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Dr Edwardson - Immunosuppression II Flashcards

1
Q

What are the cells of the adaptive immune system?

A

Antigen presenting cells
B cells
Th1 and Th2 cells
Memory B and T cells

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2
Q

What is the effect do glucocorticoids have on the adaptive immune system?

A

Powerfully suppress the cascade process

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3
Q

Give some examples of disease which involve Th1 cells?

A

Insulin-dependent diabetes mellitus, MS, aplastic anaemia and rheumatoid arthritis

Also implicated in allograft rejection

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4
Q

Give some examples of disease which involve a Th2 cell response?

A

Predominates in allergic conditions such as asthma

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5
Q

Draw the pathway of glucocorticoid synthesis and the exogenous glucocorticoids that can act upon it

A

eeofine

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6
Q

Draw a diagram depicting the interaction of glucocorticoids with their receptor

A

efoi

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7
Q

How does the glucocorticoid receptor bind to DNA?

A

Through the use of a zinc finger motif

Binds as a dimer

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8
Q

What are the anti-inflammatory genes glucocorticoids upregulate?

A

Lipocortin-1
Secretory leukocyte inhibitory protein
IL-1 receptor antagonist
IκB

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9
Q

What are the inflammatory genes downregulated by glucocorticoids?

A

IL-1
TNFα
iNOS
COX-2

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10
Q

What is Cushing’s syndrome? What causes it?

A

Syndrome characterised by:

  • hypertension
  • thinning of skin
  • thin arms and legs
  • easily bruised
  • increased abdominal fat

Caused by excess endogenous or exogenous steroid

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11
Q

Hydrocortisone

A

Short acting corticosteroid (<24hrs)

Used in the treatment of asthma, rheumatoid arthritis and in immunosuppression

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12
Q

Prednisone

A

Short acting corticosteroid (<24hrs)

Prodrug of prednisolone

Used in the treatment of asthma, rheumatoid arthritis and in immunosuppression

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13
Q

Prednisolone

A

Short acting corticosteroid (<24hrs)

Active form of prednisolone

Used in the treatment of asthma, rheumatoid arthritis and in immunosuppression

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14
Q

Triamcinolone

A

Intermediate acting corticosteroid (24-48hrs)

Used in the treatment of asthma, rheumatoid arthritis and in immunosuppression

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15
Q

Dexamethasone

A

Long acting corticosteroid (>48hrs)

Used in the treatment of asthma, rheumatoid arthritis and in immunosuppression

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16
Q

What are the characteristic of asthma?

A

Variable airflow

Airway hyper-responsiveness to various stimuli

Episodic bronchoconstriction

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17
Q

What are the features of an asthmatic attack?

A

Narrowed airway

Tightened muscles constrict airway

Inflamed/thickened airway wall

Mucus

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18
Q

What is the time-course of an asthmatic attack?

A

Intermediate asthmatic response (Reduced pulmonary function for ~1hr)

Late asthmatic response = 2-6hrs

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19
Q

What are the inflammatory event in an asthmatic attack?

A

Allergen activates T cells to release cytokines

These stimulate B cells cause production of IgE = Mast cell degranulation (release of histamine, leukotrienes, cytokines)

Also stimulates eosinophils to release leukotrienes chemotactic factors

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20
Q

What are the treatments for asthma?

A

Inhaled glucocorticoids

Selective β(2) receptor agonist eg salbutamol or salmeterol

Mast cells stabilizers eg cromolyn sodium

Blockers of leukotriene synthesis or receptors eg zileuton and zafirlukast

Muscarinic antagonists eg ipratropium

Theophylline (PD inhibitor)

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21
Q

Cromolyn sodium

A

Used in treatment of asthma

Mast cell stabilizer - however this is unlikely to be its MODA as other mast cell stabilizers don’t work

More likely that it acts by inhibiting the response of sensory C fibres, inhibiting local axon reflexes and may inhibit the release of T cell cytokines
(Garland 1991)
May be via inhibtion of chloride channels

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22
Q

Zileuton

A

Blocks leukotriene synthesis through inhibition of 5-lipoxygenase

Used in the treatment of asthma

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23
Q

Zarfirlukast

A

Leukotriene receptor antagonist used in the treatment of asthma

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24
Q

How do PDE inhibits help in the treatment of asthma?

A

Prevent the breakdown of cAMP

cAMP => relaxation

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25
How do muscarinic receptor antagonists help in the treatment of asthma?
Reduce stimulation of IP3 through M(3) receptor = reduced Ca+ release and reduced contraction
26
How do β(2) agonists help in the treatment of asthma?
Stimulate the β2 receptor to stimulate adenylyl cyclase = ^cAMP and inhibition of MLCK
27
What are the stimuli that cause histamine release from mast cells? How do these stimuli work?
Cross-linking of IgE bound to FCεR1 Complement components C3a and C5a Basic drugs eg morphine, tubocurarine and codeine Mechanical damage All cause increase in Ca2+ concentration
28
What are the stimuli that act to inhibit the release of histamine from mast cells? How do these work?
β-agonists Phosphodiesterase inhibitors Sodium cromoglycate Increase cAMP levels
29
What are the airway changes in COPD?
Disrupted alveolar attachments, Mucosal inflammation, fibrosis Mucus hypersecretion
30
What are the cell types involved in COPD?
Neutrophils T-lymphocytes (CD8+) Macrophages
31
What do neutrophils secreted in COPD?
IL-6, IL-8, GM-CSF, TNFα, PGE(2), NE, cathepsins and MMPs
32
What do CD8+ Tcells secrete in COPD?
Perforins Granzymes Cyc-LTs
33
What do macrophages secrete in COPD?
TNFα, IFNγ, GROα, MMPs and LTB(4)
34
What are the drug target in the treatment of COPD?
Stop smoking Immunosuppressants Mediator antagonists Neutrophil inhibitors Protease inhibitors Mucoregulators
35
What is multiple sclerosis?
An autoimmune disease in which their is autoimmune attack of oligodendrocytes
36
Which joints are most affected in rheumatoid arthritis? What else does it affect?
Affects proximal phalanges but also feet, spine etc Effects on heart, lung, kidney, skin, sclera of the eye
37
What are glucocorticoids?
Endogenous steroids regulating glucose metabolism
38
What are corticosteroids?
Artificial steroids used in therapy Includes endogenous glucocorticoids
39
Describe the activation of the glucocorticoid receptor
Glucorticoid receptor (major form = GCRα) is present in the cytoplasm complexed with other proteins eg HSP90 On binding the ligand, the receptor dissociates and is translocated to the nucleus where it acts as a transcriptional regulator that increases/decrease gene expression
40
What are the three ways in which the glucocorticoid receptor can alter gene expression when activated?
Directly by activating transcription Indirectly by enhancing the action of a transcription factor by binding to it By enhancing the action of a transcription factor by interacting with it cooperatively
41
What is the important effect of prolonged treatment with corticosteroids?
Shuts down endogenous production of glucocorticoids
42
Type I diabetes
Immune attack on pancreatic beta cells
43
Hyper and hypothyroidism
Graves disease and Hashimoto's thyroiditis respectively
44
Vitiligo
Immune attack on melanocytes, causing uneven skin pigmentation
45
Behcet's disease
Immune attack on blood vessels and anterior chamber of the eye
46
Ulcerative colitis and Crohn's disease
Immune attack on large bowl
47
What is the major downside to the use of corticosteroids in immunosuppression?
Requires high dose treatment Large number of side effects
48
Cyclophosphamide
Used for aggressive short-term treatment of sever autoimmune diseases Prodrug from which the active compound (a nitrogen mustard alkylating agent) is released in the liver (by cyt p450) Adds an alkyl group to guanosine and so preventsDNA replication, causing apoptosis of rapidly dividing cells (eg T and B cells) Side effects = hair loss, haemorrhagic cystitis and infertility
49
What are the sites of action of immunosuppressive drugs?
Resting T lymphocytes - Early and late activation IL-2 IL-2R Proliferation
50
What is calcineurin?
A protein phosphatase that activates nuclear factor of activated T cells (NFATc) by dephosphorylation NFATc = upregulation of IL-2R
51
How do calcineurin inhibitors act as an immunosuppressant?
Calcineurin activates NFATc by dephosphoylation causing an upregulation of IL-2R Therefore inhibition of calcineurin prevents upregulation of IL-2R
52
Cyclosporin
Calcineurin inhibitor used as an immunosuppressant Prevents upregulation of IL-2R by preventing the dephosphorylation of NFATc by calcineurin Binds to cyclophilin to inhibit calcineurin
53
Tacrolimus
Calcineurin inhibitor used as an immunosuppressant Prevents upregulation of IL-2R by preventing the dephosphorylation of NFATc by calcineurin Binds to FK-binding protein
54
How does cyclosporin interact with calcineurin? What does this mean?
By bind to cyclophilin A CsA-CypA binary complex lies at the base of the helical arm of the catalytic subunit of calcineurin (CnA) that binds the regulatory subunit (CnB) CsA sits in a hydrophobic groove in intimate contact with both subunits at a region unique to calcineurin Means that CsA has a high specificity
55
How do inhibitors of mTOR help to cause immunosuppression?
mTOR is a protein kinase that regulates cell growth/proliferation and is stimulated by activation of the IL-2R There inhibits proliferation of T-cells/B-cells
56
Rapamycin
Macrocyclic triene from a soil bacterium Binds to FKBP and inhibits mTOR (a serine/threonine protein kinase involved in cell proliferation following activation of IL-2R
57
Azathioprine
Active metabolite inhibits guanosine synthesis and so inhibits DNA synthesis in B, T cells Other cell can obtain guanosine via the salvage pathway
58
Mycophenolate
Inhibits guanosine synthesis (IM dehydrogenase) and so inhibits DNA synthesis in B and T cells Other cells can obtain guanosine via the salvage pathway
59
To which region of the antibody do antigens bind?
The hypervariable region at the tips of the light and heavy chains
60
What is a chimeric antibody?
One that has mice variable light and heavy chains
61
What is a humanized antibody?
One that has mouse complementarity determining regions
62
Infliximab
TNFα mAb used in the treatment of rheumatoid arthritis and Crohn's disease
63
Adalimumab
TNFα mAb used in the treatment of rheumatoid arthritis and Crohn's disease
64
Omalizumab
IgE mAb used in the treatment of asthma Prevents binding of the IgE Fc domain to the Fc receptor and so inhibits release of inflammatory mediators from basophils and mast cells
65
Alemtuzumab
CD52 mAb used in the treatment of B cell leukaemia and MS (trials) Resets acquired immunity to a naive state Still functional innate system
66
What is the difference between drugs with the suffix -mab, -imab and -umab?
- mab = monoclonal antibody - imab = chimeric monoclonal antibody - umab = fully humanized antibody
67
Etanercept
Artificially construct of the TNFαR fused to an antibody Fc domain
68
What are the benefits of antibodies as therapeutic agents over chemicals?
``` High target affinity High target specificity Low off-target toxicity Blocks protein-protein Long serum half life Effector mechanisms ```
69
What are the benefits of chemicals as therapeutic agents over antibodies?
``` Access to small sites Extravascular targets Intracellular targets Oral route Immunogenicity ```
70
What are the new techniques to improve antibodies?
``` Bispecific antibodies Supercharged ADCC Drug conjugations Longer PL Shrinkage of the scaffold - even by mimicking binding domain ```
71
How do bispecific antibodies work?
Bind different targets on two cell types, bringing them into proximity of each other Allows ADCC Eg CD19 on B-lymphoma cell and CD3 on CD8+ Tcells
72
How do supercharged ADCC antibodies work?
Killing action of Abs can be improved by improving binding of AbFc to receptors on NKcells (FcγRIII) by: Changes in Ab Fc protein Changes in Ab Fc sugars (afucosylated glycoforms)
73
How do Ab drug conjugates work?
Conjugation of small highly toxic chemical drugs to Abs Abs bind to target on cells and are taken up Bound drug kills cells
74
MMAE (monomethyl auristatin E)
An antimitotic which inhibits cell division by blocking the polymerization of tubulin Conjugated to Ab then cleaved in the cell by cathepsin
75
Maytansine
Inhibits microtubule assembly Recently shown to improve survival when conjugated to trastuzamab
76
Calichaemycin
Binds to DNA in the minor groove and causes strand scission
77
What are the implication of improving the PK of antibodies? Give an example
Slow release formulation and long biological action could lead to injection of Abs once a year eg Denusomab is given every 6 months
78
Denusomab
Binds to RANKL (receptor activator of NFκB ligand) a ligand for osteoprotegerin and functions as a key factor for osteoclast differentiation and activation Inhibits bone loss in osteoporosis, RA and multiple myeloma

MODA (8 decks)

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