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).
why does TCDD affect the thymis?
TCDD affects the AhR which is highly expressed on the thymus
AhR negative mice were ___ to thymic atrophy caused by TCDD
resistant
Th17 cells in the thymus are
proinflammatory
Tr1 cells int he thymus are
regulatory T cells
the binding of FIGZ (any ligand*) from tumors to AhR causes
proinflammatory Th17 cell to become a REGULATORY (and NOT proinflammatory) Tr1 cell –> so T cell = can’t respond to tumor.. They basically go into a resting state and are no longer pro-inflammatory).
Tryptophan depletion leads to
T cell death
trp enzymatically breaks down into ______.
- Describe a mechanism by which CANCER cells force the T cells into a DORMANT STATE adn immunosuppression.
kynurenine metabolite.
- Tumor cells upregulate enzymes that breakdown TRYPTOPHAN so it can make MORE KYN METABOLITE to BIND to AhRs and put the cell into dormant mode!!!! This also induces IL-10 release which further shifts the cells into ANTI-INFLAMMATOYR MODE.
–> this mech is PUSHED BY CNACER CELLS. ***These 2 effects lead to IMMUNOSUPPRESSION!!
-
tumor cells upregulate enzymes to breakdown ____= ___ and related metabolites bind to and activates the _____
trp
kyn
AhR –> result: shifts T cell into DORMANT state (i.e. leads to immunosuppression)
binding to AhR by Kyn and related metabolites induces _______ and __________ = ___________
IL-10 release and T reg cell development = immunosuppression
receptor mediated inhibition of T cells = increase in PD- ____
PD-L1
2 responses of AHR activation (fyi)
proviral role (negatively regulates cellular antiviral responses)
modification of pathology outcome (exacerbates inflam immune response)
(FYI slide)
polyisocyanates
- clinical presentation
- source
- pathway
- mechanism
lung disease
occupational
skin, inhalational
protein binding induced hypersensitivity (I-IV)
acid anhydrides
- clinical presentation
- source
- pathway
- mechanism
asthma
occupational
skin, inhalational
protein binding induced hypersensitivity (I-IV)
metals know
- clinical presentation
- source
- pathway
- mechanism
Latex know
- clinical presentation
- source
- pathway
- mechanism
Food
- mechanims?
contact dermatitis
various (drugs, medical devices, jewlery)
skin, occupational inhalation
type 4 know
- dermatitis
- occupational
-dermal - gloces
- Type 1 (acute) and 4.
Food
- diverse (type 1-4)
formaldehyde
- clinical presentation
- source
- pathway
- mechanism
asthma, airway inflam
occupational
inhalational
type 1 and 4
protein binding causes ___________________ formation
immunogen/ allergen/ antigen formation
what is a hapten
- what is the antigen?
a small molecule that is capable of chemically modifying a large molecule to cause antibody production specific to that modified protein.
- The antigen is the ENTITY ALTOGETHER (hapten covalently bound to drug) –> abys form to THIS ANTIGEN.
what is an antigen in the context of protein bindng
the therapeutic agents account for ____ of ADRs protein to which antibodies are produced??????
Antigen: is the haptenated protein to which abys are produced against (it’s the whoel unit).
key example**: PENICILLIN -> hypersensitivity is from hapten binding to pen.
xenobiotic induced autoimmunity mostly affects the
skin and lungs
xenobiotic induced autoimmunity results in conditions like
SLE, sjoergen’s sx, rheumatoid arthritis
T or F: there are very few therapeutic drugs now that cause autoimmunity
T
which 3 drugs cause SLE like sx
hydralazine, isoniazid, procainamide
what is the determinant for hydralazine and isoniazide toxicity
myeloperoxidase
what is the determinant for procainamide toxicity
DNA
rank the following from least to most likely to find data: in vivo exposure in human studies, in vivo exposure in animal studies, in vitro exposure in animal studies, in vitro exposure in human studies
in vivo humans < in vitro humans < in vivo animals = in vitro animals
what 3 findings are indicative of immune suppression
decreased WBCs, increased incidence of lymphoma, infectious complications
what 4 complications are indicative of immune stimulation
___sx
A___
A_____
_____ storm
flu like sx
allergy
autoimmunity
cytokine storm
primary screening tests are used in
general health panels
primary screening tests include assay methods that have been _______________, _________________ with RR _______________
extensively standardized among labs + clinically interpretable
RR well established across age groups
additional confirmatory tests are often less ___________ and may be difficult to ___________ with RR ____________
less standardized
difficult to interpret
RR not well established across age groups
cromolyn sodium blocks ____ into _____
Ca2+ into mast cells
theophylline prolongs high _____ in _____ by inhibiting phosphodiesterase, which cleaves cAMP to 5’-AMP
high cAMP levels in mast cells
cortisone reduces histamine levels by:
Blocking what? And stimulating what?
blocking conversion of histidine to histamine and stimulates mast cell production of cAMP
What are the 5 drugs that can be used to treat Type 1 IgE Hypersensitivty?
antihistamines, cromolyn sodium, theophylline, epinephrine, and cortisone.
** key: they all block action of mast cells/degranualtion of histmaine.
