suppressing the immune system Flashcards
what are the ways to suppress the immune system
Steroids
Anti-proliferative agents
Plasmapheresis
Inhibitors of cell signalling
Agents directed at cell surface antigens
Agents directed at cytokines and their receptors
what are the steroids that are used
No mineralocorticoid activity
Prednisolone in Europe
Prednisone in USA - metabolised by liver into prednisolone
Endogenous secretion equivalent to 3-4 mg prednisolone
generally, what are steroids used for
Allergic disorders
Auto-immune disease
Auto-inflammatory diseases
Transplantation
Malignant disease
how do steroids suppress the immune system
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
how do steroids effect phagocytes
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
effect of steroids on lymphocyte function
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
SE of steroids
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
what are the anti-proliferative immunosuppressants
Cyclophosphamide – not in preg
Mycophenolate – not in preg
Azathioprine – can use in preg
action of anti-proliferative immunosuppressants
Inhibit DNA synthesis
Cells with rapid turnover most sensitive
toxicty of anti-proliferative immunosuppressants
Bone marrow suppression
Infection (immunosuppression)
Malignancy (immunosuppression )
Teratogenic
side effects of cyclophosphamide
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
side effects of azithioprine
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
SE of mycophenolate mofetil
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
what is plasmapheresis and plasma exchange
Patient’s blood passed through cell separator
Own cellular constituents reinfused
Plasma treated
* remove immunoglobulins
* -> reinfused (or replaced with albumin in ‘plasma exchange’)
when is plasma exchange and plasmapheresis useful
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
problem with plasma exchange and plasmapheresis
Rebound antibody production limits efficacy, because still have plasma cells making Ab
therefore usually given with anti-proliferative agent
what are calcineurin inhibitors and what are they used in
Inhibit T cell proliferation/function
stop upreg of expression of IL2 which stims T cell proliferation
Ciclosporin
Tacrolimus
Used in:
* Transplantation
* SLE
* Psoriatic arthritis
what are mTOR inhibitors and what are they used for
Inhibit T cell proliferation and function
rapacycin
sirolimus
Used in:
Transplantation
what are JAK inhibitors (Jakinibs) and what are they used for
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
what are PDE4 inhibitors and their use
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
actions of agents against cell surface ag
Block signalling
Cell depletion
Inhibit migration
what is the action of anti-thymocyte globulin and how are the Ab formed
- Inject rabit with thymocyte
- make Ab against them (anti-T cell) range of specificities (CD2 3 4 8 28 11a. HLA class I and II)
- If inject into human -> anti-T cell response:
- Lymphocyte depletion
- Modulation of T cell activation
- Modulation of T cell migration
use of anti-thymocyte globulin
Allograft rejection (renal, heart)
used in tranplant
Daily intravenous infusion
toxicity of anti-thymocyte globulin
Infusion reactions - Heterogenous group of cells
Leukopenia
Infection
Malignancy
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
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
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
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
agents against TNFa and applications for this
agents against IL-1 and applications for this
agents against IL-6 and applications for this
agents against IL17/23 and applications for this
agents against IL4/5/13 and applications for this
agents against RANK and applications for this
what is the role of TNFa
cytokine made by macrophages
what is infliximab
anti TNF-a Ab
action of TNFa antagonist
Receptor fusion protein
Construct of TNF- receptor fused to IgGFc
Receptor for TNFa – reduce the concentrations
inhibit TNFa and TNFB
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
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)
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
