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CP > immunomodulation and immunosupression > Flashcards

immunomodulation and immunosupression Flashcards

1
Q

what is immunomodulation?

A

it is the manipulation of the immune system using immunomodulatory drugs to achieve a desired immune response

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2
Q

why does immunomodulation improve the function of the immune system?

A

a therapeutic effect of immunomodulation may lead to immunopotentiation, immunosupression and induction of immunological tolerance

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3
Q

what are biologic immunomodulants?

A

they are medicinal products that are designed using molecular biological techniques including recombinant DNA technology and cloning - can generate complex molecules

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4
Q

what are the main classes of immunomodulants?

A

monoclonal antibodies
substances that are almost identical to the body’s own key signalling proteins
fusion proteins

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5
Q

what do the drugs do and how do they differ?

A

they all target the same thing but through different characteristics

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6
Q

does the immune system react to the drug?

A

it can react to the drug given that there is a foreign component to it - chimeric - some part will be of animal origin

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7
Q

what is a fusion protein?

A

TNF receptor 2 that is naturally occurring on cells and has high specificity - it is spliced to the Fc region which is the fusion protein and replaces the Fab region

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8
Q

how can the stability of antibodies be improved?

A

PEG attached to a fragment of the antibody

cetrolizumab - humanised monovaletn Fab-PEG

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9
Q

what is adalimumab and inflixmab?

A

adalimumab - human IgG1 monoclonal antibody

infliximab is a chimeric mouse human IgG1 monoclonal AB

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10
Q

what is an example of a fusion protein?

A

etanercept - Fc-TNFR2 extracellular domain

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11
Q

what types of immunopotentiation are there?

A

vaccination - active or passive, immune stimulants and replacement therapies

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12
Q

what is passive immunisation?

A

it is the transfer of specific, high titre antibody from donor to recipient - immediate but transient protection - protective ABs from those exposed in past - protective in circulation - small amount of time

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13
Q

what are the problems of passive immunisation?

A

risk of transmission of viruses and serum sickness in a type III hypersensitivity reaction

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14
Q

what are the types of passive immunisation?

A

pooled specific human immunoglobulin and animal sera (antivenins vs antitoxins)

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15
Q

what are the uses of passive immunisation?

A

hep B prophylaxis, botulisms, VZV, diptheria, snake bites

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16
Q

what is active immunisation?

A

it is delayed protection to stimulate a protective immune response and immunological memory

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17
Q

what is given in active immunisation?

A

immunogenic material

weakened, killed/inactivated, adjuvants, purified material

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18
Q

what are problems of the active immunisation method?

A

limited usefulness in immunocompromised, allergies and delays in achieving protection

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19
Q

what happens in replacement therapies?

A

the blood is segregated into cellular components and the serum into Igs - different Igs are taken out of donor and given in combination to recipient to make response to multitude of pathogens

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20
Q

what is used to treat antibody deficiency states?

A

pooled human immunoglobulin through SC or IV

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21
Q

what does G-CSF or CM-CSF act on?

A

the bone marrow - production of mature neutrophils

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22
Q

how would you administer interferons?

A

exogenously - the innate immune system produces them in early infection

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23
Q

what is gamma used for?

A

intracellular infections such as TB

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24
Q

what is the main use of a-interferon for?

A

treatment of Hep C

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25
Q

what is y-interferon used for?

A

certain intracellular infections with atypical mycobacteria and also in chronic granulomatous disease and IL-12 deficiency

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26
Q

what is used in neutropenia and what is this?

A

GCSF - stimulate neutrophil production as is a cytokine that stimulates progenitor cells in bone marrow to produce neutrophils

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27
Q

what can you use for immunosupression?

A

corticosteroids, cytotoxic agents, antiproliferatives/activation agents, DMARDs and biological DMARDs

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28
Q

what is the usual use of corticosteroids?

A

they are produced naturally during infection to limit the unintended damage from the immune system due to inflammatory response

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29
Q

what is the effects of corticosteroids?

A

they have a multitude of effects on the immune system including lymphopenia, reducing neutrophil margination, reduced production of inflammatory cytokines and inhibition of phopholipase A2 (from reduced arachidonic acid metabolites), decreased T cell proliferation and reduced immunoglobulin production - reduce response quickly overall

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30
Q

what are side effects of corticosteroids if used long term?

A

they alter carbohydrate and lipid metabolism resulting in diabetes, secondary cushing’s syndrome and hyperlipidaemia, reduced protein synthesis resulting in poor wound healing, osteoporosis, glaucoma and cataracts and occassionally psychiatric complications such as depression and anxiety

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31
Q

what are the uses of corticosteroids?

A

autoimmune disease - CTD, RA and vasculitis
inflammatory disease such as GCS/polymyaliga rheumatica, crohns and sarcoid
malignancies - they directly kill malignant b and t cell clones
allograft rejection

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32
Q

how does malignancy of the T cell work?

A

T cell receptors are fully stimulated by co-stimulatory molecules. The T cell secretes IL-2 which allows for continual activation and clones which multiply when the T cell is with the correct receptor. Transcription factors then lead to the generation of signals that allow for cell proliferation and IL2 generation for further stimulation

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33
Q

how can corticosteroids affect the T cell malignant process?

A

they can interfere with activation or proliferation stages, or DNA synthesis such as MMF - anti-metabolite - T cell cannot generate DNA so cannot multiply

34
Q

what are the types of drugs that target lymphocytes and examples?

A

antimetabolites (azathioprine and mycophenolate motefil)
calcineurin inhibitors (ciclosporin A and tacrolimus)
M-TOR inhibitors (sirolimus)
IL-2 receptors mABs (basiliximab and dacizulimab)

35
Q

what is the action of cyclosporin?

A

binds to the intracellular protein cyclophilin

36
Q

what is the action of tacrolimus?

A

binds to intracellular protein FKBP-12 - stops signal being propogated further

37
Q

what are the general actions of calcineurin inhibitors?

A

they stop the activation of NFAT and therefore T cell activation and factors which stimulate cytokine gene transcription such as IL-2 and IFN-gamma

38
Q

what are the T cell effects of calcineurin inhibitors?

A

they result in the reversible inhibition of T cell activation, proliferation and clonal expansion - the immune system is reactivated if the drugs are removed

39
Q

what is sirolimus?

A

it is a macrolide antibiotic that also binds to FKBP12 but with different effects and inhibits the mammalian target of rapamycin

40
Q

what is the mode of action of sirolimus?

A

it inhibits the repsonse to IL-2

41
Q

what is the T cell effect of sirolimus (rapamycin)?

A

cell cycle stops at G1-S phase and the T cells are only partially activated

42
Q

how can you reduce the side effects of calcineurin / mTOR?

A

modulation

43
Q

when are the side effects of mTOR and calcineurin more likely?

A

long term use

44
Q

what are the side effects of calcineurin/mTOR?

A

hypertension, nephro and hepatotoxicity, hirsutism, lymphoma, opportunistic infections, nephrotoxicity, multiple drug interactions that induce CYP450

45
Q

what is the clinical use of calcineurin and mTOR?

A

transplation - allograft rejection

autoimmune disease

46
Q

what do antimetabolites do?

A

they inhibit nucleotide (purine) synthesis

47
Q

what is the action of azathioprine?

A

guanine anti-metabolite - will rapidly convert to 6-mercaptopurine

48
Q

what is the action of mycophenolate mofetil?

A

prevents the production of guanosine triphosphate

49
Q

what are B and T effects of anti-metabolites?

A

impaired DNA production, prevents the early stages of cell proliferation

50
Q

what is methotrexate for and what is it’s action?

A

MND and cancer - folate antagonist

51
Q

what is the role of cyclophosphamide?

A

crosslinks DNA

52
Q

what are the side effects that are a) common to all anti-metabolites, b) unique to cyclophosphamide and c) unique to methotrexate?

A

a) hepatitis, gastric upset, bone marrow suppression and susceptibility to infection
b) cystitis
c) MTX - pneumonitis

53
Q

what is the clinical use of a) AZA/MMF, b) MTX and c) cyclophosphamide?

A

a) autoimmune disease such as vasculitis, SLE and IBD and allograft rejection
b) GvHD in BMT and RA, PsA, polymyositis and vasculitis
c) vasculitis Wagner’s and CSS) and SLE

54
Q

what do steroids do?

A

they downregulate many pathways but become less effective over time - can target each chemical of importance

55
Q

what are examples of biologics?

A

anti-cytokines (TNF, IL6 and IL1), anti B cell therapies, ant T cell activation, anti adhesion molecules, checkpoint and complement inhibitors

56
Q

what happens with more targeted biologics?

A

there are unintended consequences on that system as they have wide effects

57
Q

what is anti-TNF and what is a risk of it?

A

it was the first biologic to be used in the treatment of RA and is now used in a number of inflammatory conditions such as ankylosing spondylitis, Crohns and psoriasis but it can increase the risk of TB

58
Q

what is AOSD?

A

adult onset stills disease

59
Q

what is anti-IL-6?

A

tocilizumab - blocks interleukin-6 receptor used in RA and AOSD - it may cause problems with control of serum lipids

60
Q

what is anti-IL-1 used for?

A

AOSD and autoinflammatory syndromes

61
Q

what is rituximab?

A

it is a chimeric mAB against CD20 on the B cell surface - first used for chemo against resistant DLCL

62
Q

what are common used for rituximab?

A

lymphoma, leukaemia, transplant rejection and autoimmune disorders

63
Q

how does lymphoma generate?

A

immature or activated B cells or autoimmune disease

64
Q

what is the benefit of rituximab?

A

repopulation of B cells with a non-agressive B cell population - does not affect the plasma cells that produce ABs producing protection

65
Q

what is adoptive immunotherapy?

A

it is a therapy that enhances the patient’s own immune system and leads to the killing of a specific tumour cell

66
Q

what is the main type of adoptive immunotherapy?

A

bone marrow/stem cell transplant

67
Q

what is osteopetrosis?

A

it is a disease that makes normal bones abnormally dense and prone to fracture. There are many types which are characterised by their inheritance patterns

68
Q

what are the uses of adoptive immunotherapy?

A

autoimmune disease, leukaemia and lymphoma, immunodeficiencies (SCID) and inherited metabolic disorders (osteopetrosis)

69
Q

what do check points inhibitors require?

A

interaction with a T cell

70
Q

what is the basis of the check point inhibitor?

A

they interfere with the CD80/86 interaction with CTLA-4 - artificial stimulation to CTLA-4

71
Q

why does the interference from a checkpoint inhibitor result in loss of T cell activation?

A

there is no co-stimulation and therefore T cells become anergic - some will turn into Tr cells. The T cells will start to express PD-1 and after interaction with surrounding tissue are deactivated

72
Q

what does anti-PDL 1 do?

A

it is an anticancer therapy - restarts the immune system leading to effective tumour recognition and killing

73
Q

what is a side effect of checkpoint inhibitors?

A

they may cause an autoimmune disease

74
Q

what immunomodulation can be used for allergies?

A

allergen specific immunotherapy, anti-IgE monoclonal therapy, anti-Il-5 monoclonal treatment, immune supressants - allergic disorder can be managed with steroids

75
Q

what is allergic specific immunotherapy indications?

A

allergy rhinoconjunctivitis not controlled on maximum medical therapy and anaphylaxis to insect venoms

76
Q

what are the mechanisms of allergic specific immunotherapy?

A

switching from the Th2 allergic response to Th1 non allergic response and development of T reg cells and tolerance

77
Q

how is allergic specific immunotherapy administered?

A

SC or sublingual for aero-allergens

78
Q

what are the side effects of allergic specific immunotherapy?

A

systemic or localised allergic reactions

79
Q

what is omalizumab?

A

it is a mAB against IgE molecules that are in the type II hypersensitivity reaction. It is used in the treatment of asthma and is NICe approved from treatment of chronic urticaria and angiodema. It may cause sever systemic anaphylaxis.

80
Q

what is mepolizumab?

A

it is a mAB against IL-5. It prevents eosinophil recruitment and activation and is NICE approved for asthma but has no clinical efficacy in hypereosinophilic syndrome

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