Immuno: Immune modulating therapies 1 Flashcards
List some approaches to boosting the immune system.
- Vaccination
- Replacement of missing components (e.g. replacing immune cells)
- Cytokine therapy
- Blocking immune checkpoints
What happens when cells of the adaptive immune system engage with an antigen that it recognises?
Becomes activated - will proliferate and differentiate
What happens to T-cells when activated?
Proliferate and differentiate into effector cells (cytokine secreting, cytotoxic)
What are the two ways in which B cells can undergo clonal expansion once activated?
- They can differentiate into T-cell independent IgM plasma cells
- They can undergo a germinal centre reaction (T cell dependent) and become IgG/A/E memory and plasma cells
Which type of T cell undergoes a more pronounced proliferation following activation?
CD8 > CD4
List three types of antigen-presenting cell.
- Dendritic cells
- Macrophages
- B lymphocytes
What are some important characteristics of memory cells?
Longevity
- Memory T cells persist for a long time in the absence of antigen due to low level continual proliferation in response to cytokines
Different pattern of cell surface proteins involved in chemotaxis cell adhesion
- Allows memory cells to rapidly access non-lymphoid tissues
Rapid, robust response to subsequent antigen exposure
- Memory cells are more easily activated than naive cells
- B cell memory involves that circulation of pre-formed high-affinity IgG antibodies
What are the aims of vaccines?
- MEMORY – preformed antibodies, memory T cells, memory B cells, to provide long-lasting, protective immunity
- No adverse reactions
- Practical considerations – one shot, easy storage, inexpensive
Which cell surface receptor is used in the influenza vaccine?
Haemagglutinin (HA) - this is a receptor-binding and membrane fusion glycoprotein
ie. the reason influenza can infect cells
What are haemagglutination assays used for?
Describe how do they work.
Used to detect viral antibodies
How long does protection from the influenza vaccine last?
Starts 7 days after the vaccine and protection lasts for 6 months.
What agent is used in the BCG vaccine?
Attenuated strain of Mycobacterium bovis.
Describe the protection that is achieved by using the BCG.
- Some protection against primary infection
- Mainly protects against progression to active TB
NOTE : T cell response is important in protection against primary and progression to active TB
NOTE: protection lasts for 10-15 years
What is the Mantoux test?
- A small amount of liquid tuberculin (PPD) is injected intradermally
- The area of injection is examined 48-72 hours after the injection
- A reaction would appear as a wheel around the injection site (this is suggestive of latent TB, active TB or previous BCG)
What is a live attenuated vaccine? List some examples.
The organism is alive but modified to limit its pathogenesis.
V-BOY
Examples:
- MMR,
- Varicella zoster,
- BCG,
- Oral polio (Sabin)
- Yellow fever,
- nasal influenza, typhoid,
List some advantages of live attenuated vaccines.
- Raises broad immune response to multiple antigens – more likely to protect against different strains
- Activates all phases of immune system. T cells, B cells – with local IgA, humoral IgG
- May confer lifelong immunity, sometimes just after one dose
List some disadvantages of live attenuated vaccines
Possible reversion to virulence (recombination, mutation).
- Vaccine associated paralytic poliomyelitis (VAPP, ca. 1: 750,000 recipients)
- Spread to contacts (immunosuppressed patients)
- Storage problems
List some examples of inactivated vaccines
- Inlfuenza (quadrivalent)
- Cholera
- Polio (Salk)
- Hep A
- Pertussis
- Rabies
List some examples of the following types of vaccine:
- Toxoids
- Component/Subunit
- Toxoids (inactivated toxins)
- Diphtheria
- Tetanus
- Component/Subunit
- Hep B (HBsAg)
- HPV (capsid)
- Influenza (HA)
What are the advantages of inactivated/component vaccines?
- No risk of reversion to virulent form
- Can be used with immunodeficient patients
- Storage easier
- Lower cost
What are some disadvantages of inactivated/component vaccines?
- Often do not follow normal route of infection (reduced local protection)
- Some components have poor immunogenicity
- May need multiple injections
- May require modification to enhance immunogenicity e.g. conjugate to protein carrier, adjuvant
Describe how conjugate vaccines work.
Polysaccharide and protein carrier
- Polysaccharides weakly immunogenic - induces a T-cell independent B cell response (transient)
- Addition of the protein carrier promoted T cell immunity which enhances B cell/antibody responses
List some examples of conjugate vaccines.
encapsulated bacteria
- Haemophilus influenzae type B
- Meningococcus
- Pneumococcus
What are adjuvants and descibe how they work.
Adjuvants increase the immune response to a vaccine
- They mimic the action of PAMPs on TLR and other PRRs
- Increases the immune response without altering its specificity
List some examples of adjuvants.
- Aluminium salts (MOST COMMON)
- Lipids (monophosphoryl lipid A)
How SARS-CoV mRNA vaccines work
- Infect E-coli with DNA for spike protein
- Harvest DNA and transcribe to mRNA
- Complexed with lipids, injected into arm
- Once injected, mRNA enters human cells which is then translated
- Spike protein then expressed by cells to stimulate immune response
What is another technique of SARS-CoV vaccination?
Adenovirus vector vaccines
What are dendritic cell vaccines?
- Used against cancer
- Dendritic cells collected from patient and exposed to tumour antigens to try and boost the immune response against the cancer
Give an example of a dentritic cell vaccine
Sipuleucel-T (Provenge)
- Used in prostate cancer
- Dendritic cells are harvested from patient and exposed to recombinant PAP-GMCSF (PAP is the tumour antigen, GMCSF stimulates the dendritic cell response)
- Dendritic cells reinfused back into patient to stimulate immune response
What is human normal immunoglobulin?
- Immunoglobulin prepared from thousands of pooled donors
- Covers wide range of unspecified antigens
- Contains pre-formed IgG
- Administered IV or SC
What is the aim of cytokine therapy and give some examples
Modifies immune response
Examples:
- IL-2 - stimulates T cells in renal cancer
- IFN-gamma - enhance macrophage function in CGD
- IFN-alpha - enhance antiviral response in hepatitis B and C
What are two therapies which replace missing immune system components?
- Hematopoietic stem cell transplantation (SCID, CML)
- Antibody replacement
What are the main indications for haematopoietic stem cell transplantation?
- Life-threatening immunodeficiency (SCID)
- Haematological malignancy
- Severe haematological disease (e.g. thalassaemia)
What is antibody replacement?
Normal human immunoglobulin
Pooled from >1000 healthy donors
Contains preformed IgG to a wide range of unspecified organisms
List some indications for antibody replacement
- Primary antibody defect
- X-linked agammaglobulinaemia
- X-linked hyper IgM syndrome
- Common variable immunodeficiency
- Secondary antibody defect
- CLL
- Multiple myeloma
- After bone marrow transplantation
When might specific immunoglobulin be given?
Passive immunity as post-exposure prophylaxis for:
- Varicella Zoster
- Tetanus
- Hepatitis B
- Rabies
Derived from donors with high plasma IgG titres to specific pathogens
List four types of T cell adoptive cell transfer (cellular immunotherapy)
- Virus-specific T cells
- Tumour infiltrating T cells (TIL)
- T cell receptor T cells (TCR)
- Chimeric antigen receptor T cells
Using an disease example, describe how virus-specific T cells therapy works
Used for EBV in patients who are immunosuppressed to prevent the development of lymphoproliferative disease
- Blood is taken from the patient or from a donor
- Peripheral blood mononuclear cells are isolated and stimulated with EBV peptides
- This creates and expansion of EBV-specific T cells which are then reinfused into the patient
NOTE: tumour infiltration T cell therapy follows the same principle but uses tumour antigens
Describe how tumour infiltration T cell therapy works
Same principle as virus-specific T cell therapy
Describe how TCR and CAR T cell therapy works and how these 2 therapies differ
T cells are taken from the patient and vectors are used to insert gene fragents that encode receptors
- In TCR therapy, the gene will encode a specific TCR (e.g. against tumour antigen), but it requires tumour cells to express MHC to be activated
- In CAR therapy, the receptors are chimeric and can be activated by tumour antigens alone
Describe a use of CAR T cell therapy.
Tisagenlecleucel - targets CD19 (present on B cells)
Used to treat ALL and NHL
What is ipilimumab and how does it work?
- Ipilimumab is a monoclonal antibody that blocks CTLA4 (inhibitory T cell receptor)
- Allows for greater T cell activation
- It is used in advance melanoma
Explain the use of antibodies against PD-1 in treating cancer.
- Pembrolizumab and nivolumab are monoclonal antibodies that block PD-1 (inhibitory T cell receptor)
- Prevents tumours expressing PD-L1 from inhibiting T cell response
- Used in advanced melanoma, NSCLC, metastatic renal cell carcinoma
What is the main complication with targetting T cell inhibitory receptors?
Autoimmunity
