Immunotoxicity Flashcards
- Immunotoxicity
- Also called “immune-mediated toxicity”
- Involved the study of adverse effects on the immune
system resulting from exposure to drugs or chemicals - The adverse effects can be on the immune system itself,
or lead to non-immune organ damage
Immune System: two components
Innate Adaptive
So the key with the adaptive is the presence of B cells and T cells.
As soon as you see details B cell, it should
give you the reminder of that B cell. How it can turn into have. You can have memory B sales and then
generate antibodies, and that’s what leads into the next line the Efront mechanism. So how these cells contribute to the mechanisms. So the key difference. Antibody production right? That’s the adaptive immune system. You get antibodies.
You do get cytokines in both systems as well. But really the
most important is the B cell and the cell mediated killing
the adaptive, immune system. Yes, it has memory. It will remember.
Macrophages
Kupffer cells - other functions
Kupffer cells
* Resident macrophages in the liver
* Largest macrophage population in body
* Fxn: remove foreign material from portal circulation that
streams into liver
Kupffer cells - other functions
* Synthesize and release proinflammatory mediators
* Cytokines, ROS, RNS
* These can increase during xenobiotic injury
They’re on a surveillance mode, so they’re ready to go and gear up in case something is not good
those mechanisms that are applied for a cy of kinds and other kinds of chemical mediators that we’ll talk about. And the big deal is that these can increase during some kind of drug injury.
Role of macrophages
- NADPH oxidase
- NO production
- Protease release
- Cytokine release (TNFα,
IL-1β & 8) - Can signal for neutrophil
recruitment - Cathepsin G
- Elastase
There’s this chemical mechanism right, this nadph oxidase enzyme, which is all found on a many Luco sites, and their kind of system that’s geared to go.
This enzyme is absolutely critical for us. Because
If you lack it you are seriously immunocompromised
There’s a problem, These there’s cell debris. There’s some kind of there’s leakage all kinds of signals that can be sent and sensed by the cooper cell which activates it. So you get the activation phase, and then it can go on to produce its various intermediate. So basically, this will produce a kind of a chemical mediated
a sort of response, this
nitric oxide production as well. And then there’s some enzymes that are released proteases to degrade.
basically to to initially degrade the surface, so that then they they can be repaired.
s it’s a 2 Way Street. It’s. The one part is kind of
kind of attacking. To make sure there is not to make the environment environment sterile before a repair is done by like if you have to lay down fibrootic tissue or collagen, or something.
Cytoknes released are proinflammatory, IL 8 is important for neutrophils
Two waves of attack:
Wave 1: macrophage-catalyzed
Wave 2: neutrophil-catalyzed
Macrophage depletion is
protective: the example of CCl4
Therefore, macrophages have a role in CCl4 hepatotoxicity
This is a compound that was used in dry cleaning. It’s no longer used, - hepatotoxic
it was thought it was a one way street that you deplete the macrophages.
and you could do this chemically
and that that, using this compound that that would cause a depletion in macrophages, and then compare the toxic
compound to see if it’s causing more or less injury.
So the take on point is when the macrophages were thought to be depleted, the liver injury was less,
it’s a little bit more involved than that. So It’s not that easy, actually
Other examples of drug toxicity that is
attenuated when macrophages are depleted
- Alkylating agents (melphalan)
- Thioacetamide
- Acetaminophen
Using a specific inhibitor produces
different results!
it’s not that simple that macrophages cooper cells contribute to damage, and that’s it. It’s over.
So if you actually use a better chemical inhibitor than I showed previously.
you’re the cooper, sell depleted animals, and this is the grade of hepato toxicity. So how necrotic the damage is.
andyou can see that when there’s a high level of ipadic necrosis more the animals that actually had
their macro, the cooper cells depleted. There were more numbers that were in bigger trouble than those that did not have their macrophages or cooper cells depleted. This is for the high grade injury. Things get a little hazier when you’re talking a low grade or medium grade in these
the injury, the extent of injury which can be based on dose. You can see that there is a contribution. There’s a very important sort of finding here that well, you do need some macrophages, and part of it is because of the a repair mechanism
that’s needed. S
Mechanisms of drug-induced liver injury through innate or
adaptive immune mechanisms. (
njury through innate or
adaptive immune mechanisms. (a) General scheme of the
drug-induced formation of reactive metabolites and protein
adducts, which trigger necrosis and initiate a sterile
inflammatory response by release of damage-associated
molecular patterns (DAMPs), the promotion of cytokine and
chemokine formation by activating pattern-recognition
receptors, such as toll-like receptors (TLRs), and the
consequent activation and recruitment of inflammatory
cells, which can aggravate the initial injury (see text for
details). (b) Sterile inflammatory response after
acetaminophen-induced liver injury. Part of the
acetaminophen dose is metabolized to a reactive
metabolite, which triggers mitochondrial dysfunction and
eventually DNA fragmentation resulting in necrotic cell
death. The release of DAMPs induces a sterile inflammatory
response, which recruits neutrophils and monocyte-derived
macrophages. The preponderance of evidence suggests that
the inflammatory response does not aggravate the initial
injury but removes necrotic cell debris and supports
regeneration (see text for details). Abbreviations: HMGB1,
high mobility group box 1 protein; HOCl, hypochlorous acid;
ICAM-1, intercellular adhesion molecule-1; IL, interleukin;
MHCII, major histocompatibility complex; MCP-1, monocyte
chemoattractant protein-1; mtDNA, mitochondrial DNA;
RAGE, receptor for advanced glycation end products; TLR,
toll-like receptor
People change, so does science: The Yin
and Yang Macrophages
ok
Immunosuppression
- Causes: chemo, drugs, infections, radiation!,
autoimmune diseases, aging, malnutrition. - E.g. Xenobiotic-induced impairment of maturation and
development of immune cells - Halogenated Aromatic Hydrocarbons, HAH (PCBs, PBBs,
PCDFs, TCDD) most likely occupational - Phenoytpe:
- Pancytopenia (bone marrow); neutropenia; anemia.
- Thymic atrophy/involution ↓ making T cells
- ↓ proliferation, differentiation, cytokine production,
and cell responses - Consequences
- Tumour promotion, opportunistic infections, worsensing
of underlying conditions
TCDD - dioxin
Experiments with mice
* 1 ug/kg TCDD prior to influenza A virus
* Pulmonary damage
* Unexposed mice (to TCDD) were not affected
* Cause: TCDD-mediated decrease in thymus mass
(organ where T-cells are produced).
* T-cell depletion, less T-cell differentiation
* More regulatory T-cells -> ↓ T cell proliferation (and less
killer T-cell formation)
Thymus – AhR
- Thymus has ↑↑
expression of AhR - AhR -/- mice resistant
to thymic atrophy
caused by TCDD
(pro-inflammatory)
(Regulatory T-cells)
This is sort of the problem of what happens
during activation of the arl hydrocarbon receptor.
And if, whatever the source may be now, if the source is something like an organic pollutant, fine, but we’ll see in a moment that cancer cells can manipulate this pathway as well to go from a pro inflammatory T cell to a regulatory, more dormant t cell.
Here, I mean you can look at there all these really interesting pathways that i’m not going to ask you about or discuss. But really the point here is this arrow hydrocarbon receptor. If there’s a ligand binding to it.
it can then shift gears and go into this regulatory mode. and that’s part of the reason why there’s dynamic atrophy, but also importantly, that that basically the t cells are going into a more
sort of resting state not pro-inflammatory where they can wipe out. Let’s say, an infection or a tumor.
Immunosuppression and cancer
- Trp depletion (i.e., low levels) leads to T-cell death.
- Trp enzymatically* breaks down into kynurenine.
- The tumor cells upregulate enzymes to breakdown Trp
- Kyn and related metabolites binds to and activates (as
ligands) the AhR - This induces IL-10 release and Treg development
- These 2 effects lead to immunosuppression
- Receptor-mediated inhibition of T-cells (↑PD-L1
It’s well known to break down into a metabolic called kine urine.
kinderning, and it’s metabolites bind to the arrow hydrocarbon receptor. So
what tumor cells do they up regulate kind of a very sneaky trick enzymes to break down tryptophan, so it can generate more of the metabolite to activate the arrow hydrocarbons receptor to send the t cells into a regulatory dormant mode.
and so that’s one mechanism of immunosuppression that’s actually
pushed and facilitated by a cancer cells.
backgrounds, effects that happen like well interlooking 10 is a more anti. It’s not a pro inflammatory it’s.
It’s an anti inflammatory side of kind so it’s really going away from the pro-inflammatory to kind of an anti-inflammatory mode.
This is where some drug development has occurred with large molecule antibiotics.
pdl one. And and so it goes up. This is on the tumor cells, and so there are drugs that get in the way that are well known.
slide 35
q
Agents causing hypersensitivity
slide 26-27`
Polyisocyanates
(cross-linking
agents)
Acid Anhydrides
(varnishes, etc)
Metals
latex
food
formaldehyde
