Week 11 Flashcards
What Are Dendritic cells?
A special type of immune cell that is found in tissues, such as the skin, and boosts immune responses by showing antigens on its surface to other cells of the immune system
What do the distinctions between human and murine dendritic cells reflect?
Differences in tissue origin and differences between cultured and freshly isolated DCs
How are different subsets of human and mouse dendritic cells separated?
On the basis of surface antigen differences
What are the different distinctions between dendritic cell subtypes?
Respond differently to microbial products, produce different cytokines and regulate the responses of the T cells they activate
What are the dendritic cell subtypes products of?
Separate developmental sublineages with different immediate precursors
What do some dendritic cells only produce?
DCs from pDCs in response to microbial products or other danger signals
When do dendritic cell subtypes exit their mature, quiescent state?
When activated by microbial products or other danger signals
What determines the balance between tolerance and immunity?
The dynamics of these shifts in the DC system in response to microbial invasion
What are conventional dendritic cells?
Innate immune cells
What does the term cDC refer to?
All DCs other than plasmacytoid DCs
Where do conventional dendritic cells reside?
In tissues and, following tissue infection or injury, they become activated and migrate to draining lymph nodes to promote adaptive immune responses
What are plasmacytoid dendritic cells?
A unique subset of dendritic cells specialised in secreting high levels of type I interferons
What is the function of active pDC?
Link innate immunity and adaptive immunity to viruses
What is the role of dendritic cells in the innate immune system?
As a component of the innate immune system, DC organize and transfer information from the outside world to the cells of the adaptive immune system
What are the three distinct signals of primary T cell activation?
(1) anti- gen recognition
(2) costimulation
(3) cytokine- mediated differentiation and expansion
What occurs during dendritic cell maturation?
During maturation, the DCs begin to synthesize peptides that include major histocompatibility complex (MHC) II molecules, CD40, CD80, and CD86 costimulatory molecules and proteins like CD83 and DC-LAMP that have little known functions
What does antigen recognition by B cells involve?
Direct binding of immunoglobulin to the intact antigen and antibodies typically bind to the surface of protein antigens, contacting amino acids that are discontinuous in the primary structure but are brought together in the folded protein
What do you mean by co stimulation?
Co-stimulation is a secondary signal which immune cells rely on to activate an immune response in the presence of an antigen-presenting cell
Which are pattern recognition receptors?
Pattern Recognition Receptors (PRRs) are proteins capable of recognizing molecules frequently found in pathogens (the so-called Pathogen-Associated Molecular Patterns—PAMPs), or molecules released by damaged cells (the Damage-Associated Molecular Patterns—DAMPs)
What are the three major dendritic cell subsets?
Plasmacytoid DC (pDC), myeloid/conventional DC1 (cDC1) and myeloid/conventional DC2 (cDC2)
How do pattern recognition receptors emerge?
They emerged phylogenetically prior to the appearance of the adaptive immunity and, therefore, are considered part of the innate immune system
What do the signals from the pattern recognition receptors activate?
Microbicidal and pro-inflammatory responses required to eliminate or, at least, to contain infectious agents
How does the innate immune system detect viruses?
Through molecular sensors that trigger the production of type I interferons (IFN-I) and inflammatory cytokines
Why are multiple sensors needed to detect viruses?
Because viruses vary tremendously in size, structure, genomic composition, and tissue tropism
What are the similarities between type I and type III IFN signalling?
Type III IFNs, like type I, are induced upon PRR recognition of PAMPs and signal through the shared JAK-STAT pathway to induce a similar antiviral transcriptional program
What are IFNs?
Secreted cytokines that activate a signal transduction cascade leading to the induction of hundreds of interferon-stimulated genes
What are type I interferons?
Polypeptides that are secreted by infected cells and have three major functions
Where do dendritic cells originate from?
Progenitors in the bone marrow through hematopoiesis, a highly regulated developmental process involving multiple cellular and molecular events
What does the activation of Flt3 play an important role in?
Proliferation, resistance to apoptosis, and prevention of differentiation of leukemic blasts in acute myeloid leukemia
What does the signal transduction of Flt3 involve?
Activation of several conserved pathways, including the RAS/MAP-Kinase and the phosphoinositide-3-kinase/Akt signaling cascades
What is FLT3 in leukemia?
FLT3 is a gene change, or mutation, in leukemia (blood cancer) cells
What are the yielded results of treating a humanized mouse model with FLT3 ligand?
FLT3-L increased numbers of human CD141+ DC, CD1c+ DC, and, to a lesser extent, plasmacytoid DC (pDC) in the blood, spleen, and bone marrow of humanized mice. CD1c+ DC and CD141+ DC subsets were expanded to a similar degree in blood and spleen, with a bias toward expansion of the CD1c+ DC subset in the bone marrow
What is Lupus?
An inflammatory disease caused when the immune system attacks its own tissues
What does type I IFN imprint?
Unique molecular signatures in a list of autoimmune diseases
What induces IFN?
Diverse nucleic acid-containing complexes, which trigger innate immune activation of plasmacytoid dendritic cells
What is IFN signalling essential for?
The initiation and/or progression of lupus in several experimental models
What does the heterogenous nature of lupus require?
Better characterization on how IFN pathways are activated and subsequently promote the advancement of autoimmune diseases
What does plasmacytoid dendritic cells produce?
Large amounts of type I IFN (IFN-I), cytokines convincingly linked to systemic lupus erythematosus (SLE) pathogenesis
What is BIIB059?
A humanized mAb that binds blood DC antigen 2 (BDCA2), a pDC-specific receptor that inhibits the production of IFN-I and other inflammatory mediators when ligated
What are the key immune cells involved with severe COVID-19-induced lung damage mediated by aldosterone?
Stimulated dedrictic cells that produce IL-6 and transforming growth factor-β1 via the mineralocorticoid receptor
What is the result of individuals lacking IFNs?
They are more susceptible to infectious diseases
What is severe COVID-19 characterised by?
Overproduction of immune mediators, but the role of interferons (IFNs) of the type I (IFN-I) or type III (IFN-III) families remains debated
What is the drug development pathway?
Research for a new drug begins in the laboratory. Drugs undergo laboratory and animal testing to answer basic questions about safety. Drugs are tested on people to make sure they are safe and effective
How can the development of a new drug be described?
A complex process which can take 12–15 years and cost in excess of $1 billion
Where does the idea of a target come from?
A variety of sources including academic and clinical research and from the commercial sector
What happens once a target has been chosen?
The pharmaceutical industry and more recently some academic centres have streamlined a number of early processes to identify molecules which possess suitable characteristics to make acceptable drugs
What does lung cancer account for?
Most cancer-related deaths worldwide and has an overall 5-year survival rate of ~15%
What do cell lines play an important role in?
The study of cancer biology and potential therapeutic targets, as well as pre-clinical testing of novel drugs
What is crucial in reducing attrition in drug development?
To consider the development and implementation of translational phenotypic assays as well as decipher diverse molecular mechanisms of action for new molecular entities
What has simplified the simultaneous identification and quantification of various cellular processes?
High-throughput fluorescence and confocal microscopes with advanced analysis software
What does high-content screening permit?
Automated identification of modifiers of accessible and biologically relevant targets and can thus be used to detect gene interactions or identify toxic pathways of drug candidates to improve drug discovery and development processes
What are cell line models?
in vitro model systems that are widely used in different fields of medical research, especially basic cancer research and drug discovery
What are in vitro cell models?
In vitro models can be used to study the effects of both common and rare genetic variation on early human brain development at a cellular and molecular level, in both typical development and neurodevelopmental and psychiatric disorders
What is meant by high throughput screening?
A key process used in drug discovery to identify hits from compound libraries that may become leads for medicinal chemistry optimization
What do cancer organoids represent?
An emerging approach for creating patient-derived in vitro cancer models that closely recapitulate the pathophysiological features of natural tumorigenesis and metastasis
What has the COVID-19 pandemic emphasised?
The need to develop effective treatments to combat emerging viruses
What does the Mouse Models of Human Cancer Database integrate?
Data on the frequency, incidence, genetics, and pathology of neoplastic disorders, emphasizing data on tumors that develop characteristically in different genetically defined strains of mice
What are some examples of immune-deficient mice used in xenograft models?
Nude mice, non-obese/diabetic mice (NOD), severe combined immunodeficient mice (SCID), and the combination NOD/SCID and NOD/SCID/interleukin IL2 receptor γnull (NSG) mice
What is meant by preclinical study?
In drug development, preclinical development, also termed preclinical studies or nonclinical studies, is a stage of research that begins before clinical trials (testing in humans) and during which important feasibility, iterative testing and drug safety data are collected, typically in laboratory animals
What are clinical trials?
A type of research that studies new tests and treatments and evaluates their effects on human health outcomes
What is the criteria for clinical trials?
The criteria are based on such factors as age, sex, type and stage of disease, previous treatment history, and other medical conditions. This helps to reduce the variation within the study and to ensure that the researchers will be able to answer the questions they plan to study
What is a Phase 1 clinical trial?
A phase I clinical trial tests the safety, side effects, best dose, and timing of a new treatment. It may also test the best way to give a new treatment (for example, by mouth, infusion into a vein, or injection) and how the treatment affects the body
What is a Phase II clinical trial?
A study that tests whether a new treatment works for a certain type of cancer or other disease
What is a Phase III clinical trial?
A study that tests the safety and how well a new treatment works compared with a standard treatment
How long does the process of developing a new drug take?
It might take 10 to 15 years or more to complete all 3 phases of clinical trials before the licensing stage. But this time span varies a lot
How much is a Phase 1 clinical trial?
The average cost of phase 1, 2, and 3 clinical trials across therapeutic areas is around $4, 13, and 20 million respectively
What is the success rate of clinical trials?
Only 1 out of 10 drug candidates successfully passes clinical trial testing and regulatory approval
What is a drug development pipeline?
A drug pipeline is the set of drug candidates that an individual pharmaceutical company or the entire pharmaceutical industry collectively has under discovery or development at any given point in time
How has the development of oncogenic therapies been traditionally performed?
In a sequence of clinical trials intended to assess safety (phase I), preliminary efficacy (phase II), and improvement over the standard of care (phase III) in homogeneous (in terms of tumor type and disease stage) patient populations
