L20-21 - Fundamentals of immunotherapy
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Q: What are non-steroidal anti-inflammatory drugs (NSAIDs - Ex. Ibuprofen, Naproxen)?
NSAIDs are medications commonly used to:
Relieve pain (analgesic).
Reduce inflammation (anti-inflammatory).
Lower fever (antipyretic).
Q: What are corticosteroids, and how do they differ from NSAIDs?
Corticosteroids are synthetic drugs that mimic naturally occurring hormones such as cortisol and are used to reduce inflammation.
Unlike NSAIDs, corticosteroids are steroid-based medications.
They can have serious side effects, particularly with long-term use.
Q: What is the main alternative to NSAIDs for pain relief?
A: Acetaminophen (Tylenol), which relieves pain and reduces fever but has minimal anti-inflammatory effects.
Q: Is acetaminophen (Tylenol) classified as an NSAID?
A: No. Acetaminophen is an analgesic and antipyretic but is not considered an NSAID because it lacks significant peripheral anti-inflammatory activity.
Q: What is the primary mechanism of action of NSAIDs?
A: NSAIDs inhibit cyclooxygenase (COX) enzymes, reducing the production of prostaglandins involved in pain, inflammation, and fever.
Q: How do NSAIDs reduce inflammatory responses?
A: NSAIDs decrease prostaglandin synthesis, which helps reduce pain, swelling, and other inflammatory responses.
Q: How do NSAIDs differ from corticosteroids in their anti-inflammatory mechanisms?
NSAIDs: Primarily inhibit COX enzymes, reducing prostaglandin production.
Corticosteroids: Have broader anti-inflammatory and immunosuppressive effects by regulating gene expression and suppressing multiple inflammatory pathways.
Q: Are NSAIDs considered traditional immunosuppressive or immunomodulatory medications?
A: No. Although NSAIDs reduce inflammation, they are not generally classified as traditional immunosuppressive medications.
Their primary therapeutic mechanism involves reducing prostaglandin production, rather than broadly suppressing immune cell activity.
Q: Do NSAIDs have immunomodulatory effects beyond prostaglandin inhibition?
A: NSAIDs can indirectly influence immune responses by altering prostaglandin signaling, and some have additional effects that are not fully understood.
However, COX inhibition and reduced prostaglandin synthesis remain their primary established mechanisms.
Q: What are prostaglandins, and what are their primary functions in inflammation?
Prostaglandins are hormone-like lipid signaling molecules that contribute to:
Inflammation
Pain
Fever
Blood vessel dilation (vasodilation)
Q: How do prostaglandins contribute to redness and swelling during inflammation?
A: Prostaglandins cause vasodilation, increasing blood flow to affected tissues and contributing to redness and swelling.
They also promote vascular changes that contribute to fluid accumulation in inflamed tissues.
Q: How do prostaglandins contribute to fever?
A: Prostaglandins, particularly PGE2, act on the hypothalamus to raise the body's temperature set point, causing fever.
Q: How do prostaglandins contribute to pain?
A: Prostaglandins sensitize pain receptors (nociceptors), making them more responsive to painful stimuli.
Q: What conditions or symptoms can NSAIDs be used to treat?
NSAIDs can help relieve:
Rheumatoid arthritis symptoms (pain and inflammation)
Headaches
Menstrual cramps
Backaches
General pain and inflammation
Fever
Q: Can NSAIDs cure rheumatoid arthritis?
A: No. NSAIDs help reduce pain and inflammation associated with rheumatoid arthritis but do not prevent the underlying autoimmune disease from progressing.
Q: What are the risks of long-term NSAID use?
Long-term NSAID use can cause adverse effects, including:
Gastrointestinal irritation, ulcers, and bleeding
Kidney damage
Increased blood pressure
Increased cardiovascular risk with certain NSAIDs
Q: Why do NSAIDs reduce pain, inflammation, and fever?
By inhibiting COX enzymes, NSAIDs reduce prostaglandin production, resulting in:
Less pain: Reduced sensitization of pain receptors.
Less inflammation: Reduced prostaglandin-mediated vasodilation and swelling.
Lower fever: Reduced PGE2 signaling in the hypothalamus.
Q: What are traditional disease-modifying antirheumatic drugs (DMARDs)?
A: Traditional DMARDs are medications that suppress or modify immune and inflammatory responses to reduce inflammation, pain, and tissue damage while slowing disease progression.
Q: What conditions are traditional DMARDs used to treat?
Autoimmune diseases (e.g., rheumatoid arthritis)
Chronic inflammatory conditions
Some medications in this group are also used to prevent organ transplant rejection.
Q: What are the four traditional DMARDs mentioned in the lecture?
Methotrexate
Sulfasalazine
Cyclosporine
Azathioprine
Q: What are the major disadvantages of traditional (first-generation) DMARDs?
A: Traditional DMARDs are generally less selective than newer targeted therapies, potentially affecting multiple immune pathways and causing more systemic side effects.
However, many remain effective and are still commonly used.
Q: Why are traditional DMARDs useful for chronic inflammatory conditions?
A: They suppress or modify persistent inflammatory responses, helping prevent long-term tissue damage and slow disease progression.
Q: What is the difference between NSAIDs and traditional DMARDs?
NSAIDs: Reduce pain, inflammation, and fever primarily by inhibiting prostaglandin synthesis, but do not prevent autoimmune disease progression.
DMARDs: Modify immune and inflammatory activity to reduce tissue damage and slow disease progression.
Q: Are traditional DMARDs still used despite the development of newer targeted therapies?
A: Yes. Although newer medications may target specific immune pathways, traditional DMARDs remain important treatments.
(Methotrexate, for example, is still a first-line medication for many patients with rheumatoid arthritis.)
Q: What are the three general mechanisms of action of DMARDs?
DMARDs can reduce inflammation through three major mechanisms:
Antimetabolic activity: Inhibits cellular replication (interfere with proliferation.
Induction of apoptosis: Promotes programmed cell death in target cells.
Inhibition of signaling pathways: Blocks cellular signaling involved in inflammation.
Q: What is the primary function of antimetabolic drugs?
A: Antimetabolic drugs interfere with cellular metabolism, particularly DNA synthesis, to inhibit cellular replication and proliferation.
Q: Why can antimetabolic drugs be used to treat both autoimmune diseases and cancer?
Because they inhibit cellular proliferation.
Autoimmune diseases: Reduce the proliferation and activity of immune cells contributing to inflammation.
Cancer: Inhibit the replication of rapidly dividing cancer cells.
Q: What does it mean that antimetabolic DMARDs can be cytotoxic?
A: Cytotoxic means toxic to cells. These drugs can damage or kill cells, including healthy rapidly dividing cells, potentially causing serious side effects.
Q: Why can antimetabolic DMARDs have more serious side effects than NSAIDs?
A: Antimetabolic DMARDs can interfere with cell replication and damage healthy cells, whereas NSAIDs primarily reduce prostaglandin production.
As a result, antimetabolic DMARDs may cause serious adverse effects, including bone marrow suppression and increased susceptibility to infections.
Q: What is maintenance therapy in the context of DMARD treatment?
A: Maintenance therapy refers to the long-term administration of DMARDs to control chronic inflammation, prevent disease flare-ups, and slow disease progression.
Q: Why are DMARDs often prescribed for long-term use?
A: Because many autoimmune and chronic inflammatory diseases require ongoing suppression or modification of inflammatory responses to prevent progressive tissue damage.
Q: Why are rapidly proliferating immune cells particularly susceptible to antimetabolic DMARDs?
Activated immune cells have high metabolic demands and rapidly proliferate during an immune response.
They require large amounts of energy, including glucose.
They need increased nucleotide synthesis to replicate their DNA.
Antimetabolic DMARDs interfere with essential metabolic pathways, particularly nucleotide synthesis, reducing immune cell proliferation.
Q: How do antimetabolic DMARDs suppress the immune response?
Antimetabolic DMARDs interfere with the synthesis of molecules needed for cell division, preventing activated immune cells from rapidly multiplying.
This reduces the number of immune cells contributing to inflammation.
Q: Why is the high metabolic activity of immune cells important for understanding antimetabolic DMARDs?
A: Activated immune cells require substantial energy and resources to proliferate. Antimetabolic DMARDs exploit these increased metabolic demands to suppress immune cell proliferation and reduce inflammation.
Q: What are biologic response modifiers (BRMs)?
A: BRMs, also called biologics, are targeted immunotherapies that stimulate, suppress, or modify specific components of the immune system to treat disease.
Q: How are biologic response modifiers (BRMs) produced?
BRMs are biological substances that may be naturally derived or manufactured using biotechnology.
Many are proteins produced through recombinant DNA technology.
They are generally designed to target specific immune cells or molecules.
Q: What are the four examples of biologic response modifiers (BRMs)?
Cytokines
Interferons
Depleting antibodies
Growth factors
Q: How do biologic response modifiers (BRMs) affect the immune system?
BRMs target specific immune components to:
Stimulate immune responses.
Suppress or inhibit immune activity.
Modify cellular responses.
Help restore immune balance.
Q: Why are biologic response modifiers (BRMs) generally more selective than traditional DMARDs?
A: BRMs target specific molecules, receptors, or immune cells, whereas many traditional DMARDs affect broader cellular processes.
This selectivity may reduce certain systemic side effects, although biologics can still cause serious adverse reactions.
Q: What are cytokines, and what is their function in the immune system?
A: Cytokines are signaling proteins that regulate communication between immune cells.
They can stimulate or suppress inflammation, promote immune cell activation, and regulate immune responses.
Q: What are interferons, and what is their function in the immune system?
Interferons are a type of cytokine that help regulate immune responses.
Type I interferons (IFN-α and IFN-β): Promote antiviral defenses.
IFN-γ: Activates macrophages and promotes cell-mediated immunity.
Q: What are depleting antibodies, and what is their function in immunotherapy?
Depleting antibodies are therapeutic antibodies designed to bind specific molecules on target cells and promote their elimination.
Can eliminate selected immune cell populations.
Can reduce harmful immune responses.
Example: Rituximab targets CD20 on B cells, leading to B-cell depletion.
Q: What are growth factors, and what is their function in the immune system?
Growth factors are signaling proteins that stimulate cell growth, survival, differentiation, and proliferation.
Example: G-CSF stimulates neutrophil production in the bone marrow.
Q: Why can biologic response modifiers trigger an immune response against the medication itself?
A: Many BRMs are proteins. If the immune system recognizes parts of the therapeutic protein as foreign (as in it was not synthetically made and instead from another human or animal), it may produce antibodies against the medication.
This is called immunogenicity.
Q: Why are non-human biologic proteins generally more likely to cause immune reactions?
Non-human proteins contain amino acid sequences that may be recognized as foreign by the recipient's immune system.
This can lead to sensitization and production of anti-drug antibodies.
Q: What is sensitization to a biologic medication?
Sensitization occurs when the immune system recognizes the medication as foreign and develops an adaptive immune response against it.
Upon subsequent exposure, the patient may experience an immune-mediated adverse reaction.
Q: What is serum sickness, and how can biologic medications cause it?
Serum sickness is a Type III hypersensitivity reaction caused by immune complexes formed between foreign proteins and antibodies.
Immune complexes can deposit in tissues.
Complement activation causes inflammation.
Symptoms may include fever, rash, and joint pain.
Q: What type of hypersensitivity reaction is classically associated with serum sickness caused by biologic medications?
A: Type III hypersensitivity (immune complex-mediated).
Q: Can biologic medications cause Type II hypersensitivity reactions?
Yes, certain biologic therapies can cause Type II reactions when antibodies target antigens on cells, resulting in cell destruction.
However, serum sickness is Type III, not Type II.
Q: What is the difference between Type II and Type III hypersensitivity reactions involving biologic medications?
Type II: Antibodies bind to antigens on cells, potentially causing cell destruction.
Type III: Antibodies form soluble immune complexes with antigens, which can deposit in tissues and cause inflammation (e.g., serum sickness).
Q: What is the main difference between traditional DMARDs and biologic response modifiers (BRMs)?
Traditional DMARDs: Often affect broader immune or metabolic pathways to reduce inflammation.
BRMs: Target specific immune cells, receptors, cytokines, or signaling molecules to modify immune responses.
Q: Why might biologic response modifiers have fewer side effects than traditional DMARDs?
Their greater target specificity may reduce some unintended effects on healthy cells and tissues.
However, biologics can still cause serious adverse effects, including infections, infusion reactions, and immune-mediated reactions
Q: How can disruption of normal immune regulatory networks lead to disease?
A: Disruption of immune regulation can cause inappropriate or excessive immune responses, leading to immunopathology (tissue damage caused by the immune system).
Q: What diseases can biologic response modifiers (BRMs) be used to treat?
BRMs can be used to treat immune-mediated diseases, including:
Autoimmune diseases
Allergic conditions
Asthma
Q: How do biologic response modifiers (BRMs) help treat immune-mediated diseases?
A: BRMs target specific components of the immune system to restore immune balance, reduce abnormal inflammation, and limit immunopathology.
Q: What medications were traditionally used to treat immune-mediated diseases before biologic response modifiers?
A: Potent, broadly acting immunosuppressive medications, including traditional DMARDs.
Q: What are the major disadvantages of traditional immunosuppressive medications?
Limited effectiveness: They may not always achieve the desired clinical response.
Low specificity: They can affect healthy cells in addition to the intended targets.
Toxicity: They may cause significant adverse effects.
Severe immunosuppression: They can weaken normal immune defenses.
Opportunistic infections: Suppression of the immune system increases susceptibility to certain infections.
Q: What are the major advantages of biologic response modifiers (BRMs) compared with traditional DMARDs?
Greater selectivity: Target specific immune cells, molecules, or signaling pathways.
Potentially reduced toxicity: May avoid some adverse effects associated with broadly acting immunosuppressants.
Targeted effectiveness: Can treat specific immune abnormalities that traditional medications may not adequately control.
Q: Why can biologic response modifiers cause less toxicity than traditional DMARDs?
A: BRMs are designed to target specific components of the immune system, reducing unintended effects on healthy cells and tissues.
However, biologics can still cause serious side effects, including infections and immune-mediated reactions.
Q: What are opportunistic infections, and why can immunosuppressive medications increase their risk?
A: Opportunistic infections occur when microorganisms take advantage of weakened immune defenses.
Immunosuppressive medications reduce the body's ability to fight infections, increasing susceptibility to these pathogens.
Q: What is the main advantage of biologic response modifiers over traditional immunosuppressive drugs?
A: Greater target specificity, which may improve treatment effectiveness and reduce certain toxicities associated with broadly acting immunosuppressive medications.
Q: What are the three major mechanisms of action of biologic response modifiers (BRMs)?
BRMs modify immune responses through three main mechanisms:
Cytokine regulation: Modify cytokine signaling to stimulate or suppress immune responses.
Cell surface protein targeting: Target receptors or proteins involved in immune cell activation or inhibition (e.g., CTLA-4).
Cell depletion: Eliminate specific immune cell populations contributing to disease.
Q: How do biologic response modifiers (BRMs) use cytokines to regulate immune responses?
A: BRMs can stimulate, inhibit, or modify cytokine signaling to regulate immune cell activity and reduce abnormal inflammation.
Q: How do biologic response modifiers (BRMs) alter immune cell activity through cell surface proteins?
A: BRMs target specific cell surface proteins involved in activating or inhibiting immune cells, allowing them to increase or decrease immune responses.
Q: What is CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), and what is its function?
A: CTLA-4 is an inhibitory receptor on T cells that reduces T-cell activation and helps suppress excessive immune responses.
Q: How does CTLA-4 suppress T-cell activation?
A: CTLA-4 binds to B7 (CD80/CD86) on antigen-presenting cells, competing with CD28 for costimulatory signaling.
This reduces T-cell activation and helps limit inflammation.
Q: How can CTLA-4 be used therapeutically to reduce inflammation?
A: Medications that mimic CTLA-4 activity, such as CTLA-4-Ig fusion proteins, bind B7 on APCs and prevent B7 from interacting with CD28.
This blocks T-cell costimulation and reduces T-cell activation.
Q: Why might CTLA-4-based therapies be useful in organ transplantation?
A: They can reduce recipient T-cell activation against donor antigens, potentially helping prevent graft rejection.
Q: What is the difference between CD28 and CTLA-4 in T-cell activation?
CD28: Provides costimulatory signals that promote T-cell activation.
CTLA-4: Inhibits T-cell activation by competing for B7 binding.
Memory trick: CD28 = T-cell ON; CTLA-4 = T-cell OFF.
Q: How can biologic response modifiers (BRMs) eliminate specific immune cell populations?
A: BRMs can use targeted antibodies that bind surface proteins on selected immune cells, marking those cells for destruction.
Q: What is the role of the Fc portion of therapeutic antibodies in cell depletion?
A: The Fc region interacts with complement proteins and Fc receptors on immune cells, helping eliminate antibody-coated target cells.
Q: What are the two major mechanisms by which depleting antibodies destroy target cells?
Complement-dependent cytotoxicity (CDC): Antibody binding activates complement, which can damage or lyse target cells.
Antibody-dependent cellular cytotoxicity (ADCC): Immune cells, particularly NK cells, recognize antibody-coated targets through Fc receptors and kill them.
Q: What is antibody-dependent cellular cytotoxicity (ADCC)?
A: ADCC occurs when immune cells, especially NK cells, bind the Fc portion of antibodies attached to a target cell and release cytotoxic molecules that kill the target.
Q: How does complement-dependent cytotoxicity (CDC) destroy antibody-coated cells?
A: Antibodies bound to target cells activate the classical complement pathway, which can lead to formation of the membrane attack complex (MAC) and cell lysis.
Q: What is the primary function of IFN-α (interferon-alpha)?
A: IFN-α is a Type I interferon that promotes antiviral defenses by inhibiting viral replication and increasing MHC class I expression.
Q: What is the primary function of IFN-β (interferon-beta)?
IFN-β is a Type I interferon that promotes antiviral defenses and regulates immune responses.
Inhibits viral replication.
Increases MHC class I expression.
Therapeutically used to reduce inflammatory activity in multiple sclerosis.
Q: What is the primary function of IFN-γ (interferon-gamma)?
IFN-γ is a Type II interferon that primarily activates macrophages and promotes cell-mediated immunity.
Enhances macrophage killing of intracellular pathogens.
Increases MHC class I and II expression.
Promotes Th1 immune responses.
Q: What is the major difference between Type I and Type II interferons?
Type I (IFN-α and IFN-β): Primarily antiviral defense.
Type II (IFN-γ): Primarily macrophage activation and cell-mediated immunity.
Q: What is the primary function of TNF (tumor necrosis factor)?
A: TNF is a pro-inflammatory cytokine that promotes inflammation, immune cell recruitment, and activation of vascular endothelial cells.
Q: What is the function of TNF inhibitors as biologic response modifiers?
TNF inhibitors block TNF signaling, reducing inflammation and tissue damage in autoimmune and chronic inflammatory diseases.
Examples: Adalimumab and infliximab.
Used in conditions such as rheumatoid arthritis and inflammatory bowel disease
Q: What is the primary function of IL-1 (interleukin-1)?
A: IL-1 is a pro-inflammatory cytokine that promotes fever, inflammation, and immune cell recruitment.
Q: What is the function of IL-1 inhibitors as biologic response modifiers?
IL-1 inhibitors block IL-1 signaling to reduce inflammation and fever.
Example: Anakinra (IL-1 receptor antagonist).
Used to treat certain inflammatory and autoinflammatory diseases.
Q: What is the primary function of IL-2 (interleukin-2)?
IL-2 is a cytokine that promotes T-cell proliferation, survival, and differentiation.
Supports activated T-cell expansion.
Helps maintain regulatory T cells (Tregs).
Supports NK-cell activity.
Q: How can IL-2 be used as a biologic response modifier?
IL-2 can be administered to stimulate immune cell activity, particularly T cells and NK cells, to enhance immune responses against certain cancers.
Q: What is the primary function of CTLA-4 (cytotoxic T-lymphocyte-associated protein 4)?
A: CTLA-4 is an inhibitory receptor on T cells that suppresses T-cell activation by competing with CD28 for binding to B7 on antigen-presenting cells.
Q: How can CTLA-4-based biologic therapies suppress immune responses?
CTLA-4-Ig fusion proteins bind B7 (CD80/CD86) on APCs, preventing CD28 costimulation and reducing T-cell activation.
Example: Abatacept.
Belatacept is used to help prevent kidney transplant rejection.
Q: What happens when CTLA-4 is blocked rather than mimicked?
A: Blocking CTLA-4 removes an inhibitory signal, increasing T-cell activation. This approach can be used in cancer immunotherapy.
Q: What is CD20, and which immune cells express it?
A: CD20 is a cell surface protein expressed primarily on mature B cells (but generally not plasma cells).
Q: What is the function of anti-CD20 biologic therapies?
Anti-CD20 antibodies bind CD20 on B cells and promote B-cell depletion, reducing B-cell-mediated immune responses.
Example: Rituximab.
Used for certain B-cell cancers and autoimmune diseases.
Q: How do anti-CD20 antibodies eliminate B cells?
They can trigger:
ADCC: Immune cells, particularly NK cells, kill antibody-coated B cells.
CDC: Complement activation damages antibody-coated B cells.
Other mechanisms, including phagocytosis.
Q: What are colony-stimulating factors (CSFs)?
A: CSFs are growth factors that stimulate the production, differentiation, and survival of blood cells in the bone marrow.
What is the primary function of G-CSF (granulocyte colony-stimulating factor)?
A: G-CSF stimulates the bone marrow to produce and release neutrophils.
Example: Filgrastim.
Commonly used to treat or prevent chemotherapy-induced neutropenia.
Q: What is the primary function of GM-CSF (granulocyte-macrophage colony-stimulating factor)?
A: GM-CSF promotes the production and function of granulocytes and monocytes/macrophages.
?: Antiviral defense (Type I interferons).
?: Macrophage activation (Type II interferon).
?: Block TNF-mediated inflammation.
?: Reduce IL-1-mediated inflammation and fever.
IFN-α / IFN-β: Antiviral defense (Type I interferons).
IFN-γ: Macrophage activation (Type II interferon).
TNF inhibitors: Block TNF-mediated inflammation.
IL-1 inhibitors: Reduce IL-1-mediated inflammation and fever.
?: Promotes T-cell proliferation and supports NK cells.
?: Inhibits T-cell activation.
?: Depletes B cells.
?: Stimulate blood cell production in bone marrow.
IL-2: Promotes T-cell proliferation and supports NK cells.
CTLA-4: Inhibits T-cell activation.
Anti-CD20: Depletes B cells.
CSFs: Stimulate blood cell production in bone marrow.
Q: Do all biologic response modifiers (BRMs) suppress the immune system?
A: No. BRMs can either stimulate or suppress immune responses depending on their specific mechanism of action.
Q: Which biologic response modifiers primarily stimulate immune activity?
IFN-α / IFN-β: Promote antiviral defenses.
IFN-γ: Activates macrophages.
IL-2: Stimulates T-cell proliferation and supports NK-cell activity.
CSFs: Stimulate blood cell production in the bone marrow.
Q: Which biologic response modifiers primarily suppress immune activity?
TNF inhibitors: Block TNF-mediated inflammation.
IL-1 inhibitors: Block IL-1-mediated inflammation.
CTLA-4-Ig: Inhibits T-cell activation.
Anti-CD20: Depletes B cells, reducing B-cell-mediated immune responses.
Q: Which biologic response modifier promotes T-cell proliferation rather than inhibiting it?
A: IL-2, which stimulates T-cell proliferation and supports NK-cell activity.
Q: Which biologic response modifier inhibits T-cell activation?
A: CTLA-4-Ig, which blocks CD28 costimulation by binding B7 on antigen-presenting cells.