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NK Cell-Based Cancer Immunotherapy

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889199341 Year: Pages: 222 DOI: 10.3389/978-2-88919-934-1 Language: English
Publisher: Frontiers Media SA
Subject: Medicine (General) --- Allergy and Immunology
Added to DOAB on : 2016-01-19 14:05:46
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Natural killer (NK) cells are innate lymphoid cells that have a significant role in regulating the defenses against cancer development and certain viral infections. They are equipped with an array of activating and inhibitory receptors that stimulate or diminish NK cell activity, respectively. Inhibitory receptors include, among others, the MHC class I ligands killer cell immunoglobulin-like receptors (KIR) in humans, and members of the Ly49 family of receptors in mice, and CD94/NKG2A. Activating receptors include cytokine and chemokine receptors, and those that interact with ligands expressed on target cells, such as the natural cytotoxicity receptors or NCRs (NKp30, NKp44 and NKp46), NKG2D, CD244 and DNAM-1. In addition, NK cells express Fc?RIIIA or CD16, the receptor that exerts antibody-dependent cell mediated cytotoxicity (ADCC). NK cells also express the death ligands FasL and TRAIL. The killing or sparing of target cells depends on the integration of distinct signals that originate from NK cell receptors. NK cells spare healthy cells that express normal levels of MHC class I molecules and low amounts of stress-induced self-molecules, whereas they kill target cells that down-regulate MHC class I molecules and/or up-regulate stress-induced self-molecules. The latter are common signatures of virus-infected cells and tumors. All the accumulated knowledge on NK cell biology, along with many clinical observations, is driving multiple efforts to improve the arsenal of NK cell-based therapeutic tools in the fight against malignant diseases. Indeed, NK cell-based immunotherapy is becoming a promising approach for the treatment of many cancers. It is well known that NK cells have a significant role in the anti-tumor effect of therapeutic antibodies that use ADCC as a mechanism of action. In addition to this, administration of autologous and allogeneic NK cells after activation and expansion ex vivo is used in the treatment of cancer. Moreover, adoptive transfer of NK cell lines has been tested in humans, and genetically modified NK cells expressing chimeric antigen receptors are being studied in preclinical models for potential use in the clinic.

The Second Life of Natural Killer (NK) Cells

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889455461 Year: Pages: 118 DOI: 10.3389/978-2-88945-546-1 Language: English
Publisher: Frontiers Media SA
Subject: Medicine (General) --- Allergy and Immunology
Added to DOAB on : 2019-01-23 14:53:42
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Natural Killer (NK) cells are innate lymphocytes, now recognized as members of a larger family of “Innate lymphoid cells” (ILCs). Both murine and human NK cells are well characterized effector cells with cytotoxic as well as cytokine production ability which mainly react in response to microbial and cell stress stimuli, thus playing a central role in the defense against pathogen infection, in tumor surveillance and in regulating immune homeostasis. Despite these established concepts, our understanding of the complexity of NK cells, also in view of their developmental and functional relationship with other ILC subsets, is only recently emerging. This Research Topic highlights the recent advances in NK cell (and ILC) research in human and mouse from basic research to clinical applications.

Protective Immune Response to Dengue Virus Infection and Vaccines: perspectives from the field to the bench

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889195114 Year: Pages: 97 DOI: 10.3389/978-2-88919-511-4 Language: English
Publisher: Frontiers Media SA
Subject: Allergy and Immunology --- Medicine (General)
Added to DOAB on : 2015-12-03 13:02:24
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Dengue is the most important mosquito-transmitted viral disease in humans. Half of the world population is at risk of infection, mostly in tropical and sub-tropical areas. The World Health Organization (WHO) estimates that 50 to 100 million infections occur yearly, with 50,000 to 100,000 deaths related to dengue, mainly in children. Recent estimates show higher numbers, up to three times more, with 390 million estimated dengue infections per year, among which 96 million apparent infections (Bhatt et al. 2013). Initially localized to South-East Asia, dengue virus (DENV) started its spread in Latin America in the 80s. Little is known about DENV spread in Africa, but multiple seroprevalence surveys over several years are now clearly showing endemic areas in East and West Africa (Brady et al. 2013). Finally, due to global warming and intense traveling there is a risk of global spread towards more temperate regions, and both US Key islands (FL) and southern Europe recently faced DENV outbreaks. There are currently no specific treatments or vaccines available. Even though several dengue vaccines are in the pipeline, clear correlates of protection are still lacking. The recent failure of the live-attenuated Sanofi vaccine Phase 2b trial (Sabchareon et al. 2013) and the lack of correlation between clinical protection and in vitro neutralization assays, clearly underlines the necessity to better understand the role of the different components of the immune system in protection against dengue virus infection and the requirement for the development of additional and/or improved predictive assays. The aim of this research topic is to provide novel data, opinions and literature reviews on the best immune correlates of protection and recent advances in the immune response to DENV infection that can allow rapid progress of dengue vaccines. Authors can choose to submit original research papers, reviews or opinions on pre-clinical or clinical observations that will help unify the field, with perspectives from epidemiology, virology, immunology and vaccine developers. This research topic will discuss different aspects of the protective immune response to DENV that can influence vaccine development. It will include a review of epidemiological data generated in the field, which will address spatio-temporal diversity of DENV epidemics, the importance of cross-reactive protection and of the time-interval between infections as a predictor of disease. It will further include a review of the role of both the innate and adaptive immunity in DENV infection control, and discuss the usefulness of new improved animal models in dissecting the role of each immunological compartment, which will help define new correlate of immune protection. New data concerning the DENV structure and anti-dengue antibody structure will address the necessity of improved neutralization assays. The ultimate test to prove vaccine efficacy and study immune correlates of protection in humans before large trials will open up the discussion on human DENV challenges using controlled attenuated viral strains. Finally, the role of vaccines, administered in flavi-immune populations, in the modification of future epidemics will also be approached and will include novel studies on mosquitoes infection thresholds.

Immunomodulatory Effects of Drugs for Treatment of Immune-Related Diseases

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889452880 Year: Pages: 108 DOI: 10.3389/978-2-88945-288-0 Language: English
Publisher: Frontiers Media SA
Subject: Medicine (General) --- Allergy and Immunology
Added to DOAB on : 2018-02-27 16:16:44
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More than 90% of diseases possess immunological abnormalities. Disorders such as inflammation, hypersensitivity, autoimmunity and immunodeficiency are simple examples of how the immune system misinterprets its surroundings and goes awry. Multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel diseases, among many others are manifestations of immune cells attacking normal tissues. On the other hand, damping the immune system leads to diseases such as cancer, AIDS, and severe combined immunodeficiency. The last ten years witnessed an explosion in developing drugs that target the immune system. Several novel monoclonal antibodies have been approved for treatment of various diseases confirming that personalized medicine approach is robust in combating diseases. Hence, the future holds great promise for using personalized and targeted medicine rather than generalized medications that, in most circumstances, proven to be ineffective and characteristically exert side effects. Approaches such as generating novel adjuvants that can stimulate the immune system without harmful side effects, targeting inflammatory cytokines and chemokines, harnessing and activating innate immune cells such as natural killer cells or dendritic cells, are examples of future approaches to treat autoimmune diseases, AIDS, and various forms of cancer resulting from chronic inflammation. More recently, targeting immune checkpoint molecules have shown therapeutic response against lung cancer and melanoma. Identifying molecules involved in autophagy is another example of how personalized medicine might help treat patients with refractory asthma and autoimmune diseases. This topic introduces the reader to these novel approaches of manipulating the immune system and developing targeted therapeutic strategies for treatment of various diseases.

NK Cell Subsets in Health and Disease: New Developments

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889453504 Year: Pages: 243 DOI: 10.3389/978-2-88945-350-4 Language: English
Publisher: Frontiers Media SA
Subject: Medicine (General) --- Allergy and Immunology
Added to DOAB on : 2018-02-27 16:16:45
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Natural Killer (NK) cells were discovered ca 1975, as the first group of lymphoid cells that were neither T cells nor B cells. Since then, the dissection of the biology of NK cells has been growing exponentially with many seminal discoveries from the identification of MHC class I-specific inhibitory receptors to the discovery of receptor-ligand pairs involved in NK cell activation and to the manipulation of NK cells in cancer. In this research topic, we asked a group of thought leaders in NK cell biology to review recent advances in their origins and biology, and their roles in cancer, infection and inflammation. Together, these 25 articles provide a timely survey of NK cells as critical immunologic components of health and disease. They will hopefully prompt further dialogue and developments in basic and translational immunology.

Molecular mechanisms regulating cytotoxic lymphocyte development and function, and their associations to human diseases

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889192793 Year: Pages: 163 DOI: 10.3389/978-2-88919-279-3 Language: English
Publisher: Frontiers Media SA
Subject: Allergy and Immunology --- Medicine (General)
Added to DOAB on : 2015-12-10 11:59:06
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Cytotoxic lymphocytes, comprised of NK cells and cytotoxic T cells, play a pivotal role in immune defense. By directed release of perforin-containing lytic granules, NK and cytotoxic T cells can eradicate pathogen-infected, tumorigenic, and otherwise stressed cells. By the virtue of cytokine and chemokine secretion, they can influence other cells of the immune system. Through these processes, cytotoxic lymphocytes also contribute to the maintenance of immune homeostasis. In recent years, much progress has been made with respect to the mechanisms by which cytotoxic lymphocytes develop, differentiate, and exert their effector functions. In a clinical perspective, a wide variety of mutations impairing cytotoxic lymphocyte development and/or function have been associated with immunodeficiency and severe diseases in humans. Aberrant activity of cytotoxic T cells and/or NK cells has been linked to an increased susceptibility to viral infections, persistent inflammation, cancer and autoimmunity. In addition, lymphocyte cytotoxic activity may be harnessed therapeutically to target tumor cells in different adoptive cellular therapy regimes, or through the use of recombinant antibodies. Still, a number of questions remain in regards to how cytotoxic lymphocytes develop, their relationships and plasticity, as well as the mechanisms dictating target cell discrimination, lytic granule release and induction of target cell death. In this Research Topic we encourage submission of research articles, reviews, perspectives, or methods on cytotoxic lymphocyte development and function, their relation to the pathogenesis or treatment of different diseases, as well as comparison between similarities and/or differences in their effector functions. Considering the clinical significance of NK cells and cytotoxic T cells, we aim to provide a range of articles summarizing the current knowledge on the identification and elucidation of the mechanisms governing cytotoxic lymphocyte activity.

Evolution of NK-mediated target recognition under the pressure of physiologic or pathologic stimuli

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889194520 Year: Pages: 190 DOI: 10.3389/978-2-88919-452-0 Language: English
Publisher: Frontiers Media SA
Subject: Allergy and Immunology --- Medicine (General)
Added to DOAB on : 2016-02-05 17:24:33
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Since their discovery NK cells have come out as potential tools to fight cancer and viruses. This finding early urged different groups to study the mechanisms governing NK cell function. The identification of the MHC-I-specific inhibitory receptors (i.e. KIRs, NKG2A and certain Ly49 molecules) allowed defining rather rapidly how NK cells could avoid self-aggression and how they could be directed towards targets that were forced, by viral infection or tumor transformation, to down-regulate MHC-I expression. In a second time, also the repertoire of surface activating receptors addressing NK cytotoxicity towards tumors and pathogens was mostly defined. In spite of the first findings, however, most recent studies may suggest that NK cells and their receptors might not have been evolved to kill tumor targets and, perhaps, they might have been only partially influenced, in their evolution, by the need of recognizing viruses. Indeed certain NK receptors known to activate NK cell cytotoxicity (NKp30, DNAM-1, NKp80) can also participate at regulatory interactions occurring between NK and myeloid cells. In addition, a peculiar NK cell subset which intensively populate decidua during the first trimester of pregnancy, through the engagement of specific receptors and the interaction with decidual DC, produce chemokines and pro-angiogenic cytokines, and induce Tregs. Thus, in this context, NK cells favor decidua vascularization and development of the (semiallogeneic) foetus in a tolerant environment. Viruses have nevertheless played an important role in shaping the NK cell receptor repertoire. Several studies have unveiled clues of the evolutionary struggle between these pathogens and NK cells. Different NK receptors, including NKp46, NKp30, NKp44, NKG2D, NKG2C, Ly49, and certain KIRs have been demonstrated to recognize virus-encoded or virus-induced ligands. The expression of TLR specifically recognizing microbial products, together with the unexpected role of KIR3DL2 in shuttling these products to TLR-containing endosomes have also been documented in NK cells. On the other side, different viral immune evasion molecules have been shown to interfere with the expression of ligands for T or NK cell activating receptors. In addition, viral infections can occur in the reproductive stage of life cycle, and may represent a serious threat for the species propagation. Thus the control of viruses, together with the maintenance of foetus during pregnancy, should represent major evolutionary forces in shaping NK-receptors. Along this line, the NK-mediated control of tumors should not be under the same evolutionary pressure, as tumors mostly appear later in the life cycle, and the recognition of tumor-encoded ligands may be less efficient (as the NK cell receptors might have not been selected for such aim). This may be the reason why, although displaying strong antitumor activity in vitro, NK cells could hardly contain tumor burden in vivo. In addition the pathogen-driven evolution of NK cell function may also favor the role of NK cells in the insurgence of immune-mediated diseases. This research topic will collect contributions that may clarify the relationships between the evolution of the NK receptors and their role in an efficient recognition of viruses and tumor cells or in immune-mediated diseases.

Tailoring NK Cell Receptor-Ligand Interactions: An Art in Evolution

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889454648 Year: Pages: 407 DOI: 10.3389/978-2-88945-464-8 Language: English
Publisher: Frontiers Media SA
Subject: Medicine (General) --- Allergy and Immunology
Added to DOAB on : 2018-11-16 17:17:57
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Recognition and killing of aberrant, infected or tumor targets by Natural Killer (NK) cells is mediated by positive signals transduced by activating receptors upon engagement of ligands on target surface. These stimulatory pathways are counterbalanced by inhibitory receptors that raise NK cell activation threshold through negative antagonist signals. While regulatory effects are necessary for physiologic control of autoimmune aggression, they may restrain the ability of NK cells to activate against disease. Overcoming this barrier to immune surveillance, multiple approaches to enhance NK-mediated responses are being investigated since two decades. Propelled by considerable advances in the understanding of NK cell biology, these studies are critical for effective translation of NK-based immunotherapy principles into the clinic. In humans, dominant inhibitory signals are transduced by Killer Immunoglobulin Like Receptors (KIR) recognizing cognate HLA class I on target cells. Conversely, KIR recognition of “missing self-HLA” - due to HLA loss or HLA/ KIR mismatch - triggers NK-mediated tumor rejection. Initially observed in murine transplant models, these antitumor effects were later found to have important implications for the clinical outcome of haplotype-mismatched stemcell transplantation. Here, donor NK subsets protect against acute myeloid leukemia (AML) relapse through missing self recognition of donor HLA-C allele groups (C1 or C2) and/or Bw4 epitope. These studies were subsequently extended by trials investigating the antileukemia effects of adoptively transferred haplotype-mismatched NK cells in non-transplant settings. Other mechanisms have been found to induce clinically relevant NK cell alloreactivity in transplantation, e.g., post-reconstitution functional reversal of anergic NK cells. More recently, activating KIR came into the spotlight for their potential ability to directly activate donor NK cells through in vivo recognition of HLA or other ligands. Novel therapeutic monoclonal antibodies (mAb) may optimize NK-mediated effects. Examples include obinutuzumab (GA101), a glyco-engineered anti-CD20 mAb with increased affinity for the FcγRIIIA receptor, enhancing antibody-dependent cellular cytotoxicity; lirilumab (IPH2102), a first-in-class NK-specific checkpoint inhibitor, blocking the interaction between the major KIR and cognate HLA-C antigens; and elotuzumab (HuLuc63), a humanized monoclonal antibody specific for SLAMF7, whose anti-myeloma therapeutic effects are partly due to direct activation of SLAMF7-expressing NK cells. In addition to conventional antibodies, NK cell-targeted bispecific (BiKEs) and trispecific (TriKEs) killer engagers have also been developed. These proteins elicit potent effector functions by binding target ligands (e.g., CD19, CD22, CD30, CD133, HLA class II, EGFR) on one arm and NK receptors on the other. An additional innovative approach to direct NK cell activity is genetic reprogramming with chimeric antigen receptors (CAR). To date, primary NK cells and the NK92 cell line have been engineered with CAR specific for antigens expressed on multiple tumors. Encouraging preclinical results warrant further development of this approach. This Research Topic welcomes contributions addressing mechanisms of NK-mediated activation in response to disease as well as past and contemporary strategies to enhance NK mediated reactivity through control of the interactions between NK receptors and their ligands.

Tailoring NK Cell Receptor-Ligand Interactions: an Art in Evolution. 2nd Edition

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889456635 Year: Pages: 407 DOI: 10.3389/978-2-88945-663-5 Language: English
Publisher: Frontiers Media SA
Subject: Medicine (General) --- Allergy and Immunology
Added to DOAB on : 2019-01-23 14:53:43
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Recognition and killing of aberrant, infected or tumor targets by Natural Killer (NK) cells is mediated by positive signals transduced by activating receptors upon engagement of ligands on target surface. These stimulatory pathways are counterbalanced by inhibitory receptors that raise NK cell activation threshold through negative antagonist signals. While regulatory effects are necessary for physiologic control of autoimmune aggression, they may restrain the ability of NK cells to activate against disease. Overcoming this barrier to immune surveillance, multiple approaches to enhance NK-mediated responses are being investigated since two decades. Propelled by considerable advances in the understanding of NK cell biology, these studies are critical for effective translation of NK-based immunotherapy principles into the clinic. In humans, dominant inhibitory signals are transduced by Killer Immunoglobulin Like Receptors (KIR) recognizing cognate HLA class I on target cells. Conversely, KIR recognition of “missing self-HLA” - due to HLA loss or HLA/ KIR mismatch - triggers NK-mediated tumor rejection. Initially observed in murine transplant models, these antitumor effects were later found to have important implications for the clinical outcome of haplotype-mismatched stemcell transplantation. Here, donor NK subsets protect against acute myeloid leukemia (AML) relapse through missing self recognition of donor HLA-C allele groups (C1 or C2) and/or Bw4 epitope. These studies were subsequently extended by trials investigating the antileukemia effects of adoptively transferred haplotype-mismatched NK cells in non-transplant settings. Other mechanisms have been found to induce clinically relevant NK cell alloreactivity in transplantation, e.g., post-reconstitution functional reversal of anergic NK cells. More recently, activating KIR came into the spotlight for their potential ability to directly activate donor NK cells through in vivo recognition of HLA or other ligands. Novel therapeutic monoclonal antibodies (mAb) may optimize NK-mediated effects. Examples include obinutuzumab (GA101), a glyco-engineered anti-CD20 mAb with increased affinity for the FcγRIIIA receptor, enhancing antibody-dependent cellular cytotoxicity; lirilumab (IPH2102), a first-in-class NK-specific checkpoint inhibitor, blocking the interaction between the major KIR and cognate HLA-C antigens; and elotuzumab (HuLuc63), a humanized monoclonal antibody specific for SLAMF7, whose anti-myeloma therapeutic effects are partly due to direct activation of SLAMF7-expressing NK cells. In addition to conventional antibodies, NK cell-targeted bispecific (BiKEs) and trispecific (TriKEs) killer engagers have also been developed. These proteins elicit potent effector functions by binding target ligands (e.g., CD19, CD22, CD30, CD133, HLA class II, EGFR) on one arm and NK receptors on the other. An additional innovative approach to direct NK cell activity is genetic reprogramming with chimeric antigen receptors (CAR). To date, primary NK cells and the NK92 cell line have been engineered with CAR specific for antigens expressed on multiple tumors. Encouraging preclinical results warrant further development of this approach. This Research Topic welcomes contributions addressing mechanisms of NK-mediated activation in response to disease as well as past and contemporary strategies to enhance NK mediated reactivity through control of the interactions between NK receptors and their ligands.

Immune Interactions during the Reproductive Cycle

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889195640 Year: Pages: 158 DOI: 10.3389/978-2-88919-564-0 Language: English
Publisher: Frontiers Media SA
Subject: Allergy and Immunology --- Medicine (General)
Added to DOAB on : 2016-01-19 14:05:46
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Mammalian pregnancy represents a unique immunological riddle in that the mother does not reject her allogeneic fetus. In part this is largely due to a general sequestration or diminution of T cell activity, and an increased involvement of the innate immune system. The field of immunology is concerned primarily with how innate and adaptive mechanisms collaborate to protect vertebrates from infection. Although many cellular and molecular actors have evidently important roles, antibodies and lymphocytes are considered to be the principal players. Yet despite their importance, it would be definitely simplistic to conclude that they are solely essential for immunity overall. A major distinction between adaptive and innate immunity is the spontaneity of the innate immune response, which utilizes an already pre-existing but limited repertoire of responding modules. The slower onset of adaptive immunity compensates by its ability to recognize a much broader repertory of foreign substances, and also by its power to constantly improve during a response, whereas innate immunity remains relatively unaffected. The interactions between the reproductive system and the immune system are of particular interest, since the reproductive system is unique in that its primary role is to assure the continuity of the species, while the immune system provides internal protection and thus facilitates continued health and survival. The modus operandi of these two morphologically diffuse systems involves widely distributed chemical signals in response to environmental input, and both systems must interact for the normal functioning of each. Furthermore, dysregulation of normal physiological interactions between the reproductive and immune systems can lead to severe pregnancy-related disorders or complications. On the other hand, by ameliorating auto-inflammatory conditions such as MS and RA, pregnancy may provide a unique insight into novel immune modulatory strategies. The scientific focus on reproductive–immune research has historically provided substantial insight into the interface between these two physiological systems. A translational research approach would involve a tight interaction between diverse scientific and clinical disciplines including immunology, obstetrics, haematology, haemostasis and endocrinology. With so much recent progress in the field, we believe that it is valuable and well-timed to review the broad variety of the relevant physiologic and pathologic aspects – from menstruation to fertilization and implantation, and from placentation and pregnancy per se to the post partum condition - in which the immune system takes part. We are looking forward to a wide and vivid discussion of these and related issues, and we sincerely expect that our readers profoundly benefit from new exciting insights and fruitful collaborations.

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