Anatoli Chkaroubo - PowerPoint PPT Presentation
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Title: Anatoli Chkaroubo
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Chemically Induced AutoimmunityIdiosyncratic
Drug Reactions
- Anatoli Chkaroubo
- Jessica Fitzgerald
- Alison Hulme
- Naomi Steenhof
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Idiosyncratic Drug Reactions
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Clinical Characteristics
- Incidence predicted that out of all ADRs 20 are
idiosyncratic - Time to onset in almost all cases there is a
delay between starting the drug and the onset of
the adverse reaction - Dose dependence Drugs given at low doses are
less likely to cause an IDR. - Adaptation In many cases the initial reaction
will resolve despite continued treatment. - Clinical Features highly variable being
dependent on both the drug and the patient. There
are non-specific manifestations such as fever,
rash, arthralgia and eosinophilia.
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Immunology simplified
- Both Signal 1 and Signal 2 are required for an
immune response - Signal 1 - recognition of drug-modified peptide
fragments presented in the MHC groove of the APCs
by T cells - Signal 2 co-stimulation of T-cells by APCs
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Mechanism Hypotheses
- Hapten Hypothesis
- PI Hypothesis
- Danger Hypothesis
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The Hapten Hypothesis
- Studies by Landstiner (1935) small molecules
cannot induce immune response unless they are
chemically reactive, and bound to protein. - Led to Hapten Hypothesis a small molecule
(called hapten) binds to cellular protein, this
modified protein is what induces an immune
response - Drug-modified protein is seen as foreign
immune response
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Hapten Pathway
- 1.Reactive drug/metabolites bind to protein
- 2. Taken up by APC
- 3. Processsed
- 4. Presented in MHC groove to T cells
- 5. Gives immune response
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- Evidence for Hapten
- Penicillin-induced anaphylaxis
- Penicillin chemically reactive because of
beta-lactam ring - Reacts irreversibly with free amino and
sulfhydryl groups on proteins - Generates immune response against
penicillin-protein adduct - If sufficient IgE antibodies produced severe
allergic reaction can result (anaphylaxis) - Studies in support Most antibodies associated
with penicillin allergies are directed against
penicillin-modified proteins
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Pharmacological Interaction Hypothesis
- Studies by Pichler (2002) T cell clones from
patients with IDR history proliferated in the
presence of drug, in the absence of metabolism - Led to PI Hypothesis Drugs bind reversibly to
MHC complex, induces immune response can lead
to IDR - Drug binds to MHC immune response
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PI Pathway
- 1.Drug binds reversibly to MHC complex
- 2. Presented in MHC groove to T cells
- 3. Gives immune response
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Evidence for PI
- Sulfamethoxazole
- major drug in original studies
- primary aromatic amine
- associated with significant IDR incidence (if
given 10mg/day) - Undergoes oxidation to reactive metabolites
- controversy What is binding and causing immune
response? Is it the parent drug, or reactive
metabolites??
- Ximegalatran
- does not form reactive metabolites
- structurally similar to a small peptide
- evidence that it binds directly and reversibly to
MHC
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The Danger Hypothesis
- Proposed by Polly Matzinger (1994)
- challenges the classical self-nonself hypothesis
of immunology - responding to something unless it was causing
injury or was dangerous to an organism is
inefficient - in general, foreign proteins do not generate a
significant immune response, unless an adjuvant
stimulates APCs - Damage to cells causes them to release danger
signals - The danger signals up-regulate Signal 2 and cause
the immune response. - No Signal 2 is immune tolerance
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Danger Pathway
- In IDRs, it may be that some reactive metabolites
cause cell damage, which generates a danger
signal - The metabolites themselves could act as danger
signals rather than as haptens - Or they could do both
- Some drugs may form reactive metabolites but do
not cause IDRs because the metabolites dont
cause/dont signal danger
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Evidence for Danger Hypothesis
- Therefore, other types of injuries or infections
could increase the incidence of IDRs. - In fact, some viral infections do increase the
risk of IDRs, as do episodes of inflammation.
A. Roth et al. JPET 307 (2003) 1-8
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- danger signals are not all known but are likely
different for different types of cell stress and
different types of cells.
M. Pirmohamed et al. / Toxicology 181182 (2002)
5563
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Drug Induced Lupus Erythematosus
- A classic IDR
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Drug Induced Lupus Erythematosus (DILE)
- an autoimmune disease that can affect skin,
joints, heart, lungs, kidneys and brain. - presents with similar symptoms to idiopathic
systemic lupus erythematosus (SLE) but resolves
when causative drug removed - as many as 10 of SLE cases could actually be
DILE - DILE is equally probable in males and females
while SLE is more common in women than in men
(ratio of 91) - must be cautious during diagnosis to confirm that
it is DILE and not a drug-associated exacerbation
of SLE or another underlying autoimmune disease.
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DILE - Causes
- Generally caused by continuous drug exposure
ranging from one month to as long as a decade and
can begin anytime from 3 weeks to 2 years after
exposure. - Physical and clinical problems resolve within
days to months of withdrawing the causative drug - Drugs that can cause DILE hydralazine,
procainamide, quinidine, isoniazid, diltiazem
(over 80 confirmed medications that can cause
DILE) - 20 incidence of DILE in procainamide patients at
normal doses for one year. - People who have deficiencies of the
N-acetyltranserase enzyme are predisposed to
experiencing DILE
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DILE - Diagnosis and Treatment
- no standard diagnostic criteria but generally
patients have arthritis, serositis, anti-nuclear
and antihistone antibodies . - patients frequently present with arthalgia (often
the only symptom). Can also have myalgia, fever
and pericarditis. - changes of the skin are less common with DILE
than SLE - NSAIDS to control the symptoms.
- Corticosteroids and immunosuppressive agents
should - be reserved for patients with organ damage.
- should not rechallenge because will result in
recurrence.
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Strategies to decrease the risk of ADRs
- Decreasing Reactive Metabolites
- Developing biomarkers to Predict IDR risk
- Personalized drug therapy
- Developing a better understanding of IDR
mechanism
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References
- Kauffman, C. Lisa Lupus Erythematosus,
Drug-Induced, 2007. http//emedicine.medscape.com
/article/1065086-overview - Matzinger, P. Annu. Rev. lmmunol. 12 (1994)
991-1045 - Pirmohamed, M. et al. Toxicology 181182 (2002)
5563 - Roth, A. et al. JPET 307 (2003) 1-8
- Uetrecht , J., Annu. Rev. Pharmacol. Toxicol. 47
(2007) 51339 - Uetrecht, J. Autoimmunity Reviews 4 (2005)
309314 - Vedove CD. Archives of Dermatological Research,
Drug Induced lupus erythematosus - 2009 Jan 301 (1) 99-105
- Images (accessed March 3 2009)
- http//www.eorthopod.com/public/patient_education/
6590/systemic_lupus_erythematosus.html - http//www.flickr.com/photos/listsanddiagrams/2389
358590/ - http//users.rcn.com/jkimball.ma.ultranet/BiologyP
ages/T/Tolerance.html
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