scholarly journals Evolution of Cellular Immunity Effector Cells; Perspective on Cytotoxic and Phagocytic Cellular Lineages

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1853
Author(s):  
Edna Ayerim Mandujano-Tinoco ◽  
Eliya Sultan ◽  
Aner Ottolenghi ◽  
Orly Gershoni-Yahalom ◽  
Benyamin Rosental
Keyword(s):  
Current Knowledge ◽  
Immune Effector ◽  
Effector Cells ◽  
Molecular Features ◽  
Self Recognition ◽  
Ability To Regenerate ◽  
Infected Cells ◽  
Parasitic Pathogens ◽  
Cellular Immune ◽  
Immune Effector Function

The immune system has evolved to protect organisms from infections caused by bacteria, viruses, and parasitic pathogens. In addition, it provides regenerative capacities, tissue maintenance, and self/non-self recognition of foreign tissues. Phagocytosis and cytotoxicity are two prominent cellular immune activities positioned at the base of immune effector function in mammals. Although these immune mechanisms have diversified into a wide heterogeneous repertoire of effector cells, it appears that they share some common cellular and molecular features in all animals, but also some interesting convergent mechanisms. In this review, we will explore the current knowledge about the evolution of phagocytic and cytotoxic immune lineages against pathogens, in the clearance of damaged cells, for regeneration, for histocompatibility recognition, and in killing virally infected cells. To this end, we give different immune examples of multicellular organism models, ranging from the roots of bilateral organisms to chordate invertebrates, comparing to vertebrates’ lineages. In this review, we compare cellular lineage homologies at the cellular and molecular levels. We aim to highlight and discuss the diverse function plasticity within the evolved immune effector cells, and even suggest the costs and benefits that it may imply for organisms with the meaning of greater defense against pathogens but less ability to regenerate damaged tissues and organs.

scholarly journals eCD4-Ig Variants That More Potently Neutralize HIV-1

2018 ◽  
Vol 92 (12) ◽  
Author(s):  
Ina Fetzer ◽  
Matthew R. Gardner ◽  
Meredith E. Davis-Gardner ◽  
Neha R. Prasad ◽  
Barnett Alfant ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Entry Inhibitor ◽  
Immune Effector ◽  
Effector Cells ◽  
Antibody Recognition ◽  
Immunodeficiency Virus ◽  
Latently Infected ◽  
Infected Cells ◽  
Prophylaxis Therapy ◽  
Hiv 1

ABSTRACTThe human immunodeficiency virus type 1 (HIV-1) entry inhibitor eCD4-Ig is a fusion of CD4-Ig and a coreceptor-mimetic peptide. eCD4-Ig is markedly more potent than CD4-Ig, with neutralization efficiencies approaching those of HIV-1 broadly neutralizing antibodies (bNAbs). However, unlike bNAbs, eCD4-Ig neutralized all HIV-1, HIV-2, and simian immunodeficiency virus (SIV) isolates that it has been tested against, suggesting that it may be useful in clinical settings, where antibody escape is a concern. Here, we characterize three new eCD4-Ig variants, each with a different architecture and each utilizing D1.22, a stabilized form of CD4 domain 1. These variants were 10- to 20-fold more potent than our original eCD4-Ig variant, with a construct bearing four D1.22 domains (eD1.22-HL-Ig) exhibiting the greatest potency. However, this variant mediated less efficient antibody-dependent cell-mediated cytotoxicity (ADCC) activity than eCD4-Ig itself or several other eCD4-Ig variants, including the smallest variant (eD1.22-Ig). A variant with the same architecture as the original eCD4-Ig (eD1.22-D2-Ig) showed modestly higher thermal stability and best prevented the promotion of infection of CCR5-positive, CD4-negative cells. All three variants, and eCD4-Ig itself, mediated more efficient shedding of the HIV-1 envelope glycoprotein gp120 than did CD4-Ig. Finally, we show that only three D1.22 mutations contributed to the potency of eD1.22-D2-Ig and that introduction of these changes into eCD4-Ig resulted in a variant 9-fold more potent than eCD4-Ig and 2-fold more potent than eD1.22-D2-Ig. These studies will assist in developing eCD4-Ig variants with properties optimized for prophylaxis, therapy, and cure applications.IMPORTANCEHIV-1 bNAbs have properties different from those of antiretroviral compounds. Specifically, antibodies can enlist immune effector cells to eliminate infected cells, whereas antiretroviral compounds simply interfere with various steps in the viral life cycle. Unfortunately, HIV-1 is adept at evading antibody recognition, limiting the utility of antibodies as a treatment for HIV-1 infection or as part of an effort to eradicate latently infected cells. eCD4-Ig is an antibody-like entry inhibitor that closely mimics HIV-1's obligate receptors. eCD4-Ig appears to be qualitatively different from antibodies, since it neutralizes all HIV-1, HIV-2, and SIV isolates. Here, we characterize three new structurally distinct eCD4-Ig variants and show that each excels in a key property useful to prevent, treat, or cure an HIV-1 infection. For example, one variant neutralized HIV-1 most efficiently, while others best enlisted natural killer cells to eliminate infected cells. These observations will help generate eCD4-Ig variants optimized for different clinical applications.

Potent Anti-Leukemic Activity of a Cationic Lipid-DNA Complex.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4891-4891
Author(s):  
Zachary Herse ◽  
Stella Chang ◽  
Denny Liggitt ◽  
Jeffery Fairman ◽  
David F. Claxton
Keyword(s):  
Cationic Lipid ◽  
Green Fluorescence Protein ◽  
Acute Leukemias ◽  
Immune Effector ◽  
Effector Cells ◽  
Bacterial Plasmid ◽  
Fluorescence Protein ◽  
Cellular Immune ◽  
Antigen Presenting ◽  
Dna Complex

Abstract Cationic Lipid and DNA Complex (CLDC) is a chemically defined preparation of lipids and non-coding bacterial plasmid DNA able to activate antigen presenting and immune effector cells and thereby enhance cellular immune responses. We tested this preparation subcutaneously (SC) in two models of transplantable murine leukemia: 32D -(bcr-abl)p210 (leukemogenic in C3H/HEJ animals) and WEHI-3B cells (leukemogenic in BALB-C mice.) In multiple experiments using the 32Dp210 model a single SC dose of CLDC (200 ul) prevented or significantly delayed death from leukemia when delivered between -1 and 16 days from leukemic challenge. Specifically, control animals died at 28 days (SD=2.73) of leukemia whereas 20/24 similarly leukemia challenged but CLDC treated animals were alive >71 days (p<0.0001 − 4/20 animals died of leukemia). Animals dying of leukemia had swollen spleens and leukemic infiltration of spleen and liver on histopathological evaluation. Similarly Balb-C animals challenged with WEHI-3B cells died at a median of 30 days unless treated with CLDC (1 dose day 6 − 4/5 alive >day 40 p=0.0017). A green fluorescence protein (GFP) expressing subclone of 32Dp210 allowed quantitation of leukemia in peripheral blood (PB). PB leukocytes were 20% GFP positive on day 19. After CLDC on day 19, day 21 PB showed only 2% GFP. Animals receiving 32D-p210-GFP and treated with CLDC and CD8 antibody on day 19 showed higher GFP in followup and died earlier (median day 35) than animals treated with CLDC alone (>42 days) but later than animals receiving no treatment after leukemic challenge (median 23 days, p=0.0002.) See Figure below. We conclude that CLDC shows potent anti-leukemia activity in two murine models of AML. Antibody experiments suggest that CD8 positive effector cells contribute to this effect. Additional experiments are maturing and will be reported. This preparation has promise for activity in human acute leukemias. Figure Figure

scholarly journals Immunological Aspects ofCandidaandAspergillusSystemic Fungal Infections

2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
Christoph Mueller-Loebnitz ◽  
Helmut Ostermann ◽  
Anke Franzke ◽  
Juergen Loeffler ◽  
Lutz Uharek ◽  
...  
Keyword(s):  
High Risk ◽  
Defense Mechanisms ◽  
Fungal Infections ◽  
Current Knowledge ◽  
Immunosuppressive Drugs ◽  
Immune Defense ◽  
Immunological Mechanism ◽  
Immune Effector ◽  
Effector Cells ◽  
Risk Patients

Patients with allogeneic stem cell transplantation (SCT) have a high risk of invasive fungal infections (IFIs) even after neutrophil regeneration. Immunological aspects might play a very important role in the IFI development in these patients. Some data are available supporting the identification of high-risk patients with IFI for example patients receiving stem cells from TLR4 haplotype S4 positive donors. Key defense mechanisms against IFI include the activation of neutrophils, the phagocytosis of germinating conidia by dendritic cells, and the fight of the cells of the innate immunity such as monocytes and natural killer cells against germlings and hyphae. Furthermore, immunosuppressive drugs interact with immune effector cells influencing the specific fungal immune defense and antimycotic drugs might interact with immune response. Based on the current knowledge on immunological mechanism inAspergillus fumigatus, the first approaches of an immunotherapy using human T cells are in development. This might be an option for the future of aspergillosis patients having a poor prognosis with conventional treatment.

scholarly journals From Tumor Immunosuppression to Eradication: Targeting Homing and Activity of Immune Effector Cells to Tumors

2011 ◽  
Vol 2011 ◽  
pp. 1-15 ◽  
Author(s):  
Oana Draghiciu ◽  
Hans W. Nijman ◽  
Toos Daemen
Keyword(s):  
Tumor Microenvironment ◽  
Current Knowledge ◽  
Cancer Development ◽  
Detailed Knowledge ◽  
Immune Effector ◽  
Effector Cells ◽  
Immune Effector Cells ◽  
Tumor Immunosuppression ◽  
Tumor Eradication ◽  
Induction Of Tolerance

Unraveling the mechanisms used by the immune system to fight cancer development is one of the most ambitious undertakings in immunology. Detailed knowledge regarding the mechanisms of induction of tolerance and immunosuppression within the tumor microenvironment will contribute to the development of highly effective tumor eradication strategies. Research within the last few decades has shed more light on the matter. This paper aims to give an overview on the current knowledge of the main tolerance and immunosuppression mechanisms elicited within the tumor microenvironment, with the focus on development of effective immunotherapeutic strategies to improve homing and activity of immune effector cells to tumors.

The PI3K Delta Selective Inhibitor Idelalisib Minimally Interferes with Immune Effector Function and B Cell Depletion Mediated By Obinutuzumab (GA101) and Rituximab

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3342-3342 ◽  
Author(s):  
Sylvia Herter ◽  
Adam Palazzo ◽  
Marina Bacac ◽  
Laura Grosmaire ◽  
Christian Frey ◽  
...  
Keyword(s):  
B Cell ◽  
Whole Blood ◽  
Nk Cell ◽  
Effector Function ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
Immune Effector ◽  
Effector Cells ◽  
Immune Effector Function ◽  
The Impact

Abstract Introduction: Idelalisib is a highly selective oral inhibitor of the phosphoinositide 3-kinase delta (PI3Kδ) that is hyperactive in many B-cell malignancies and is critical for the activation, proliferation, survival and trafficking of B lymphocytes. Idelalisib is approved in the US for the treatment of chronic lymphocytic leukemia (CLL) in combination with rituximab and as monotherapy for patients with relapsed follicular B-cell non-Hodgkin lymphoma and small lymphocytic lymphoma who have received at least two prior systemic therapies. Obinutuzumab (GA101) is a glycoengineered type II, CD20 antibody that induces a high level of direct cell death. As a result of glycoengineering, obinutuzumab has increased affinity for FcγRIII on innate immune effector cells resulting in enhanced induction of ADCC and ADCP. Obinutuzumab has been approved for first line treatment of CLL patients in combination with chlorambucil in the US and Europe and is currently in pivotal clinical trials in indolent NHL and DLBCL. Previous work has shown the covalent BTK inhibitor ibrutinib can interfere with the immune effector function and ultimately in vivo efficacy of rituximab in preclinical models (Kohrt et al., Blood, 2014). As PI3K isoforms also play a role in immune effector cells and FcγR signaling we investigated the impact of PI3Kδ inhibition by the PI3Kδ selective inhibitor idelalisib on the immune effector function of obinutuzumab and rituximab. Experimental methods: The impact of idelalisib on NK cell mediated ADCC induction by obinutuzumab and rituximab was investigated in LDH release assays using WIL2-S, SU-DHL4 and Z138 target cells at plasma protein-binding adjusted clinically relevant concentrations mimicking exposure in patients. As a surrogate for NK cell activation CD16 levels and up-regulation of the degranulation marker CD107a were assessed by FACS. The impact on monocyte-derived macrophage mediated ADCP of WIL2-S cells was measured in a flow cytometry-based phagocytosis assay. Finally, depletion of CD19 positive B cells was determined in whole blood from healthy volunteers in flow cytometry-based whole blood assay. Results: In ADCC assays, no impact of idelalisib on ADCC at saturating concentration of obinutuzumab or rituximab (>1ug/ml) can be detected in LDH release assays with tumor cells targets (N=9 donors for WIL2-S, N>3 donors for SU-DHL-4 and Z138). Idelalisib did not alter obinutuzumab or rituximab ability to kill tumor cells by ADCC at low E:T ratio. Little to no increase of obinutuzumab or rituximab EC50 for LDH release, CD16 down regulation, or degranulation of NK cells could be detected depending on donor effector cells. ADCP assays were conducted with M2c polarized macrophages using WIL2-S as targets. Less than 30% inhibition of ADCP was observed in this assay at idelalisib concentration at protein binding-adjusted clinical Cmax. At idelalisib Cmax (4200 nM) the EC50 of obinutuzumab-mediated B cell depletion in healthy human whole blood was increased 3 to 5 times, whereas at Cmin (760 nM) idelalisib did not significantly influence obinutuzumab EC50 or maximal B cell depletion. Conclusions: PI3Kδ inhibition by idelalisib has minimal impact on the immune effector function of obinutuzumab (GA101) and rituximab as measured in NK cell-mediated ADCC, macrophage-mediated ADCP and whole blood B-cell depletion. Disclosures Herter: Roche: Employment. Palazzo:Gilead Sciences: Employment. Bacac:Roche: Employment. Grosmaire:Gilead Sciences: Employment. Frey:Gilead Sciences: Employment. Pflanz:Gilead Sciences: Employment. Liu:Gilead Sciences: Employment. Tannheimer:Gilead Sciences: Employment. Umana:Roche: Employment. Klein:Roche: Employment, Equity Ownership, Patents & Royalties. Queva:Gilead Sciences: Employment.

scholarly journals Interleukin-7 or Interleukin-15 Enhances Survival of Mycobacterium tuberculosis-Infected Mice

2000 ◽  
Vol 68 (5) ◽  
pp. 2962-2970 ◽  
Author(s):  
Markus J. Maeurer ◽  
Peter Trinder ◽  
Gerhard Hommel ◽  
Wolfgang Walter ◽  
Kirsten Freitag ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Bacterial Load ◽  
Antigen Presenting Cells ◽  
Spleen Cells ◽  
Necrosis Factor Alpha ◽  
Immune Effector ◽  
Effector Cells ◽  
Interleukin 7 ◽  
Cellular Immune ◽  
Antigen Presenting

ABSTRACT Both antigen-presenting cells and immune effector cells are required to effectively eradicate or contain Mycobacterium tuberculosis-infected cells. A variety of cytokines are involved to ensure productive “cross talk” between macrophages and T lymphocytes. For instance, infection of macrophages with mycobacteria leads to effective interleukin-7 (IL-7) and IL-15 secretion, and both cytokines are able to maintain strong cellular immune responses of α/β and γ/δ T cells. Here we show that either cytokine is able to enhance survival of M. tuberculosis-infected BALB/c mice significantly compared to application of IL-2, IL-4, or phosphate-buffered saline (as a control). Enhanced survival could be achieved only when IL-7 or IL-15 was delivered as a treatment (i.e., 3 weeks postinfection), not when it was administered at the time of infection. Increased survival of M. tuberculosis-infected animals was observed following passive transfer of spleen cells harvested from M. tuberculosis-infected, IL-7- or IL-15-treated animals, but not after transfer of spleen cells obtained from mice which received either cytokine alone. Histological examination revealed that IL-7 and IL-15 failed to significantly impact on the number and composition of granulomas formed or the bacterial load. Our data indicated that administration of IL-7 or IL-15 toM. tuberculosis-treated animals resulted in a qualitatively different cellular immune response in spleen cells as reflected by increased tumor necrosis factor alpha and decreased gamma interferon secretion in response to M. tuberculosis-infected antigen-presenting cells.

scholarly journals Battle between Host Immune Cellular Responses and HCMV Immune Evasion

2019 ◽  
Vol 20 (15) ◽  
pp. 3626 ◽  
Author(s):  
Manandhar ◽  
Hò ◽  
Pump ◽  
Blasczyk ◽  
Bade-Doeding
Keyword(s):  
Immune Evasion ◽  
Human Leukocyte ◽  
Hla Class I ◽  
Human Organism ◽  
Transplant Recipients ◽  
Immune Effector ◽  
Effector Cells ◽  
Leukocyte Antigens ◽  
Wide Range ◽  
Infected Cells

Human cytomegalovirus (HCMV) is ubiquitously prevalent. HCMV infection is typically asymptomatic and controlled by the immune system in healthy individuals, yet HCMV can be severely pathogenic for the fetus during pregnancy and in immunocompromised persons, such as transplant recipients or HIV infected patients. HCMV has co-evolved with the hosts, developed strategies to hide from immune effector cells and to successfully survive in the human organism. One strategy for evading or delaying the immune response is maintenance of the viral genome to establish the phase of latency. Furthermore, HCMV immune evasion involves the downregulation of human leukocyte antigens (HLA)-Ia molecules to hide infected cells from T-cell recognition. HCMV expresses several proteins that are described for downregulation of the HLA class I pathway via various mechanisms. Here, we review the wide range of immune evasion mechanisms of HCMV. Understanding the mechanisms of HCMV immune evasion will contribute to the development of new customized therapeutic strategies against the virus.

scholarly journals THE PERITONEAL EXUDATE LYMPHOCYTE

1971 ◽  
Vol 134 (5) ◽  
pp. 1170-1186 ◽  
Author(s):  
David L. Rosenstreich ◽  
J. Thomas Blake ◽  
Alan S. Rosenthal
Keyword(s):  
Peritoneal Exudate ◽  
In Vitro Assays ◽  
Antigenic Determinants ◽  
Horse Radish Peroxidase ◽  
Immune Effector ◽  
Effector Cells ◽  
Accessory Cells ◽  
Immune Effector Cells ◽  
Cellular Immune

Peritoneal exudate lymphocytes from guinea pigs immunized with horse radish peroxidase, dinitrophenyl guinea pig albumin, or ferritin in complete Freund's adjuvant have been shown to be significantly more reactive than other lymphocytes in two in vitro assays of cellular immune function: production of macrophage migration inhibitory factor and antigen-induced lymphocyte proliferation. The enhanced reactivity of peritoneal exudate lymphocytes cannot be accounted for by artifacts introduced by column purification or by the presence of nonlymphoid accessory cells. These observations suggest that the peritoneal exudate lymphocyte pool is a highly enriched source of cellular immune effector cells with specificity directed towards those antigenic determinants to which an animal has been recently exposed.

scholarly journals Macrophages—the immune effector guardians of the lung: impact of corticosteroids on their functional responses

2020 ◽  
Vol 134 (13) ◽  
pp. 1631-1635
Author(s):  
Stephan F. van Eeden ◽  
Kentaro Akata
Keyword(s):  
Functional Properties ◽  
Inflammatory Responses ◽  
Inhaled Corticosteroids ◽  
Current Knowledge ◽  
Chronic Obstructive ◽  
Macrophage Phenotype ◽  
Functional Responses ◽  
Immune Effector ◽  
Effector Cells ◽  
The Impact

Abstract Lung macrophages (LMs) are key immune effector cells that protect the lung from inhaled particulate matter, noxious gases and pathogens. In Chronic Obstructive Pulmonary Disease (COPD), there is an abundance of macrophages in airspaces and lung tissues suggesting that they play an important role in the pathogenesis of the disease. Furthermore, macrophage phenotype and functional properties are altered in COPD toward a more pro-inflammatory state, characterized by reduced pathogen recognition and processing ability and dysfunctional tissue repair qualities. Inhaled corticosteroids (ICSs), used in the management of COPD, has been shown to reduce acute exacerbations of COPD but is also associated with increased occurrence of pneumonia. Corticosteroids treatment altered LM phenotypic characteristics and their functional properties, and this commentary discusses current knowledge and also the gaps in our understanding of the impact of ICS on LMs phenotype and function. A better understanding of how ICSs impact the immune-inflammatory responses in the lung, in particular ICSs’ effects on LMs, could allow more selective personalized tailoring of the use of ICSs in COPD to improve disease progression, morbidity and mortality.

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