30: Immunotoxicity Flashcards
Immunotoxicity is also known as
immune mediated toxicity
immunotoxicity involves the study of _______ on the immune system resulting from exposure to _________ or ______
adverse effects
drugs or chemicals
immunotoxicity can be on
1. the immune system
2. nonimmune organs (i.e. lead to non-immune organ damage)
3. all of the above
3
which of the following lists the cells in the adaptive immune system
1. NK cell, T cell, B cell, dendritic cell
2. eosinophil, macrophage, basophil, mast cell
3. eosinophil, NK cell, T cell, B cell
4. T cell, B cell, dendritic cell, neutrophil
1
what is the purpose of the innate immune system
to alert other innate and adaptive immune cells to pathogen presence, directly kill the pathogen, encourage the response of the adaptive immune system. (FYI)
kupffer cells are _______ ____ in the ________
- macrophages are found _____, but ___ are in the liver.
macrophages in the liver
- everywhere, 90%.
where is the largest macrophage population in the body
kupffer cells in the liver
list the 6 functions of kupffer cells
- remove what?
- synth what
- induces what enzyme?
- ___ production
5 and 6. _______ and____ release.
- remove foreign material from portal circulation that streams into liver
- synthesize and release proinflammatory mediators (cytokines, ROS, RNS) that can incr during xenobiotic/drug injury. [fxn: on surveillance mode; ready to gear up in case of attack]
- induce NADPH oxidase –> forms ROS and helps with immune response. but can also be pro-inflammatory if goes unchecked.
- NO production
- protease release
- cytokine release
what kinds of proinflammatory mediators do kupffer cells synthesize and release when they sense xenobiotic induced damage?
cytokines (TNF-1, IL-8 ** recruits neutrophils) , ROS, RNS.
mechanism:
Xenobiotic/drug can cause initial damage –> kupffer cell senses damage (i.e. leakage of cell debris ) –> goes on to produce chemicals (NO production, protease release (to degrade surface so can be repaired) and cytokine release to cause cell death. THIS IS A PRO-INFLAMMATOYR RESPONSE, AND NOT AN IDEAL REPAIR MECHANISM* (KNOW)
the cytokines produced by kupffer cells include____ and ____ and signal for
cathepsin G, elastase
neutrophil recruitment
what happens after TNFalpha and IL1 act upon circulating PMNs
the neutrophils undergo Transendothelial migration, adhere to hepatocytes, and cause hepatocyte cell death (FYI)
macrophage depletions is _________ while a specific inhibitor ____________
protective
may increase liver damage
what other drug’s toxicities are attenuated when macrophages are depleted? (3)
alkylating agents
thioacetamide
acetaminophen** –> when macrophages depleted, get enhanced toxicity.
how does CCI4 cause hepatotoxicity
is a chemoattractant that induces state of oxidative stress
what happens to hepatotoxicity when a kupffer cell inhibitor is used
- when there was a HIGH LEVEL OF liver damage =
________________. - HOWEVER, when there’s only low-med injury=____________.
increased liver damage.
Explanation:
- when there was a HIGH LEVEL OF liver damage = more had their kupffer cells depeleted.
- HOWEVER, when there’s only low-med injury, a lack of KUPFFER cells is WORSE (i.e. kupffer cells are actually BAD!!).
classical activation of macrophages results in
cytotoxicity and tissue injury
alternative activation of macrophages results in
immune suppression and tissue repair
BOTTOM LINE:
Macrophages can go both ways –> macrophages can be portective or lead to cytotoxicity!!!! The way they’re polarized depends on “degree of injury by the hepatotoxic drug”!!!
causes of immunosuppression may include (list 2)
chemo, drugs, infections, radiation, autoimmune disease, aging, malnutrition
immunosuppression from halogenated aromatic hydrocarbons (PCPs, TCDD, PBBs) is most likely _________ exposure
occupational
3 things that happen in immunosuppression (AKA: What are the phenotypes immunosupprssion presents as (3)?)
-> consequence of thse changes?
1) pancytopenia, neutropenia, anemia
2) thymic atrophy/ involution leading to decreassed T cell production.
3) decreased proliferation, differentiation, cytokine production, cell responses
–> consequenc eof these changes:
- tumor more likely to develop (cuz immune system can’t defend against cancer cells hijacking t cells), opp. inf., worsening of underlyign conditions.
consequences of immunosuppression includes (3)
tumor promotion, opportunistic infections, worsening of underlying conditions
TCDD of dioxin is a
Dioxin is also known as what?
potent agonist for the AhR (Aryl hydride receptor)
The grandaddy of toxicants!
TCDD prior to influenza A virus exposure = ___________
influenza A virus exposure only = _________
pulmonary damage
less pulmonary damage
why does TCDD + influenza exposure result in more pulmonary damage?
TCDD caused a decrease in thymus mass where T cells are produced = T cell depletion, ↓ T cell differentiation, ↑ regulatory T cells = ↓ T cell proliferation and ↓ killer T cell formation = ↑ damage from virus
Basically: TCDD decreases Thymus mass (and therefore hampers T killer cell production).
