balancing immune response Flashcards
Immune responses from lymphocytes are a balance between – & – signals (via – & – receptors)
+ve n -ve
inhibitory n activator
activatory receptors:
Signal 1: —
CD3 – role in –
CD4 or CD8 co-receptor
Signal 2: – receptor on T cell
binds to – (CD80/86) on APC
- instructive – secretion + – molecules leads to —
inhibitory receptors:
CTLA-4 and PD-1 on T cells are – receptors structurally related to –
CTLA-4 on T cell binds – (CD80/86) on APC
or – on T cell binds PD-L1 on APC
this leads to –
TCR-peptide MHC
signalling
CD28
B7
cytokines
adhesion
T cell activation
co inhibitory
CD28
B7
PD-1
no T cell activation
1-the outcomes of T cell stimulation:
2- instructive cytokines by apc: t helper subset : response:
IL-12 — > — —> fights —
IL-10 —> —- —-> fights — and — via —
IL-23 –> —- —> fights — and —
TGF-B —> — —> —
- suppression by treg cells
- anergy
- apoptosis
- proliferation
( check slide 9,10)
TH1 fights intracellular pathogens
TH2 fights helminth infection and allergy via mast cells
TH17 fights extracellular bacterial and yeast infection
Treg immunosuppressive
Downregulation of T cell immune responses- via regulatory T cells (Treg):
How do Treg cells act to suppress the immune response?
Known mechanisms include:
* Secretion of – (eg. TGFb, IL-10)
* Engagement of – pathway rather than B7/CD28
* – “consumption”…less CK available for – of activated T cells
inhibitory cks
CTLA-4
IL-2
proliferation
( check slide 12)
- What happens when the immune response can’t / won’t switch off?
Inappropriate / excessive immune responses – > – - — disorders:
Group of diseases linked with uncontrolled production of lymphocytes; often in immunocompromised patients
immunopathology
Lymphoproliferative
Autoimmune lymphoproliferative syndrome (ALPS):
1-Defect of —
2-Immune cells fail to undergo — when they should
3-Cause: mutation(s) in the – pathway of apoptosis (Fas, Fas ligand, Caspase-10)
4-Extent of the defect determines disease –
- – may die in infancy
- disease in – can wax and wane
lymphocyte haemostasis
programmed cell death
FAS
severity
homozygots
heterozytes
diagnosis of ALPS:
-Suspect ALPS if:
* – (swollen lymph nodes, spleen, liver etc).
* — (eg. various lymphopenias, some hepatitis or nephritis)
* – (especially EBV-linked)
* Skin –
* Family history of – disorders
-Definitive diagnosis:
Must have both - – (>6 months) – lymphadenopathy or splenomegaly
- – a/b double-negative T cell count
and one of - lab findings of defective – (2 assays)
- – in FAS, FAS ligand or Caspase-10
chronic lymphoproliferation
autoimmune disease
lymphoma
skin rashes
lymphoproliferative
chronic
non malignant
elevated
defective lymphocyte
gene mutation
management of ALPS:
Only cure = — or — (severe cases only)
- Usually treat the manifestations of the condition (autoimmune cytopenias, lymphomas etc)
- Often adults are — symptomatic than children
- Regular surveillance is important
- Genetic counselling for family members
haematopoetic stem cell transplant or bone marrow transplant
less
What happens when the immune response won’t switch on when required —> —- which can increase the risk of — and —
inadequate immune protection
infection and cancer incidence/ progression
immune response to tumours:
-Tumours arise from “ – ” cells that have gone wrong….
-Immune system recognises and responds to them as it would other “altered self” situations (eg. virally-infected cells)
self ( check slide 18)
innate immune response to tumours and the role of nk cells:
NK cells activated to generate an — response
* Tumour cells may lose – expression –> – receptor on NK cells not engaged
* Activating receptors are engaged by ligands expressed by —
* Activated NK cells can also secrete— that activate – and – cells
anti tumour
lose MHC class 1
inhibitory
tumour cells
pro inflammatory cks
macrophages n dendritic cells
Innate/adaptive IS cooperation in anti-tumour immunity -role of antibodies in ADCC:
tumour cells coated w — will can — onto nk cells bearing – receptors which can lead to –
anti tumour antibodies
dock
Fc
Antibody-dependent cellular cytotoxicity (ADCC)
— are principle of anti tumour response
process:
The process:
* Tumour – are processed; some peptides displayed on cell surface on —
* Recognised by – CTL with receptor specific for
that antigen
* — etc
* Activated CTL binds and releases – and – to destroy tumour cell
CTLS ( cytotoxic cell )
tumour antigen
MHC class 1
CD8+
co stimualtion
perforin n granzym
how tumours evade the immune response:
Strategy 1: “ – ”
- Tumour cells – surface antigens
- Tumour cells – or – the –
which is harder for T cells to recognise tumours
Strategy 2: “Attack is the best defence ”
- Tumour cells produce – CKs
- Tumour cells express – surface proteins
( both of these will lead to inhibition of T cell activation )
- Enlist the help of other cells in the tumour – which will lead to – (etc) can inhibit CTL function and differentiation
of Th cells into – subtype
hide
deregulate
mutuate or down regulate mhc-1
immunosuppressive cks
inhibitory surface proteins
microenvironment
tumour-associated macrophages
TH1
( check slide 26 so important )
cancer immunotherapy:
– and – affect normal proliferating cells –> significant mortality and morbidity
- – often unsuccessful in achieving durable benefits
-Can we “train” the immune system to better recognise or target tumours?
chemo n radio
cytotoxic drugs
approaches towards cancer immunotherapy:
* Use – antibodies to target cancer cells
* Use — to “take the brakes off” the immune response (eg. checkpoint inhibitors)
*— stimuli to boost the immune response
* “ – ” our own (autologous) T cells to recognise cancer antigens
* Cancer –
synthetic anti tumour anitbodies
synthetic antibodies
pro inflammatory
train
vaccines
using antibodies to target tumour cells:
ideally…synthetic antibodies should be designed against targets which are — for tumour cells, or at least — on tumour cells or— expressed at particular differentiation stages.
Targets should also be important for — or— signalling…or may get dumped!
specific
overexpressed
only expressed
cell survival and tumprogenic signalling
( check slide 30 so important )
checkpoints inhibitors in cancer immunotherapy:
- Use – as drugs to “inhibit the inhibitors” – > stimulate —- immune responses — > tumour –
- * — : Ipilimumab approved for advanced melanoma,
mesothelioma, colorectal, some lung cancers…
Works by inhibiting CTLA-4 and by depleting Treg cells
* — , — : Nivolumab and Pembrolizumab approved
for melanoma, lung, renal, bladder, colorectal, gastric cancer…;
Atezolizumab approved for melanoma, urothelial, breast, some
lung cancers…
- More – and less – than anti-CTLA-4
- Can be used combined: but more side effects
MAbs
t cell
cell death
anti-CTLA-4
anti- PD1 , anti PD-L1
effective and less toxic
boosting the immune response:
1- cytokinę therapy approach :
-Eg. Interferon therapy for –
- – MHC class I on tumour cells leading to – antigen presentation & attack by –
(but – from activation of immune response)
2- non specific inflammatory approach:
Eg. — of killed BCG in bladder cancers
-Get strong – immune response via –
Bacteria act as “ – ” promoting – activation
melanomas
up regulates
increased
t cells
side effects
local instillation
inane
macrophages
adjuvant
T cell
training our own T cells to kill cancer:
- Adoptive cellular therapy…
Chimeric Antigen Receptor (CAR) T cell therapy
* Currently used for –
malignancies (ALL, CLL)
* In development for – , – tumours
b cell
malignant melanoma and brain tumours
cancer vaccines could be:
* — : – vaccinate against viral antigens implicated in cancer
eg. Hepatitis B virus
Human Papilloma virus (HPV) – GardasilTM
* — : – assuming the existence of a target antigen which is
– (or at least tumour-overexpressed)
—
Important for – / —
– and assuming that enough APCs can be activated to generate a good T cell response
(use adjuvants just like in “normal” vaccination against infectious organisms!)
preventative
therapeutic
tumour specific
immunogenic
cell survival and tumour progression
limitation of cancer immunotherapy:
* Enhancing the immune response has — effects….eg. autoimmune-like disease, inflammation
* Skin rashes and autoimmune-like conditions are common following — treatment
(but can be easily managed with anti-inflammatories in most patients)
* – used to manage inflammation may promote infectious complications
* Risk-benefit ratio is not always simple (Eg. in immunocompromised, pregnant, transplant pts etc??)
* Side-effects may occur – after treatment and are not yet routinely recognized in primary care
*– are very expensive
* CAR T cell therapies not – outside specialist centres
knock on
checkpoint inhibitors
steroids
months
Mars
practicle
overall perspective:
* Often desirable to – the immune response – > reduce excessive or inappropriate –
* Harnessing the immune response is a powerful tool
– > – the immune response to target tumours
down regulate
inflammation
up regulate
