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MODA Lent > Inflammation and Immunosuppression > Flashcards

Inflammation and Immunosuppression Flashcards

1
Q

4 Signs of Inflammation?

A
  1. Rubor/Redness - increase in local blood flow caused by vasodilator action of inflammatory mediators
  2. Tumor/ Swelling - increase in vascular permeability, proteins and fluid leak from vasculature
  3. Calor/ Heat - increased blood flow
  4. Dolor/ Pain - direct action on nociceptors
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2
Q

Causes of inflammation (3)

A
  1. Noxious Stimulation
  2. Bacterial/Viral/Fungal infection
  3. Autoimmune reactions (when adaptive immune system attacks the body’s own tissues)
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3
Q

Triple Response of Lewis

A
  1. Flush - drawing a pointed instrument forcefully across the skin produces a band of redness that matches the size and shape of the stimulus due to local release of vasodilator substances e.g. histamine
  2. Neurogenic inflammation - Activation of sensory fibres will send APs to the spinal cord + brain (pain), and to other collateral branches. Branches release CALCITONIN GENE RELATED PEPTIDE and SUBSTANCE P –> results in local production of histamine causing vasodilatation and increased vascular permeability
  3. Wheal - leakage of plasma from blood to the extracellular space causes swelling due to increased vascular permeability
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4
Q

Dermatographic utcaria

A

A condition in which the triple response is exaggerated; largely idiopathic and generally treated with H1-receptor antagonists

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5
Q

Omalizumab

A
  • Monoclonal antibody
  • Recognises IgE, decreases mast cell activation
  • Allergen bound IgE induces mast cell degranulation when bound to its receptor FcERI
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6
Q

Where is histamine made and found?

A
  • Made from histidine by histidine decarboxylase
  • Found in 4 cell types: mast cells, basophils, enterochromaffin-like cells (ECL) in the gut, histaminergic neurones in brain
  • In mast cells + basophils - histamine is packaged into acidic granules with a high molecular weight MACROHEPARIN
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7
Q

Sodium Cromoglycate

A

Mast cell stabiliser; inhibits degranulation
Decreased Ca2+ influx upon mast cell stimulation, inhibits inward Cl- conductance required to maintain a negative enough membrane potential to enable sustained influxes of extracellular Ca2+
- Used to treat mastocytosis + used as eye drop for hayfever (opticrom)

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8
Q

Mepyramine

A

First generation H1 antagonist - classical antihistamine used in treating histamine-mediated inflammatory responses
- Rapidly permeate blood brain barrier + caused drowsiness; not suited for systemic use but used a topical creams for insect bites

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9
Q

Terfenadine

A

Second generation H1 antagonist
- Cannot cross the blood brain barrier
- Inhibits Kv11.1 or hERG causing Long QT syndrome
Pro-drug that is metabolised by p450 3A4 into fexofenadine.
Diminished p450 3A4 activity enhances risk of death

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10
Q

Bergamottin

A

A component of grapefruit juice which inhibits p450 3A4, thus increasing the potency of Terfenadine (Long QT syndrome)

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11
Q

Fexofenadine/ Loratadine

A

Third generation H1 antagonists

  • Non-drowsy, lack cardiac side effects
  • Mainly used in treating hay fever, allergies and urticaria
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12
Q

Adrenaline

A

Administered intramuscularly in anaphylaxis to counteract systemic vasodilatation and reduction in tissue perfusion

  • Relieves bronchospasm
  • Co-administered with hydrocortisone (anti-inflammatory)
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13
Q

Why is noradrenaline not used in anaphylaxis

A

Highly potent vasoconstrictor, which can cause reflex bradycardia

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14
Q

Imatinib

A

Receptor tyrosine kinase inhibitors used in the treatment of mastocytosis
- Only efficacious in patients that are NOT presenting with the D816V c-Kit mutation

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15
Q

Oclacitinib

A

Inhibits Janus Kinases (JAK) - JAKs involved in many cytokine signalling pathways associated with allergic skin diseases

  • Lowers pro-inflammatory signalling, can be used as an alternative to corticosteroids/ciclosporin
  • Treats Atopic Dermatitis in dogs (10%)
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16
Q

Somatostatin

A

Negative regulator of H+ release from parietal cells. 2 modes of action…
Direct - Activation of SSRT2 Gi coupled receptors on parietal cells counteracts histamine
Indirect - Activation of SSRT2 on ECL and G cells reduces histamine + gastrin respectively

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17
Q

Proglumide

A

CCK2 receptor antagonist , reduces histamine secretion from ECL which inhibits gastric acid secretion
- Role in treating peptic ulcers has been surpassed

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18
Q

Cimetidine/ Ranitidine

A

H2 antagonists used in treating peptic ulcers

Note: Cimetidine inhibits CYP450 and has been displaced by ranitidine

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19
Q

Omeprazole

A

Proton pump inhibitor (PPI), used preferentially to H2 receptor antagonists

  • Authorised for use in treating peptic ulcers In horses
  • PPIs are converted to active form in the acidic environment of parietal cells and form disulphide bonds with K+/H+ pump
  • PPIs are broken down by H+ and have slow onset to maximal effectiveness
  • Predominantly metabolised by CYP2C19 which exhibits genetic polymorphism
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20
Q

Vonoprazan

A

Potassium competitive acid blocker (P-CAB); competes with K+ binding site, has greater stability than PPIs in H+ and CYP2C19 is less important in its metabolism

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21
Q

Clarithromycin

A

Eradication of Helicobacter Pylori - causative agent in many cases of human peptic ulcers. Dogs may present with gastric ulcers, which can have a variety of causes, Helicobacter are not generally thought to be the cause

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22
Q

Misoprostal

A

Synthetic prostaglandin E1 (PGE1) analogue given to patients with gastric complications who have been prescribed NSAIDs

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23
Q

Arthrotec

A

Combination tablet = NSAID diclofenac + misoprostal

  • Used in chronic treatment against rheumatoid arthritis
  • Misoprostal acts a prophylactic against NSAID induced ulceration
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24
Q

Activation of bradykinin B1 and B2 receptors in the vascular endothelium causes…

A

Calcium influx –> Activates cytosolic phospholipase A2 (cPLA2) –> Prostacyclin (PGI2) production + endothelial nitric oxide synthase (eNOS) resulting in NO production –> PGI2 + NO diffuse to vascular smooth muscle –> Increase cAMP and cGMP respectively –> Mediate vasodilatation

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25
Q

ACE (Angiotensin converting enzyme)

A

Kininase II is a peptidyl dipeptidase that inactivates kinins by removing two C-terminal amino acids, this enzyme is angiotensin converting enzyme

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26
Q

Action of ACE inhibitors

A
  • Reduce angiotensin II levels, thus reducing vasoconstriction, but they also cause an increase in bradykinin levels and thus enhance vasodilatation
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27
Q

Hereditary Angioedema (-0.01%)

A

Mutation in the gene encoding C1-INH (C1-esterase inhibitor) causes excessive levels of bradykinin - sufferers experience periods of severe and painful swelling

  • Type I HAE - mutations that compromise the secretion/synthesis of C1-INH
  • Type II HAE - mutations that result in inactive C1-INH
  • There is also ACE-inhibitor associated angioedema (0.1%)
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28
Q

Icatibant

A

B2 antagonist used in the treatment of HAE

- HAE also treated using recombinant C1-INH, kallikrein inhibitors and B2 antagonists

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29
Q

4 groups of cytokines?

A
  • Chemokines
  • Interleukins
  • Interferons
  • Colony stimulating factors
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30
Q

Interleukins

A

Observed to communicate between leukocytes.

  • Key pro-inflammatory ILs are IL1 and TNFa. Predominantly released from macrophages and induce expression of further cytokines (TNFa) and promote proliferation and maturation of other immune cells, as well as causing fever (IL1).
  • Anti-inflammatory cytokines inhibit cytokine production and inhibit T-cell responses (IL1- and IL-ra)
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31
Q

Chemokines

A

Chemoattractant cytokines…
CCL3 acts on CCR1 receptors to induce mast cell degranulation
Characterised by cysteine residues at the N-terminus of the peptide chain
CXC chemokine - single amino acid separating two cysteines
CC chemokine - two adjacent chemokine
C chemokine - only one cysteine at N terminus
CX3C - 3 amino acids separating two cysteine.
Sometimes termed alpha, beta, gamma, delta

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32
Q

Chemokine receptors

A

GPCRs

Note: Most non-chemokine cytokine receptors are receptor tyrosine kinases

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33
Q

Interferons

A

3 classes: Alpha, Beta, Gamma
Alpha + Beta - have some role in antiviral activity
Gamma - role in the induction of Th1 response

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34
Q

Colony stimulating factors

A

Stimulate formation of maturing colonies of leukocytes and are primarily used to overcome deficits in a person’s white blood cell count

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35
Q

Tanezumab

A

Anti-NGF antibody; currently in clinical trials for therapeutic use against osteoarthritis
- NGF elevated in synovial fluid of OA patients, NGF cause pain
Side effects: Pain relief is so great that patients may over-use damaged joints and exacerbate damage

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36
Q

Annexin A1

A

Anti-inflammatory protein produced by many cells.

  • Downregulates inflammatory cells activation and mediator release
  • Actions brought about by binding to GPCR formylpeptide receptor 2 (FPR2)
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37
Q

Aspirin

A

Irreversibly inactivates COX, through acetylating Ser530, rather than forming hydrogen bond with Arg120.

  • Aspirin is acetylsalicylate and by donating an acetyl group to COX - salicylate is formed, reversible COX inhibitor.
  • Reduce the risk the platelet aggregation: platelets express COX-1 and TX synthase = major source of TXA2 (induces platelet aggregation and vasoconstriction), whereas endothelial cells predominantly produce PGI2 (inhibits platelet aggregation + vasodilatation)
  • Acetylated COX-1 can be replaced by newly synthesised protein in endothelial cells, but TXA2 production by platelet is switched off for their lifetime (10 days)
  • Overall, anti-thrombotic effect + lower risk of stomach ulcers, but PPIs are co-prescribed
  • Acetylation of COX-2, results in COX-2 no longer producing intermediates for PG + TXA2 synthesis but instead 15R-HETE (stereoisomer of 15S-HETE).
  • 5-LO converts 15R-HETE to aspirin triggered lipoxin (ATL) –> anti-inflammation and pro-resolution
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38
Q

How can asthma and COPD be distinguished using immune cells?

A

Bronchial biopsies from asthmatics are characterised by activated mast cells and eosinophils, biopsies from those with COPD are enriched with neutrophils and macrophages. In COPD fibroblast proliferation is common leading to small airway fibrosis which explains the irreversible nature of airway narrowing in COPD.
- Alveolar tissue destruction + epithelial cell proliferation is also observed in COPD.

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39
Q

Treating COPD…

A

Short acting bronchodilators are ineffective due to limited reversible nature of bronchoconstriction. Instead, LABAs such formoterol + indacaterol are used in combination with long-acting muscarinic antagonists (LAMA) e.g. tiotropium

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40
Q

Additive effects of LABA-LAMA combination inhalers?

A

LABA - B2 adrenoreceptor activation - ↑ AC activity - ↑ cAMP/PKA activity - MLCK phosphorylation and inactivation
LAMA - M3 inhibition - prevention of PLC activation and IP3 generation

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41
Q

Why are inhaled corticosteroids ineffective in treating COPD

A

Reduction in expression and activation of histone deacetylase 2 (HDAC2); due to superoxides and nitric oxides produced from cigarette smoking and activate immune cells –> results in formation of peroxynitrate which nitrates HDAC2 at active site leading to inactivation, ubiquitination and degradation.
- Lowered levels of HDAC2 - increased acetylation of GR-alpha which prevents it from inhibiting NF kB driven inflammation

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42
Q

Theophylline

A

Sustained release preparation to treat COPD.

  • Acts as a bronchodilator through ↑ cAMP
  • ↑cAMP in neutrophils + other immune cells to decrease chemotaxis + activation
  • PDE inhibitor
43
Q

Roflumilast

A
  • Selective PDEIV inhibitor approved for treatment of COPD. PDE4 main PDE expressed in neutrophils, T cells and macrophages
  • Add on therapy to LABAs
44
Q

Other potential treatments/ therapies for COPD

A
  • Modulation of neutrophil chemotaxis
  • Anti-fibrotic therapy
  • Inhibition of elastase activity, elevated in COPD - may contribute to the development of COPD
  • Long term O2 therapy for those with low blood O2 levels
45
Q

Examples of autoimmune diseases?

A
  • Grave’s disease/hyperthyroidism (autoantibodies activate the thyrotropin receptors causing increased thyroxine release)
  • Hashimoto’s (autoantibodies against proteins involved in thyroxine synthesis e.g. thyroglobulin, initially hyperthyroidism followed by hypothyroidism)
  • myasthenia gravis (autoantibodies against nAChR, prevents effects of Ach)
  • Type 1 diabetes mellitus (islet b-cells)
  • Primary biliary cirrhosis (immune attack against bile duct of liver)
  • Rheumatoid arthritis (immune attack on synovium surrounding joints)
46
Q

Rheumatoid arthritis

A

Common autoimmune disease, prevalence 1%

  • Joint damage driven by activated Th1 cells > Macrophages release IL1 and TNFa > Release of metalloproteinases from osteoclasts + fibroblasts causing cartilage + bone destruction > Effect exacerbated by neutrophils that release proteases and ROS to cause damage
  • Hyperplasia of synovium = pannus formation
47
Q

Naproxen

A

NSAID used to relieve pain + lessen inflammation in RA. Has superseded the use of diclofenac
- Associated with decreased cardiovascular risk

48
Q

Etorixcoxib

A

COX2 selective NSAIDs

- Significant reduction in GI bleeding

49
Q

Oral prednisolone

A

Corticosteroids provide symptomatic relief and suppress disease activity for RA

  • Decreased transcription of IL2, important for driving Th cell proliferation > Decreased transcription of IL1 and TNFa
  • Many side effects, so are used to treat flare ups or as bridging therapy when waiting for DMARD.
50
Q

Methotrexate

A
  • Folic acid antagonist (DHFR antagonist + competition with folic acid transport into cells) lower production of tetrahydrofolate required for purine and thymidylate synthesis - anti-proliferative
  • Effects seen after 3-12 weeks
  • Adverse effects: bone marrow suppression + GI disturbance
  • Taken orally once a week, or administered by weekly subcutaneous injections
51
Q

Sulfasalazine

A

DMARD
Also used to treat inflammatory bowel disease, alongside RA
- Mechanism of action is poorly understood
- Administered orally, broken down by colonic bacteria to produce sulfapyradine (sulphonamide) and 5-aminosalacylic acid (salicylate)
- 5-aminosalacylic acid might scavenge neutrophil derived ROS
- Daily tablets, effects observed >3 months
- Can cause GI disturbance, tears/contact lenses stained yellow/ urine orange/ hepatotoxicity

52
Q

Hydroxychloroquine

A

Used in treating malaria but treats RA in patients refractory to other DMARDs

  • Lipophilic weak base - accumulates in cytoplasmic acidic vesicles reducing antigen presentation by macrophages and neutrophil ROS production
  • Adverse effects: ocular toxicity, GI upset, skin reactions, seizures
53
Q

Leflunomide

A

DMARD

  • Inhibits dihydroorotate dehydrogenase, key enzyme in pyrimidine synthesis > inhibits synthesis of DNA and RNA - main effect on rapidly dividing cells.
  • Adverse effects: GI disturbance, bone marrow suppression, hepatotoxicity
54
Q

Etanercept

A
  • Biological DMARD

- Fusion protein of soluble TNFa and Fc portion of Ig1G1 - mops up high levels of TNFa characteristic of RA

55
Q

Infliximab/ Adalimumab

A
  • Biological DMARD
  • Chimeric/ human monoclonal anti-TNFa antibodies
    Adverse effects: allergic reactions, bone marrow suppression, increased susceptibility to infections
  • Several cases of multiple sclerosis reported following anti-TNFa treatment for inflammatory arthritis
  • Adalimumab = human mAbs
56
Q

Tocilizumab

A

mAb that binds to IL6 receptor; like TNFa, IL6 is upregulated in RA
- IL6 is a pro inflammatory cytokine that drives CRP production, commonly measured in blood tests. Therefore tocilizumab is targeted to those with elevated CRP levels.

57
Q

Rituximab

A

Biological DMARD, mAb
- Targets CD20, primarily expressed by B cells, induces their destruction
↑ risk of opportunistic infections + risk of progressive multifocal leukoencephalopathy caused by reactivation of John Cunningham virus (Fatal brain infection)

58
Q

Abatacept

A

Fusion protein of CTLA 4 and Fc fragment of human IgG1

- Binds to CD80/CD86 on T cells and interferes with antigen presenting cell activating T cells

59
Q

Anakinra

A
  • Recombinant IL1 receptor antagonist, higher affinity for IL-1R than IL-1, does not initiate signalling
  • Given by injection, response <2-12 weeks, increased susceptibility to infection
  • On balance of clinical benefits and cost-effectiveness, it is not a recommended treatment of RA in the UK.
60
Q

Key hallmarks of Osteoarthritis

A
  • Bone remodelling; early stage thinning of subchondral plate, but in late stage there is a decrease in bone resorption but no decrease in bone formation resulting in subchondral sclerosis and osteophyte formation
  • Synovium is also inflamed, despite this inflammation OA is considered to be non-inflammatory due to low leucocyte count in synovial fluid.
  • Decrease range of joint movement + join pain
61
Q

Capsaicin creams

A
  • Applied to affected area 3/4 times a day

- Activates TRPV1 on nociceptors, warming sensation followed by depolarising block and nociceptor degeneration

62
Q

Horse IRAP for treatment of osteoarthritic synovitis

A

IL-1 receptor antagonist protein
- Blood is collected from a horse in a syringe with glass beads coated in a way that induces IRAP production, 24 hours later serum containing IRAP is collected + stored at -80 degrees and injected into affected joints

63
Q

Other, non-pharmacological treatments for OA?

A
  • Autologous chrondocyte implantation/ transplantation
  • Injection of mesenchymal/bone marrow derived stem cells - both procedures reduce pain and increase function
  • In severe damage = arthroplasty (joint replacement)
64
Q

When blood glucose starts to fall (sleep), glucagon is released from alpha cells and stimulates…

A
  • Hepatic glycogenolysis
  • Gluconeogenesis
  • Lipolysis in fat
65
Q

Following ingestion of food a rise in blood glucose causes insulin release from beta cells…

A

Insulin binds to insulin receptor > Tyrosine kinase autophosphorylation > IRS-1 binds to RTK via SH2 domain > IRS-1 phosphorylated and interacts with SH2-domain containing proteins such as PI3K
↑ glucose uptake by muscle/fat
↑ lipogenesis (glucose to lipids)
↓ hepatic gluconeogenesis + glycogenolysis

66
Q

How does insulin release occur?

A

Glucose enters beta-cells via GLUT2 transporters and is metabolised to ATP. Beta cells express KATP, usually open and contribute to resting membrane potential - K+ moves down its concentration gradient.
KATP closure increases intracellular K+ > depolarisation activates CaV and Ca2+ influx induces fusion of insulin containing vesicles.

67
Q

Structure of KATP channels?

A

Octameric = core of 4 inwardly rectifying K+ channels (Kir6.2), forming pore of ion channels. Surrounded by 4 sulphonylurea receptor 1 (SUR1 subunits).
ATP binds to Kir6.2 subunits to induce channel closure + beta-cell depolarisation

68
Q

Structure of Insulin

A

51 amino acid protein - 2 polypeptide chains (A and B) linked by disulphide bonds.

  • Oral administration has low bio-availability so injected subcutaneously/intramuscularly
  • Once injected forms a hexamer under the skin, which then dissociate to be absorbed into the bloodstream.
69
Q

Insulin lispro

A
  • fast acting
  • swaps lysine and proline residues towards the end of the C terminus of the B chain reduces dimer and hexameter formation - larger amounts of active monomeric insulin available
  • onset 5-15 minutes post injection, duration 4 to 6 hours
70
Q

Insulin actrapid

A
  • Short acting

Onset within 30-60 minutes duration 8-10 hours

71
Q

Neutral Protamine Hagedorn (NPH) insulin

A

Intermediate acting

  • Suspension of protamine + insulin which forms relatively insoluble crystals thus slowing absorption
  • Onset within 2-4 hours; duration up to 12-18 hours
72
Q

Glargine

A
  • Long acting
  • An insulin analogue in which changes to amino acids in A and B chains change the molecule’s isoelectric point to a more neutral pH.
  • Form a microprecipate + higher aggregates, which retard + prolong absorption
  • Onset within 2-4 hours, duration 20-24 hours
73
Q

Side effects of insulin analogues?

A
  • Hypoglycaemia: trembling/sweating/confusion/ irritability/drowsiness/coma
  • Lipodystrophy: lipohypertrophy (fat build up due to local anabolic action) or lipoatrophy (fat loss due to immune response, far less common)
74
Q

Effect of exercise and changes to diet on T2DM?

A

Exercise increases insulin sensitivity
- insulin stimulated PI3K activation > Upregulation of GLUT4 transporters on skeletal muscle > Increased insulin mediated glucose uptake

75
Q

Metformin

A

First-line T2DM medication

  • decreased hepatic gluconeogenesis/ increased glucose uptake in skeletal muscle/ reduced intestinal carbohydrate absorption/ reduced circulating levels of VLDLs and LDLs / reduced appetite
  • MODA: Activation of AMPK decreases expression of genes involved in hepatic gluconeogenesis
  • Does not cause hypoglycaemia, but can cause GI disturbances and lactic acidosis.
76
Q

Glibenclamide/Glipizide

A

Sulphonylureas (SUs)

  • Bind to SUR1 subunit of KATP, closure of channel, depolarisation, Ca2+ influx + insulin release
  • Glipizide metabolised in the liver to inactivate products and excreted in urine
  • Glibenclamide converted to active products in the liver before urinary excretion so people with renal inefficiency have potentiated effects of glibenclamide
  • SUs cross placenta + enter breast milk, hypoglycaemia + increase appetite
  • Blockade of cardiac KATP is a potential risk but SUR2A subunit expressed in the heart, and SUs have higher affinity and efficacy for SUR1
77
Q

Repaglinide

A

Meglitinides

- Inhibit KATP by binding to SUR1 but faster onset + offset kinetics

78
Q

What is an incretin?

A
  • Substance that reduces blood glucose levels e.g. GLP 1 and GIP, released by L and K cells respectively from gut in response to ingested food
  • GLP1 + GIP, increase insulin stimulation, inhibit glucagon, reduce gastric emptying
  • GLP1 acts in brain to reduce appetite
  • Incretins broken down by DPP4 (dipeptidyl peptidase 4)
79
Q

Exenatide

A

Synthetic version of extendin4, found in saliva of Gila monster, mimics GLP-1 but longer acting
- Injected subcutaneously, more stable than GLP 1

80
Q

Sitagliptin

A

Gliptins

  • Inhibit DPP4 so incretins aren’t broken down
  • Taken orally
81
Q

SGLT1

A

Sodium-glucose co-transporter allows absorption of glucose in small bowel (active transport)

82
Q

SLGT2

A

Reabsorption of glucose filtered in the kidneys at the PCT

83
Q

Dapagliflozin

A

For DM, inhibit SGLT2 or combined SGLT1/2 inhibition

  • Increase urinary glucose loss + reduce GI glucose absorption
  • Side effects: Increased urinary/genital infection, increased urinary frequency, increase in ketone production in liver
84
Q

Pioglitazone

A

Thiazolidinediones

  • Activate PPARy - transcription factor highly expressed in adipose tissue + liver + muscle
  • Increased lipogenesis + glucose/ fatty acid uptake + increases transcription of many genes incl. GLUT4
  • Side effects: Weight gain + increased fluid retention due to enhancement in amiloride-sensitive Na+ reabsorption
85
Q

Acarbose

A

Alpha-glucosidase inhibitors

  • Slow the break down of starch/disaccharides, and reduce the amount of glucose entering bloodstream
  • Side effects: Flatulence + diarrhoea
86
Q

Main diagnostic test for SLE (systemic lupus erythematous)

A

Blood tests against anti-nuclear antibodies, and anti-dsDNA.
- Defective clearing of apoptotic cells by macrophages results in APCs presenting apoptotic material resulting in the development of anti-nuclear antibodies (ANAs)

87
Q

Azathioprine

A

Immunosuppressant + steroid sparing agent

  • Prodrug 6 mercaptopurine (6-MP) - converted by hypoxanthine phosphoribosyl transferase (HRRT) to thioinosic monophosphate (TIMP)
  • TPMT converts TIMP to 6-methyl-TIMP = inhibits de novo purine synthesis
  • Inosine monophosphate dehydrogenase (IMPDH) converts TIMP to 6-TGN, incorporated into cellular nucleic acids, inhibiting nucleotide and protein synthesis
  • Inhibits T + B cell proliferation, prevents transplant rejection + autoimmune diseases
  • Side effects: GI upset, hepatotoxicity
88
Q

3 steroid sparing agents?

A
  • Azathioprine
  • Methotrexate
  • Mycophenolic acid
89
Q

Mycophenolic acid

A
  • Derived from fungus Penicillium stoloniferum
  • Inhibits IMPDH required fro guanosine synthesis
  • Used to treat transplant rejection
90
Q

Cyclophosphamide

A

Alkylating agent. Prodrug converted by P450 first to aldophosphamide –> active phosphoramide mustard.

  • Phosphoramide mustard: two alkylating groups and cross links guanine in DNA via N7 groups
  • DNA replication defective because 7-alkylguanine pairs with thymine, also causes guanine excision and chain breakage
  • Immunosuppressive effect is due to killing of T and B cells
  • Side effects: Bone marrow depression, potential infertility, bladder irritation and cancer
91
Q

Ciclosporin A (CsA)

A
  • Immunosuppressive
  • Cyclic, 11 amino acid peptide > prevents T cell proliferation via suppression of IL2 synthesis
  • CsA binds to cyclophilin = CsA-CpN complex –> inhibits calcineurin (serine-threonine phosphatase which dephosphorylates nuclear factor of activated T cells enabling translocation to nucleus) –> CaN retained in cytoplasm, preventing IL2 upregulation
92
Q

Tacrolimus (FK506)

A
  • Macrolide antibiotic, binds to immunophilin called FK-binding protein (FKBP). Tacrolimus-FKBP complex inhibits CaN – NF-AT retained in cytoplasm and IL-2 synthesis is inhibited
  • Used to suppress rejection of transplanted organs
93
Q

Basiliximab

A
  • Monoclonal antibody against CD25 alpha subunit of IL-2 receptor
  • IL2 receptor antagonist. IL2 unregulated on activated T + B cells, so basiliximab decreases incidence + severity of acute rejection
94
Q

Belatacept

A

Fusion protein of CTLA-4 and IgG1

  • Acts to bind CD80/86 and prevents T cell co-stimulation; CTLA-4 domain has 2 amino acid variation that confer greater affinity + slower dissociation
  • Used in association with other drugs to prevent transplant rejection
95
Q

TGN1412

A

Anti-CD28 agonist monoclonal antibody = cause activation and proliferation of regulatory T cells, involved in preventing autoimmune reactions

96
Q

Sirolimus

A
  • Macrolide antibiotic by Streptomyces hygroscopicus
  • Sirolimus-FKBP complex inhibits rapamycin (mTOR) = serine/threonine kinase involved in cycle progression/ protein synthesis
  • Decrease T cell activation and proliferation = decreased immune response
  • Coat coronary stents to prevent restenosis
97
Q

FcyRI

A

Expressed by neutrophils - respiratory burst + phagocytosis

98
Q

FcyRII

A

Expressed by macrophages - phagocytosis

99
Q

FcyRIII

A

Expressed by natural killer cells - antibody-dependent cell mediated cytotoxicity ADCC

100
Q

Muromonab-CD3

A

Murine mAb that targets CD3, first mAb to be approved for clinical use
- Reduce acute transplant rejection

101
Q

Alemtuzumab

A

Binds to CD52, an antigen on mature lymphocytes but not the stem cells from which they derive - targets them for destruction; used in treating chronic lymphocytic leukaemia, T cell lymphoma and MS

102
Q

Catumaxomab

A
  • Bispecific antibodies
  • rat/mouse hybrid mAb; binds epithelial cell adhesion molecules, CD3 on tumours cells, and T cells –> destruction of cancer cell
  • Used to treat ascites in cancer patients
103
Q

Trastuzumab

A

anti-HER2 mAb, used to treat HER2 positive breast cancers

104
Q

Trastuzumab emtansine (T-DM1)

A

anti-HER2 mAb coupled to antimicrotubule compound maytansine (DM1), used to treat HER2 positive breast cancers

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