Curriculum vitae

NAME

: Prof. Dr. H. Iwin Sumarman. dr., SpTHT, KAI, KRA.

Place & date of birth: Tasikmalaya, Indonesia, June 19th 1939

Qualification:

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

: Jalan Jati Indah II No. 11 City of Bandung 40275, Indonesia

: 62 22 7310166; HP: +62 811203445 Fax: 62 22 2040984
: isumar@bdg.centrin.net.id.

Immunotherapy on Allergic Rhinitis:

Methods and Its Evaluation

A Recent Review

Iwin Sumarman
Department of ENT Head and Neck Surgery
Faculty of Medicine, University of Padjadjaran/
Dr. Hasan Sadikin General Hospital BANDUNG

Presented at: Instructional Course

KODI Rinologi-Allergi PERHATI
Jakarta, 16th Febr 2008

Fig.1: Allergic Rhinitis symptoms

Sneezing

Nas
al c
res
t

Rhinorhea

Mouth breathing

Eye Shiner
Nose obstruction
Old classification
Grade: 1th up to 34th

Fig 2. Treatment of allergic rhinitis

(ARIA WHO-2001) (Allergic Rhinitis and its Impact on Asthma)

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

Allergen and irritant avoidance

ARIA (2001)

Bachert EAACI 2002

Immunotherapy

Treat co-morbidities and complications

4
Routine adequate physical fitness exercise (added by Sumarman, 2002)

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

(- )

(-)

IL-10 is another effective

inhibitive indicator of
allergic inflammation

(-)

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)

Allergen Specific Immunotherapy

(ASIT)
Definition of ASIT:
Administration (injection) of specific allergen
to an allergic subject, in which :
The dose of injection / administration
gradually be increased
Time interval of administration gradually
be increased
(Bousquet et al, 1989)
9

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
)

(+)

IgG4 & IgA production

(+)

(CD4 + T

T Reg
IL10/TGF

(-)

(-)

Allergic diseases:
IL-4, IL-13, IL-5, dll
(+)
(+)

B cells

IgE producFig 7. The recent ASIT theory

tion
from Creticos 1998 &

Adapted
Akdis et al 2005) (Modified by
Sumarman, 2007)

en
g
r
e
All

on allergic Inflammation

Eos &
Baso

Accumulation
12

Allergen Specific Immunotherapy (ASIT)

The rational basis theory of ASIT to date is
already well establish.
So, since 2003, the ASIT to an allergic
rhinitis patient is already recommended by 3
main world allergic associations: the ACCAI,
the AAAAI, dan JCAAI
(Li JT et al, Ann Allergy Asthma Immunol, 2003).

13

The Allergen Specific Immunotherapy

(ASIT)

Practitioners have to know well about some

technical details on ASIT:
1. The patient selection and the indication
2. The allergen extract be chosen
3. The type and route of administration
4. The gradually increasing dose of allergen
5. The safe optimal allergen dose
6. Time interval of administration
7. Duration of administration
But, practitioner and the experts, up to now,
still debated about some off these technical
details.
14

1.
1. The
The Patients
Patients Selection
Selection
and
and Indications
Indications of
of
Allergen
Allergen Specific
Specific
Immunotherapy
Immunotherapy

(ASIT)
(ASIT)

15

1.1. The Patient Selection of ASIT

(ASIT according to WHO ARIA consensus, 2001)

Patient selection indicated for ASIT:

Has a place in selected patient with

demonstrable IgE-mediated diseases:
who either have a long duration of
symptoms, or
in whom insufficiently controlled by
conventional pharmacotherapy, or
in whom pharmacotherapy produce
undesirable side effect, or
16

1.2 The Patient Selection of ASIT

(ASIT according to WHO ARIA consensus, 2001)

Patient selection indicated for ASIT:

Has a place in selected patient with

demonstrable IgE-mediated diseases:
in patients who do not wish to be on
pharmacotherapy, or
in patients who do not want to receive long
term pharmacological treatment

17

1.3 The Patient Selection of ASIT

(ASIT according to WHO ARIA consensus, 2001)

Patient have a long duration of AR

symptoms, but show insufficiently controlled, especially if one or more of these
invasive treatment had already done:
electro-cauterization,
conchotomy,
septum correction
sinus maxillary wash out
and or FESS
and or Caldwell Luc
18

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

Skin Prick Test

2.1 The tool for allergen selection:
The 3+ or 4+ allergen
Fig 9.

21

Table 1. The influence of allergens against symptoms

Independent
variable
(The Lapi
Allergen SPT
scores, and
the sinusitis)

of AR

Dependent variable (Symptoms score)

Sneezing

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

Mite Dpt is the allergen extract of choice for

Multiple logistic regression analysis: OR=od ratio; TNSS = total nasal symptoms score.
22
ASIT
in Indonesian
Sumarman
et al. ASEAN
ORL Congress Singapore 2001AR (LAPI Product)

2.2: The Allergens used on injection ASIT:

Practitioner and also the experts had
already used one or several allergens:
1.House dust mite (HDM)
2.Grass pollen
3.Fungus spores
4.Cat dander
5.Dog dander
6.Hymenophthera venom
7.ect
23

2.3: THE NUMBER OF ALLERGEN SELECTION

Tabel 2. Mean Blood Sitokin Profile (IL-4 dan IFN- ) of Each ASIT
Group (Mono Allergens vs Multiple allergens)

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

Pra ITS Post ITS

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.

Ahwil C. Tesis Unpad 2005. (Madiadipura T,

Boesoirie TB, Sumarman I) 24

3. The Types and Routes

of Allergen Specific
Immunotherapy

25

3. Recent Advance on Type of ASIT on

Allergic Rhinitis (and Asthma):

a. The Allergen Specific

Immunotherapy (ASIT)
b. The Recombinant DNA Technology

Nelson HS. Advances in upper airway diseases and allergen immunotherapy.

J Allergy Clin Immunol 2006;1047-53

Allergen immunotherapy: Where is it now? J Allergy Clin Immunol

26
2007;119:769-77.

2.a:

The Route of Allergen Administration

on ASIT:

The Route of Allergen Administration on

ASIT:
1. The injection ASIT:
a: The SCIT (Nelson HS. 2006)
b: The ID-ASIT prior to SCIT (Sumarman model, 1996)
2. The SLIT
3. The LNIT
Nelson HS. Advances in upper airway diseases and allergen immunotherapy.
J Allergy Clin Immunol 2006;1047-53
27

2.a:

The Route of Allergen Administration

on ASIT:

The Route of Allergen Administration on

ASIT:
1. The injection ASIT:
1.a: The subcutaneous immunotherapy
(SCIT) (Nelson HS. 2006)
1.b: The intra-dermal ASIT (ID ASIT) prior
to subcutaneous; Sumarman model, 1996
2. The sublingual immunotherapy (SLIT)
3. The local nasal immunotherapy (LNIT)
Nelson HS. Advances in upper airway diseases and allergen immunotherapy.
J Allergy Clin Immunol 2006;1047-53
28

Tabel 3.

The SCIT, SLIT, and LNIT of ASIT on AR:

An observation in Italia (2005) on 2774 children, in a 3 year IT program

(The discontinuing % of children and the cause):

Percentage of children discontinued
SCIT

10.9 % (after first year)

SLIT

21.5 % (after first year)

LNIT

73.6% (before first year)

Expensive

Ineffective

Unpleasant

SCIT

36.9%

12.0%

8.7%

SLIT

36.4%

24.9%

5.8%

LNIT

Discontinued before first year

because of local nasal side effect

Pajno GB et al. Compliance to allergen immunotherapy according to its different

29
routes of administration, a pediatric survey. J Allergy Clin Immunol 2005;116:1380-1

The ASIT on AR:

base on the route of allergen administration:
The SCIT : the most suitable.
The SLIT : well accepted
The LNIT : unpleasant (local nasal side effect)
Pajno GB, Vita D, Caminiti L, La Grutta S,Incorvaia C, Barbario G. Compliance to
allergen immunotherapy according to its different routes of administration, a pediatric
survey. J Allergy Clin Immunol 2005;116:1380-1

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

2.a.1: The Injection ASIT on

Allergic Rhinitis:

32

The Injection ASIT on

Allergic Rhinitis:

1.Conventional Subcutaneous ASIT

(conventional weekly build up schedule :

CWBS)

(Adapted from Grammar, Shugnessy, Patterson, 1991)

2. Subcutaneous

2003;111(3) Spl:S783-8

Rush ASIT

(Nelson HS. JACI

3. Subcutaneous ASIT based on SET

4.Cluster subcutaneous ASIT

(Tabar AI et al. JACI

2005;116:109-18)

5.Intradermal ASIT (ID ASIT) prior to

Subcutaneous ASIT (Sumarman, 1996)
33

2.a.1: The Injection ASIT on

Allergic Rhinitis:

The Safe Optimal Dose

34

Problems on Injection ASIT:

Principle: The highest the dose, the
better the result, but :
If the allergen dose is to low, then
the symptoms would be higher than
before ASIT (higher hypersensitivity)
But if the allergen dose is too
high then systemic reaction
could occur.
35

Fig. 10 Low AG dose, APLs, Type II DC

TCR

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.

Strong AG stimuli Type 1 DC

TCR

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

(Nel AE and Slughter,

JACI, 2002;109(6):907)

Nucleus

37

Table 4. The Weekly Increasing (Build up) Dose of Allergen Extracts

Schedule of

conventional Subcutaneous: CWBS ASIT

(Adapted from Grammar, Shugnessy, Patterson, 1991)

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

First 12 injections (1st AND 2nd

20
50
100
300
500

38
build up doses)

Table 5. The Weekly Increasing (Build up) Dose of Allergen Extracts

Schedule of

conventional Subcutaneous: CWBS ASIT

(Adapted from Grammar, Shugnessy, Patterson, 1991)

Concentration

Concentration

Volume

Concentration

(PNU/ml)

(W/V)

(ml)

PNU

1000

1:1000 (12th injection)

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

(In Hospital ward)

One year ASIT with mite Der p1, maintenance
dose was reach within a mean of 8 injections,
but adverse effect 1,7% systemic reaction.

(Nelson HS. JACI 2003;111(3) Spl:S783-8

The cluster schedule for the initial phase

of ASIT with incremental doses of Mite Dpt
is a safe alternative and achieving clinical
and immunological improvement sooner.
But systemic Rx : 0.15% of injections
(Tabar AI et al. JACI 2005;116:109-18)

40

Initiating Injection of ASIT:

(Using Mite Dpt):

cluster approach

1.Can achieve maintenance injections and

likely clinical response more rapidly 6
weeks earlier than the CWBS (conventional
weekly build-up schedule).
2.Can achieve immunologic improvement
3.There was no difference in the rate of
systemic reactions compare with the CWBS
Tabar AI, Echechipia S, Garcia BE, Olaguibel JM, Lizaso MT, Gomez B, et al. Double
blind comparative study of cluster and conventional immunotherapy schedules with
Dermatophagoides pteronyssinus. J Allergy Clin Immunol 2005;116:109-18

41

2.a.1: The Injection ASIT on

Allergic Rhinitis:

The Safe Optimal Dose

42

Maintenance dose (MD)

is

the highest dose of allergen

should be given to an allergic
patient. It could be:
The optimal dose (OD) or
The safe tolerable dose (sTD).

43

Starting dose (SD)

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.

Optimal dose (OD)

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

Safe Tolerable dose (sTD)

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.

What kind of indicator should be used

to decide the sTD ?
45

Intradermal ASIT (ID ASIT)

prior to Subcutaneous ASIT
on Allergic Rhinitis (AR)
(Sumarman, 1996)

46

Intra-dermal ASIT (ID ASIT)

(Sumarman, 1996):

ID ASIT prior to Subcutaneous ASIT with Mite

DPt and or House dust allergen on high grade AR without

sinusitis (n=85), during 12 months. Maintenance dose was
reach within 9 13 (mean 11) injections;

The symptom grade highly significant

decrease than before (p<0.001) during 2
months interval injection (n=85);
The number of EOS (biopsy specimen) of
inferior turbinate was significantly lower
than before (p<0.001).
Conclusion: ID ASIT is a shorter effective
rational treatment strategy for Subcutaneous
ASIT on AR.

47

Intra-dermal ASIT (ID ASIT)

(Sumarman, 1996):

ID ASIT prior to Subcutaneous ASIT with Mite DPt and

or House dust allergen on high grade AR without
sinusitis (n=85), during 12 months. Maintenance
dose was reach within 9 13 (mean 11) injections;

Local reaction: yes found (wheal and

flare)
But, no systemic reaction found
Conclusion: ID ASIT is a shorter and safe rational

treatment strategy for Subcutaneous ASIT on

AR.

48

How deciding the Safe Optimal Dose

Fig 12.

Wheal 0

Wheal 15

Wheal 0 and 15 as indicators

for detecting the optimal dose
or the tolerable dose
49

15 wheal and flare

of ID ASIT
(Sumarman Doc. 2007)

??
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

Man, 30 yrs; SPT Mite Dpt: 4+

Sumarman
Doc 2003

Mite Dpt 4 PNU

Very Low Dose (Safe Tol Dose)
Wheal 15: 32 x 27 mm

Fig 15 Intradermal ASIT

52

Fig. 16
Intradermal
(ID) ASIT

Ratio W15 / W0 = 2.5

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

Wheal ratio 15 / 0 = (30 + 25) : 2

Sumarman
Doc 2005

vs (13 + 9) : 2 = 27,5 : 11 = 2,5

M2 1,0 ml = 100 PNU.

Conclusion: M2 100 PNU is safe tolerable dose
53
So, MD: M2 100 PNU (The usual optimal dose : 500-1000 PNU; LAPI LAB)

Table 6: Dose regimen on ID ASIT prior to Subcutaneous ASIT

(Once a week) (Male, 22 yrs, SPT: MDpt 4+). Example 1 of sTD
Dose of Mite Dpt (M-1)
W

E
E

mL

N
U

Wheal diamt (mm)

0

15

Dose of Mite Dpt (M-2)

W
E

RATIO

15/0

mL

P
N
U

Wheal Diamt (mm)

0

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

Safe TD : 0.25 M2=25 PNU

Mite Dpt:
M1/ml = 10 PNU
M2/ml = 100 PNU
M3/ml = 1000 PNU

Sumarman

safeTD:= M2 25 PNU = MD, then subcutaneous ASIT

Usual optimal Mite allergen dose : 500 up to 1000 PNU (LAPI)

2007

Table 7: Example: Dose regimen on Intradermal prior to

Subcutaneous ASIT (Once a week) . The
Patient no 2nd : SPT MDpt 4+
Dose of Mite (M-2) Alg then M3
W
E
E
K

Wheal diameter (mm)

mL

P
N
U

15

Ratio
15/ 0

sTD and the OD

Patient no 3rd : SPT MDpt 3+

W
E
E
K

Dose of Mite (M-2) Alg then M3

Wheal Diameter (mm)

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

Table 8: The sTD on ID ASIT prior to Subcutaneous ASIT

(Once a week, on 6 patients) (SPT: MDpt 4+ or more)

Sumarman
2005

Dose of Mite Dpt Allergen extract as sTD

Patient
No

A
G
E
(Yrs)

LER-

15

M2

0.40

24

M2

30

AL
GEN

P
mL

Wheal diameter (mm)

Ratio

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

sTD of ID ASIT = Wheal ratio 15 / 0 2.5

or Wheal diameter 30 mm
Usual optimal Mite allergen dose : 500 PNU up to 1000 PNU

Table 9 : Intradermal precede the Subcutaneous ASIT

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

Mite Dpt dose

(PNU)

Wheal of 15

diameter (mm)

House dust
dose (PNU)

Wheal 15
diameter
(mm)

B: n = 17 Highly sensitive SPT 4+; Low ASIT dose

B 1. TT

29

M3 0.40 ml

(400)

24 x 30

L2 0.25 ml: 125

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: n = 25, Sensitive SPT 3+; High ASIT dose

A. 1 YA

20

M3 0.5 ml (500)

12 x 14

L2 1.0 ml: 500

11 x 14

A. 12 ML

24

M3 0.5 ml (500)

21 x 25

L2 1.0 ml: 500

25 x 28

A. 16 RM

21

M3 0.5 ml (500)

25 x 15

L2 1.0 ml: 500

23 x 29

A. 19 EF

14

M3 0.5 ml (500)

18 x 18

L2 1.0 ml: 500

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

Sumarman and Asnominanda 2001

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

The s-TD, which lower than the OD, decided on intra-dermal

ASIT, prior to subcutaneous, gives the same beneficial effects
on decreasing the AR symptoms, safe, and both less time
consumption compare with the conventional.
58
Sumarman and Asnominanda 2001

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

Safe tolerable dose (sTD)

59

Table 11: Modified conventional ASIT:

Intradermal injection schedule prior to Subcutaneous ASIT
Time interval of ASIT injections
During the increasing dose :

once a week for 9 13 weeks (Intra dermal)

During the maintenance dose (Subcutaneous)

Once
Once
Once
Once
Once
Once
Once
Once

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

Maintenance dose can be

achieved in 9-13 injections,
median: 11 (Shorter than if
conventional sub-cutaneus =
19 injections)
Sumarman 2000

The total number of ASIT injections: 31 35 in

50 months

NO SYSTEMIC REACTION POST ASIT WAS FOUND

60

Other Immunotherapy Approach on

Allergic Diseases:
B. The Recombinant DNA Technology

Nelson HS. Advances in upper airway diseases and allergen immunotherapy.

J Allergy Clin Immunol 2006;1047-53
61

The Recombinant DNA Technology

Background: Allergen extracts also contain

numerous non allergenic proteins that are
not relevant to the treatment
Recombinant DNA technology:
1. Higher pharmaceutical standards vaccine
2. Improved quality in terms:
a. purity
b. consistency
c. composition, and
d. Dosage
3. DNA allergen vaccine is a prospective as
new approach in immunotherapy (IT)
Nelson HS. Advances in upper airway diseases and allergen immunotherapy.
62
J Allergy Clin Immunol 2006;1047-53

Evaluation
Evaluation of
of
Allergen
Allergen Specific
Specific
Immunotherapy
Immunotherapy
(ASIT)
(ASIT)
Effectiveness
Effectiveness
63

Fig.9

The Classic Allergic Inflammatory Reactions (AIR)

The Early Phase of AIR

Rhinorhea
Sneezing
Nasal
congestion
Allergen
Antigen
Presenting
Cells

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

Adapted from Creticos, 1998

(modified by Sumarman, 2002)

IgE Antibodi

Cytokines

Chronic
Inflammation
& Symptoms

Rhinorea
Sneezing
Congestion

64
The Late phase of AIR

The development of ASIT rational theories:

Up to 1990: ASIT on seasonal and perennial

allergic rhinitis reduced significantly the
Total Nasal Symptoms Score (TNSS)
(Researchers all over the world)

1996: AR patients, post mite Dpt ASIT

during 12 months, show highly significant

reduction of eosinophil number in the nasal
mucous membrane than before (pre ASIT) as
well as the TNSS (Sumarman, 1996)
65

Allergen

Fig. 7

ASIT on AR and Asthma

IgE Spes Fig 8:

EPR

Histamine
PAF1
ECFA2
NCFA
Leukotriene
Tryptase

ASIT Hipotesis

Sumarman, 1996:
ASIT REDUCES EOS
ACCUMULATION IN
NASAL MUCOUS
MEMBRANE

Eos accumulation
LPR

EOS CELLS accumulation

X
Secondary Mediators

LPR

Rak et al., 1990

2
Kue-Hsiung Hsieh, and
Cheng-Koon Ng, 1993.
1

Sumarman. Dissertation. Unpad 1996.

66 BW)
(Promoters: Surahman S, Sambas WH, Karnen

The development of ASIT rational theories:

1999-2000: IFN- /IL4 ratio theory:
ASIT reduces the IL4, enhances the IFN- . So
the ratio of IFN- /IL4 was higher than before
(Haugaard, 1999; Akdis 2000, Cools & Brever 2000)

2007: According to IFN- /IL-4 ratio, BCG

vaccination prior to ASIT on allergic rhinitis
show better improvement than ASIT only
(Suprihati, Diponegoro University Indonesia, Dissertation, 2007. Promotors:
Bambang SS, Iwin Sumarman, Ign Riwanto )

67

Fig.9:

Other Hypothesis of ASIT

Higher Ratio
of
IFN-/IL-4

_
(Benjaponpitak
1999; Haugaard,
1999; Akdis 2000,
Cools & Brever
2000)

ASIT enhances the TH1 on IFN- production.

The IFN- inhibit the TH2 on IL-4 production

68

Table 3: The ratio of % of different titer of IL-4/IFNpre and

post tretment between 3 Groups of

AR patients

BCG+IT = ASIT using BCG Vacination prior to Mite DPt

(In Vivo & In Vitro study) (Logaritmic transformation data)

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*

Statistic Test: One side Man Whitney test.

CONCLUSION: On AR, post ASIT using BCG prior

to IT using mite Dpt, reduced the ratio IL4/IFN

better than IT alone
Suprihati. UNDIP Dissertation: Pebr 2007.
Promoters: Bambang SS, Iwin Sumarman, Ignatius Riwanto

69

The up date rational theory of ASIT :

TReg cell theory:

1999-2004: ASIT enhances the functions of
TReg on enhances the production of IL-10,
TGF- . (Bernjaponpitak, 1999; Akdis et all, 2005)
2006: ASIT using mite Dpt on allergic rhinitis
enhances the blood serum IL-10 higher than
cetirizine group

(Arif D. Sumarman, Thesis Unpad,

2006; Tety Madiadipura, Tony Sarbini)

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
)

IgG4 & IgA production

(+)

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

IgE producFig 16. The recent ASIT theory

tion
from Creticos 1998 &

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

(- )

(-)

IL-10 is another effective

inhibitive indicator of
allergic inflammation

(-)

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.

Fig.12. The titer of blood serum IL-10 between ASIT and

Cetirizine Group of AR, prae and post treatment
Conclusion:
ASIT using Mite
Dpt on AR
enhances the
IL-10 blood
serum, better
than Cetirizine

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

5. The SCIT was the most suitable,

the SLIT was well accepted, and the
LNIT : unpleasant (local nasal side
effect)
75

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

79