scholarly journals HLA-B and cysteinylated ligands distinguish the antigen presentation landscape of extracellular vesicles

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Julia Bauzá-Martinez ◽  
Albert J. R. Heck ◽  
Wei Wu
Keyword(s):  
Immune Responses ◽  
Antigen Presentation ◽  
Extracellular Vesicles ◽  
Therapeutic Potential ◽  
Critical Evaluation ◽  
Peptide Ligands ◽  
Human Immune System ◽  
Whole Cells ◽  
Cancer Antigens ◽  
Human Immune

AbstractExtracellular vesicles can modulate diverse processes ranging from proliferation and tissue repair, to chemo-resistance and cellular differentiation. With the advent of tissue and immunological targeting, extracellular vesicles are also increasingly viewed as promising vectors to deliver peptide-based cancer antigens to the human immune system. Despite the clinical relevance and therapeutic potential of such ‘cell-free’ approaches, the natural antigen presentation landscape exported in extracellular vesicles is still largely uncharted, due to the challenging nature of such preparations and analyses. In the context of therapeutic vesicle production, a critical evaluation of the similarity in vesicular antigen presentation is also urgently needed. In this work, we compared the HLA-I peptide ligandomes of extracellular vesicles against that of whole-cells of the same cell line. We found that extracellular vesicles not only over-represent HLA-B complexes and peptide ligands, but also cysteinylated peptides that may modulate immune responses. Collectively, these findings describe the pre-existing provision of vesicular HLA complexes that may be utilized to carry peptide vaccines, as well as the propensity for different peptide and post-translationally modified ligands to be presented, and will outline critical considerations in devising novel EV vaccination strategies.

scholarly journals Development of a new patient-derived xenograft humanised mouse model to study human-specific tumour microenvironment and immunotherapy

Gut ◽  
2018 ◽  
Vol 67 (10) ◽  
pp. 1845-1854 ◽  
Author(s):  
Yue Zhao ◽  
Timothy Wai Ho Shuen ◽  
Tan Boon Toh ◽  
Xue Ying Chan ◽  
Min Liu ◽  
...  
Keyword(s):  
Immune System ◽  
Immune Responses ◽  
Immune Checkpoint ◽  
Drug Testing ◽  
Checkpoint Inhibitors ◽  
Tumour Microenvironment ◽  
Human Immune System ◽  
Patient Derived Xenograft ◽  
Human Immune ◽  
Human Specific

ObjectiveAs the current therapeutic strategies for human hepatocellular carcinoma (HCC) have been proven to have limited effectiveness, immunotherapy becomes a compelling way to tackle the disease. We aim to provide humanised mouse (humice) models for the understanding of the interaction between human cancer and immune system, particularly for human-specific drug testing.DesignPatient-derived xenograft tumours are established with type I human leucocyte antigen matched human immune system in NOD-scid Il2rg−/− (NSG) mice. The longitudinal changes of the tumour and immune responses as well as the efficacy of immune checkpoint inhibitors are investigated.ResultsSimilar to the clinical outcomes, the human immune system in our model is educated by the tumour and exhibits exhaustion phenotypes such as a significant declination of leucocyte numbers, upregulation of exhaustion markers and decreased the production of human proinflammatory cytokines. Notably, cytotoxic immune cells decreased more rapidly compared with other cell types. Tumour infiltrated T cells have much higher expression of exhaustion markers and lower cytokine production compared with peripheral T cells. In addition, tumour-associated macrophages and myeloid-derived suppressor cells are found to be highly enriched in the tumour microenvironment. Interestingly, the tumour also changes gene expression profiles in response to immune responses by upregulating immune checkpoint ligands. Most importantly, in contrast to the NSG model, our model demonstrates both therapeutic and side effects of immune checkpoint inhibitors pembrolizumab and ipilimumab.ConclusionsOur work provides a model for immune-oncology study and a useful parallel-to-human platform for anti-HCC drug testing, especially immunotherapy.

scholarly journals Characterization of Human Antiviral Adaptive Immune Responses during Hepatotropic Virus Infection in HLA-Transgenic Human Immune System Mice

2013 ◽  
Vol 191 (4) ◽  
pp. 1753-1764 ◽  
Author(s):  
Eva Billerbeck ◽  
Joshua A. Horwitz ◽  
Rachael N. Labitt ◽  
Bridget M. Donovan ◽  
Kevin Vega ◽  
...  
Keyword(s):  
Immune System ◽  
Virus Infection ◽  
Immune Responses ◽  
Human Immune System ◽  
Adaptive Immune Responses ◽  
Adaptive Immune ◽  
Human Immune

scholarly journals Mathematical model of a personalized neoantigen cancer vaccine and the human immune system

2021 ◽  
Vol 17 (9) ◽  
pp. e1009318
Author(s):  
Marisabel Rodriguez Messan ◽  
Osman N. Yogurtcu ◽  
Joseph R. McGill ◽  
Ujwani Nukala ◽  
Zuben E. Sauna ◽  
...  
Keyword(s):  
Mathematical Model ◽  
T Cells ◽  
Immune System ◽  
Immune Responses ◽  
Cancer Vaccine ◽  
Tumor Size ◽  
Cancer Vaccines ◽  
Patient Specific ◽  
Human Immune System ◽  
Human Immune

Cancer vaccines are an important component of the cancer immunotherapy toolkit enhancing immune response to malignant cells by activating CD4+ and CD8+ T cells. Multiple successful clinical applications of cancer vaccines have shown good safety and efficacy. Despite the notable progress, significant challenges remain in obtaining consistent immune responses across heterogeneous patient populations, as well as various cancers. We present a mechanistic mathematical model describing key interactions of a personalized neoantigen cancer vaccine with an individual patient’s immune system. Specifically, the model considers the vaccine concentration of tumor-specific antigen peptides and adjuvant, the patient’s major histocompatibility complexes I and II copy numbers, tumor size, T cells, and antigen presenting cells. We parametrized the model using patient-specific data from a clinical study in which individualized cancer vaccines were used to treat six melanoma patients. Model simulations predicted both immune responses, represented by T cell counts, to the vaccine as well as clinical outcome (determined as change of tumor size). This model, although complex, can be used to describe, simulate, and predict the behavior of the human immune system to a personalized cancer vaccine.

scholarly journals The immune system as a biomonitor: explorations in innate and adaptive immunity

2013 ◽  
Vol 3 (2) ◽  
pp. 20120099 ◽  
Author(s):  
Niclas Thomas ◽  
James Heather ◽  
Gabriel Pollara ◽  
Nandi Simpson ◽  
Theres Matjeka ◽  
...  
Keyword(s):  
Immune System ◽  
Immune Responses ◽  
Lymphoid Tissue ◽  
Tissue Injury ◽  
Great Sensitivity ◽  
The Body ◽  
Human Immune System ◽  
Ligand Interactions ◽  
Human Immune ◽  
Body Self

The human immune system has a highly complex, multi-layered structure which has evolved to detect and respond to changes in the internal microenvironment of the body. Recognition occurs at the molecular or submolecular scale, via classical reversible receptor–ligand interactions, and can lead to a response with great sensitivity and speed. Remarkably, recognition is coupled to memory, such that responses are modulated by events which occurred years or even decades before. Although the immune system in general responds differently and more vigorously to stimuli entering the body from the outside (e.g. infections), this is an emergent property of the system: many of the recognition molecules themselves have no inherent bias towards external stimuli (non-self) but also bind targets found within the body (self). It is quite clear that the immune response registers pathophysiological changes in general. Cancer, wounding and chronic tissue injury are some obvious examples. Against this background, the immune system ‘state’ tracks the internal processes of the body, and is likely to encode information regarding both current and past disease processes. Moreover, the distributed nature of most immune responses (e.g. typically involving lymphoid tissue, non-lymphoid tissue, bone marrow, blood, extracellular interstitial spaces, etc.) means that many of the changes associated with immune responses are manifested systemically, and specifically can be detected in blood. This provides a very convenient route to sampling immune cells. We consider two different and complementary ways of querying the human immune ‘state’ using high-dimensional genomic screening methodologies, and discuss the potentials of these approaches and some of the technological and computational challenges to be overcome.

Development of CD40L-modified tumor small extracellular vesicles for effective induction of antitumor immune response

Nanomedicine ◽  
2020 ◽  
Vol 15 (17) ◽  
pp. 1641-1652
Author(s):  
Wen Liu ◽  
Yuki Takahashi ◽  
Masaki Morishita ◽  
Makiya Nishikawa ◽  
Yoshinobu Takakura
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Dendritic Cells ◽  
Immune Responses ◽  
Antigen Presentation ◽  
Extracellular Vesicles ◽  
Tumor Antigen ◽  
Tumor Antigens ◽  
Cd40 Ligand ◽  
Further Development

Aim: Tumor-derived small extracellular vesicles (TEVs) are considered for use in inducing tumor antigen-specific immune responses as they contain tumor antigens. The delivery of tumor antigens to the antigen presentation cells (especially dendritic cells [DCs]), and the activation of DCs are the main challenges of TEV therapy. Materials & methods: TEVs were modified with CD40 ligand (CD40L), which can target CD40 expressed on the surface of DCs and can activate them via CD40L-CD40 interactions. Results: It was found that CD40L-TEVs were efficiently taken up by DCs and also activated them. Moreover, tumor antigens were efficiently presented to the T cells by DCs treated with CD40L-TEVs. Conclusion: This study proved that CD40L-modification of TEVs will be helpful for further development of TEV-based tumor vaccination.

scholarly journals Molecular mimicry of HIV gp120: Possible implications on prevention and therapy of AIDS

2005 ◽  
Vol 13 (3-4) ◽  
pp. 126-130
Author(s):  
Nevena Veljkovic
Keyword(s):  
Immune System ◽  
Immune Responses ◽  
Molecular Mimicry ◽  
Human Immune System ◽  
Host Cell Proteins ◽  
Immunodeficiency Virus ◽  
Human Proteins ◽  
Human Immune ◽  
Hiv Gp120 ◽  
Hiv 1

A broad range of similarities between HIV-1 gp120 and human proteins-especially those participating in immune responses-highlight gp120 as a pleiotropic protein which can influence many important functions of the human immune system. The molecular mimicry that serves to the human immunodeficiency virus as potent destructive arms against immune system could be the weak point we are in search of over decades. Examples involving sequence and informational similarities of HIV-1 gp120 and immunerelated host cell proteins important for prevention and treatment of HIV infection are presented. .

scholarly journals A comprehensive logic-based model of the human immune system to study the dynamics responses to mono- and coinfections

2020 ◽  
Author(s):  
Bhanwar Lal Puniya ◽  
Robert Moore ◽  
Akram Mohammed ◽  
Rada Amin ◽  
Alyssa La Fleur ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Immune Responses ◽  
Immune Cells ◽  
Computational Models ◽  
Single Infection ◽  
Human Immune System ◽  
Adaptive Immune ◽  
Adaptive Immune Cells ◽  
Human Immune

AbstractThe human immune system, which protects against pathogens and diseases, is a complex network of cells and molecules. The effects of complex dynamical interactions of pathogens and immune cells on the immune response can be studied using computational models. However, a model of the entire immune system is still lacking. Here, we developed a comprehensive computational model that integrates innate and adaptive immune cells, cytokines, immunoglobulins, and nine common pathogens from different classes of virus, bacteria, parasites, and fungi. This model was used to investigate the dynamics of the immune system under two scenarios: (1) single infection with pathogens, and (2) various medically relevant pathogen coinfections. In coinfections, we found that the order of infecting pathogens has a significant impact on the dynamics of cytokines and immunoglobulins. Thus, our model provides a tool to simulate immune responses under different dosage of pathogens and their combinations, which can be further extended and used as a tool for drug discovery and immunotherapy. Furthermore, the model provides a comprehensive and simulatable blueprint of the human immune system as a result of the synthesis of the vast knowledge about the network-like interactions of various components of the system.

scholarly journals Enterovirus A71 Infection Activates Human Immune Responses and Induces Pathological Changes in Humanized Mice

2018 ◽  
Vol 93 (3) ◽  
Author(s):  
Yanyan Ke ◽  
Wai Nam Liu ◽  
Zhisheng Her ◽  
Min Liu ◽  
Sue Yee Tan ◽  
...  
Keyword(s):  
Immune Responses ◽  
Humanized Mice ◽  
Human Immune System ◽  
Humanized Mouse ◽  
Humanized Mouse Model ◽  
Drug Candidates ◽  
Cell Responses ◽  
Human T Cell ◽  
Enterovirus A71 ◽  
Human Immune

ABSTRACT Since the discovery of enterovirus A71 (EV-A71) half a century ago, it has been recognized as the cause of large-scale outbreaks of hand-foot-and-mouth disease worldwide, particularly in the Asia-Pacific region, causing great concern for public health and economic burdens. Detailed mechanisms on the modulation of immune responses after EV-A71 infection have not been fully known, and the lack of appropriate models hinders the development of promising vaccines and drugs. In the present study, NOD-scid IL2Rγ−/− (NSG) mice with a human immune system (humanized mice) at the age of 4 weeks were found to be susceptible to a human isolate of EV-A71 infection. After infection, humanized mice displayed limb weakness, which is similar to the clinical features found in some of the EV-A71-infected patients. Histopathological examination indicated the presence of vacuolation, gliosis, or meningomyelitis in brain stem and spinal cord, which were accompanied by high viral loads detected in these organs. The numbers of activated human CD4+ and CD8+ T cells were upregulated after EV-A71 infection, and EV-A71-specific human T cell responses were found. Furthermore, the secretion of several proinflammatory cytokines, such as human gamma interferon (IFN-γ), interleukin-8 (IL-8), and IL-17A, was elevated in the EV-A71-infected humanized mice. Taken together, our results suggested that the humanized mouse model permits insights into the human immune responses and the pathogenesis of EV-A71 infection, which may provide a platform for the evaluation of anti-EV-A71 drug candidates in the future. IMPORTANCE Despite causing self-limited hand-food-and-mouth disease in younger children, EV-A71 is consistently associated with severe forms of neurological complications and pulmonary edema. Nevertheless, only limited vaccines and drugs have been developed over the years, which is possibly due to a lack of models that can more accurately recapitulate human specificity, since human is the only natural host for wild-type EV-A71 infection. Our humanized mouse model not only mimics histological symptoms in patients but also allows us to investigate the function of the human immune system during infection. It was found that human T cell responses were activated, accompanied by an increase in the production of proinflammatory cytokines in EV-A71-infected humanized mice, which might contribute to the exacerbation of disease pathogenesis. Collectively, this model allows us to delineate the modulation of human immune responses during EV-A71 infection and may provide a platform to evaluate anti-EV-A71 drug candidates in the future.

scholarly journals Chitin, Chitinase Responses, and Invasive Fungal Infections

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Karina Vega ◽  
Markus Kalkum
Keyword(s):  
Immune Responses ◽  
Fungal Infections ◽  
Pathogenic Fungi ◽  
Therapeutic Approaches ◽  
Human Immune System ◽  
Cell Wall Component ◽  
Diagnostic Assays ◽  
Host Immune Responses ◽  
Human Immune ◽  
Novel Therapeutic

The human immune system is capable of recognizing and degrading chitin, an important cell wall component of pathogenic fungi. In the context of host-immune responses to fungal infections, herein we review the particular contributions and interplay of fungus and chitin recognition, and chitin-degrading enzymes, known as chitinases. The mechanisms of host chitinase responses may have implications for diagnostic assays as well as novel therapeutic approaches for patients that are at risk of contracting fatal fungal infections.

scholarly journals Scrutiny of human lung infection by SARS-CoV-2 and associated human immune responses in humanized mice

2021 ◽  
Author(s):  
Zheng Hu ◽  
Renren Sun ◽  
Zongzheng Zhao ◽  
Cong Fu ◽  
Yixin Wang ◽  
...  
Keyword(s):  
Immune Responses ◽  
Immune Cell ◽  
Human Lung ◽  
Defense Responses ◽  
Humanized Mice ◽  
In Vivo Model ◽  
Bodyweight Loss ◽  
Human Immune System ◽  
Live Virus ◽  
Human Immune

There is an urgent need for animal models of COVID-19 to study immunopathogenesis and test therapeutic intervenes. In this study we showed that NSG mice engrafted with human lung (HL) tissue (NSG-L) could be infected efficiently by SARS-CoV-2, and that live virus capable of infecting Vero cells was found in the HL grafts and multiple organs from infected NSG-L mice. RNA-seq examination identified a series of differentially expressed genes, which are enriched in viral defense responses, chemotaxis, interferon stimulation, and pulmonary fibrosis between HL grafts from infected and control NSG-L mice. Furthermore, when infecting humanized mice with human immune system (HIS) and autologous HL grafts (HISL mice), the mice had bodyweight loss and hemorrhage and immune cell infiltration in HL grafts, which were not observed in immunodeficient NSG-L mice, indicating the development of anti-viral immune responses in these mice. In support of this possibility, the infected HISL mice showed bodyweight recovery and lack of detectable live virus at the later time. These results demonstrate that NSG-L and HISL mice are susceptible to SARS-CoV-2 infection, offering a useful in vivo model for studying SARS-CoV-2 infection and the associated immune response and immunopathology, and testing anti-SARS-CoV-2 therapies.

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