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Immunotoxicology
Adverse effects
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Immunosuppression:
Infectious complications (virus, hepatitis), virus-induced neoplasia’s (cervical cancer – men can’t get
this although they can spread it, so they should get the jab before being sexually active)
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Hypersensitivity:
Atopic (asthma), systemic body hypersensitivity (anaphylactic shock)
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Two properties that make the immune system vulnerable:
1) Breaking bones = Breaking stem cell source
Immune system develops until puberty so if children break their bones then activation and renewal of
immune cells is affected
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Innate immune system:
The immune system is decentralised, meaning lymphatic system provides highways for the immune cells to
travel around your body
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They are pumped around in the blood so identification of foreign
substances is quick
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1
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WBC have receptors on their surface that recognise bacteria’s PAMPs (pathogen associated molecular
patterns: sugar coating) that have been around for years
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WBC release cytokines (IL-1, TNF-α, prostaglandin, histamine) upon binding to bacteria [first line of
defence]
4
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Innate system recognises worms and other foreign materials too, but not viruses
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2
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4
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Protein: Complement
Phagocytes: Macrophages, neutrophils, natural killer cells, dendritic cells

Adaptive immune system:
Virus infection (TB, flu, malaria, HIV, Ebola)
Viruses do not display antigens and so innate immune cells cannot spot them
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APC’s then identify the hijacked cell, engulf it, express the viral proteins via
MHC-2 and then alert the immune system
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1
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This acts as a force field
around them cells, meaning the virus cannot get into the cell
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Innate system communicates with lymph nodes via cytokines to get B & T cells activated to recognise the
antigens displayed on MHC’s of phagocytes
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Cytotoxic T cells (CTL): Eradicate virus or cancer cells, identified by CD8 marker
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B cells: Morph into plasma cells which contain RNA and ER to form antibodies, identified by CD20 marker
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Homeostatic mechanisms in the body increase to produce more heat = sweat, body temperature increases
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Mutations
HIV continually mutates so once you create an immune response against it, it then mutates and so you cannot
fight it
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No B/T cells?
You end up like the boy in the bubble who cannot interact with the environment as you cannot product
antibodies (B cells), cannot kill (CTL) or allow cells to receive help (Th)
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Function of MHC
Our antigen presenting cells (dendritic cells, macrophages) take what’s inside the cell and displays antigens
using MHC
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Every cell has a MHC molecule except RBC as it does not have a nucleus
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MHC-2: Things that have been phagocytosed are expressed
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Within 12 days, the donor skin is completely killed off and the graft turns
black… Ulcerated
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 They cannot function immunologically at a high level as they are exposed to a lot
Cheetah: They are inbred (similar) so they can give a skin graft to another and it won’t get rejected as they
have limited MHC’s
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The inactive form can either be the whole organism (bacteria/virus) OR purified macromolecules (toxoids
that stimulate immune response, capsular polysaccharides – sugar coating, surface antigen)
Purpose: Train the immune system to fight it effectively
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Requirements:
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Don’t want over/under stimulation
Want single dose
Ease of use
Stable
Life-long protection
Active against all variants (though HIV is difficult as it changes every 35 days)

Addition of adjuvants
They stimulate the immune system to increase the response to a vaccine via 5 mechanisms:
1
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Physically protects the antigen
3
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therefore increasing local reactions and chemokine releasing cells such as Th and mast cells
5
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Every time you encounter the same virus, you end up with a higher number of memory cells
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However, if you have
an overstimulation of your immune system, you use your entire cohort of T cells and create no memory cells
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So scrapings
from a pussy spot were taken from a cowpox-infected individual and given to one that had not been exposed
in order to demonstrate that they won’t get smallpox
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1955: “the cutter incident” – 1
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So 2
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Measles
Dangerous! Gives you brain damage, fever, infertility, disrupts the immune system and ends up killing you
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Usually if you
contract at an older age, you’re more likely to die
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If 1 infected person comes into contact with 100
healthy people, 90 will catch it and 7 will have complications, therefore, herd immunity is important as
babies cannot have the measles jab until they’re 1 so it’s important that no one around them has measles
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The vaccine stops the virus from passing round, though boys don’t receive the vaccine despite ‘herd
immunity’ as they don’t get symptoms
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Diseases where improved/new vaccines are needed
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Herpes simplex virus
TB
Malaria
Worms
Hepatitis C
Other cancers
Autoimmune diseases
Inflammatory diseases

But the barriers involve high cost, approx
...
Though the biggest challenge is people convincing others not to get vaccine = Achieving herd
immunity would then be harder
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Symptoms: hayfever, asthma, eczema

Development of allergies over time
Before 1960: 5% children had an allergy
20 years ago: 25% children had an allergy (increased!)
It may not be down to environment/country as it varies massively for neighbouring countries
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Genetics: May not produce many Th-1 cells
b
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This data led onto the hygiene hypothesis – the cleaner you are, the less you’re exposed to bad things
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Our immune system has been designed to deal with dirt over the duration of evolution
2
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Types of allergies
1
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g
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Xenobiotic allergy: e
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penicillin
3
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g
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This relies upon mast cells and a tangible antibody (IgE)
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1
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3
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Dendritic cell eats allergen
Th cell gets activated, becoming Th-2
Th-2 produces cytokines IL-4 and IL-5
The cytokines then activate B cells and eosinophils
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5
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7
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9
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If this is systemic then it’ll cause an immune response throughout your whole body = anaphylactic shock
(Normal IgG usually binds to an antigen on a microbe whilst the FC region binds to a phagocyte = microbe
eaten
...
)
Anti-histamine (block histamine receptors) can be taken but by the time you feel these symptoms, it is the
end stage (meaning the immune response has already occurred) so it is best to take antihistamines when
you expect it to occur
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2
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4
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Allergen pricked onto your skin
If Allergic, mast cells activate
Mast cells degranulate
Histamine gets released
Histamine causes vessels to leak, making area red and inflamed = swelling

Bacterial reaction vs
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2
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4
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6
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This prevents you breathing and so you
cannot get O2 across airways
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g
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 Get balance back for Th-1 and 2 cells
 Get more IgG than IgE
 Produce T cell tolerance = doesn’t attack allergen
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Blocking initiation of immune response = don’t get Th-2 response (usually given to children)
2
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Stop effector molecules by giving:
 Antihistamines,
 Antagonists
 AB’s that stop cytokines
 AB’s that remove IgE
= [+] stop symptoms BUT [-] have weird Th cells and dendritic cells

Helminth
Those who have a high incidence of parasitic worms don’t have an allergy yet they do have a high Th-2
response (which is associated with allergy), why?
Th-2 preferentially binds to the worm rather than your airways or shrimp
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Worms can’t be phagocytosed as they
go up to 6ft long so what happens is:
1
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3
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The worm gets covered in opsonic fragments e
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IgE
Mast cells bind to IgE (they bind to all mast cell receptors = reducing type 1 hypersensitivity)
Enzymes and histamine are released on top of the helminth
Helminth dies

Cats
If you’re allergic to cats, you may not be allergic to your own cat over pro-longed exposure, how?
When proteins are made, chromosome 14 opens up…

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IgG, A, M, E & D are all next to each other
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Usually IgE gets made but
IgG4 (normal) mistakenly ends up being made and so you don’t end up being allergic anymore as they don’t
bind to mast cells – “class switching”
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30% of people that die with cancer had an I
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Carcinogens
They induce cancer by influencing your body to make a cell that keeps growing and ends up taking energy
from you = kills you
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2
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4
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There’s a link between obesity and the predisposition of cancer
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g
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RAG knockout mice
Animal models show I
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Mice share the same I
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RAG knockout (don’t possess Recombinant Activating Gene, RAG -/-) mice were bred, they do not have NK
cells, T cells and B cells = adaptive immune system is affected
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This also applies to many other cancers
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The biology
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Histopathological studies (areas of body taken out and studied) show that tumours are surrounded by
mononuclear cells (monocytes, macrophages, NK cells, T-cells)
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These are called metastases – meaning a part has broken off the tumour and is travelling around in your
body to brain/liver/wherever
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If you have localised cancer, it can be surgically removed
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Pancreatic
cancer is also difficult to fight
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Tumour cell characteristics
1) Produce their own antigens (tumour marker): I
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To grow larger, they
release cytokines and undergo angiogenesis for blood vessels to come in = tumour gets blood,
oxygen and nutrients! (= now vascularised)
You can stop the release of cytokines that cause angiogenesis BUT this is only applicable if you stop
the tumour early enough
3) Decrease expression of MHC-1 on their own cells: tumour cells won’t display their tumour specific
antigens = T-cells won’t end up spotting it = tumour disguised as ‘self’
The body can recognise tumours if
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our self-protein is mutated (induced by ionising radiation)
defensive suppressor tumour genes are switched off
over-expression of certain self-proteins
foreign recognition of viruses e
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HPV (that’s why vaccines are used)

Response to tumours
Innate response:
1
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Macrophages and dendritic cells activate and phagocytose the tumour, releasing cytokines
3
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Macrophages and dendritic cells then go up to the lymph: expressing the antigen on its MHC-2,
which then binds to the Th cell… Whilst it’s MHC-1 binds to CTL
5
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NK cells (via AB’s) kills tumour cells the same way CTL’s do – through FASS ligand, perforin and
granzymes = kills tumour
7
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NK cells do function like CTL’s as perforin, granzymes and FASS ligand interactions occur BUT here’s the
difference: CTL’s require MHC and an antigen for recognition, whereas, NK cells just require an AB that’s
bound to a tumour
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Take out dendritic cell
2
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Stick antigen in dendritic cell
4
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S =
activation
5
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S or kill tumour cells
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(-) Need to bind to tumour cells only, not normal cells as you don’t want SE’s if something nasty is attached
onto the material that’s going to be introduced
E
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Death
People still die as tumour cells have invaded your I
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S may not be working efficiently: dysfunctional – too many T regs or suppressive cells
 Induction of tolerance to tumour antigens
This death graph shows the [T reg] and the survival of patients
with ovarian carcinoma
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You cannot cure someone with ovarian cancer, you can only
pro-long their life, as shown by the graph ending at 0 every
time
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g
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Symptoms: Muscle weakness and increased fatigue
Cause: Failure of neuromuscular transmission – loss of nicotinic acetylcholine receptors (~70%) from
neuromuscular junctions (synapse)
The skeletal muscle ACh receptor is a “primary autoantigen” (the target of an autoimmune disease)
1
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DC presents the protein to T/B cells
3
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B cells produce high affinity AB’s
5
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Also, modified CD4 T cells will be against the receptors too
NOTE: If you have a blockage of this via an AB which sticks to the post synaptic receptor, ACh cannot
bind… However, you can compete with it as it is reversible
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g
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Atropine inhibits the breakdown of ACh so that it outcompetes with the AB, causing the receptors to close
= normalise the effect of an action potential
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 Procainamide metabolite interferes with education in thymus = makes T cells autoreactive = induces an
autoimmune reaction such as systemic lupus (autoreactivity to everything), arthritis and respiratory
problems
Bearing in mind, our body already has a defence against autoreactive T cells: T regs!

Function of thymus
1
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Hematopoietic stem cells become T cells in thymus
3
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Pro T cells are double negative (CD4- CD8-) but express CD25 which is what they all start with
2
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They drop one and differentiate into CD4+ CD8- OR CD4- CD8+ = mature

(2) Repertoire selection/functional maturation: Recognise non-self and ignore self-antigens
This knowledge is given in the thymus – corticomedullary junction, how?
The cells of the outer layer of the thymus are covered in MHC-1 & 2 and are self-antigen expressed
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Outcompeting with T cells – if you have a dendritic cell then a lot of T regs will bind so that
autoreactive T cells don’t
2
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Switch off T cells themselves – release inhibitory cytokines upon contact
 Useful when you’ve gotten over an illness
 Over production switches off I
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g
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This can be helpful for organ transplants if you can create and inject them
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MOA of T regs
1) Convert T cells to T regs (block activation)
2) Interfere with T cell function: Deactivate Th and CTL (functionally unresponsive)
3) Interfere with APC’s: Induce DC to apoptosed AND downregulate B7 or MHC = no stimulation =
create T reg or apoptosed

T cell antigen recognition
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Activation of T cell and the cell gets killed
Cytokine release
Induce tolerance/anergy (lack of co-stimulation – opposite of energy)
Apoptosis

Activation of CD4 & CD8
CD4: (Th cells) help CTL and B cells by releasing cytokines
CD8: (CTL) kills cells that express antigens that caused their activation
(SWITCH ON) Activation requires 2 signals for immune cells to become effector cells and memory cells
1) Antigen-MHC (with CD4/CD8 complex) with TCR
2) B7-CD28 ligand interaction = proliferate
A lack of this co-stimulation = anergy = die
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CD28 stimulates intracellular signals
 IL-2 production
 IL-2 receptor expression
 Cell cycle switched on
If activation doesn’t occur, the cell dies by the receptors being blocked
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(SWITCH OFF)
 Immature dendritic cells can’t stimulate T cells until it’s been stimulated by something (phagocytosed
something in order to express B7)
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Anergic T cells
T regs are also known as anergic T cells of whom are functionally unresponsive
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They produce regulatory cytokines such as IL-10
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Epstein Barr Virus: Virus attacks B cells, causing them to proliferate
2
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Transplantation
We reject foreign organs as MHC’s and antigens displayed on the cells are foreign to our I
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Matching MHC’s as much as possible does help, BUT the protein the cell expresses on the MHC is still foreign
= rejection as B & T cells are activated
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Though it’s not that efficient or safe, but if you induce T regs then it’ll accept the organ, switching off T cell
responses to that organ
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Liver and kidney: increasing as livers regenerate and we have two kidneys = if donated whilst alive, can
still live
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2
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3
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 High level of success as it’s not a very vascularised piece of tissue = ability for WBC to fight off
foreign material is minimal
 No real SE’s
4
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Bone marrow is more popular than blood transfusion due to the cells still being plastic and blank, and so you
aren’t giving someone the same proportion as your WBC’s BUT you still need to immunosuppress the person
as the plastic cells are still foreign
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(-) You can also get Graft vs
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So try and match as many genetic similarities between the people
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Skin grafts: If you have a large area to cover, you can inflate a balloon under your skin = grows and
stretches = transplant = no rejection

Types of transplant
1)
2)
3)
4)

Autograft: Self tissue transferred from one body site to another
Isograft: Tissue transferred between genetically identical individuals
Allograft: Tissue transferred between genetically diff
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species (pigs, mice)

HLA
Allogenic MHC molecules: Genetically different but is from the same species is from allografts
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The probability of
surviving grafts is higher in those who have more matching MHC’s
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NOTE: Identical twins have no rejection
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1) 1% of the T cells recognise the intact MHC molecules = “direct allorecognition”
2) APC’s then migrate to the lymph (desensitisation)
3) Th, CTL, B cells activate and seek to attack the foreign organ with the release of cytokines, causing
fever and pain symptoms (rejection)
Direct allorecognition: Host T cell recognises antigen on MHC from graft’s very own APC

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Indirect allorecognition: Host APC chews up the graft cell and presents it as foreign… T cells react against the
antigen and kills anything that expresses it
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Hyper acute rejection: Happens the minute you put the graft in
i
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Complement system activates = endothelial damage = inflammation
iii
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If unfortunate, you get a thrombosis 

b
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c
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Characterised by fibrosis and vascular abnormalities = lose graft function
ii
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S it’s foreign
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Give WBC of donor before TP via bone marrow TP
2
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Overtime the foreign organ becomes immunogenic somehow (the start of a new immune response/attack)
and the body doesn’t know how to switch it off, this is why grafts/transplants fail within time

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