Drug-specific in vitro release of IL-2, IL-5, IL-13 and IFN-γ in patients with delayed-type drug hypersensitivity
Speaker: Jui-Yun Weng
Advisor: Ching-Tsan Huang PhD
Date: 2009-11-30
P. Lochmatter, A. Beeler, T. T. Kawabata, B. O. Gerber, and W. J. Pichler
Allergy 64(9): 1269-1278, 2009.
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93.6.20 蘋果日報A16版
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SJSTEN
(http://adr.doh.gov.tw/default.asp)
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(http://www.who.int/medicines/areas/quality_safety/safety_efficacy/advdrugreactions/en/)
Adverse drug reactions (ADR)
Harmful, unintended reactions to medicines that occur at doses normally used for treatment are called adverse drug reactions (ADRs). --according to WHO
Type A: augmented pharmacologic effects
- dose dependent and predictable
Type B: bizarre effects (or idiosyncratic)
- dose independent and unpredictable
hypersensitivity:
immunological mechanisms involved
*History and testing
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75~80%
General problems of diagnosing drug hypersensitivity
Is it a drug hypersensitivity reaction?
Which type of immune reaction is involved?
What is the eliciting drug?
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Allergy/hypersensitivity testing
Skin test Food allergy
Mold, pollen, animal, and other allergies that cause allergic rhinitis and asthma
Penicillin allergy
Venom allergy
Allergic contact dermatitis
Elimination test Allergens from food
Blood test Level of IgE to a specific allergen
Provocation (challenge test)
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Hypersensitivity
Type Alternative names Mediators
I Allergy (immediate) •IgE
IIAntibody-dependent cell-mediated
cytotoxicity
•IgM or IgG
•(Complement)
III Immune complex disease•IgG
•(Complement)
IV
Delayed-type hypersensitivity
(DTH), cell-mediated immune
memory response, antibody-
independent
•T-cells
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Coombs and Gell classification
(http://en.wikipedia.org/wiki/Hypersensitivity)
Drug hypersensitivity
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IgE IgM, IgG
•Atopy
•Anaphylaxis
•Asthma
•Autoimmune
hemolytic
anemia
•Thrombocytope
nia
•Erythroblastosis
fetalis
Drug hypersensitivity
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IgGT cell
•Serum sickness
•Contact dermatitis
•Chronic transplant rejection
•Multiple sclerosis
Th1/Th2
10http://en.wikipedia.org/wiki/T_helper_cell
Cell-mediated immunity— T-cell–mediated defense
mechanism
Contact hypersensitivity
– immunogen:
hapten + host proteins
24 - 72 hours to developed
Protein
carrier
Delayed-type hypersensitivity (DTH)
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Drug-induced DTH
Culprit drugs (hapten):
Penicillin (b-lactam)
Sulfonamides
Symptoms: Maculopapular exanthema (MPE)
Drug reaction with eosinophilia and systemic symptom (DRESS)
Erythema exsudativum multiforme (EEM)
Stevens-Johnson syndrome(SJS)
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The symptoms DTH patients might have
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(http://tray.dermatology.uiowa.edu/EMult003.htm)
Erythema multiforme
Maculopapular exanthema
(http://www.phac-aspc.gc.ca/publicat/uvpd-mjmepv/vol6-1/index-eng.php)
(http://dilantininjury.com/)
Previous studies
Lymphocyte transformation test, LTT
T cell proliferation and activation test in vitro
3H-thymidine
CD69
Express while CD4+/CD8+ T cell activated
Flowcytomerty
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This study
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monocyte
Peripheral Blood Mononuclear Cell(PBMC)
~75%
(+)
Tetanus toxoid(TT)
Sulfonamides:
Sulfamethoxazole (SMX)
Sulfapyridine (SPD)
b-lactam:
Ampicillin (AMP)
Amoxicillin (AMX)
Cytokines/chemokinesexpression detection
From patients and healthy donors
Stimulatory drugs:
IL-5, IL-13, IFN-g, IL-2,
IL-4, IL-17, IL-6, IL-10,
TNF-a, GM-CSF,
CCL4,
G-CSF, CXCL8, CCL2,
IL-1b, IL-12, IL-7
Screen for the guidelines to diagnose DTH
Patient no. Age/sex Culprit drug Disease Skin test LTT CD69 Time interval
(months)
32 64/m AMX MPE - + + 19
249 26/f AMX MPE + + n.d. 2
31 35/m AMX MPE - + + 8
244 35/f AMX MPE - + n.d. 5
358 41/f AMX EEM + + + 6
DTH patients
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Patient
no.
Age/sex Culprit drug Disease Skin test LTT CD69 Time interval
(months)
11 45/m SMX MPE/Malaise + + + 144
38 48/m SPD DRESS - + + 13
245 71/m SMX SJS - + + 2
32 64/m SMX Erythroderma - + + 19
295 41/f SPD DRESS - + + 6
Sulfonamides-allergic
b-lactam-allergic
Baseline cytokine secretion
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pg/mL
Healthy donors’ PMBC stimulated
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Fold increase
TNF-a
Secreted by leukocytes , epithelia, fibroblasts
Stimulate IL-12 production and Th1 cells
IL-12: induction of Th1 cell
Stimulation of NK cells
MHC I induction
Antivirus
19*P<0.05; **P<0.01; ***P<0.001
INF-g
Secreted by T cell, NK cell, epithelia, fibroblasts
Macrophage activation
Antivirus
20*P<0.05; **P<0.01; ***P<0.001
c
IL-2
Secreted by Th0 and Th1 cell
T cell proliferation and differentiation
Activate CTL and macrophage
21*P<0.05; **P<0.01; ***P<0.001
IL-5
Secreted by Th2 cell
B cell growth and differentiation
Eosinophil activation
*P<0.05; **P<0.01; ***P<0.00122
IL-13
Secreted by activated T cell
B cell growth and differentiation
Inhibits proinflammatorycytokine production
23*P<0.05; **P<0.01; ***P<0.001
T-cell dependent cytokine secretion
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Sulfonamides:
b-lactam:
Summary
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monocyte
~75%
Cytokines/chemokinesexpression detection
Allergic drugs
IL-5, IFN-g, IL-2, IL-13Sulfonamides
b-lactam
Need more patients and controls to determine the exact
sensitivity and specificity
ADRs Drug-induced DTH
Thank you all~
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