scholarly journals Immune Organs and Immune Cells on a Chip: An Overview of Biomedical Applications

Micromachines ◽  
2020 ◽  
Vol 11 (9) ◽  
pp. 849 ◽  
Author(s):  
Margaretha Morsink ◽  
Niels Willemen ◽  
Jeroen Leijten ◽  
Ruchi Bansal ◽  
Su Shin
Keyword(s):  
Immune System ◽  
Human Immune System ◽  
Immune Organs ◽  
Future Challenges ◽  
Human Immune ◽  
Conventional Models ◽  
On Chip ◽  
And Behavior

Understanding the immune system is of great importance for the development of drugs and the design of medical implants. Traditionally, two-dimensional static cultures have been used to investigate the immune system in vitro, while animal models have been used to study the immune system’s function and behavior in vivo. However, these conventional models do not fully emulate the complexity of the human immune system or the human in vivo microenvironment. Consequently, many promising preclinical findings have not been reproduced in human clinical trials. Organ-on-a-chip platforms can provide a solution to bridge this gap by offering human micro-(patho)physiological systems in which the immune system can be studied. This review provides an overview of the existing immune-organs-on-a-chip platforms, with a special emphasis on interorgan communication. In addition, future challenges to develop a comprehensive immune system-on-chip model are discussed.

scholarly journals In Vitro Immune Organs-on-Chip for Drug Development: A Review

Pharmaceutics ◽  
2018 ◽  
Vol 10 (4) ◽  
pp. 278 ◽  
Author(s):  
Aya Shanti ◽  
Jeremy Teo ◽  
Cesare Stefanini
Keyword(s):  
Immune System ◽  
Drug Development ◽  
Attrition Rate ◽  
Human Immune System ◽  
Drug Candidates ◽  
Immune Organs ◽  
On Chip ◽  
High Attrition Rate

The current drug development practice lacks reliable and sensitive techniques to evaluate the immunotoxicity of drug candidates, i.e., their effect on the human immune system. This, in part, has resulted in a high attrition rate for novel drugs candidates. Organ-on-chip devices have emerged as key tools that permit the study of human physiology in controlled in vivo simulating environments. Furthermore, there has been a growing interest in developing the so called “body-on-chip” devices to better predict the systemic effects of drug candidates. This review describes existing biomimetic immune organs-on-chip, highlights their physiological relevance to drug development and discovery and emphasizes the need for developing comprehensive immune system-on-chip models. Such immune models can enhance the performance of novel drug candidates during clinical trials and contribute to reducing the high attrition rate as well as the high cost associated with drug development.

Transient accumulation of human mature thymocytes and regulatory T cells with CD28 superagonist in “human immune system” Rag2-/-γc-/- mice

Blood ◽  
2006 ◽  
Vol 108 (1) ◽  
pp. 238-245 ◽  
Author(s):  
Nicolas Legrand ◽  
Tom Cupedo ◽  
Anja U. van Lent ◽  
Menno J. Ebeli ◽  
Kees Weijer ◽  
...  
Keyword(s):  
T Cells ◽  
Immune System ◽  
T Cell ◽  
Opportunistic Infections ◽  
Human Immune System ◽  
Independent Manner ◽  
Human T Cell ◽  
Human Immune

Efficient and quick reconstitution of T-cell compartments in lymphopenic patients is of great importance to prevent opportunistic infections, but remains difficult to achieve. Human T-cell proliferation in a T-cell-receptor (TCR)-independent manner is possible in vitro with superagonist anti-CD28 antibodies, and such molecules are therefore promising therapeutic tools. Here, we investigated the in vivo effects of superagonist anti-CD28 treatment on human developing and mature T cells, in the recently developed model of “human immune system” BALB/c Rag2-/-γc-/- mice. Our results show that superagonist anti-CD28 treatment transiently induces a 7-fold increase in thymocyte numbers and up to 18-fold accumulation of mature thymocytes. The increased thymic production lead to transient accumulation of mature T cells in the periphery at the peak of treatment effect (day 6). In addition, long-term peripheral T-cell depletion was induced. Furthermore, the concomitant selective expansion and accumulation of suppressive CD4+CD25+FoxP3+ T cells was induced in a transient manner. Superagonist anti-CD28 therapy could therefore be of clinical interest in humans, both for beneficial effect on thymic T-cell production as well as regulatory T-cell accumulation. (Blood. 2006;108:238-245)

scholarly journals P06.07 In vivo studies of immunomodulatory a-CTLA-4 antibody in a humanized mouse model

2021 ◽  
Vol 9 (Suppl 1) ◽  
pp. A22.1-A22
Author(s):  
C Reitinger ◽  
F Nimmerjahn
Keyword(s):  
Immune System ◽  
Mouse Model ◽  
Cancer Immunotherapy ◽  
Model Systems ◽  
Checkpoint Control ◽  
Human Immune System ◽  
Humanized Mouse ◽  
Humanized Mouse Model ◽  
Human Immune

BackgroundRecent findings in cancer immunotherapy have reinforced the hypothesis that the immune system is able to control most cancers. Immunomodulatory antibodies can enhance immune responses, having the potential to generate anti-cancer immunity.1–4Materials and MethodsMost current studies addressing this question are performed in murine mouse model systems or use in vitro culture systems, which do not reflect the human in vivo situation, potentially leading to results that cannot be fully translated into human cancer therapy. Therefore, it is necessary to establish a new mouse model, which allows the study of cancer immunotherapy in the context of a human immune system. We focused on the establishment of a humanized mouse model, in which different immunomodulatory antibodies can be tested in the presence of a human immune system.ResultsFirst experiments concerning the suitability to test immunomodulatory antibodies in the humanized mouse model, revealed that effects of checkpoint-control antibody a-CTLA-4 were similar to the effects seen in patients of clinical studies. To analyse the anti-tumor activities of immunomodulatory antibodies in vivo we are establishing a human melanoma-like tumor model in humanized mice.ConclusionsThis enables us to test the efficacy of immunomodulatory agonistic antibodies (such as CP-870,893) and checkpoint control antibodies (such as anti-CTLA-4) in eliminating a melanoma-like tumor. Furthermore, parameters like tumor infiltrating human cells und cytokine/chemokine production can be analysed.ReferencesSchuster M, Nechansky A, Loibner H. Cancer immunotherapy. Biotechnol J 2006;1:138–147.Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature rev 2011;480:480–489.Finn OJ. Immuno-oncology: understanding the function and dysfunction of the immune system in cancer. Annals of Oncology 2012;23:vii6–vii9.Langer LF, Clay TM, Morse MA. Update on anti-CTLA-4 in clinical trials. Expert Opin Biol Ther 2007;8:1245–1256.Disclosure InformationC. Reitinger: None. F. Nimmerjahn: None.

scholarly journals Mesenchymal Stem Cells in COVID-19: A Journey from Bench to Bedside

2020 ◽  
Vol 52 (1) ◽  
pp. 24-35
Author(s):  
Kamal Kant Sahu ◽  
Ahmad Daniyal Siddiqui ◽  
Jan Cerny
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Immune System ◽  
Therapeutic Option ◽  
Antiviral Agent ◽  
In Vitro Models ◽  
Human Immune System ◽  
Economic Sectors ◽  
Human Immune

Abstract The COVID-19 pandemic has led to a major setback in both the health and economic sectors across the globe. The scale of the problem is enormous because we still do not have any specific anti-SARS-CoV-2 antiviral agent or vaccine. The human immune system has never been exposed to this novel virus, so the viral interactions with the human immune system are completely naive. New approaches are being studied at various levels, including animal in vitro models and human-based studies, to contain the COVID-19 pandemic as soon as possible. Many drugs are being tested for repurposing, but so far only remdesivir has shown some positive benefits based on preliminary reports, but these results also need further confirmation via ongoing trials. Otherwise, no other agents have shown an impactful response against COVID-19. Recently, research exploring the therapeutic application of mesenchymal stem cells (MSCs) in critically ill patients suffering from COVID-19 has gained momentum. The patients belonging to this subset are most likely beyond the point where they could benefit from an antiviral therapy because most of their illness at this stage of disease is driven by inflammatory (over)response of the immune system. In this review, we discuss the potential of MSCs as a therapeutic option for patients with COVID-19, based on the encouraging results from the preliminary data showing improved outcomes in the progression of COVID-19 disease.

scholarly journals Immunomodulatory Effects of Edible and Medicinal Mushrooms and Their Bioactive Immunoregulatory Products

2020 ◽  
Vol 6 (4) ◽  
pp. 269
Author(s):  
Shuang Zhao ◽  
Qi Gao ◽  
Chengbo Rong ◽  
Shouxian Wang ◽  
Zhekun Zhao ◽  
...  
Keyword(s):  
Bioactive Compounds ◽  
Immune Modulation ◽  
Essential Amino Acids ◽  
Current Status ◽  
Human Immune System ◽  
Mushroom Species ◽  
Medicinal Mushrooms ◽  
Human Immune

Mushrooms have been valued as food and health supplements by humans for centuries. They are rich in dietary fiber, essential amino acids, minerals, and many bioactive compounds, especially those related to human immune system functions. Mushrooms contain diverse immunoregulatory compounds such as terpenes and terpenoids, lectins, fungal immunomodulatory proteins (FIPs) and polysaccharides. The distributions of these compounds differ among mushroom species and their potent immune modulation activities vary depending on their core structures and fraction composition chemical modifications. Here we review the current status of clinical studies on immunomodulatory activities of mushrooms and mushroom products. The potential mechanisms for their activities both in vitro and in vivo were summarized. We describe the approaches that have been used in the development and application of bioactive compounds extracted from mushrooms. These developments have led to the commercialization of a large number of mushroom products. Finally, we discuss the problems in pharmacological applications of mushrooms and mushroom products and highlight a few areas that should be improved before immunomodulatory compounds from mushrooms can be widely used as therapeutic agents.

scholarly journals Human NK cells of mice with reconstituted human immune system components require preactivation to acquire functional competence

Blood ◽  
2010 ◽  
Vol 116 (20) ◽  
pp. 4158-4167 ◽  
Author(s):  
Till Strowig ◽  
Obinna Chijioke ◽  
Paolo Carrega ◽  
Frida Arrey ◽  
Sonja Meixlsperger ◽  
...  
Keyword(s):  
Immune System ◽  
Cord Blood ◽  
Nk Cells ◽  
Nk Cell ◽  
Human Immune System ◽  
Hematopoietic Progenitor ◽  
Human Adult ◽  
System Components ◽  
Human Immune

Abstract To investigate human natural killer (NK)–cell reactivity in vivo we have reconstituted human immune system components by transplantation of human hematopoietic progenitor cells into NOD-scid IL2Rγnull mice. We demonstrate here that this model allows the development of all NK-cell subsets that are also found in human adult peripheral and cord blood, including NKp46+CD56− NK cells. Similar to human cord blood, NK cells from these reconstituted mice require preactivation by interleukin-15 to reach the functional competence of human adult NK cells. Mainly the terminally differentiated CD16+ NK cells demonstrate lower reactivity without this stimulation. After preactivation, both CD16+ and CD16− NK cells efficiently produce interferon-γ and degranulate in response to stimulation with NK cell–susceptible targets, including K562 erythroleukemia cells. NK-cell lines, established from reconstituted mice, demonstrate cytotoxicity against this tumor cell line. Importantly, preactivation can as well be achieved by bystander cell maturation via poly I:C stimulation in vitro and injection of this maturation stimulus in vivo. Preactivation in vivo enhances killing of human leukocyte antigen class I negative tumor cells after their adoptive transfer. These data suggest that a functional, but resting, NK-cell compartment can be established in immune-compromised mice after human hematopoietic progenitor cell transfer.

scholarly journals Human innate responses and adjuvant activity of TLR ligands in vivo in mice reconstituted with a human immune system

Vaccine ◽  
2017 ◽  
Vol 35 (45) ◽  
pp. 6143-6153 ◽  
Author(s):  
Liang Cheng ◽  
Zheng Zhang ◽  
Guangming Li ◽  
Feng Li ◽  
Li Wang ◽  
...  
Keyword(s):  
Immune System ◽  
Human Immune System ◽  
Adjuvant Activity ◽  
Human Immune

scholarly journals Stable Engraftment of a Human Gut Bacterial Microbiome in Double Humanized BLT-mice

2019 ◽  
Author(s):  
Lance Daharsh ◽  
Amanda E. Ramer-Tait ◽  
Qingsheng Li
Keyword(s):  
Immune System ◽  
Gut Microbiome ◽  
Human Disease ◽  
Humanized Mice ◽  
Rrna Gene ◽  
Human Immune System ◽  
Human Gut ◽  
Healthy Human ◽  
Human Immune

AbstractBackgroundHumanized mice featuring a functional human immune system are an important pre-clinical model for examining immune responses to human-specific pathogens. This model has been widely utilized to study human diseases that are otherwise impossible or difficult to investigate in humans or with other animal models. However, one limitation of using humanized mice is their native murine gut microbiome, which significantly differs from the one found in humans. These differences may be even greater for mice housed and bred in specific pathogen free conditions. Given the importance of the gut microbiome to human health and disease, these differences may profoundly impact the ability to translate the results from humanized mice studies to human disease. Further, there is a critical need for improved pre-clinical models to study the complex in vivo relationships of the gut microbiome, immune system, and human disease. We therefore created double humanized mice with both a functional human immune system and stable human-like gut microbiome.ResultsSurgery was performed on NOD.Cg-PrkdcscidII2rgtm1Wjl/SzJ (NSG) mice to create bone-marrow, liver, thymus (BLT) humanized mice. After immune reconstitution, mice were treated with broad spectrum antibiotics to deplete murine gut bacteria and then transplanted with fecal material from healthy human donors. Characterization of 173 fecal samples obtained from 45 humanized mice revealed that double humanized mice had unique 16S rRNA gene profiles consistent with those of the individual human donor samples. Importantly, transplanted human-like gut microbiomes were stable in mice for the duration of the study, up to 14.5 weeks post-transplant. Microbiomes of double humanized mice also harbored predicted functional capacities that more closely resembled those of the human donors compared to humanized mice.ConclusionsHere, we describe successful engraftment of a stable human microbiome in BLT humanized mice to further improve this preclinical humanized mouse model. These double humanized mice represent a unique and tractable new model to study the complex relationships between the human gut microbiome, human immune system, and human disease in vivo.

scholarly journals Building the Next Generation of Humanized Hemato-Lymphoid System Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Tijana Martinov ◽  
Kelly M. McKenna ◽  
Wei Hong Tan ◽  
Emily J. Collins ◽  
Allie R. Kehret ◽  
...  
Keyword(s):  
Immune System ◽  
Adaptive Immunity ◽  
Humanized Mice ◽  
Human Immune System ◽  
Functional Interactions ◽  
Life Saving ◽  
Mouse Tissues ◽  
Fundamental Biology ◽  
Human Immune

Since the late 1980s, mice have been repopulated with human hematopoietic cells to study the fundamental biology of human hematopoiesis and immunity, as well as a broad range of human diseases in vivo. Multiple mouse recipient strains have been developed and protocols optimized to efficiently generate these “humanized” mice. Here, we review three guiding principles that have been applied to the development of the currently available models: (1) establishing tolerance of the mouse host for the human graft; (2) opening hematopoietic niches so that they can be occupied by human cells; and (3) providing necessary support for human hematopoiesis. We then discuss four remaining challenges: (1) human hematopoietic lineages that poorly develop in mice; (2) limited antigen-specific adaptive immunity; (3) absent tolerance of the human immune system for its mouse host; and (4) sub-functional interactions between human immune effectors and target mouse tissues. While major advances are still needed, the current models can already be used to answer specific, clinically-relevant questions and hopefully inform the development of new, life-saving therapies.

scholarly journals Pathophysiological Role and Therapeutic Implications of Vitamin D in Autoimmunity: Focus on Chronic Autoimmune Diseases

Nutrients ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 789 ◽  
Author(s):  
Mattia Bellan ◽  
Laura Andreoli ◽  
Chiara Mele ◽  
Pier Paolo Sainaghi ◽  
Cristina Rigamonti ◽  
...  
Keyword(s):  
Vitamin D ◽  
Immune System ◽  
Autoimmune Diseases ◽  
Convincing Evidence ◽  
In Vivo Studies ◽  
Human Immune System ◽  
Therapeutic Implications ◽  
Wide Range

Vitamin D is a pleiotropic secosteroid yielding multiple actions in human physiology. Besides the canonical regulatory activity on bone metabolism, several non-classical actions have been described and the ability of vitamin D to partake in the regulation of the immune system is particularly interesting, though far stronger and convincing evidence has been collected in in vitro as compared to in vivo studies. Whether vitamin D is able to regulate at physiological concentrations the human immune system remains unproven to date. Consequently, it is not established if vitamin D status is a factor involved in the pathogenesis of immune-mediated diseases and if cholecalciferol supplementation acts as an adjuvant for autoimmune diseases. The development of autoimmunity is a heterogeneous process, which may involve different organs and systems with a wide range of clinical implications. In the present paper, we reviewed the current evidences regarding vitamin D role in the pathogenesis and management of different autoimmune diseases.

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