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University Hospital Zürich. New Routes for Allergen Immunotherapy Thomas M. Kündig Dermatology Zurich University Hospital. T cells. B cells. 10. -. 2. Immunological Memory. 10. -. 4. -. 7. 10. Years. Weeks. Months. Immunological Memory. Strong Memory. Weak Memory. - PowerPoint PPT Presentation
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New Routes forAllergen Immunotherapy
Thomas M. KündigDermatology
Zurich University Hospital
University HospitalZürich
Immunological Memory
10-7
Immunological Memory
Weeks Months Years
10-4
10-2
T cellsB cells
Dose +++
UK Immunotherapy Study Group JACI 2006
Sym
ptom
sPlacebo
10‘000 SQ-U
100‘000 SQ-U
Dose Dependence
Spreading
intolymph node
Subcutaneous
Distribution Allergen Extract (25h)
Senti et al.Curr Opin AllergyClin Immunol 2009
Subcutaneous injection
Injektion intolymph node
Intralymphatic Immunotherapy
102 103 104 105 102 103 104 105
Pollen concentration IU/ml
Gra
ss p
olle
nS
ympto
m s
core
0
2
4
6
intralymphatic subcutaneous
0 12 24 36
Maxi
mum
tole
rate
dconcentr
atio
n (
log10)
4.5
5.0
5.5
6.0
0 12 24 36
subcutaneousintralymphatic
Time (months)
VA
S s
ympto
m s
core
0
2
4
6
8
10 hayfever nasal congestion nasal itching sneezing
0
2
4
6
8
10 red eyes ocular itching
Time (years)
asthma dry cough
0 1 3 0 1 30 1 30 1 3
102 103 104 105 102 103 104 105
subcutaneous
intralymphatic
YearsMedications0 1 3 0 1 3 0 1 3 0 1 31 2 3 4
Pa
tien
ts (
%)
Sym
pto
m s
core
(V
AS
)
A B
DC
Grass pollen extract (SQ-U) Months
102 103 104 105 102 103 104 105
Pollen concentration IU/ml
Gra
ss p
olle
nS
ympto
m s
core
0
2
4
6
intralymphatic subcutaneous
0 12 24 36
Maxi
mum
tole
rate
dconcentr
atio
n (
log10)
4.5
5.0
5.5
6.0
0 12 24 36
subcutaneousintralymphatic
Time (months)
VA
S s
ympto
m s
core
0
2
4
6
8
10 hayfever nasal congestion nasal itching sneezing
0
2
4
6
8
10 red eyes ocular itching
Time (years)
asthma dry cough
0 1 3 0 1 30 1 30 1 3
102 103 104 105 102 103 104 105
subcutaneous
intralymphatic
YearsMedications0 1 3 0 1 3 0 1 3 0 1 31 2 3 4
Pa
tien
ts (
%)
Sym
pto
m s
core
(V
AS
)
A B
DC
Grass pollen extract (SQ-U) Months
Intralymphatic Immunotherapy
Senti et al. PNAS 2008
3Injections
Hyalnder et al. JACI 2013
Intralymphatic Immunotherapy
Malling et al.(EAACI 2012)
IgG4 IgE
IgG4 IgE
IgG4 IgE
1wk
4 wk Senti et al. PNAS 2009
Hylander et al.(JACI 2013)
Symptoms worse Symptoms improved
J Exp Med 1996
“Increasing the treatment dose cannot be advised since systemic reactions were seen in app. 10% of the patients”
Is intralymphatic specific immunotherapy with grass pollen allergen ready for clinical use? Malling, H; Blom, L; Poulsen, B; Poulsen, L; Witten, M
3%of 174inj.
Bakterial DNA
Viral RNA
LPS
…. PAMPS….
Creticos et al. NEJM 2006
Allergen + CpG
6Injections
Allergen + MPL
Rosewich, Hum Vaccin Immunother 2013
Route ?
Densitiy of AntigenPresenting Cells
Epicutaneous Immunotherapy
Ch
an
ge o
f hay
fev
er s
ym
pto
ms
-100
-50
0
50
100
Placebo 1mg 5mg 10mg Placebo 1mg 5mg 10mg
2008 2009
Treatment group
1005010Placebo 10010Placebo
Impr
ovem
ent (
%)
50
HEP HEP
Senti et al. JACI 2012
Impr
ovem
ent (
%)
P = 0.002
P = 0.04
12Patches
6Patches
Epicutaneous Immunotherapy
Patel et al. J Allergy Clin Immunol 2013
Intradermal Cat-PAD
4Injections
Rotiroti et al. J Allergy Clin Immunol 2012
Low Dose Intradermal Grasspollen
6Injections
Dose SIT
Distribution SIT
Adjuvant SIT
Route SCIT
Dose SIT
Distribution SIT
Adjuvant SIT
Route SIT
diameter = 30 nm
NN
O
NO
O
O
O O
O
SMPH chemical linker
N
N
O
O
O
N
N
O
O
O
N
N
O
O
O
N
N
O
O
O
N
N
O
O
O
N
N
O
O
O
N
N
O
O
O
N
N
O
O
O
N
N
O
O
O N
N
O
O
O
N
N
O
O
O
N
N
O
O
O
N
N
O
O
O
N
N
O
O
O
N
N
O
O
O
N
N
O
O
O
VLPs
Transport into
lymph node
Uptake into pDC
Degradation of
protein shell
Release of CpG
Activation of TLR-9
QbG10 G10
Organization: low absenthigh
Antibody response ++ -+++
- -Induction ofauto-antibodies
+++
Antigen Organisation
Bachmann et al. Science 1993
T helpIndependent
Type 1
Kündig JACI 2006
Virus Like Allergen: 1 Injection
IgG
(lo
g 10)
1Injection
AllergenFel d 1
IgG in saliva Fel d 1 in saliva
IPCIT: Zero Injections
Allergic patients
SCIT
SLIT
ILIT
EPIT
IPCIT
Rolf Zinkernagel
Gabriela Senti
Martin BachmannLars French
Pal JohansenFranziska Zabel
Antonia FettelschossDeepa Mohanan
Ying Wäckerle-MenChristine Tivig
Fabian Tay
Regine HofmannBarbara Riond
AlleCure Corp.CTLImmunoTherapiesMannKind Corp.Cytos BiotechnologyImVisionColby Pharmaceuticals
