Immune Modulation - Boosting the immune system Flashcards
What immune response does immune memory depend on?
Adaptive immune response: B and T cells
Name the features of the adaptive immune response.
What are antigen presenting cells?
What events follow exposure to antigen?
Summarise the T cell response.
How long does T cell memory last? Where does T memory lie? How do they respond to activation?
Describe the B cell response.
How long does B cell memory last? What happens during secondary infection?
What do we want from a vaccine?
- Memory (to generate protective, long-lasting immune response)
- No adverse reactions
- Practical (single shot, easy storage, cheap)
What is the aim of a vaccine for influenza?
- Although CD8 T cells control the viral load, the antibody is responsible for providing a protective response
- Haemagglutinin (HA) is the membrane fusion glycoprotein of influenza virus (i.e. a target for ABs)
- These antibodies can be detected using a haemagglutinin inhibition assay__:
- If normal red cells in a dish → clump at the bottom forming a red spot
- If add influenza virus to RBCs, the HA will make cells stick together → diffuse coloration across the well
- If add serum of someone who has a lot of ABs against HA with the virus and red cells, it will inhibit the HA from causing the above effect → cells clumping at the bottom as if the virus was not present
- Can be done on large scale (lots of wells containing blood and virus with dilutions of patient’s serum)
- Higher the dilution with an inhibitory effect, the greater level of antibodies the patient has against HA
- The higher the antibody level the lower the likelihood of infection
- Antibody protection begins 7 days after vaccine and protection can last for around 6 months
What is the aim of Tuberculosis protection? How do we test for protection
- BCG = attenuated strain of bovine tuberculosis
- Provides some protection against primary infection
- Mainly provides protection against progression to active TB
- T cell response is important in protection
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Mantoux Test – checks for previous exposure to TB:
- Inject a small amount of liquid tuberculin (AKA purified protein derivative / PPD) intradermally
- Area of injection is examined 48-72 hours after tuberculin injection
- The reaction is an area of swelling around the injection site
- Positive reaction wheal:
- >5mm (high-risk – i.e. immunocompromised, living with someone with TB)
- >10mm (medium-risk – i.e. healthcare workers)
- >15mm (low-risk)
What are the different types of vaccines?
What are live attenuated vaccines? What are examples of them?
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Live attenuated vaccines (e.g. MMR, BCG, Yellow fever, Typhoid, Polio (Sabin), Vaccinia)
- The organism is modified to limit pathogenesis
What are the advantages of live vaccines?
- Establishes infections (ideally mild symptoms)
- Raises broad immune response to multiple antigens (offer protection against different strains)
- Activates all phases of immune system (T cells, B cells – local IgA, humoral IgG, etc.)
- Often confer life-long immunity after one dose
What are the disadvantages of live vaccines?
- Disadvantages:
- Storage problems
- Possible reversion to virulence
- Spread to contacts (i.e. spread to immunocompromised/immunosuppressed)
Give examples of inactivated, component and toxoid vaccines.
What are the advantages of inactivated vaccines?
- No mutation or reversion
- Can be used in immunodeficient patients
- Easier storage
- Lower cost
What is a conjugate vaccine? Give examples.
What is an adjuvant? What does it stimulate?
Cells from the innate immune system.
Explain the use of mRNA vaccines in SARS-CoV
How do you make mRNA vaccines?¿
How do mRNA vaccines work?
How do adenovirus vector vaccines work? What are examples of them?
How do dentritic cell vaccines work?
Describe the Sipuleucal-T Provenge.
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Dendritic cell vaccines (e.g. Sipuleucel-T Provenge – an immunotherapy against prostate cancer):
- Used against tumours where dendritic cell function may be compromised
- Take a patient’s dendritic cells and load them with a tumour antigen and reintroduce them to the patient to try and boost the immune response against the tumour antigens
- Requires antigens specific to the tumour and distinct from normal cells
What are haematopoietic stem cell transplantation? How is it done? What are the indications?
How do we replace antibodies?
What are the indications of antibody replacement therapy?
When do you give specific immunoglobulins?
What are the types of T cell transfer being used?
How do you carryout virus specific T cell therapy? What is it being used for?
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ViS-T Virus specific T cell therapy:
- I.E. in EBV in those immunosuppressed to prevent development of B cell lymphoproliferative disease
- (1) Blood is taken from the patient or from a matched individual
- (2) Peripheral blood lymphocytes isolated → stimulated with EBV peptides
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(3) Expansion of EBV-specific T cells → infused back into the patient
- This is done without any stimulation of B-cells, hence no B cell lymphoproliferative disease
EBV and adenovirus
How do you carry out Tumour infiltrating lymphocyte T cell therapy?
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TIL-T Tumour infiltrating T cells (TIL – T cell therapy):
- (1) Remove tumour from patient
- (2) Stimulate T cells within tumour with cytokines (e.g. IL-2) so they develop a response against tumour
- (3) Select and expand the tumour infiltrating lymphocytes and reinfuse back into the patient
How do you carry out TCR and CAR T cell therapy?
- (1) T cells taken from patient and viral / non-viral vectors used to insert gene fragments into T cells
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(2) Gene fragments encode receptors:
- TCR therapy → insert a gene that encodes a specific TCR (e.g. against a tumour cell antigen)
- Recognises MHC presented peptides
- CAR therapy → receptors are chimeric (it contains both B and T cell components)
- Recognises cell surface CD markers
- CAR therapy → receptors are chimeric (it contains both B and T cell components)
- Recognises MHC presented peptides
- TCR therapy → insert a gene that encodes a specific TCR (e.g. against a tumour cell antigen)
How does Standard CAR therapy work? What does it target?
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Standard CAR therapy = targeting CD19 (which is present on B cells)
- Receptors on the CAR cell have an Ig-variable domain at the end which is joined onto the remainder of the TCR (CD28 + CD3) → signals through the usual TCR pathway but recognises CD19 through an Ig-domain → harnesses the T cells to kill the B cells
- This is increasingly being used in ALL and NHL (not useful in solid tumours)
Describe the use of ANTIBODIES specific for CTLA 4? What are the indications and complications?
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Ipilimumab (antibody specific for CTL-A4) → treat melanoma:
- CTLA4 and CD28 both expressed by T cells and both recognise the same antigens on APCs (CD80 and CD86)
- APC CD80 and CD86 interact with CD28 → transmit a stimulatory signal
- APC CD80 and CD86 interact with CTLA4 → transmit an inhibitory signal
- Ipilimumab will bind to CTLA4 meaning that all of the interactions of CD80 and CD86 occur through CD28 thereby boosting the T cell response (you get more active T cells)
- CTLA4 and CD28 both expressed by T cells and both recognise the same antigens on APCs (CD80 and CD86)
Describe the use of antibodies specific for PD-1. What are the indications and complication?
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Pembrolizumab and Nivolumab (specific for PD-1) treat advanced melanoma:
- PD-1 (prevent death 1) is found on T-regulatory cells
- Its ligands (PDL-1 and PDL-2) are present on APCs and some tumour cells (i.e. can prevent death)
- ABs against PD-1 prevent the inhibitory effect of binding PD1 and PD1-L → activating the T cells to kill
- As these approaches (CTLA4 and PD-1 ABs) involve invigorating the immune response, the patients tend to develop autoimmune diseases (e.g. rheumatoid arthritis, thyroid disease, diabetes, SLE)
When are recombinant cytokines used?
B and T lymphocytes
BCG
Nivolumab, an antibody specific for PD-1
