Lectire 18 - Immunopharmacology Flashcards by Monica acinoM

Q

What are the key characteristics of Innate Immunity?

A

Immediate response, works quickly
Non-specific recognition (recognizes general features) or memory of pathogens
Physical barriers (skin, musus, etc), cellular defenses (Phagocytes, NK cells), and inflammatory response (readness, swelling, pain, etc)

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Q

What are the key characteristics of Adaptive Immunity?

A

Delayed response, faster upon reexposure
Targets specific pathogens or antigens and remembered them
B cells (produce antibodies that bind to and neutralize pathogens) and T cells (helper, cytotoxic, etc)
Antibodies, cytokines

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Q

List the cells seen in innate immunity

A

Mast cell, macrophage, dendritic cell, NK cell, basophil, eosinophil, granulocyte, NKT cells, gamma-delta T cells

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Q

List the cells seen in adaptive immunity

A

CD4+ T cell –> regulatory T cell
CD8+ T cell –> cytotoxic T cell
B cell –> plasma cell –> antibodies

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Q

What do macrophages do in immune response?

A

Phagocytize infectious organisms and foreign substances
- Nonspecific defense
- Type of antigen-presenting cell

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Q

What do Helper T cells (CD4+) do in immune response?

A

Multiply in number when antigen is recognized and activate killer T cells and B cells

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Q

What do killer T cells (CD8+) do in immune response?

A

Respond to IL-1 or other cytokines
Release perforins, granzymes and interferons (TNF-alpha, IFN)
Attack and kill cells that are infected with foreign organisms
Cellular immunity

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Q

What do B cells do in immune response?

A

-Can serve as APCs
- Produce antibodies
- Respond to IL-2 or other cytokines
- Humoral immunity

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Q

What is immunosuppressive drugs used to treat?

A

Severe allergic reactions
Autoimmune diseases (MS, type 1 diabetes, etc)
Inflammatory diseases (Crohn’s, spondylitis, RA, etc)
Infection (COVID-19, SARS)
Prevention of organ rejection

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Q

What are the mechanisms of pharmacologic immunosuppression?

A

Inhibition of gene expression to modulate immune response
Attack clonally expanding lymphocyte populations
Specific inhibition of intracellular signaling of lymphocytes
Neutralization of cytokines and cytokine receptors required for T cell stimulation
Depletion of specific immune cells
Inhibition of co-stimulation by APCs
Blockade of cell adhesion

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Q

What is the cluster of differentiation?

A

A protocol used for the identification and investigation of cell surface molecules providing targets for immunophenotyping of cells (cluster of designation, classification determinant)

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Q

Inhibition of gene expression to modulate immune response

How do glucocorticoids affect immune response?

A

Potent anti-inflammatory and anti-allergic effects

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Q

Inhibition of gene expression to modulate immune response

How do corticosteroids affect immune response?

A

Reduce lymphoid tissue and cells in the lymph nodes and spleen
Reduced number of macrophages, T cells, and B cells
Inhibit synthesis of inflammatory mediators (prostaglandins, leukotrienes, cytokines
Increase expression of anti-inflammatory cytokines and proteins
Used to prevent rejection of transplanted organs and threat severe allergic reactions

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Q

Inhibition of gene expression to modulate immune response

Physiological function of glucocorticoids (glucocorticosteroids)

A

Metabolism regulation - promote gluconeogenesis which maintains blood sugar levels, influences breakdown of fats, proteins, and carbohydrates
Immune function - Inhibit production of pro-inflammatory cytokines, suppresses activity of immune cells (ex macrophages)
Stress response - cortisol mobilizes energy stores, suppresses inflammation, and enhances alertness

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Q

Inhibition of gene expression to modulate immune response

What are some clinical applications of glucocorticoids?

A

Asthma, RA, IBD, and certain skin disorders

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Q

Inhibition of gene expression to modulate immune response

What are the metabolic effects and subsequent adverse effects of Glucocorticoids?

A

Increased gluconeogenesis –> obesity, diabetes mellitus
Increased protein catabolism –> muscle weakness and wasting, osteoporosis, decreased wound healing, increased infections

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Q

Inhibition of gene expression to modulate immune response

What are the metabolic effects and subsequent adverse effects of mineralcorticoids (aldosterone)?

A

Sodium and water retention –> edema, increased blood volume, hypertension
Loss of potassium –> muscle weakness and cramps

Q

Attack clonally expanding lymphocyte populations

What are antimetabolites?

A

drugs that interfere with one or more enzymes or their reactions that are necessary for DNA synthesis
- structures relate to normal
metabolites
- affect DNA or RNA synthesis by acting as a substitute to the actual metabolites that would be
used in the normal metabolism
- cause cytotoxic effect in S phase of mitosis

Q

Attack clonally expanding lymphocyte populations

What are alkylating agents?

A

Compounds that add an alkyl group to the guanine base of DNA
- Prevents proper linking causing breakage
- nonselective, target all proliferating cells

Q

Attack clonally expanding lymphocyte populations

Azathioprine - Mechanism of action

Antimetabolite (prodrug)

A

Transforms into 6-mercaptopurine (6-MP)
Inhibits the synthesis of purine nucleotides
Inhibits DNA synthesis leading to the death of existing lymphocytes
Suppresses the formation of new lymphocytes

Used for organ rejection prevention

Q

Attack clonally expanding lymphocyte populations

Leflunomide - Mechanism of action

Antimetabolite

A

Inhibits pyrimidine synthesis

Q

Attack clonally expanding lymphocyte populations

Cyclophosphamide - Mechanism of action

Alkylating agent (prodrug)

A

Cytotoxic drug that kills and supresses the function of lymphocytes

Used in treatment of cancers, bone marrow transplants, and autoimmune di

Q

Specific inhibition of intracellular signalling of lymphocytes

Tacrolimus (FK-506) - Effects

A

Macrolide antibiotic that inhibits T cell lymphocyte activity and suppresses IL-2 expression

Q

Specific inhibition of intracellular signalling of lymphocytes

Cyclosporine - Effects

A

Polypeptide metabolite produced by a particular fungus which suppresses T cell function and inhibits IL-2 production
- potent immunosuppressive, not cytotoxic

Drug of choice for organ rejection prevention

# Specific inhibition of intracellular signalling of lymphocytes Tacrolimus and Cyclosporine - Mechanism of action

Both cyclosporin-cyclophilin and tacrolimus-FKBP complexes bind to calcineurin --> prevents activationof calcineurin phosphatase activity by Ca2+/calmodulin --> NFAT cannot become active --> no gene expression of IL-2

# Specific inhibition of intracellular signalling of lymphocytes What is sirolimus? | Sirolimus is structurally similar to tacrolimus

Naturally occuring compound originally isolated from soil saprophyte that has immunosuppressive, antifungal, antiviral, and antineoplastic properties

# Specific inhibition of intracellular signalling of lymphocytes Sirolimus - Mechanism of action

Inhibition of mTOR pathway - Sirolimus binds to FKBP --> inhibits mTOR --> PHAS-1 and p70 S6 kinase not activated --> no translation of mRNAs needed for cell proliferation --> T cells arrest in G1 | Net effect of mtor activation is to increase protein synthesis

# Neutralization of cytokines/receptors required for T cell stimulation Etanercept - Mechanism of actions

Binds TNF-alpha and TNF-beta in circulation which prevents access of TNF to target tissues - Made up of the extracellular domain of human TNF receptor fused to the Fc domain of human IgG1

# Neutralization of cytokines/receptors required for T cell stimulation Infliximab - Mechanism of action

Binds to and inhibits the activity of TNF-alpha - An artificial antibody that prevents TNF-alpha from binding to its receptors | Used to treat Crohn's, ankylosing spondylitis, RA, etc

# Neutralization of cytokines/receptors required for T cell stimulation What is Adalimumab (Humira)?

First fully human monoclonal antibody approved by the FDA

# Neutralization of cytokines/receptors required for T cell stimulation What is TNF-alpha?

A pro-inflammatory cytokine produced by macrophages/monocytes during acute inflammation and i sresponsible for a diverse range of signaling evenst leading to necrosis or apoptosis - Also functions as a pathological component of autoimmune disease

# Depletion of specific immune cells What is CD3 required for?

CD3 is a T cell co-receptor of the TCR that is required for T cell activation (helper and cytotoxic)

# Depletion of specific immune cells Muromonab - Mechanism of action

An anti-CD3 antibody that bInds specifically to T cells and decreases the activity | Prevents organ rejection after renal transplantation

# Depletion of specific immune cells Daclizumab - Mechanism of action

An anti-IL-2 receptor (CD-25) that binds to and blocks the IL-2 receptor and T cell proliferation | Used to prevent renal allograft rejection

# Depletion of specific immune cells Basiliximab - Mechanism of action

A monoclonal antibody directed against CD25 (high-affinity IL-2 receptor)

# Inhibition of co-stimulation by APCs What is co-stimulation?

The paradigm that cells of the immune system typically require two signals for activation - If a first signal is provided in the absence of a second, the target immune cell may become anergic

# Inhibition of co-stimulation by APCs What is necessary for T cell response?

APC MHC interacting with T cell receptor/CD4 **and** CD28 from the T cell must interacts with B7 from the APC

# Inhibition of co-stimulation by APCs Abatacept - Structure

Consists of CTLA-4 (homologous to CD28) fused to an IgG1 constant region (modified antibody)

# Inhibition of co-stimulation by APCs Abatacept - Mechanism of action

Complexes with the co-stimulatory B7 molecules on the surface of APCs - Prevents 'signal 2' causing T cell anergy and apoptosis

# Blockade of cell adhesion What are critical to immune-cell adhesion and homing?

Alpha-4 integrins

# Blockade of cell adhesion What does Alpha4Beta1 integrin mediate?

The immune-cell interactions with cells expressing vascular cell adhesion molecule 1 (VCAM-1)

# Blockade of cell adhesion What is the name of the first drug developed in the class of selective adhesion molecule inhibitors and what does it treat?

Natalizumab - Treats MS and IBD