Immuno: Immune modulating therapies 1 Flashcards
List some approaches to boosting the immune system.
- Vaccination
- Replacement of missing components (e.g. replacing immune cells)
- Blocking immune checkpoints
- Cytokine therapy
Describe the variety of antigen receptors found in the adaptive immune system.
- Contains a wide variety of antigen receptors
- Not entirely genetically encoded as genes are rearranged and recombined
- This has the potential to generate autoreactive cells but these are removed
- The adaptive immune system has exquisite specificity
What happens when cells of the adaptive immune system engage with an antigen that it recognises?
Undergoes massive clonal expansion
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 (with help from T helper cells) and become IgG 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 T cells?
- Longevity - memory T cells persist for a long time in the absence of antigen due to low level 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 subsequenct antigen exposure (lower threshold for activation of naïve T cells)
NOTE: memory B cells have similar characteristics and are able to produce rapid and robust responses
What are the aims of vaccines?
- Generate protective, long-lasting immunity - induce antibody, memory B and memory T cell production,
- No adverse reactions
- Single shot
- Easy storage
Which cell surface receptor is used in the influenza vaccine?
Haemagglutinin (HA) - this is a receptor-binding and membrane fusion glycoprotein
Describe how haemagglutinin inhibition assays work.
- If you put normal red blood cells in a petri dish, they will clump at the bottom forming a red spot
- If you add influenza virus, the HA makes red cells stick together and causes a diffuse coloration across the well
- If you add the serum of someone who has a lot of antibodies against HA, it will inhibit the haemagglutination effects of HA so the red cells remain as a discrete red spot
- The higher the dilution of serum at which the red cells remain as a little dot, the more antibodies are present in the serum
NOTE: sialic acid receptors on RBCs bind to HA leading to haemagglutination
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
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 virus vaccine? List some examples.
The organism is alive but modified to limit its pathogenesis.
Examples:
MMR, BCG, yellow fever
Oral -polio, typhoid, rotavirus (oral)
Nasal - flu
What live attenuated vaccines are contraindicated in HIV+ve
BCG and Yellow fever are contraindicated
MMR is FINE to give
List some advantages and disadvantages of live attenuated virus vaccines.
- Advantages: establishes infections, raised broad immune response against multiple antigens, activates all phases of the immune system, often confer life-long immunity after one dose
- Disadvantages: storage problems, possible reversion to virulence (paralytic poliomyeltis - very rare), spread to contacts, cannot be used in immunocompromised patients
NO BOOSTERS needed
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```List some examples of the following types of vaccine:
- Toxoids
- Component/Subunit
- Inactivated
- Toxoids
- Diphtheria
- Tetanus
- Component/Subunit
- Hep B (HBsAg)
- HPV (capsid)
- Influenza (HA)
- INacitvated
* flu
* cholera
* bubonic plague
* Polio (injectedD)
* Hep A
* Pertussis
* Rabies
What are the advantages and disadvantages of inactivated/component vaccines?
- Advantages - no mutation or reversion, can be used in immunodeficient patients, easier storage, lower cost
- Disadvantages - often do not follow normal route of infection, poor immunogenicity, may need multiple injections, may require conjugates/adjuvants
Describe how conjugate vaccines work.
- Polysaccharide and immunogenic protein carrier (adjuvant(
- Polysaccharide 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.
- Haemophilus influenzae type B
- Meningococcus
- Pneumococcus
These are the Ag polysaccharide, paired with the tetanus toxoid as adjuvant
conjugate give protection against encapsulated organism
Describe how adjuvants work.
- Increases the immune response without altering its specificity
- They mimic the action of PAMPs on TLF and other PRRs
Stimulate T cell response which improves B cell response
List some examples of adjuvants.
- Aluminium salts (MOST COMMON)
- Lipids (monophosphoryl lipid A) - HPV vaccine
NOTE: the mechanism of action of aluminium salts is not fully understood but it may allow antigens to be released slowly over time, may induce a mild inflammatory reaction or may activate Gr1 + IL4 + eosinophils
mRNA vaccines for COVID
Create plasmids with DNA for spike protein
Harvest the plasmid
Excise DNA and transcribe to mRNA
Make mRNA with lipid complex –> enters cell
mRNA transcribed + translated –> spike protein expressed on cells
Adenoviral vector vaccines
Void spike protein DNA inserted into viral vector
Viral vector infects cell
Cell produces the protein
List some example of experimental vaccine adjuvants.
- ISCOMs - immune-stimulating complexes (enhances cell-mediated immunity)
- CpG - cytosine-phosphate-guanosine motif that can bind via PRR to induce an immune response
- DNA vaccines - plasmid containing a gene of choice (e.g. from a pathogen) is inserted into a muscle cell which will then express the antigen. This stimulates T cells responses (WARNING: this can lead to autoimmunity)
What are dendritic cell vaccines?
- Used against tumours
- Leukoparesis - remove white cells
- Collect dendritic cells from the patient
- Load them with the antigen from the tumour to try
- Reimplant the APCs and boost the immune response against tumour antigens
e.g. Provenge in prostate cancer
What are the main indications for haematopoietic stem cell transplantation?
- Life-threatening immunodeficiency (SCID)
- Haematological malignancy
How cna antibodies be replaced
general (IVIG) - primary and secondary Ig deficiencies
or
specific - used to give passive immunity for post exposure prophylaxis
What is human normal immunoglobulin?
- Immunoglobulin prepared from thousands of screened pooled donors - HIV, Hep B, Hep C -ve
- Contains pre-formed IgG to wide number of organisms
- Administered IV or SC
List some indications for IVIG
- Primary antibody defect
- X-linked agammaglobulinaemia
- X-linked hyper IgM syndrome
- Common variable immunodeficiency
- Secondary antibody defect
- CLL
- Multiple myeloma
- After bone marrow/stem cell transplantation
When might specific immunoglobulin be given?
Passive immunity as post-exposure prophylaxis
Hep B
Rabies
Tetanus
VZIG - although aciclovir often used now
List four types of T cell adaptive cell transfer.
- Virus-specific T cells
- Tumour infiltrating T cells (TIL)
- T cell receptor T cells (TCR)
- Chimeric antigen receptor T cells (CAR T Cell Therapy)
Using an example, describe how virus-specific T cells are used.
- 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
chronic EBV normally controlled, imunocomprise -> reactivate -> lymphoma
Describe how TCR and CAR T cell therapy works.
- 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)
- In CAR therapy, the receptors are chimeric (containing both B and T cell components)
Describe a use of CAR T cell therapy.
- Used to target CD19 (present on B cells)
- Receptors on the CAR cell have an immunoglobulin variable domain and is joined to a TCR
- This means that it recognises CD19 through an immunoglobulin domain but signals through the TCR pathway
NOTE: this is used in ALL and NHL
What is ipilimumab and how does it work?
- CTLA4 and CD28 are both expressed by T cells and they recognise antigens (CD80 and CD86) on APCs
- Signalling through CD28 results in a stimulatory response
- Signalling through CTLA4 results in an inhibitory response
- Ipilimumab is a monoclonal antibody that blocks CTLA4 thereby removing this inhibitory response
- It is used in advance melanoma
Explain the use of antibodies against PD-1 in treating cancer.
- PD-1 and PD-2 ligands are present on APCs and interact via PD-1 receptors on T cells to cause an inhibitory response
- They can also be expressed by some tumour cells
- Pembrolizumab and nivolumab are antibodies that are specific to PD-1, thereby blocking this effect
- This is also used in advanced melanoma
NIvolumab - AB for PD-1, Pembrolizumab - PDL-1
List some examples of the therapeutic use of recombinant cytokines.
- Interferon alpha - used as an adjunct in the treatment of Hep B, Hep C, Kaposi sarcoma, CML and multiple myeloma
- Interferon beta - Behcet’s disease, relapsing MS
- Interferon gamma - chronic granulomatous disease
Side effect of immune checkpoint inhibitors
Non-specific T cell activation –> Auto-Immunity
