7. Switching off the immune system Flashcards
What is tolerance?
Switching off the immune response
What are the points of tolerance for B cells?
Failure of T cell help
Central tolerance in bone marrow
Peripheral tolerance
What are the points of tolerance for T cells?
Positive and negative selection
Absence of co-stimulatory signal
Active regulation by cytokines
What are the steps in the T cell activatory response?
MHC and CD3, 4 and 8 co-receptors
Co-stimulatory receptor CD28 binds to B7 on the APC
What is the inhibitory T cell response?
CTLA-4 binds to B7
or PD-1 to PD-L1 on APC
What are the results of the inhibitory T cell response?
Apoptosis
Anergy
Suppresion by T regulatory cells
What are the functions of T regulatory cells?
Create an immunosuppressive environment
CTLA-4 pathway
Consume IL-2 (autocrine T cell growth factor)
How do T regulatory cells create an immunosuppressive environment?
Produce inhibitory cytokines TGFB and IL-10
What is ALPS?
Autoimmune Lymphoproliferative Syndrome
Mutation in FAS pathway of apoptosis so immune cells don’t die when they should
What diseases can ALPS be associated with?
Chronic lymphoproliferation Autoimmune disease Lymphomas Skin rashes Family history
How is ALPS diagnosed?
BOTH: >6 months non-malignant lymphadenopathy/spenomegaly
and increase a/B double negative T cell count
AND ONE OF
-2 assays of defective lymphocyte apoptosis
-gene mutation in FAS, FAS ligand or caspase-10
How is ALPS cured?
Haematopoietic stem cell transplant or BMT
What are the methods tumour cells use to evade immune detection?
Invisibility by reducing MHC
Tumour produces proteins which reduce the immune response
Exploiting macrophages
How do tumour cells exploit macrophages?
Use them to secrete immunosuppressive cytokines
- Suppress NK cells
- Reduce T cell activity and recruitment
What are the methods of cancer immunotherapy?
Synthetic anti-tumour antibodies Checkpoint inhibitors Boost immune response CAR T cell therapy Cancer vaccines
What is necessary for synthetic anti-tumour antibodies to work?
Antigen must be on tumour surface
Must be specific to tumour (antibody to something upregulated or at a specific stage of differentiation)
Must be important to a tumour’s life or it could switch it off
How do checkpoint inhibitors work?
Inhibit inhibition of immune cells
What is a side effect of checkpoint inhibitors and how is it managed?
May cause autoimmune conditions
Manage with anti-inflammatories
Name a synthetic CTLA-4 antibody which is used to treat melanoma
Ipilimumab
Name 2 anti-PD1 drugs
Nivolumab
Pembrolizumab
Name 2 methods of boosting the immune response towards cancer
CK/interferon therapy
Non-specific inflammatory response
How does CK/ interferon therapy work?
Increasing MHC on tumour cells which enhances antigen presentation to T cells
How is a non-specific inflammatory response used to treat cancer?
Induce inflammation to a toxin in the area to increase the response
Eg. BCG vaccine and bladder cancer
What is CAR T cell therapy?
‘Training’ of T cells out of the body to kill cancer
Used in B cell malignancies
What factors are needed for an effective anti-cancer vaccine?
Tumour antigen is specific, increases T cell response and important to tumour survival
What are the components of an anti-cancer vaccine?
Killed tumour cells/recombinant tumour antigens/DCs incubated with the antigen
and
adjuvants used to increase T cell response
What are the limitations of anti-cancer immunotherapy?
Risk/benefit in immunocompromised patients
Autoimmune and inflammatory effects
Effects of steroids used to manage drug side effects
Side effects appear late
Monoclonal antibodies are expensive
CAR T cells are difficult to produce
