay, virus yield reduction assay, and bright-field microscopy (cytopathic effect, immunofluorescence). Fisetin’s modulatory potential on TLR-mediated antiviral response was evaluated by immunofluorescence assay (expression of TLR proteins), qRT-PCR (mRNA level of antiviral genes), human cytokine array, and the immunoblotting of key transcription factors. The present study showed fisetin induced the expression of the antiviral genes at an early time-point by promoting the phosphorylation of IRF3 and IRF7. Fisetin reduced excessive inflammatory cytokine responses in CHIKV-infected Huh7 cells by impeding the over-phosphorylation of NF-κB. Fisetin also reduced CHIKV-induced cytopathic effects in CHIKV-infected Huh7 cells. Altogether, our study suggests that fisetin modulates TLR-mediated antiviral responses by affecting the CHIKV-induced inflammatory responses. Full article