NAME
Consultant of Rhinology and Allergy Sub.Div of ENT Dept Faculty of Medicine, Univ
of Padjadjaran / Hasan Sadikin General Hospital Bandung
EDUCATION:
Dokter, Faculty of Medicine, University of Indonesia, 1965
ENT specialist, University of Padjadjaran, 1970.
Doctor in Health Sciences, University of Padjadjaran, 1996
TRAINING/COURSES:
1. HNO Weiterbildung. Rudolf Virchow Krankenhaus 1970-1972. West Berlin
2. Functional Endoscopy Sinus Surgery of ASEAN ORL Congress 1985
3.Allergy-Immunology-pharmacology Training. Machidol University, 1987
4. Several short courses in Indonesia and international
ORGANIZATION:
Former President of Indonesian ORL-HN Surgery Society (1992-1995)
Vice Chairman of National College of The Indonesian ORL-HNS Society (1999-07)
Member of PERALMUNI, IFOS, ASEAN ORL-HNS Society, ASEAN Rhinology Society
Adress
Phone
Email
Iwin Sumarman
Department of ENT Head and Neck Surgery
Faculty of Medicine, University of Padjadjaran/
Dr. Hasan Sadikin General Hospital BANDUNG
Nas
al c
res
t
Rhinorhea
Mouth breathing
Eye Shiner
Nose obstruction
Old classification
Grade: 1th up to 34th
Moderatesevere
persistent
Mild
intermittent
Mild
Moderate
persistent
severe
intermittent
Intra-nasal steroid
Local chromone
Oral or local non-sedative H1-blocker
Intra-nasal decongestant (<10 days) or oral decongestant
Immunotherapy
The
The Update
Update Advance
Advance on
on
Allergic
Allergic Inflammatory
Inflammatory
Reaction
Reaction
(AIR):
(AIR):
The
The T
T Regulator
Regulator
cells
cells
5
IgE
Eos
ll
e
C
t
Mas
FcRI expression
and
IgE-dependent
mast cell activation
Eosinophil survival
and activation
(-)
ell
Bc
IL-10
4
I gG
IgE-dependent
antigen
presentation
(- )
(-)
(-)
g
T re
(-)
Th2
Cytokines and
proliferation
IL-10 produced by
T Reg
Fig 15. The potential anti allergic properties of IL-10 on different limbs of the allergic immune
response. (Till et al. J Allergy Clin Immunol 2004;113:1025-34)
6
EOS = Eosinophil; T reg = T regulatory cell.
These
These main
main environment
environment factors
factors
and
and the
the complexity
complexity of
of allergic
allergic
inflammatory
inflammatory reaction,
reaction, cause
cause
the
the allergic
allergic diseases
diseases difficult
difficult to
to
be
be treated
treated and
and avoided.
avoided.
So,
So, some
some experts
experts switch
switch
the
the conventional
conventional treatment
treatment
combined
combined with
with Allergen
Allergen
Specific
Specific Immunotherapy
Immunotherapy
(ASIT)
(ASIT)
7
The
The Allergen
Allergen
Specific
Specific
Immunotherapy
Immunotherapy
(ASIT)
(ASIT)
The Aim of
Allergen Specific Immunotherapy (ASIT)
The aim of ASIT is to modulate the immune
system which on allergic subjects are already
been disturbed. (Bousquet et al, 1989)
Duration of ASIT injection: 2-3-4 yrs !!!!!
10
The
The T
T regulator
regulator cell
cell
theory
theory on
on the
the Allergen
Allergen
Specific
Specific Immunotherapy
Immunotherapy
(ASIT)
(ASIT)
11
All
er
S
CD
4+
ce T
ll
tim
g
ula en
tio
n
Aller
ge
Imm n Specifi
unot
c
he ra p
y
Activate M/DC
Inducing CMI:
IFN-, IL-2, TNF, ect
B cells
APC
Th0 Th0
IL-12
rgen
e
l
l
A
M cell
as APC Humoral immunity
Th 1
Th 2
(CD4 + T
)
(+)
(+)
(CD4 + T
T Reg
IL10/TGF
(-)
(-)
Allergic diseases:
IL-4, IL-13, IL-5, dll
(+)
(+)
B cells
Adapted
Akdis et al 2005) (Modified by
Sumarman, 2007)
en
g
r
e
All
on allergic Inflammation
Eos &
Baso
Accumulation
12
13
(ASIT)
1.
1. The
The Patients
Patients Selection
Selection
and
and Indications
Indications of
of
Allergen
Allergen Specific
Specific
Immunotherapy
Immunotherapy
(ASIT)
(ASIT)
15
17
2. The Allergens
Selection:
on injection ASIT
19
Boy, 16 Yrs
Skin Prick Test :
2.1: The tool for allergen selection
Fig 8.
Buffer
D
o
g
d
a
n
d
er 3+
Mite Dpt 4+
SPT (duplo)
Histamine
20
21
of AR
Rhinorrhea
Congestion
TNSS
p
value
OR
p
value
OR
p
value
OR
p
value
OR
Mite Dpt
0.421
1.43
0.309
1.57
0.545
1.32
0.032
2.39
House
dust
0.124
1.87
0.380
1.44
0.013
2.11
0.366
1.46
Dog
dander
0.010
2.03
0.001
2.50
0.178
1.57
0.011
2.28
Sinusitis
0.619
0.85
0.983
0.99
0.426
1.29
0.606
1.19
IL-4
Groups
IFN-
Pra
ITS
Post
ITS
p
(Zw)
A. Mite Dpt
0,0408
0,0382
0,893
0,1402
0,1384
1,0
B.House
dust (HD)
0,0498
0,0498
0,893
0,1824
0,1172
0,345
C.MDpt + HD
0,0422
0,0466
0,500
0,1604
0,1334
0,686
Chi square
KruskalWalles Test
X2K-W=
0.846
p=0.655
X2K-W=0.846
p
(Zw)
p=0.655
Either symptoms score (not shown) or IL-4 and IFN- profile showed
no different between three groups. So, ALLERGEN for ASIT, CAN BE
USED MONO ALLERGEN ONLY.
25
2.a:
2.a:
Tabel 3.
SLIT
LNIT
Ineffective
Unpleasant
SCIT
36.9%
12.0%
8.7%
SLIT
36.4%
24.9%
5.8%
LNIT
30
Tablet on SLIT
The SLIT on Rhinoconjunctivitis using
5-grass pollen tablet:
SLIT (5-grass pollen tablet): Both the 300-IR
and 500-IR tablet significantly reduced
the rhinoconjunctivitis total symptom
compare with placebo group
(n = 628; SLIT 4 month before the season and
through out the season; p=0.0001 and p=0.0006)
Didier A, Malling H-J, Warm M, Horak F, Jger S, Montagut A, Andre C, de Beamont O,
and Melac M. J Allergy Clin Immunol 2007;120:1338-45
(Toulose, Meylan; Copenhagen, Denmark; Berlin Germany; Viena, Austria)
31
32
CWBS)
2. Subcutaneous
2003;111(3) Spl:S783-8
Rush ASIT
2005;116:109-18)
34
Th2 Signaling
IL-4
IL-4R
PIP2
Ras
ERK
Sustained
[Ca2+]
flux
Higher hypersensitivity
?Novel
signals
NFAT
(Nel AE and Slughter,
JACI, 2002;109(6):908)
NFATc
cFOS
c-Maf Nip45
IL-4
NFATp NFAT4
STAT6
IFN-promoter
GATA-3
Nucleus
36
Fig 11.
Th1 Signaling
IL-12
Lower hypersensitivity
Ras
IL-12R
PIP2
Vav
ERK
Sustained
[Ca2+]
flux
JNK2
cFOS
IFN-
JNK1
IL- 2
NFATp/
NFAT4
IL-12R
NF- B
NFAT
NFATc
ATF2/c-JUN
PKCO
P50/
p65
STAT4
T-bet
IL-4 promoter
Nucleus
37
Concentration
Concentration
Volume
Concentration
(PNU/ml)
(W/V)
(ml)
PNU
100
1:10,000
0.05
0.10
0.15
0.20
0.30
0.40
0.50
0.10
0.20
0.30
0.40
0.50
(7 injections)
1000
1:1000
(5 injections)
12th injection
20
50
100
300
500
38
build up doses)
Concentration
Concentration
Volume
Concentration
(PNU/ml)
(W/V)
(ml)
PNU
1000
0.50
0.05
0.10
0.15
0.20
0.30
0.40
500
500
1:100
10,000
The optimal
dose/ OD
(7 injections)
0.50
2000
4000
5000
The maintenance
dose
19th injection
Unfortunately,(MD)
to reach
a maintenance dose, it takes
39 )
time to long (about 19 injections in 3rd build up doses
Rush A S I T
40
cluster approach
41
42
is
43
is the dose
of allergen should be given safely for
the first time. Usually small or very
small amount dose, depend on the
sensitivity of the patients, based on
the result of skin prick test.
is the
highest dose of allergen should be
given as maintenance dose, according to
the product instruction. This OD
usually similar for most patients, and
not depend on age.
(Conventional Subcutaneous ASIT
Mite Dpt : 5000 PNU)
(Adapted from Grammar, Shugnessy, Patterson, 1991)
44
is
the highest dose of allergen should be
given, which can be tolerated safely by
the patient, without any systemic
reaction. This sTD is different amongst
AR patients, and also not depend on
age.
The higher the SPT result, the lower
the Tolerable dose. Higher than this
sTD systemic reaction could occur.
46
(Sumarman, 1996):
47
(Sumarman, 1996):
48
Wheal 0
Wheal 15
??
The biggest 15 wheal
of ID ASIT, decided as
the selected mono
allergen
(Sumarman Doc. 2007)
50
Mite Dpt
0.2 PNU
Mite 50 PNU
Mite
5 PNU
Sumarman
Doc 2003
Mite Dpt
100 PNU
Mite Dpt
400 PNU
Mite Dpt
Mite Dpt
55 PNU PNU
55
Fig. 13: Intra dermal ASIT Wheal 15 (Op Dose Mite 500 - 1000 PNU)
The Wheal 15 nearly equal, but the doses range: 0.2 PNU 400 PNU.
51
Sumarman
Doc 2003
Fig. 16
Intradermal
(ID) ASIT
Ratio of Wheal 15
vs Wheal 0: 2,5
Wheal 15 minutes: 30 X 25
mm
Wheal 0 minute: 16 X 10 mm
Wheal Ratio = 2.5 for 100 PNU
Age: 6 Yrs
Sumarman
Doc 2005
E
E
mL
N
U
15
W
E
RATIO
15/0
mL
P
N
U
15
RATIO
15/0
1st
0.03
0.3
6x5
7x8
1.4
8th
0.05
7x6
16x14
2.3
2nd
0.06
0.6
6x6
9 x 10
1.6
9th
0.08
9x8
17x23
2.4
3rd
0.10
8x8
17x13
1.9
10th
0.15
15
10x10
20x30
4th
0.20
10x10
25x19
2.2
11th
0.25
25
10x11
23x30
2,5
2.5
5th
0.25
2.5
11x12
23x33
12th
0.35
35
12x12
28x42
2.9
6th
0.25
2.5
12x11
22x13
2.4
1.5
13th
0.30
30
11x11
28x30
2.6
7th
0.35
3.5
12x12
23x20
1.8
Mite Dpt:
M1/ml = 10 PNU
M2/ml = 100 PNU
M3/ml = 1000 PNU
Sumarman
2007
mL
P
N
U
15
Ratio
15/ 0
mL
P
N
U
15
Ratio
15/ 0
6st
M2 0.40
13x15 28x28
2.0
6st
M2 0.50
50
13x13
18x20
1.5
7nd
M2 0.55
5.5
14x15 28x30
2.0
7nd
M3 0.10
100
7x7
10x13
1.6
8rd
M3 0.07
6x5
14x14
2.3
8rd
M3 0.20
200
8x7
12x13
1.5
9th
M3 0.10
10
7x7
18x16
2.4
9th
M3 0.35
350
9x9
14x15
1.6
10th
M3 0.15
15
9x8
20x22
2.5
10th
M3 0.50
500
10x10
14x16
1.5
15
S Tolerable dose
th
M3 0.15
11th dust: L1/ml
M3
House
= 50 PNU
Mite Dpt: M1/ml = 10 PNU M2/ml = 100
11PNU
(as
OD
Subcutaneous)
L2/ml = 500 PNU
LAPI LAB
M3/ml = 1000 PNU
Optimal Dose
500
Sumarman55
2005
STD2.5Subcutaneously
0.50
Sumarman
2005
Patient
No
A
G
E
(Yrs)
LER-
15
M2
0.40
24
M2
30
AL
GEN
P
mL
15
40
12x12
30x30
2.5
0.50
50
14x14
30x34
2.3
M1
0.40
14x15
26x34
2.1
14
M3
0.10
100
7x8
20x18
2.5
26
M3
0.15
150
9x9
22x24
2.6
10
M1
0.10
8x7
20x17
2.5
Mite Dpt:
M1/ml = 10 PNU
M2/ml = 100 PNU
M3/ml = 1000 PNU
15/0
Example of: Tol. dose on Group B the very sensitive (4+ SPT ) (n = 17);
Optimal dose on Group A (the sensitive (3+ SPT) (n=25)
No/ Patient
initial
Age
(yrs)
sTol Dose
Wheal of 15
diameter (mm)
House dust
dose (PNU)
Wheal 15
diameter
(mm)
B 1. TT
29
M3 0.40 ml
(400)
24 x 30
33 x 37
B 7. TT
25
M3 0.10 ml
(100)
17 x 25
L2 0.1 ml:
50
27 x 17
B 16. RH
38
M1 0.30 ml (3)
30 x 25
L1 0.4 ml:
20
27 x 17
Opt Dose
A. 1 YA
20
M3 0.5 ml (500)
12 x 14
11 x 14
A. 12 ML
24
M3 0.5 ml (500)
21 x 25
25 x 28
A. 16 RM
21
M3 0.5 ml (500)
25 x 15
23 x 29
A. 19 EF
14
M3 0.5 ml (500)
18 x 18
15 x 21
House dust:
L1/ ml = 50 PNU
L2/ ml = 500 PNU
Mite Dpt:
M1/ ml = 10 PNU M3/ ml = 1000 PNU
M2/ ml = 100 PNU
57
The result of ASIT on AR Symptoms improvement after 12 month ASIT. B-group (tolerable low
dose) compare with AR A-group (optimal high dose)
Table 10:
Symptom
s score
AR Group A
imn = 25
proveme
nt
X (SD)
Median
Range
0.84(0.62)
1
02
AR Group B
n = 17
Z M-W
0.71(0.59)
1
02
0.676
0.499
How to detect :
The Safe Tolerable Dose ?
The ratio between :
wheal 15 vs wheal 0 2,5
and or
The wheal average diameter
30 mm
every
every
every
every
every
every
every
every
2 weeks :
3 weeks :
month
:
2 monthes
3 monthes
4 monthes
5 monthes
6 monthes
6
3
3
:
:
:
:
:
X
X
X
2
2
2
2
2
X
X
X
X
X
60
Evaluation
Evaluation of
of
Allergen
Allergen Specific
Specific
Immunotherapy
Immunotherapy
(ASIT)
(ASIT)
Effectiveness
Effectiveness
63
Fig.9
A
c
u
te
Allergen
Allergen
Sensitized
Allergen
S
y
m
p
t
o
m
s
Mast cell
Histamine
Tryptase
PGD2,Lts
Cytokines
CD4+
CD25+
Class II
MHC
Immunogenic
Fragments
Tc e
ll r
Th0
IL
-4
IL-2 CD4+
IgE
13
L
/I
4
IL
Th2
IL
5/
IL
3
IL
3/
I
IFN- L4
IgE
B
B
Eos
Baso
IgE
IgE-bearing B-cells
Basic
proteins
Lts
Cytokines
Histamin
Lts
Th1
(APC)
The Sensitization phase of AIR
IgE Antibodi
Cytokines
Chronic
Inflammation
& Symptoms
Rhinorea
Sneezing
Congestion
64
The Late phase of AIR
Allergen
Fig. 7
EPR
Histamine
PAF1
ECFA2
NCFA
Leukotriene
Tryptase
ASIT Hipotesis
Sumarman, 1996:
ASIT REDUCES EOS
ACCUMULATION IN
NASAL MUCOUS
MEMBRANE
Eos accumulation
LPR
X
Secondary Mediators
LPR
67
Fig.9:
Higher Ratio
of
IFN-/IL-4
_
(Benjaponpitak
1999; Haugaard,
1999; Akdis 2000,
Cools & Brever
2000)
68
AR patients
Groups
BCG
IT
BCG + IT
Kontrol
p=0.048*
p=0.016*
p=0,29
p=0.36
p=0.082
BCG
IT
p=0.023*
69
70
All
er
S
CD
4+
ce T
ll
tim
g
ula en
tio
n
Aller
ge
Imm n Specifi
unot
c
he ra p
y
Activate M/DC
Inducing CMI:
IFN-, IL-2, TNF, ect
B cells
APC
Th0 Th0
IL-12
Th 2
(CD4 + T
)
(+)
rgen
e
l
l
A
M cell
as APC Humoral immunity
Th 1
(+)
(CD4 + T
T Reg
IL10/TGF
(-)
(-)
Allergic diseases:
IL-4, IL-13, IL-5, dll
(+)
(+)
B cells
Adapted
Akdis et al 2005) (Modified by
Sumarman, 2007)
en
g
r
e
All
on allergic Inflammation
Eos &
Baso
Accumulation
71
IgE
Eos
ll
e
C
t
Mas
FcRI expression
and
IgE-dependent
mast cell activation
Eosinophil survival
and activation
(-)
ell
Bc
IL-10
4
I gG
IgE-dependent
antigen
presentation
(- )
(-)
(-)
g
T re
(-)
Th2
Cytokines and
proliferation
IL-10 produced by
T Reg
Fig 15. The potential anti allergic properties of IL-10 on different limbs of the allergic immune
response. (Till et al. J Allergy Clin Immunol 2004;113:1025-34)
72
EOS = Eosinophil; T reg = T regulatory cell.
p=0.002
3
2.5
2
1.5
1
p< 0.001
p= 0.231
0.5
0
Prae
Post
Arif Dermawan Sumarman,
Tesis Unpad, 2006
(Teti Madiadipura, Toni Sarbini)
ASIT
(n=18)
Cetirizin
n = 18
(n=18)
73
Conclusions:
1. The immunologic effects of allergen specific
immunotherapy (ASIT), to date, can be
detected either cellular and molecular
2. The cellular effects of ASIT are decreasing the
accumulation of eosinophil on target organs,
stimulating regulatory T cells to suppress TH2
responses and to enhancing TH1 responses.
3. The molecular effects of ASIT are decreasing
the IL-4, IL-13, IL-5 cytokines, and increasing
the IFN- , TGF- and IL-10, resulting
inhibition of mast cell activation and also Eos
survival and activation.
74
Conclusions:
4.Recent Advance on Type of ASIT on
Allergic Rhinitis (and Asthma):
a.The Allergen Specific Immunotherapy (ASIT)
b.The Recombinant DNA Technology
Conclusions:
6. The safe tolerable dose, which lower than
optimal dose, decided on intra-dermal ASIT,
prior to subcutaneous, gives the same
beneficial effects on decreasing the AR
symptoms compare to the optimal dose.
7. The ratio of diameter of wheal 15 minutes
intra-dermal ASIT against 0 minute, which
less than 2.5, or the average diameter of 15
wheal 30 mm, both can be used for
deciding the safe tolerable allergen dose, as
well as safety adequate dose. This concept
take less time consumption compare to the
subcutaneous conventional ASIT.
76
Bintul 0
Bintul 15
77
ABSTRAK
Allergen specific immunotherapy (ASIT) adalah pemberian alergen spesifik terhadap
subjek alergis. Tujuan ASIT adalah memodulasi sistem imun yang pada subjek alergis
telah terganggu. Teori dasar dan efektifitas klinik dari ASIT melalui subcutaneous
immunotherapy (SCIT) telah berkembang mapan, terutama pada pasien sensitif terhadap
Hymenoptera venom dan rinitis alergi. SCIT menghambat terbentuknya sensitivitas baru
dan progresifitas dari rinitis ke asma. Manfaat keampuhan efek penurunan gejala oleh
SCIT bertahan lama setelah selesainya ASIT yang lengkap. Walaupun banyak pasien
yang menyenangi keampuhan SCIT, tetapi banyak juga pasien yang menolak atau
menghentikan pengobatan ini. Alasannya karena rasa tidak senang terhadap kunjungan
klinik berulang untuk penyuntikan. Sekitar 11% pasien SCIT dan 22% pasien sublingual
immunotherapy (SLIT) menghentikan pengobatan setelah satu tahun. Namun demikian
hal ini masih masih lebih baik dibanding local nasal immunotherapy (LNIT; sekitar 73%
sebelum tahun pertama). LNIT kurang disenangi karena perasaan tak nyaman pada
hidungnya, atau akibat tidak efektif, serta mahalnya biaya. Sampai saat ini SCIT
dianggap imunoterapi yang paling baik dan masih disenangi baik oleh anak-anak
maupun remaja. SLIT disenangi oleh lebih dari tiga-perempat pasien-pasien. Akhir-akhir
ini, alternatif lain imunoterapi adalah menggunakan recombinant DNA technology (DNA
IT). Modifikasi vaksin oleh ekstrak DNA dapat menurunkan alergenisitasnya, tanpa
menurunkan imunogenisitasnya. Baik ASIT maupun DNA IT dapat menurunkan bahkan
menghilangkan gejala, sama halnya seperti penghambatan kinerja sel TH2, mast and
basophil, serta peningkatan respon Th1 dan TReg cells. Intra dermal ASIT (ID ASIT)
sebelum SCIT, dapat digunakan sebagai strategi untuk mempercepat tercapainya dosis
optimal yang aman, dibanding SCIT konvensional.
Key words: Sublingual, subcutaneous, immunotherapy, SCIT, SLIT, asthma, rhinitis
78
ABSTRACT
Allergen specific immunotherapy (ASIT) is administration of specific allergen to an
allergic subject. The aim of ASIT is to modulate the immune system which on
allergic subjects are already been disturbed. The scientific basis and clinical
effectiveness of (ASIT) administered by subcutaneous injection (SCIT) are well
established, especially for patients which sensitive to Hymenoptera venom and for
allergic rhinitis. SCIT reduces the development of new sensitivities and
progression from rhinitis to asthma. The beneficial effects of SCIT persist long
after completing the ASIT. Although many people enjoy the benefits of SCIT, but
many others who refused or discontinued the SCIT because of the inconvenience
of repeated visits to receive the injections. About 11% patients of SCIT and 22% of
sublingually administration (SLIT) discontinued the treatment after first year, far
better than the local nasal immunotherapy (LNIT) about 73% before first year. The
LNIT was not suitable because its local nasal discomfort, or because ineffective
and the expensive cost. The SCIT be considered the most suitable immunotherapy
in children and adolescents. However, SLIT is well accepted more than three
quarters of patient. To date, other alternative of IT is through recombinant DNA
technology (DNA IT). DNA extracts are being modified to reduce their allergenicity
without reducing their immunogenicity. Either ASIT or DNA IT can reduce or
diminish the symptoms, as well as inhibition of the T, TReg cells, mast and
basophils cells responses. The intra dermal ASIT (ID ASIT) prior to SCIT can be
used as administration strategy of allergen to reach the optimal safety dose.
Key words: Sublingual, subcutaneous, immunotherapy, SCIT, SLIT, asthma, rhinitis
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