Search Results (109)

Tumor necrosis factor α (TNF-α) is a multifunctional cytokine protein acknowledged as a vital mediator in cell differentiation, proliferation, and survival. Additionally, TNF-α is a crucial component of the host’s defense by mediating inflammatory and immune responses against various aggressive agents, including viruses, bacteria parasites, and tumors. However, excessive production can be detrimental to the body and is also implicated in developing several inflammatory and immune-mediated disorders. Therefore, there is great interest in studying its role and its modulation, in various diseases, both in in vitro, in vivo, and in silico experiments. In this review, we evaluated the structures of proteins related to TNF-α available in public databases. In addition, we described the main antibodies blocking this cytokine and its applications and commented on the potential of naturally produced binding molecules, such as TNF-α-binding proteins produced by ticks. We also discuss the role of structural bioinformatics techniques in understanding the mechanisms of chronic inflammatory diseases related to TNF-α. We hope that the data presented in this review will be useful for studies that aim to better understand the mechanisms of the interactions of TNF-α with other proteins and will lead to new drugs or treatments. Full article

Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by thrombotic or obstetric events occurring in individuals who have persistent antiphospholipid antibodies. Catastrophic antiphospholipid syndrome (CAPS) is a rare and potentially fatal form of APS characterized by severe thrombotic complications occurring in multiple organs over a short period of time or simultaneously. CAPS is associated with a high (50%) death rate. Infections, multi-organ failure, and cerebral and heart thrombosis represent the main complications of this syndrome. Generally, anticoagulants, glucocorticoids, therapeutic plasmapheresis (TPE), and intravenous immunoglobulin (IVIG) are used in combination for treatment. Multidisciplinary care involving different specialists from hematology, rheumatology, nephrology, infectious disease, critical care, and obstetrics is often required due to the complexity of the disease. Recent data emphasize the effectiveness of biologics such as anti-TNF-a monoclonal antibodies (adalimumab, certolizumab), anti-CD38 monoclonal antibody (daratumumab), BAFF/Blys inhibitor (belimumab), and BTK inhibitor (zanubrutinib) against CAPS. In order to understand the underlying causes of CAPS, one future possibility involves investigating and characterizing the hereditary and acquired risk factors associated with CAPS. Full article

Liver fibrosis is a complex, dynamic process associated with a broad spectrum of chronic liver diseases and acute liver failure, characterised by the dysregulated intrahepatic production of extracellular matrix proteins replacing functional liver cells with scar tissue. Fibrosis progresses due to an interrelated cycle of hepatocellular injury, triggering a persistent wound-healing response. The accumulation of scar tissue and chronic inflammation can eventually lead to cirrhosis and hepatocellular carcinoma. Currently, no therapies exist to directly treat or reverse liver fibrosis; hence, it remains a substantial global disease burden. A better understanding of the intricate inflammatory network that drives the initiation and maintenance of liver fibrosis to enable the rationale design of new intervention strategies is required. This review clarifies the most current understanding of the hepatic fibrosis cellular network with a focus on the role of regulatory T cells, and a possible trajectory for T cell immunotherapy in fibrosis treatment. Despite good progress in elucidating the role of the immune system in liver fibrosis, future work to better define the function of different immune cells and their mediators at different fibrotic stages is needed, which will enhance the development of new therapies. Full article

Zaire ebolavirus (EBOV) poses a significant threat to public health due to its high case fatality rate and epidemic potential. This is further complicated by the lack of precise immune correlates of protection and difficulties in conducting in vivo animal studies due to species specificity of Ebola virus disease (EVD) and classification as a biosafety level 4 pathogen. Related ebolaviruses have also contributed to the public health threat; Uganda recently experienced an outbreak of Sudan ebolavirus, which also had a high case fatality rate. Vaccination targeting EBOV has demonstrated significant efficacy; however, the protective cellular and humoral responses at play are still poorly understood. Vaccination for vulnerable populations such as pregnant women, young children, and immunocompromised individuals is still limited. Understanding vaccine correlates of protection (vCOP) is key to developing alternative vaccination strategies for these groups. Components of immunity such as neutralizing antibody and cell-mediated immunity are likely responsible for protective responses; however, existing research fails to fully define their roles in protection. Here we investigated vaccine-elicited antibody avidity as a potential correlate of protection and to further characterize the contribution of antibody avidity in protective and nonprotective vaccine responses. Full article

Advancements in sequencing and screening technology have made monoclonal antibodies more accessible, cost-effective, and precise. These drugs effectively target pathogens and cancer cells and even regulate metabolic pathways by focusing on specific intermediates. Monoclonal antibodies play a key role in mitigating a rise in occupation-related cancers, neurodegenerative disorders, and multidrug-resistant organisms. Here, we review the origins, mechanisms, and applications of this important drug class and explore future avenues for research. Full article

The impact of pre-existing common cold coronavirus (CCCoV) antibodies (Abs) on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immune responses and pathogenesis remains poorly defined. We evaluated these associations in a cohort of hospitalized patients with COVID-19 and respiratory failure of varying severity. Patients with respiratory failure from other causes (non-COVID-19) were evaluated as controls. We demonstrated a positive correlation between levels of CCCoV and SARS-CoV-2 Abs using CCCoV and SARS-CoV-2 N and S protein peptide-specific ELISA. Consistent with the above, moderately increased levels of CCCoV-specific Abs in non-COVID-19 vs. COVID-19 patients suggest potential protective effects. Further, higher SARS-CoV-2 N protein-specific and CCCoV Ab levels were observed among surviving vs. non-surviving COVID-19 positive patients. However, the highest SARS-CoV-2 N and S protein-specific IgG and IgA Ab levels were noted in the patients with the most severe clinical disease. Finally, advanced age, cancer and immunosuppression were associated with significantly higher mortality and reduced SARS-CoV-2 and CCCoV Ab levels. Thus, our data highlight that sufficient SARS-CoV-2 N protein-specific Ab responses improve clinical outcomes in severely ill COVID-19 patients. We also confirmed that pre-existing CCCoV-specific Abs do not inhibit the SARS-CoV-2 Ab response and may further reduce the prevalence and/or severity of COVID-19. Full article

Bone marrow is known as the site of hematopoiesis. What is not being described in textbooks of immunology is the fact that bone marrow is not only a generative, but also an antigen-responsive, immune organ. It is also a major storage site for antigen-specific memory B and T cells. That bone marrow is a priming site for T cell responses to blood borne antigens was discovered exactly 20 years ago. This review celebrates this important discovery. The review provides a number of examples of medical relevance of bone marrow as a central immune system, including cancer, microbial infections, autoimmune reactions, and bone marrow transplantation. Bone marrow mesenchymal stem cell-derived stromal cells provide distinct bone marrow niches for stem cells and immune cells. By transmitting anti-inflammatory dampening effects, facilitating wound healing and tissue regeneration mesenchymal stem cells contribute to homeostasis of bone and other tissues. Based on the evidence presented, the review proposes that bone marrow is a multifunctional and protective immune system. In an analogy to the central nervous system, it is suggested that bone marrow be designated as the central immune system. Full article

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