scholarly journals Targeting the MHC Ligandome by Use of TCR-Like Antibodies

Antibodies ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 32 ◽  
Author(s):  
Lene Støkken Høydahl ◽  
Rahel Frick ◽  
Inger Sandlie ◽  
Geir Åge Løset
Keyword(s):  
Immune Responses ◽  
High Specificity ◽  
Infectious Agents ◽  
Presentation Of Self ◽  
Peptide Fragments ◽  
Preclinical Models ◽  
Mhc Molecules ◽  
Health And Disease ◽  
Targeting Peptide ◽  
Subsequent Activation

Monoclonal antibodies (mAbs) are valuable as research reagents, in diagnosis and in therapy. Their high specificity, the ease in production, favorable biophysical properties and the opportunity to engineer different properties make mAbs a versatile class of biologics. mAbs targeting peptide–major histocompatibility molecule (pMHC) complexes are often referred to as “TCR-like” mAbs, as pMHC complexes are generally recognized by T-cell receptors (TCRs). Presentation of self- and non-self-derived peptide fragments on MHC molecules and subsequent activation of T cells dictate immune responses in health and disease. This includes responses to infectious agents or cancer but also aberrant responses against harmless self-peptides in autoimmune diseases. The ability of TCR-like mAbs to target specific peptides presented on MHC allows for their use to study peptide presentation or for diagnosis and therapy. This extends the scope of conventional mAbs, which are generally limited to cell-surface or soluble antigens. Herein, we review the strategies used to generate TCR-like mAbs and provide a structural comparison with the analogous TCR in pMHC binding. We further discuss their applications as research tools and therapeutic reagents in preclinical models as well as challenges and limitations associated with their use.

scholarly journals Cariogenic Biofilm: Pathology-Related Phenotypes and Targeted Therapy

2021 ◽  
Vol 9 (6) ◽  
pp. 1311
Author(s):  
Xiuqin Chen ◽  
Eric Banan-Mwine Daliri ◽  
Akanksha Tyagi ◽  
Deog-Hwan Oh
Keyword(s):  
Treatment Strategies ◽  
High Specificity ◽  
Low Ph ◽  
Oral Microbiota ◽  
Extracellular Polymers ◽  
Dental Biofilm ◽  
Health And Disease ◽  
Promising Treatment ◽  
Cariogenic Biofilm

The initiation and development of cariogenic (that is, caries-related) biofilms are the result of the disruption of homeostasis in the oral microenvironment. There is a daily accumulation of dental biofilm on the surface of teeth and its matrix of extracellular polymers supports the host in its defense against invading microbes, thus helping to achieve oral microbial homeostasis. However, the homeostasis can be broken down under certain circumstances such as during long-term exposure to a low pH environment which results in the dominance of acidogenic and acid-tolerating species in the dental biofilm and, thus, triggers the shift of harmless biofilm to an acidic one. This work aims to explore microbial diversity and the quorum sensing of dental biofilm and their important contributions to oral health and disease. The complex and multispecies ecosystems of the cariogenic biofilm pose significant challenges for the modulation of the oral microenvironment. Promising treatment strategies are those that target cariogenic niches with high specificity without disrupting the balance of the surrounding oral microbiota. Here, we summarized the recent advances in modulating cariogenic biofilm and/or controlling its pathogenic traits.

scholarly journals Impact of Influenza A Virus Shutoff Proteins on Host Immune Responses

Vaccines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 629
Author(s):  
Megan M. Dunagan ◽  
Kala Hardy ◽  
Toru Takimoto
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Influenza A Virus ◽  
Influenza A ◽  
Human Populations ◽  
Lymphocyte Migration ◽  
Host Immune Responses ◽  
Mhc Molecules ◽  
The Impact

Influenza A virus (IAV) is a significant human pathogen that causes seasonal epidemics. Although various types of vaccines are available, IAVs still circulate among human populations, possibly due to their ability to circumvent host immune responses. IAV expresses two host shutoff proteins, PA-X and NS1, which antagonize the host innate immune response. By transcriptomic analysis, we previously showed that PA-X is a major contributor for general shutoff, while shutoff active NS1 specifically inhibits the expression of host cytokines, MHC molecules, and genes involved in innate immunity in cultured human cells. So far, the impact of these shutoff proteins in the acquired immune response in vivo has not been determined in detail. In this study, we analyzed the effects of PA-X and NS1 shutoff activities on immune response using recombinant influenza A/California/04/2009 viruses containing mutations affecting the expression of shutoff active PA-X and NS1 in a mouse model. Our data indicate that the virus without shutoff activities induced the strongest T and B cell responses. Both PA-X and NS1 reduced host immune responses, but shutoff active NS1 most effectively suppressed lymphocyte migration to the lungs, antibody production, and the generation of IAV specific CD4+ and CD8+ T cells. NS1 also prevented the generation of protective immunity against a heterologous virus challenge. These data indicate that shutoff active NS1 plays a major role in suppressing host immune responses against IAV infection.

Tumor Microenvironment-Triggered In-Situ Cancer Vaccines with Dual Immunogenic Cell Death Inductions for Elevated Antitumor and Antimetastatic Therapy

Nanoscale ◽  
2021 ◽  
Author(s):  
Jun Lin ◽  
Binbin Ding ◽  
Pan Zheng ◽  
Dong Li ◽  
Meifang Wang ◽  
...  
Keyword(s):  
Cell Death ◽  
Tumor Microenvironment ◽  
Immune Responses ◽  
Cancer Immunotherapy ◽  
Cancer Vaccines ◽  
High Specificity ◽  
The Body ◽  
Immunogenic Cell Death ◽  
Specific Antigens

Cancer vaccine is to make tumor-specific antigens into vaccines, which then are injected back into the body to activate immune responses for cancer immunotherapy. Despite the high specificity and therapeutic...

The ubiquitin proteolytic system and pathogenesis of human diseases: a novel platform for mechanism-based drug targeting

2003 ◽  
Vol 31 (2) ◽  
pp. 474-481 ◽  
Author(s):  
A. Ciechanover
Keyword(s):  
Cell Cycle ◽  
Inflammatory Responses ◽  
High Specificity ◽  
Research Area ◽  
Extracellular Proteins ◽  
Cellular Proteins ◽  
Cell Cycle Regulators ◽  
Class I Mhc ◽  
Surface Receptors ◽  
Mhc Molecules

Until the early 1980s, protein degradation was a neglected research area, and scientists were mostly busy deciphering the genetic code and its translation to the proteome. Destruction of cellular proteins was thought to be a scavenger, non-specific and dead-end process. Although it was known that proteins do turn over, the large extent and high specificity of the process, whereby distinct proteins have half-lives that range from a few minutes to several days, was not appreciated. The discovery of the lysosome by Christian de Duve did not change this view significantly, as it was clear that this organelle is involved mostly in the degradation of extracellular proteins, and their proteases cannot be substrate-specific. The discovery of the complex cascade of the ubiquitin pathway revolutionized the field. It is clear now that degradation of cellular proteins via the ubiquitin system is a highly complex, temporally controlled and tightly regulated process that plays major roles in a variety of basic pathways and processes during cell life and death, and in health and disease. The system is involved in targeting many cellular proteins, among them cell cycle regulators, growth- and differentiation-controlling factors, transcriptional activators, cell-surface receptors and ion channels, endoplasmic reticulum proteins, antigenic proteins destined for presentation on class I MHC molecules, and abnormal/misfolded proteins. Consequently, it is involved in regulating many basic cellular processes, such as cell cycle and division, growth and differentiation, signal transduction and transcription, modulation of the secretory and endocytic pathways, the immune and inflammatory responses, and quality control. With the multitude of substrates targeted and the numerous processes involved, it is not surprising that aberrations in the pathway have been implicated in the pathogenesis of many diseases, with certain malignancies and neurodegenerative disorders being ranked among them.

scholarly journals Inter-individual variation in health and disease associated with pulmonary infectious agents

2018 ◽  
Vol 29 (1-2) ◽  
pp. 38-47 ◽  
Author(s):  
Kirsten C. Verhein ◽  
Heather L. Vellers ◽  
Steven R. Kleeberger
Keyword(s):  
Individual Variation ◽  
Infectious Agents ◽  
Health And Disease

scholarly journals Human Dendritic Cells: Ontogeny and Their Subsets in Health and Disease

2018 ◽  
Vol 6 (4) ◽  
pp. 88 ◽  
Author(s):  
Sandra Solano-Gálvez ◽  
Sonia Tovar-Torres ◽  
María Tron-Gómez ◽  
Ariane Weiser-Smeke ◽  
Diego Álvarez-Hernández ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Immune Responses ◽  
Cd8 T Cells ◽  
Current Knowledge ◽  
Lymphoid Organ ◽  
Heterogeneous Population ◽  
Health And Disease ◽  
Human Dendritic Cells ◽  
Activation Status

Dendritic cells (DCs) are a type of cells derived from bone marrow that represent 1% or less of the total hematopoietic cells of any lymphoid organ or of the total cell count of the blood or epithelia. Dendritic cells comprise a heterogeneous population of cells localized in different tissues where they act as sentinels continuously capturing antigens to present them to T cells. Dendritic cells are uniquely capable of attracting and activating naïve CD4+ and CD8+ T cells to initiate and modulate primary immune responses. They have the ability to coordinate tolerance or immunity depending on their activation status, which is why they are also considered as the orchestrating cells of the immune response. The purpose of this review is to provide a general overview of the current knowledge on ontogeny and subsets of human dendritic cells as well as their function and different biological roles.

scholarly journals Virus-Based Immunotherapy of Glioblastoma

Cancers ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 186 ◽  
Author(s):  
Miika Martikainen ◽  
Magnus Essand
Keyword(s):  
Immune Responses ◽  
Oncolytic Virus ◽  
Early Stage ◽  
Primary Brain Tumor ◽  
Oncolytic Viruses ◽  
Preclinical Models ◽  
Adjuvant Effect ◽  
Cell Responses ◽  
Near Future ◽  
Stimulation Of

Glioblastoma (GBM) is the most common type of primary brain tumor in adults. Despite recent advances in cancer therapy, including the breakthrough of immunotherapy, the prognosis of GBM patients remains dismal. One of the new promising ways to therapeutically tackle the immunosuppressive GBM microenvironment is the use of engineered viruses that kill tumor cells via direct oncolysis and via stimulation of antitumor immune responses. In this review, we focus on recently published results of phase I/II clinical trials with different oncolytic viruses and the new interesting findings in preclinical models. From syngeneic preclinical GBM models, it seems evident that oncolytic virus-mediated destruction of GBM tissue coupled with strong adjuvant effect, provided by the robust stimulation of innate antiviral immune responses and adaptive anti-tumor T cell responses, can be harnessed as potent immunotherapy against GBM. Although clinical testing of oncolytic viruses against GBM is at an early stage, the promising results from these trials give hope for the effective treatment of GBM in the near future.

scholarly journals Distinct Contributions of Interleukin-1α (IL-1α) and IL-1β to Innate Immune Recognition of Pseudomonas aeruginosa in the Lung

2014 ◽  
Vol 82 (10) ◽  
pp. 4204-4211 ◽  
Author(s):  
Khatoun Al Moussawi ◽  
Barbara I. Kazmierczak
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Immune Responses ◽  
Bacterial Pathogen ◽  
Innate Immune ◽  
Immune Recognition ◽  
Content Type ◽  
Caspase 1 ◽  
Rapid Responses ◽  
Subsequent Activation ◽  
Deficient Mice

ABSTRACTThe bacterial pathogenPseudomonas aeruginosacauses acute infections associated with significant morbidity and mortality.P. aeruginosaelicits strong innate immune responses in immunocompetent hosts, and the resulting recruitment of neutrophils to the site of infection is necessary for bacterial clearance.P. aeruginosalipopolysaccharide and flagellin are recognized by extracellular Toll-like receptors, but the most rapid responses to infection occur when cytosolic receptors sense flagellin or type 3 secretion system (T3SS) structural proteins. The subsequent activation of the NLRC4 inflammasome and caspase-1 generates an interleukin-1β (IL-1β) signal that is required for the rapid neutrophilic response. A T3SS effector, exotoxin U (ExoU), can inhibit activation of the NLRC4 inflammasome and caspase-1. Thus, our observation that IL-1 receptor (IL-1R)-mediated signals were still required to initiate a response to ExoU-producing bacteria was unexpected. As both IL-1α and IL-1β signal via the IL-1R, we examined immune responses in mice lacking either of these cytokines. IL-1β-deficient mice responded to ExoU-producingP. aeruginosabacteria similarly to wild-type animals; however, IL-1α-deficient mice had an attenuated immune response. The situation was reversed following infections by ExoU-negative bacteria: here, IL-1α was dispensable for neutrophil recruitment, while IL-1β was required. IL-1α secretion by macrophages infected with ExoU-producingP. aeruginosaisolates was independent of both caspase-1 and caspase-11. This study documents distinct roles for IL-1α and IL-1β in the response toP. aeruginosainfection as a function of the T3SS effectors produced by the infecting strain. The redundancy of these two cytokines nonetheless allows the infected host to mount a response to ExoU-positive and -negative bacterial isolates.

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