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PATHOLOGY > suppressing the immune system > Flashcards

suppressing the immune system Flashcards

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1
Q

what are the ways to suppress the immune system

A

Steroids

Anti-proliferative agents

Plasmapheresis

Inhibitors of cell signalling

Agents directed at cell surface antigens

Agents directed at cytokines and their receptors

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2
Q

what are the steroids that are used

A

No mineralocorticoid activity

Prednisolone in Europe

Prednisone in USA - metabolised by liver into prednisolone

Endogenous secretion equivalent to 3-4 mg prednisolone

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3
Q

generally, what are steroids used for

A

Allergic disorders
Auto-immune disease
Auto-inflammatory diseases
Transplantation
Malignant disease

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4
Q

how do steroids suppress the immune system

A

inhibit phospholipase A2

phospholipase A2 breaks down phospholipids
-> arachidonic acid
-> converted to eicosanoids (eg prostaglandins and leukotrienes) by cyclo-oxygenases

therefore steroids stop arachidonic acid and prostaglandin formation -> reduce inflammation

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5
Q

how do steroids effect phagocytes

A

Decreased traffic of phagocytes to inflamed tissue
* Decreased expression of adhesion molecules on endothelium
* Blocks the signals that tell immune cells to move from bloodstream and into tissues
* -> transient increase in neutrophil counts

Decreased phagocytosis

Decreased release of proteolytic enzymes

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6
Q

effect of steroids on lymphocyte function

A

Sequestration of lymphocytes in lymphoid tissue -> lymphopenia
Affects CD4+ T cells > CD8+ T cells > B cells

Effects function
* Blocks cytokine gene expression
* Decreased antibody production
* Promotes apoptosis

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7
Q

SE of steroids

A

metabolic:

  • Diabetes,
  • central obesity,
  • moon face,
  • lipid abnormalities,
  • osteoporosis, give bone protection
  • hirsuitism,
  • adrenal suppression

cataracts
glaucoma ask about this - steroids can ppte problem
peptic ulceration give PPI
pancreatitis
avascular necrosis in hip

immunosuppression -> infection if give 20 or more - give cotrimoxazole prophylactically

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8
Q

what are the anti-proliferative immunosuppressants

A

Cyclophosphamide – not in preg

Mycophenolate – not in preg

Azathioprine – can use in preg

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9
Q

action of anti-proliferative immunosuppressants

A

Inhibit DNA synthesis

Cells with rapid turnover most sensitive

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10
Q

toxicty of anti-proliferative immunosuppressants

A

Bone marrow suppression

Infection (immunosuppression)

Malignancy (immunosuppression )

Teratogenic

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11
Q

side effects of cyclophosphamide

A

most toxic

Toxic to proliferating cells
* Bone marrow depression - monitor FBC
* Hair loss
* Sterility (male»female) – sperm storage before treat

Haemorrhagic cystitis
* Toxic metabolite acrolein excreted via urine
* -> irritate bladder
* -> haemorrhagic cystitis
* give drug to protect against this

Malignancy
* Bladder cancer
* Haematological malignancies
* Non-melanoma skin cancer

Infection
* Pneumocystis jiroveci – make sure taking cotrimoxole

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12
Q

side effects of azithioprine

A

Bone marrow suppression
* Cells with rapid turnover (leucocytes and platelets) are particularly sensitive
* Very variable – some severely and some moderately susceptable - 1:300 individuals are extremely susceptible to bone marrow suppression
* Thiopurine methyltransferase (TPMT) polymorphisms -> Unable to metabolise azathioprine -> levels build up – extremely toxic
* Check TPMT activity or gene variants before treatment if possible;
* always check full blood count after starting therapy
* Homozygous don’t use
* Heterozygous – use half dose

Hepatotoxicity - Idiosyncratic and uncommon

Infection - less common than with cyclophosphamide

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13
Q

SE of mycophenolate mofetil

A

Bone marrow suppression

Cells with rapid turnover (leucocytes and platelets) are particularly sensitive

Infection
* Particular risk of herpes virus reactivation
* Progressive multifocal leukoencephalopathy (JC virus)– fatal neuro complication

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14
Q

what is plasmapheresis and plasma exchange

A

Patient’s blood passed through cell separator

Own cellular constituents reinfused

Plasma treated
* remove immunoglobulins
* -> reinfused (or replaced with albumin in ‘plasma exchange’)

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15
Q

when is plasma exchange and plasmapheresis useful

A

when the Ab is causing disease not just a marker of disease - **type 2 hypersensitivity **

eg
* goodpastures: anti-GBM
* myasthenia gravis: anti-acetyl choline receptor bodies

antibody mediated transplant rejection/ABO incompatible - Ab directed at HLA/AB

Aim: removal of pathogenic antibody

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16
Q

problem with plasma exchange and plasmapheresis

A

Rebound antibody production limits efficacy, because still have plasma cells making Ab

therefore usually given with anti-proliferative agent

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17
Q

what are calcineurin inhibitors and what are they used in

A

Inhibit T cell proliferation/function
stop upreg of expression of IL2 which stims T cell proliferation

Ciclosporin
Tacrolimus

Used in:
* Transplantation
* SLE
* Psoriatic arthritis

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18
Q

what are mTOR inhibitors and what are they used for

A

Inhibit T cell proliferation and function

rapacycin
sirolimus

Used in:
Transplantation

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19
Q

what are JAK inhibitors (Jakinibs) and what are they used for

A

Inhibit JAK-STAT signalling which is the pathway that cytokines signal through

Influences gene transcription
Inhibits production of inflammatory molecules that are dependent on cytokine signalling

used for:
* Rheumatoid arthritis,
* psoriatic arthritis,
* axial spondyloarthritis

broad drugs
more SE - a lot of things signal through JAK-STAT

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20
Q

what are PDE4 inhibitors and their use

A

Apremilast

Inhibition of PDE4 leads
to increase in cAMP

Influences gene transcription
via protein kinase A pathway

Modulates cytokine production

Effective in
* psoriasis
* psoriatic arthritis

less commonly used

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21
Q

actions of agents against cell surface ag

A

Block signalling
Cell depletion
Inhibit migration

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22
Q

what is the action of anti-thymocyte globulin and how are the Ab formed

A
  1. Inject rabit with thymocyte
  2. make Ab against them (anti-T cell) range of specificities (CD2 3 4 8 28 11a. HLA class I and II)
  3. If inject into human -> anti-T cell response:
  • Lymphocyte depletion
  • Modulation of T cell activation
  • Modulation of T cell migration
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23
Q

use of anti-thymocyte globulin

A

Allograft rejection (renal, heart)
used in tranplant

Daily intravenous infusion

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24
Q

toxicity of anti-thymocyte globulin

A

Infusion reactions - Heterogenous group of cells

Leukopenia

Infection

Malignancy

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25
action of Ab directed at CD25 (IL-2a chain)
**Blocks IL-2 induced signalling** (bind IL2R at A B or Y chain) - block IL2 binding, signalling and proliferation and **inhibits T cell proliferation**
26
indications for Antibody directed at CD25 (IL-2Ra chain)
Prophylaxis of allograft rejection Intravenous given before and after **transplant** surgery
27
toxicity of Antibody directed at CD25 (IL-2Ra chain)
infusion reaction infection concern for lonterm risk of malignancy
28
action of CTLA4-Ig fusion protein
**Reduces costimulation of T cells via CD28** * Engineered CTLA4 on end of Fc * Bind CD80 and CD86 * Block the interaction * Normally CD28 predominates * So overall this reduces T cell activity
29
indications of CTLA4-Ig fusion protein
Rheumatoid arthritis Intravenous 4 weekly Subcutaneous weekly
30
toxicity of CTLA4-Ig fusion protein
Infusion reactions Infection (TB, HBV, HCV) Caution wrt malignancy
31
what is rituximab
**Ab specific for CD20** Not expressed by plasma cells Rituximab bind to b cells Usually after cycle – very few B cells - **deplete mature B cells** But **still have plasma cells** -> high affinity Ab – so **very little immunosuppression**
32
indications for rituximab
Lymphoma Rheumatoid arthritis SLE 2 doses intravenous 2 wks abour then every 6-12 months (RA)
33
toxicity with rituximab
over time get some plasma cell depletion Infusion reactions Infection (PML) Exacerbation CV disease malignancy NOT a complication!
34
action of Ab for a4B7
**inhibits leukocyte migration** a4 expressed with b7 integrin -> Binds to MadCAM1 to mediate leukocyte binding to endothelium and extravasation to tissue Ab to this means cant migrate
35
indication for a4B7 Ab
IBD IV every 8wks
36
toxicity of a4B7 Ab
Infusion reactions Hepatotoxic Infection (? PML) Concern re malignancy
37
agents against TNFa and applications for this
38
agents against IL-1 and applications for this
39
agents against IL-6 and applications for this
40
agents against IL17/23 and applications for this
41
agents against IL4/5/13 and applications for this
42
agents against RANK and applications for this
43
what is the role of TNFa
cytokine made by macrophages
44
what is anti TNF-a Ab used for
Rheumatoid arthritis, Ank spond Psoriasis and psoriatic arthritis, Inflammatory bowel disease, Familial Mediterranean fever *SC or IV*
45
what is infliximab
anti TNF-a Ab
46
risks of anti TNFa Ab (infliximab)
Infusion or injection site reactions Infection (TB, HBV, HCV) * double risk of acute infection * key in TB control - so **screen for TB** before give TNF-a inhib Lupus-like conditions Demyelination Malignancy * borderline increase in skin cancer * no increase in solid tumour Foreign so can make Ab against them – deplete and become less effective
47
action of TNFa antagonist
Receptor fusion protein Construct of TNF- receptor fused to IgGFc Receptor for TNFa – reduce the concentrations inhibit TNFa and TNFB
48
use of TNF antagonists
Rheumatoid arthritis Ankylosing spondylitis Psoriasis and psoriatic arthritis Subcutaneous weekly *Not good in infl;amatory eye disease or IBD – need actual Ab*
49
toxicity of TNFa antagonists
Injection site reactions Infection (TB, HBV, HCV) Lupus-like conditions Demyelination Malignancy
50
what produces IL-1 and what is the benefit of blocking it
secretion driven by inflammasome block used in: * familial mediterranean fever * gout * adult onset stills disease
51
roles of IL6
inflammation in RA Effects B cells, T cells, synovial sites, osteoclasts
52
use of anti-IL6 receptor Ab
RA GCA Large vessel vasculitis
53
use of anti-IL23 and IL17
spondyloarthritides and related conditions Axial spondyloarthritis (AS), Psoriasis and psoriatic arthritis, Inflammatory bowel disease (not anti-IL17 for IBD)
54
use of blocking IL4 5 and 13
IL-4, IL-5 and IL-13 are key cytokines in Th2 and eosinophil responses IL-4/13 blockade using anti IL4 receptor alpha subunit Ab -> eczema and asthma Anti-IL13 antibody -> eczema Anti-IL5 antibody -> eosinophilic asthma
55
use of anti-RANK ligand Ab
RANK ligand / RANK receptor pathway important in driving **osteoclast differentiation and function** * osteoclast derived from monocytes * express RANK * stim by RANK-L on osteoblasts * OPG regulate system by bind to RANK-L Anti-RANK ligand antibody (Denosumab) is used in management of **osteoporosis**
56
side effects of biologic agents for immunosuppression
Infusion reactions: * Urticaria, * hypotension, * tachycardia, * wheeze – IgE mediated * Headaches, * fevers, * myalgias – not classical type I hypersensitivity Injection site reactions – not usually severe * Peak reaction at ~48 hours * May also occur at previous injection sites (recall reactions) * Mixed cellular infiltrates, often with CD8 T cells * Not generally IgE or immune complexes
57
risk of acute infection after immunosuppression
- Risk often **> 2 x background** - Avoid contact/wash hands etc - Vaccination (**avoid live vaccines**) Temporarily **stop immunosuppression if infection** - Consider **atypical organisms** Appropriate antibiotics Young people risk is not very high Patient education – stop agent if get infection, low threshold for abx, explain to every dr they see
58
risk of TB with immune suppression
- History, Residence, Travel, Contacts, CXR, TB Elispot/Quantiferon - Prophylaxis or treatment if required – **before start drugs, do 4wks of treatment**
59
HBV and HCV with immunosuppression
Check Hep B core antibody pre-treatment Check Hep C antibody pre-treatment Further investigate for active virus infection if serology is positive
60
HIV with immunosuppression
check serology can use - balance risk - benefit
61
John Cunningham Virus (JCV) with immune suppression
Common polyomavirus that can reactivate Infects and **destroys oligodendrocytes** **Progressive multifocal leukoencephalopathy** Associated with use of **multiple immunosuppressives**
62
risk of malignancy on immunosuppression
Lymphoma (EBV) *but RA has higher background risk anyway* Non melanoma skin cancers (Human papilloma virus) ? Melanoma no evidence against solid tumour - Risks appear lower with targeted forms of immunosuppression than with regimes used in transplantation
63
autoimmune conditions that at risk of because of immune suppression
SLE and lupus-like syndromes Anti-phospholipid syndromes Vasculitis Interstitial lung disease Sarcoidosis Uveitis Autoimmune hepatitis Demyelination

PATHOLOGY (94 decks)

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