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Hypersensi)vity reac)ons to β-lactam an)bio)cs – Does the T ......maculopapular DRESS exanthema...
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Hypersensi)vity reac)ons to β-lactam an)bio)cs – Does the T cell recogni)on pa:ern influence the clinical picture? Daniel Yerly [email protected] ADR-AC 10 years symposium – March 23 rd 2017
Transcript of Hypersensi)vity reac)ons to β-lactam an)bio)cs – Does the T ......maculopapular DRESS exanthema...
Hypersensi)vityreac)onstoβ-lactaman)bio)cs–DoestheTcellrecogni)onpa:ern
influencetheclinicalpicture?
ADR-AC10yearssymposium–March23rd2017
Drughypersensi)vityreac)ons:aheterogeneouspicture
urticaria, anaphylaxis
Immediate type hypersensitivity
T cells
Delayed type hypersensitivity
SJS/TEN
DRESS maculopapular exanthema (MPE)
TCELLSRECOGNIZEANTIGENICPEPTIDESONMHCMOLECULES
APC
Tcell
MHCI
TCR
CD3ζ
CD8
HowTcellscanbeac0vatedbydrugs?
adapted from Adam et al., Br J Clin Pharmacol., 2011
Drugrecogni)onbyTcells
Haptenconcept p-iconcept(pharmacologicalinterac)onwithimmunereceptor)
APCAPC
hapten concept p-i concept
figure adapted from Yun et al., Allergy, 2012
Wuillemin et al., J. Immunol., 2013
HLAhaplotypedetermineshaptenorp-iTcellreac)vitytoflucloxacillin
• Different T cell recogni)on pa:erns might correlate withdifferentclinicaloutcomes
• T cell s)mula)on by amoxicillin and other β-lactams is not onlybased on the hapten concept but might also result fromamoxicillinrecogni)onaccordingtothep-iconcept
Hypothesis
• Inclusioncriteria• Historyofallergytoβ-lactaman)bio)c• Clearclinicalpicture:TypeI/Delayed/Severeallergy• LTTposi)vetotheculpritβ-lactam
• Currentcohortcomposi)on
Type I allergic reactions (Urticaria, Anaphylaxis)
Maculo-papular erythema (MPE)
Severe delayed allergic reactions (DRESS – SJS /TEN)
Collected patients 4 7 6
T cell reactivity
N=3 (Amoxicillin) N=1 (Cefuroxim)
N=5 (Amoxicillin) N=1 (Amoxicillin – DRESS) N=2 (Ceftriaxone - DRESS)
StudyCohort
• PBMCareisolatedands)mulatedwithamoxicillin
• Onday7,sor)ngofprolifera)ngcells
• Directcloningandexpansionofdrug-reac)ngTcells• Characteriza)onofamoxicillin-reac)ngTcells
• Ac)va)onmechanism:HaptenvsPI
• An)genprocessing
• PhenotypeàCD4/CD8
àTh1/Th2
PBMC
ExperimentalDesign
Ctrl
0.3%
Amx500
5.6%
CFSE
CD
3
Haptenforma)onandpulsingofAPC
Time Washing
APC APC+AMX APCAMX0
20
40
60
80
UrBr TCC 1A CD8
% C
D8+
CD
107a
+ c
ells
à Reac)vitytostablypresentedamoxicillin(AMX)
à Reac)vitytoAMXinsolu)on
TCC from anaphylaxis Hapten mechanism
TCC from DRESS PI reactivity KB TCC 4E
APC APC+AMX APCAMX0
10
20
30
40
50
CD8
% C
D8+ C
D10
7a+
cells
HaptenvsPI–pulsingofAPC
MPE UrBr TCC 4B
0 1500 3000 45000.9
1.0
1.1
1.2
1.3APCAPC+AMX
APCAMX
APCAMXAMX
time [s]
F/F°
à Delayed T cell activation kinetic
Hapten–CalciumInflux
PI-mechanism in T cells from DRESS pa7ents
PI-mechanism in T cells from DRESS pa7ents
Addi)onofCe_riaxon(10min)
Pat.683_H4TCCfromapa)entwithUr)cariatoCe_riaxon
PI-mechanism in T cells from DRESS pa7ents
Pat.683_H4TCCfromapa)entwithUr)cariatoCe_riaxon
Pat697_B10TCCfromapa)entwithDRESStoCe_riaxone
Addi)onofCe_riaxone(10min)
Anaphylaxis
- + - + - + - +
0
50
100
0 1051bortezomib [nM]
AMX
rela
tive
% o
f CD
107a
+ T
cel
ls
TCC from anaphylaxis patients
à Proteasome dependent à Proteasome independent
Proteasomeprocessing
- + - + - + - +0
50
100
DRESS
0 1051bortezomib [nM]
drugrela
tive
% o
f CD
107a
+ T c
ells
TCC from DRESS patients
Proteasome inhibition Endosome inhibition
à proteasomal processing not required AMX = amoxicillin
Maculo-popular-Erythema:inhibi)onoftheendosome
MPE
APC APC+AMX APCAMX
0
20
40
60
80
% o
f CD
107a
+ T c
ells
BrOl TCC 4I CD4
APC
APC+AMX
APCAMXAPC
APC+AMX
APCAMXAPC
APC+AMX
APCAMX0
10
20
30
40w/obortezomibchloroquine
% C
D10
7a+
CD
4+ cells
BrOl TCC 3F CD8
APC
APC+AMX
APCAMXAPC
APC+AMX
APCAMXAPC
APC+AMX
APCAMX0
10
20
30w/obortezomibchloroquine
% C
D10
7a+
CD
8+ cells
Proteasome inhibition Endosome inhibition
à proteasomal processing not required AMX = amoxicillin
prot inhib
0
5
10
15
20
APC+AMXAPC
1051bortezomib [nM]
0
% C
D4+ C
D10
7a+
cells
MPE
- + - + - +0
50
100
150
200
250
AMX
w/o bort chloro%
of C
D10
7a+ T
cel
ls
Maculo-popular-Erythema:inhibi)onoftheendosome
• Pa)ent697(DRESS)
• Th2clone(A19)
• Th1clone(C6)
Phenotype patient ID699
Th2 7/16
Th1 9/16
IL13 TNFα IFNγ IL5
IL13 TNFα IFNγ IL5
CD4
CD4
Ctrl
Ctrl
Cef+
Cef+
PhenotypeanalysisExampleofCe_riaxoneTCCphenotypeanalysis
• Anaphylaxis,ur)cariapa)ents(N=4)– TcellsreacttostablypresentedAMX– Reac)vitydependsonproteasomalprocessing– Delayedac)va)onkine)ctofreeAMXinCa-influxassay
• MPEpa)ents(N=7)– TcellsreacttostablypresentedAMX(6/7)andlabileAMX(1/7)– Reac)vityisindependentofproteasomalprocessing– Delayedac)va)onkine)ctofreeAMXinCa-influxassay
• SCAR(DRESS)pa)ents(N=3)– TcellsreacttolabilypresentedAMX/Ce_riaxone– Reac)vityisindependentofproteasomalprocessin– ImmediateCalciuminfluxkine)cuponac)va)onwiththesolubledrug
hapten mechanism
Hapten / PI mechanism
PI mechanism
Summaryoftheresults
• An associa)on between drug ac)va)onmechanisms and clinical picturecouldbefound– TcellsfromtypeIreac)onàHaptenmechanism– Tcellsfromdelayedreac)on
• Mildreac)onàhaptenmechanismmainly• Severereac)onàPI-mechanism
• Relevanceforimmunogenicitypredic)onbasedonhapten
– Predic)onforseverereac)onscanbemissed
• Relevanceforimmunogenicitypredic)onbasedonHLAassocia)onoronHLAdocking– HLArestric)onma:ers– InvolvementofseveralHLAorHLA-superfamiles?
Conclusion
Prof.WernerJ.PichlerDrChris)anePichlerDrOliverHausmannDrAntoniaBünterNicoleWirthTheresaFachruddinCorneliaDängeli
Dr. Natascha Wuillemin Dolores Dina Dr. Klara Eriksson Rahel Thomi Prof. Arthur Helbling The policlinic team
Prof. Barbara Ballmer-Weber Dr. Katrin Mühlethaler Andrea Odermatt
Acknowledgements
Dr. Christoph Schlapbach
