Innate immunity in asthma

Novel antibody-engineering approaches have enabled the development of targeted innate cell engagers which redirect innate immune cells to eliminate cancer or suppressive immune cells. These antibodies function through binding to surface antigens on target cells and engaging activating receptors on innate immune cells such as natural killer cells and macrophages. Although early innate cell engagers have shown promise in controlling various cancer types, several major challenges remain in the clinics, including high tumor heterogeneity, low tumor immunogenicity, and reduced efficacy in solid tumors. Here, we present a universal innate cell engager as part of a novel adaptor-based antibody platform. Our universal innate cell engager utilizes a two-step approach combining the power of an adaptor and an effector antibody. First, an Fc-silenced adaptor antibody comprising P329G LALA mutations is used to target the desired antigen in the tumor microenvironment. Then, as an effector antibody, a universal innate cell engager directed against the P329G mutation on the adaptor antibody is used. Innate immune cells are recruited by the universal innate cell engager through its active Fc, leading to antibody-dependent cellular cytotoxicity against the target cells. To maximize innate cell activation, the Fc portion of the universal innate cell engager can be glycoengineered for enhanced FcgRIII affinity.In vitro and in vivo assays showed that our universal innate cell engager is inducing innate immune cell activation and innate immune cell-mediated target cell killing when combined with different antigen-targeted adaptor antibodies. Ultimately, this approach may enable off-the-shelf personalization via combination of universal effector cell engagers and selected adaptor antibodies specific to the patient’s tumor profile. Citation Format: Idil Hutter-Karakoc, Marlena Surowka, Diana Darowski, Christina Klaus, Claudia Ferrara Koller, Thomas Hofer, Anne Freimoser-Grundschober, Ekkehard Mössner, Stephane Leclair, Pablo Umana, Christian Munz, Maria Amann, Christian Klein. Recruiting innate immune cells universally: Development of a novel universal innate cell engager for cancer-immunotherapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr A054.

A Critical Role for Type I IFN–dependent NK Cell Activation in Innate Immune Elimination of Adenoviral Vectors In Vivo

Emerging pathways in asthma: Innate and adaptive interactions

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Osteoporosis or porous bone disorder is the result of an imbalance in an otherwise highly balanced physiological process known as ‘bone remodeling’. The immune system is intricately involved in bone physiology as well as pathologies. Inflammatory diseases are often correlated with osteoporosis. Inflammatory mediators such as reactive oxygen species (ROS), and pro-inflammatory cytokines and chemokines directly or indirectly act on the bone cells and play a role in the pathogenesis of osteoporosis. Recently, Srivastava et al. (Srivastava RK, Dar HY, Mishra PK. Immunoporosis: Immunology of Osteoporosis-Role of T Cells. Frontiers in immunology. 2018;9:657) have coined the term “immunoporosis” to emphasize the role of immune cells in the pathology of osteoporosis. Accumulated pieces of evidence suggest both innate and adaptive immune cells contribute to osteoporosis. However, innate cells are the major effectors of inflammation. They sense various triggers to inflammation such as pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), cellular stress, etc., thus producing pro-inflammatory mediators that play a critical role in the pathogenesis of osteoporosis. In this review, we have discussed the role of the innate immune cells in great detail and divided these cells into different sections in a systemic manner. In the beginning, we talked about cells of the myeloid lineage, including macrophages, monocytes, and dendritic cells. This group of cells explicitly influences the skeletal system by the action of production of pro-inflammatory cytokines and can transdifferentiate into osteoclast. Other cells of the myeloid lineage, such as neutrophils, eosinophils, and mast cells, largely impact osteoporosis via the production of pro-inflammatory cytokines. Further, we talked about the cells of the lymphoid lineage, including natural killer cells and innate lymphoid cells, which share innate-like properties and play a role in osteoporosis. In addition to various innate immune cells, we also discussed the impact of classical pro-inflammatory cytokines on osteoporosis. We also highlighted the studies regarding the impact of physiological and metabolic changes in the body, which results in chronic inflammatory conditions such as ageing, ultimately triggering osteoporosis.

Laquinimod (LAQ), a new orally active immunomodulator, is currently under investigation for the treatment of multiple sclerosis (MS). In clinical trials LAQ considerably reduced the annualized relapse rate, disability progression and brain atrophy in MS patients, but its exact mechanism of action is not fully understood. Experimental data provide evidence for immunomodulatory effects of LAQ on antigen presenting cells and T cells, but the role of natural killer (NK) cells within the mechanism of action of LAQ has not been investigated yet. The aim of the present study was to evaluate effects of LAQ on innate and adaptive immune cells in mice with experimental autoimmune encephalomyelitis (EAE), with a special focus on NK cells. First, a detailed analysis of immune cells was performed in MOG35-55-immunized animals preventively treated with 25 mg/kg LAQ. Innate immune cells responded quickly to LAQ treatment, whereas major changes in the T cell compartment were detectable several days later. LAQ reduced the total number of splenic dendritic cells and the number of myeloid dendritic cells. In parallel, NK cells were activated by LAQ. As such LAQ increased the frequency of CD69+ NK cells and upregulated a number of activating NK cell receptors such as DNAM-1 and TACTILE. TIGIT, an inhibitory NK cell receptor, which shares the same ligand with DNAM-1 and TACTILE, was downregulated, suggesting that LAQ shifts the balance of inhibitory and activating NK cell receptors in favor of the latter. To test, whether the LAQ-induced NK cell activation improves classical NK cell effector functions, NK cells were sorted ex vivo from LAQ- or vehicle-treated animals. NK cells derived from LAQ-treated mice killed B16F10 melanoma cells in vitro more efficiently than NK cells derived from vehicle controls and produced more cytokines in response to IL-12 and IL-18 stimulation. In a triple co-culture system with 2D2 T cells and bone marrow-derived dendritic cells, T cell proliferation in response to MOG35-55 was significantly better inhibited by NK cells derived from LAQ-treated mice in a cell contact-dependent manner. Finally, LAQ efficacy was analyzed in NK cell-depleted and competent EAE animals. Th/+ mice were depleted by administration of PK-136 antibodies, immunized with MOG35-55 and preventively treated with 25 mg/kg LAQ. Treatment with LAQ markedly attenuated EAE severity in NK cell-competent Th/+ mice. This beneficial LAQ effect was however only transient in Th/+ mice depleted of NK cells. While LAQ treatment prevented the death of animals in the presence of NK cells, a considerable number of animals depleted of NK cells died despite LAQ therapy. In conclusion, this study identified NK cells as a novel direct cellular target of LAQ therapy with a central relevance for the therapeutic efficiency of the substance in EAE. These data indicate that the LAQ-mediated activation of NK cells is a crucial part of the immunomodulatory mechanism of LAQ in vivo. Most interestingly, LAQ specifically interfered with the DNAM-1/TACTILE/TIGIT pairwise receptor family on NK cells, favoring a central role of this pathway within the mechanism of action of LAQ. It remains to be investigated whether similar effects of LAQ on human NK cells can be detected in patients with MS. Since published data reveal defective NK cell function as one pathogenic factor in MS, LAQ-induced restoration of NK cell functions could be a major component of its protective mechanisms in the treatment of MS patients.

Targeting Innate Immunity: A New Step in the Development of Combination Therapy for Chronic Hepatitis B

Innate Immune System for Diagnostics and Therapy: Progress in Fundamental Knowledge and Clinical Application

Two arms of the immune system, innate and adaptive immunity, differ in their mode of immune recognition. The innate immune system recognizes a few highly conserved structures on a broad range of microorganisms. On the other hand, recognition of self or autoreactivity is generally confined to the adaptive immune response. Whilst autoimmune features are relatively common, they should be distinguished from autoimmune disease that is infrequent. Type 1 diabetes is an immune-mediated disease due to the destruction of insulin secreting cells mediated by aggressive immune responses, including activation of the adaptive immune system following genetic and environmental interaction. Hypotheses for the cause of the immune dysfunction leading to type 1 diabetes include self-reactive T-cell clones that (1) escape deletion in the thymus, (2) escape from peripheral tolerance or (3) escape from homeostatic control with an alteration in the immune balance leading to autoimmunity. Evidence, outlined in this review, raises the possibility that changes in the innate immune system could lead to autoimmunity, by either priming or promoting aggressive adaptive immune responses. Hostile microorganisms are identified by genetically determined surface receptors on innate effector cells, thereby promoting clearance of these invaders. These innate effectors include a few relatively inflexible cell populations such as monocytes/macrophages, dendritic cells (DC), natural killer (NK) cells, natural killer T (NKT) cells and gammadelta T cells. Recent studies have identified abnormalities in some of these cells both in patients with type 1 diabetes and in those at risk of the disease. However, it remains unclear whether these abnormalities in innate effector cells predispose to autoimmune disease. If they were to do so, then modulation of the innate immune system could be of therapeutic value in preventing immune-mediated diseases such as type 1 diabetes.

The innate immune system provides the first line of defence against infection. Through a limited number of germline-encoded receptors called pattern recognition receptors (PRRs), innate cells recognize and are activated by highly conserved structures expressed by large group of microorganisms called pathogen-associated molecular patterns (PAMPs). PRRs are involved either in recognition (scavenger receptors, C-type lectins) or in cell activation (Toll-like receptors or TLR, helicases and NOD molecules). TLRs play a pivotal role in cell activation in response to PAMPs. TLR are type I transmembrane proteins characterized by an intracellular Toll/IL 1 receptor homology domain that are expressed by innate immune cells (dendritic cells, macrophages, NK cells), cells of the adaptive immunity (T and B lymphocytes) and non immune cells (epithelial and endothelial cells, fibroblasts). In all the cell types analyzed, TLR agonists, alone or in combination with costimulatory molecules, induce cell activation. The crucial role played by TLR in immune cell activation has been detailed in dendritic cells. A TLR-dependent activation of dendritic cells is required to induce their maturation and migration to regional lymph nodes and to activate naïve T cells. The ability of different cell types to respond to TLR agonists is related to the pattern of expression of the TLRs and its regulation as well as their intracellular localization. Recent studies suggest that the nature of the endocytic and signaling receptors engaged by PAMPs may determine the nature of the immune response generated against the microbial molecules, highlighting the role of TLRs as molecular interfaces between innate and adaptive immunity. In this review are summarized the main biological properties of the TLR molecules.

The role of biomaterials and scaffolds in immune responses in regenerative medicine: macrophage phenotype modulation by biomaterial properties and scaffold architectures.

Innate and adaptive immunity work concertedly in vertebrates to restore homoeostasis following pathogen invasion or other insults. Like all homoeostatic circuits, immunity relies on an integrated system of sensors, transducers and effectors that can be analysed in cellular or molecular terms. At the cellular level, T and B lymphocytes act as an effector arm of immunity that is mobilised in response to signals transduced by innate immune cells that detect a given insult. These innate cells are spread around the body and include dendritic cells (DCs), the chief immune sensors of pathogen invasion and tumour growth. At the molecular level, DCs possess receptors that directly sense pathogen presence and tissue damage and that signal via transduction pathways to control antigen presentation or regulate a plethora of genes encoding effector proteins that regulate immunity. Notably, molecular circuits for pathogen detection are not confined to DCs or even to immune cells. All cells express sensors and transducers that monitor invasion by viruses and bacteria and elicit suitable effector barriers to pathogen propagation. Here, I discuss work from my laboratory that has contributed to our understanding of these issues over the years.

Innate sensing of cancer's non-immunologic hallmarks.

The human liver contains significant numbers of innate immune cells, such as natural killer (NK) cells and natural killer T (NKT) cells, which express both T-cell receptors and NK-cell receptors simultaneously. It has been suggested that the innate immune system plays a crucial role in the liver. In this report, the distribution of NK and NKT cells in the liver and peripheral blood of two patients with drug-induced fulminant hepatic failure (FHF) who had undergone living donor liver transplantation was examined. In both the liver and peripheral blood, the proportions of NK and NKT cells markedly decreased compared with those in healthy donors. It was also revealed that, unlike murine NKT cells, human CD56(+) T cells and CD57(+) T cells did not constitutively express CD28, which is one of the important costimulatory molecules on T cells. Additionally, the residual CD56(+) T cells and CD57(+) T cells in the patients expressed more CD28 than in controls. This result suggests that NKT cells might be more activated in FHF. Although the accumulation of further cases is required, it is suggested that both NK and NKT cells might be involved in hepatic injury in FHF.

Development of molecular genetics and cellular immunology has fundamentally changed the understanding of the relationship between mother and child during pregnancy. For a successful pregnancy, it is necessary for the mother's immune system to recognize and accept the semi-allogeneic fetus, ensuring effective penetration of fetal trophoblasts into the uterine body and protecting the fetus from external pathogens and the mother's microbiota. This is achieved through the exchange of immune and hematopoietic stem cells of the mother and the child with the formation of a cellular chimera called feto-maternal microchimerism as well as vice versa, the formation of the innate immunity of the fetus, ensuring its tolerance to the microbiota and chronic infections of the mother. Innate immunity and hematopoiesis are formed from the cells of the yolk sac mesoderm and extraembryonic mesenchymal tissue due to granule-macrophage-like precursors and pluripotent erythroid cells. During the first trimester of pregnancy and prior to the formation of the thymus and bone marrow hematopoiesis and, therefore, the implementation of the adaptive immune response, the fetus has a formed innate immune defense and cellular control over the biology of its own development represented by neutrophils, eosinophils, basophils, monocytes, macrophages, dendritic cells and the five types of innate lymphoid cells. Innate immune cells are activated by molecular pattern molecules mediated by pattern recognition receptors which provides rapid protection against microbiota pathogens and chronic infections and helps get rid of dying and/or damaged innate cells. Analysis of the interaction between the microbiome, acute and chronic maternal infections, development and functioning of innate lymphoid cells in the fetal and neonatal period is of a great clinical importance aiming at detailing the pathogenesis and developing pathogenetically based therapy, prevention and treatment of eclampsia, pregnancy complications, such as premature birth and other problems associated with placental abruption, bronchopulmonary dysplasia, necrotizing enterocolitis, pneumonia and sepsis in premature and newborn infants. Author presents an analysis of the recent data on the role of innate immunity in terms of evidence-based links with perinatal disorders in newborns and proposals for planning of further scientific research in this important area.