Lecture 11 - Manipulating the Immune Response Flashcards
What are the components of the innate response that may be manipulated?
- PRRs
- Cytokines
- Cell trafficking
How can PRRs be exploited to manipulate the immune response?
- PAMP agonist to activate PRRs
- -> increase immune response
- PAMP antagonist
- -> dampens immune response
How may cytokines be used to manipulate the immune response?
Using innate cytokines
–> boost the immune response
TLR-5 recognises …?
Flagellin
TLR-4 recognises …?
LPS
Endotoxin
TLR-9 recognises …?
CpGDNA
What is RLH?
What does it recognise?
Rig like helicase
Viral RNA
When a macrophage binds and engulfs a pathogen, what are the general groups of cytokines that it releases?
Inflammatory cytokines
Antiviral cytokines
Stimulatory cytokines
What are the Inflammatory cytokines?
IL-1
TNF-a
IL-6
What are the antiviral cytokines?
IFN-alpha
What are the stimulatory cytokines?
GM-CSF
IL-12
What is Imiquod?
What does it bring about?
What is it used to treat?
It is a TLR-7 agonist
It binds to the PRR and brings about a local antiviral response
It is used to treat some viral infections, eg. HPV
What does TLR-7 recognise?
ssRNA
What may sometimes be added to vaccine antigens to generate a more specific immune response?
- how does it do this?
Give an example
Adjuvants
- PRR agonists
For example, CpGDNA / TLR-9
Induces more, and more appropriate, cytokines
In which cases would a PRR antagonist be used?
- Septic shock
(TLR-4) - Allergies
Describe what happens in Septic Shock, and how this may be blocked
Too much bacteria present (LPS)
Excessive macrophage activation
Macrophages release too many inflammatory and stimulatory cytokines
Widespread vasodilation
Coagulation cascade activated –> fibrinous clots form
By blocking TLR-4, LPS can’t activate all the macrophages
How may cytokines be used to boost antiviral responses?
Administration of
IFN-a
IFN-B
How can antibodies be used to shape the cytokine response?
In which cases would we use this?
Abs against IL-1, IL-1R
- type 2 diabetes
- gout
- autoimmune diseases
Abs for TNF-a, TNFR
- rheumatoid arthritis
How can cell trafficking be blocked?
What would be the response ?
Blocking:
- CXCL8R
- LFA-1
- ICAM-1
This would stop neutrophils from being recruited as they are marginised in the capillary
–> dampening of inflammatory response
Compare what is administered to deliver a passive and active immune response, as well as in Immunotherapy
Passive:
- preformed antibodies
Active:
- antigen
Immunotherapy:
- adaptive immune response cytokines
What are the pros of a passive immune response?
Fast
What are the cons of a passive immune response?
- not long lived
- only a B cell (Ab) response
- only for serum, not mucosa
- only can be used a few times –> rejected after a few uses
What are the sources of Ab for passive immunity?
- animals
- blood bank serum
- recombinant antibodies
What are the pros of active immunity?
- long lasting
- humoral and cellular response activated
- can be target to tissue
What are the cons of active immunity?
- slow
- variable response in the young and old
Which diseases have been eradicated in the western world due to vaccines?
Polio
Smallpox
Which diseases do we still not have vaccines for?
HIV
TB
Why do we need to understand Pathogenesis to be able to make effective vaccines?
Need to know about:
- adhesins
- evasion mechanisms (capsules)
- toxins
So that we can block these things
Why do we need to know the localisation of an infection
Some infections are localised (gastro, respiratory tract infection), whilst others become systemic (rubella, tetanus).
This dictates where we need to target the response to
What are the four different types of vaccines?
- Live attenuated
- Subunits
- Killed
- Virus like particules
What are the pros of live attenuated vaccines?
Longer lasting response
Can be taken orally
Multiple antigens present
Replicates –> don’t need boosters
What are the cons of live attenuated vaccine?
Cold chain required
Can revert to virulence
What are the pros of killed vaccine?
Never reverts to virulence
No cold chain required
What are the cons of killed pathogen vaccines?
Short lived
Must be injected
Restricted antigens present
Boosters required
In terms of B cells, what do we want the vaccine to provide?
- isotype switching
- high affinity Ab
- memory B cells
Why is activating B cells alone insufficient to produce a good immune response?
There is no T cell response
No Th cells to induce isotype switching
- only get IgM
- not memory
- low affinity Ab
How are T cells activated?
CD4+, specifically
Signal 1: presentation of antigen by APC on MHC II Signal 2: co stimulation - CD80 and CD86 - CD28 Signal 3: cytokines - expression of CD40 L - skew response to Th1 and Th2
What happens after Th cells are activated?
After they are activated by APC, they move to the B cell area of the lymphoid tissue
- B cell presents the antigen on its MHC II for the TCR to bind
- Costimulation: CD40L and CD40
–> isotype switching, higher affinity Ab, memory B cells
Which T cells do we need to induce and why?
CD4+:
- antibody isotype switching
- help and memory for CD8+ and B cells
CD8+:
- killing infected cells
(Virus, intracellular pathogen)
How do we activate a APC so that CD4+ can be activated
Antigen presentation:
- MHC II –> antigen only needs to be in an endosome
(Easy)
Costimulatory molecule expression:
- Adjuvants mimic PAMPs induce the expression of CD80 and CD86
How do we activate APCs with a vaccine so they can activate CD8+ cells?
Antigen presentation:
Much more difficult, as the antigen must be in the cytosol if it is going to be presented on MHC I
Live vaccines:
- live viruses will get antigen into cytosol –> not a problem
Killed vaccines:
- ISCOMs
- Virus like particles
