Immuno 9 - Immune modulating therapies 1+ Flashcards
How can immune modulating therapies be categorised + examples of each?
Boosting the immune response:
- Vaccines
- Replacement (HSCT, Ig, T-cells)
- Immune checkpoint blockers
- Cytokine therapy
Suppressing the immune response:
- Non-specific immunosupression (steroids)
- Antiproliferative agents
- Specific component targets (cell surface antigens + cytokines)
- Plasmapheresis
How do vaccines provide immunity generally?
Vaccines are a form of acquired, active immunity.
They utilise the adaptive immune response to prime the immune system against a specific pathogen without causing illness
What should vaccnes induce?
Vaccines should induce production of:
- Memory T cells
- Memory B cells
- Preformed antibodies
- > in order to provide protective immunity against a specific pathogen
eg. T-cell v TB, Ab v Influenza
Describe the general immune response to exposure to foreign antigen?
- When the immune system is first exposed to an antigen, it takes time to respond.
- The innate immune system is first on the scene. In turn it stimulates the adaptive immune system to respond.
- In the primary response, IgM is the predominant antibody. Its production is T cell dependent and it has low affinity and a short half life.
- The adaptive immune system has an ‘immunological memory’.
- When the immune system is exposed to the same antigen a second time, it responds rapidly – within hours.
- Large titres of IgG, a high affinity Ab, are made. This provides protection from re-infection.
Describe the T-cell response to a vaccine
- APCs presenting Ag (via MHC Class I or II) migrate to lymph nodes
- APCs activate naïve T cells with cognate receptor via MHC binding
- MHC Class I binds to CD 8+ve (cytotoxic) T cells
- MHC Class II binds to CD4+ve (helper) T cells - Activated T cells undergo clonal expansion under influence of cytokines (e.g. IL-2)
- Mature T cells are produced:
- Helper and cytotoxic T cells die by apoptosis
- Memory T cells survive
Describe the B-cell response to a vaccine
. Naïve B cells endocytose Ag, presenting it on MHC Class II to CD4+ve (helper) T cells
- MHC Class II - T cell receptor binding stimulates T cell surface expression of CD40L
- CD40L (on T cells) - CD40 (on B cells) binding activates B cells
- Activated B cells form germinal centres:
- Ig class switching
- Somatic hypermutation
- Proliferation - Mature B cells are produced:
- Plasma cells produce IgG, IgA and IgE
- Memory B cells survive
What are the differences in longevity between T-cell and B-cell memory?
T-cell:
- Memory is retained long-term post infection
- Cytokines induce continual low-level proliferation
B-cell:
- Memory is retained long-term post infection -> Memory cells able to differentiate into plasma cells
What are the differences in site of T-cell and B-cell memory?
T-cell:
Expression of chemotaxis/adhesion related cell surface proteins allows access to non-lymphoid tissues
- Central: lymphoid tissue (spleen , lymph nodes)
- Effector: liver, lungs and gut
B-cell:
- Lymphoid tissue (spleen, lymph nodes, tonsils, Peyer’s patches)
- Bone marrow
- Gut, circulation
What are the differences in response to ag re-exposure of T-cell and B-cell memory?
T-cell:
- Rapid, robust response
- Memory cells activate more quickly than naïve cells
B-cell:
- Rapid, robust response
- Improved Ab response: higher titres, higher IgG component, higher affinity
What do the most effective vaccines do?
Induce both T and B cell memory
What are the different types of vaccines available?
Live attenuated vaccines
Inactivated vaccines
Conjugate vaccines
3rd gen vaccines
Dendritic cell vaccines
What is the mechanism of live attenuated vaccine + examples?
Live organism modified to be less virulent induces an immune response
Childhood: MMR (IMPORTANT), Fluenz Tetra
Oral: Typhoid, Polio - Sabin (IMPORTANT) (historical)
Seasonal: Influenza (IMPORTANT)
Other: Yellow Fever, Varicella (IMPORTANT)
What are the advantages and disadvantages of live attenuated vaccines?
Advantages:
- LIFELONG immunity (no boosters)
- Activates ALL PHASES of immune response
- Protection against CROSS-REACTIVE strains
Disadvantages:
- REVERSION to virulence
- SPREAD to contacts (immunodeficient)
- REFRIGERATOR storage required
What vaccines should be CI in HIV patients?
BCG
Yellow Fever
Nb: MMR is not contraindicated
What are the 3 different mechanisms of inactivated vaccines?
Inactivated: microorganism is destroyed (heat, chemicals, radiation or antibiotics)
Toxoid: inactivated toxin components
Subunit: protein components lacking viral genetic material (unable to replicate)
What are examples of each type of inactivated vaccine?
Inactivated: Pertussis (MAIN), influenza, Hep A, Polio - Salk (MAIN), rabies, cholera (MAIN)
Toxoid: Tetanus, diphtheria
Subunit: Hepatitis B, HPV, influenza (NA + HG)
What are the advantages and disadvantages of inactivated vaccines?
Advantages:
- No reversion risk
- Safe in immunodeficient patients
- Easy storage
- Low cost
Disadvantages:
- Limited T cell response (decreased level and longevity of protection)
- Multiple dose requirements (boosters)
- Immunogenicity may require enhancement (conjugation or adjuvants)
What are the differences between the types of Polio vaccines?
Polio vaccines = Sabin and Salk
Sabin = live attenuated, PO
(Outbreaks of vaccine-induced polio)
Salk = : inactivated (k for killed), IM
What is the mechanism + examples of conjugate vaccines?
Poorly immunogenic polysaccharide (Ag) paired with immunogenic protein carrier (adjuvant):
- Polysaccharide -> transient T cell-independent B cell response
- Protein carrier (e.g. tetanus toxoid) -> T cell response
Examples:
Tetanus toxoid is paired with Ag from polysaccharide encapsulated organisms (NHS):
- Neisseria meningitidis (meningococcal)
- Haemophilus influenzae B
- Streptococcus pneumoniae (pneumococcus)
What are the advantages / disadvantages of conjugate vaccines
Advantages:
Allows vaccination against encapsulated organisms
Disadvantages:
Boosters required
What are the two mechanisms of 3rd gen vaccines and some examples of each?
mRNA/DNA: uses
DNA/mRNA encoding Ag
Viral vector: modified virus (vector) delivers genetic code for Ag
Examples:
- mRNA/DNA: Pfizer-BioNTech, Moderna
- Viral vector: Ebola, Oxford-Astrazeneca, Janssen, Johnson-Johnson, Sputnik, CanSino
What are the advantages and disadvantages of 3rd generation vaccines?
Advantages:
- Activates all phases of immune response (T cells and B cells)
- Rapid and scalable production
Disadvantages:
- mRNA/DNA: anti-vector immunity eventually develops
- Viral vector: risk of plasmid integration into host genome
What are the different components found within vaccines and their function?
- Stabilisers: keep vaccine chemically stable during transport
- Adjuvants: increase the immune response without decreasing its specificity
- Preservatives: used in multi-use vials to prevent contamination
- Antibiotics: prevent bacterial contamination during production, and are subsequently removed
- Trace components: left over from manufacturing process
What is the main adjuvant used in humans? how does it work? examples of vaccines its used it
Aluminum salt – Slowly releases antigen, activates Gr1+ cells to produce IL4 -> B cell priming
Generally safe and mild
Used in Hep A, Hep B, Hib
What are some other adjuvants available
CpG DNA – Immunostimulatory, binds to pattern recognition receptors (TLR-9) -> activate APCs
IL2 – For non-responders to HBsAg vaccine -> seroconversion
Freund’s – mycobacterial cell wall components, stimulates the immune system (not used clinically)
ISCOMs – “immune stimulating complexes” adjuvant + antigen for super response (experimental)
What does pasive immunity involve?
Infusions of immunoglobulins (aka antibodies or Ig)
- can also be natural in breast milk
what Ig can be given?
Specific: VZV, tetanus, rabies, Regeneron (experimental for COVID)
General: Human Normal Immunoglobulin
Used as prophylaxis in immunocompromised
When might you give Ig? how long does it last for?
Prophylaxis in immunocompromised
Treatment of acute infections or poisoning
Short term (weeks to months) and no memory formed
What can human normal immunoglobulin be used in? how is it given
Mx of:
- Primary and acquired immunodeficiencies
- ITP, Kawasaki, Guillian Barre, Measles
- Not useful in hospitalized COVID patients
It is pooled from 1000+ donor plasma and tested for disease
can be given iv / subcut every 3-4w
What are cytokines?
Small proteins important in cell signalling secreted by certain cells to have effect on other cells (eg interferons, interleukins and growth factors)
What can be given in interferon therapy?
Interferon-alpha
Interferon-beta
Interferon-gamma
Interleukin-2
Example of dendritic cell vaccine?
Sipuleucel-T Provenge is a personalised immunotherapy for prostate cancer
When to give interferon alpha?
This is Antiviral
ABC - Alpha for Hep B and C + CML
Kaposi’s sarcoma
Hairy cell leukaemia
Multiple myeloma
When to give interferon beta
This is Immunomodulatory
Behcet’s (b for beta + bechets)
Relapsing Multiple Sclerosis
When to give interferon gamma?
This enhances macrophage function
Chronic Granulomatous disease
G for gamma / granulomatous
When to give interleukin-2
This stimulates the T cell response - Renal cell cancer
What are the different types of T-cell replacement therapies + their indications?
Viral Specific T cell therapy - Severe, persistent viral infection in immunocompromised patients
Tumour infiltrating T cell therapy - immunotherapy for metastatic cancer (e.g. melanoma)
CAR-T cell therapy - ALL and Non-Hodgkin’s lymphoma
What is the mechanism for Viral specific T cell tumour?
- Leukapheresis (autologous or allogenic)
- T cell isolation + stimulation with specific Ag
- Expansion of Ag-specific T cells
- T cells re-infused into patient
What is the mechanism of tumour infiltrating T cell therapy?
- Tumour excision
- Tumour fragments expanded (incubated with IL-2)
- Lymphocytes infiltrating tumour isolated + expanded
- T cells re-infused
What is the mechanism of CAT-T therapy?
- Leukapheresis (autologous)
- T cells engineered to express chimeric receptors that bind CD19 on B cells
- CD19 binding triggers cytotoxic killing of B cells
What is the significance of CTLA4 and CD28 markers?
T cells express CTLA4 and CD28
APCs express CD80 and CD86
CTLA4-CD80 binding inhibits T cells activation
CD28-CD80 binding stimulates T cell activation
Hence tumour cells can express CD80 to evade T cells (checkpoint evasion)
What is the significance of PD1-PD1L?
T cells express PD1. APCs express PD1L.
PD1-PD1L binding inhibits T cell activation.
Hence tumour cells can also express PD1L to evade T cells
What markers can tumours express to evade T cells?
CD80 and PD1L
What are immune checkpoint blockers?
Immune checkpoint blockers interfere with tumour immune evasion, allowing T cell activation and killing
They are: CTLA4 inhibitors (Ipilimumab) PD1 inhibitors (pembrolizumab and nivolimumab)
Describe the action, indications and complications of CTLA4 inhibitors such as Ipilimumab?
Action: mAb binds to CTLA4 on T cells, blocking the immune checkpoint and allowing T cell activation
Indications: advanced melanoma
Complications: autoimmunity
Describe the action, indications and complications ofPD1 inhibitors such as pembrolizumab and nivolimumab?
Action: mAb binds to PD1, blocking the immune checkpoint and allowing T cell activation
Indications: advanced melanoma, metastatic RCC
Complications: autoimmunity
A 65 year old man presents with left flank pain, frank haematuria and weight loss. A chest X radiograph reveals lung metastases. Which of the following may used in his treatment? A – IFNβ B – IL-6 C – IL-2 D – IFNα E – IFN-γ
C – IL-2
Which of the following is not a therapeutic option for metastatic melanoma?
A – dendritic cell vaccine B - CAR T cell therapy C – ipilimumab D – tumour infiltrating T cell therapy E – pembrolizumab
B - CAR T cell therapy
Which of the following is an indication for IVIG?
A – Severe combined immunodeficiency B – Rabies exposure C – Leukocyte adhesion deficiency D – Chronic lymphocytic leukaemia E – Hepatitis B exposure
D – Chronic lymphocytic leukaemia - the rest require specific Ig
A 50-year-old woman presents to her GP for an NHS check. She has HIV and is compliant with her medications. She has recently moved to the UK and did not receive all her vaccination as a child. She has never had chickenpox. She mentions that she is going on holiday to Gambia in 2 weeks’ time. Which of the following vaccinations should she not receive? A Hepatitis A B Varicella C Hepatitis B D MMR E Yellow Fever
E Yellow Fever
A 35-year-old man develops diarrhoea with fever and malaise 24 hours after eating a take-away meal. Stool cultures reveal the source of the infection is Salmonella spp. Which antibody is responsible for protecting against gastrointestinal infections?
IgA IgD IgE IgG IgM
IgA - generally found in GI infections
Which of the following is a subunit vaccine?
A. Diptheria B. Pneumococcus C. MMR D. Yellow Fever E. HPV
E. HPV - capsid
Ipilimumab is a licensed therapy in the treatment of metastatic melanoma, but which receptor does it bind to?
A. CD3 B. CTLA4 C. IL2 D. RANKL E. TNF-alpha
B. CTLA4 – Ipilimumab (melanoma) -> inhibits CTLA4 -> T cell activation
A. CD3 – moromonab-CD3 (transplant rejection)
C. IL2 – Dacilizumab (transplant rejection)
D. RANKL – Denosumab (osteoporosis, bone mets pain, hypercalcaemia)
E. TNF-alpha – Infliximab (IBD)
