Prof Dr Ariyanto Harsono dr SpAK

CURICULUM VITAE

Tempat /tgl lahir : Kediri, 3- JuliAgama : Islam

Status Perkawinan: MenikahPendidikan

S-1: Lulus Dokter : FK UNAIR, 1972

S-2: Spesialis Anak : FK UNAIR, 1982

S-3: Program Pascasarjana UNAIR, 2004 Pendidikan tambahan : Sertifikat “Fellowship on Food Allergy”, Academisch Ziekenhuis Utrecht, Nederland, 1990-1991Jabatan sekarang : Guru Besar Ilmu Kesehatan

Anak, Dep IKA FK UNAIR/RSU Dr.Soetomo, Surabaya.

Konsultan Alergi/Imunologi: 1992

1

Symbiotic: Manfaat Lebih Untuk Kasus Alergi Pada Anak

Prof DR Dr Ariyanto Harsono SpA(K)

PENDAHULUAN

• Mikrobiota pada usus manusia terdiri atas beberapa ratus spesies, banyak diantaranya yang sangat bermanfaat. Misalnya untuk mencegah kolonisasi kuman patogen dan memelihara integritas imunitas mukosa usus.

• Sebaliknya, sistem imun mukosa usus sehat memungkinkan bertahannya mikrobiota usus dan menghindari toleransi imunologi, mempertahankan homeostasis usus.

3Prof DR Dr Ariyantto Harsosno SpA(K)

Ag

APC MHC-II Th0

IL-12/ IL-1

Th-2

Th.1

IL-1

TNF-β, IFN-γ

IL-2, IFN-γ

B-Cell

IL-4

IL-5

SEL PLASMASEL MEMORI

IL-6

IL-10

CTL MHC-I

I L-2 IFN-γ

SEL-NK

SEL-NK AKTIFFC-R

L

L

SEL ABNORMAL

SITOTOKSINSEL-LISIS

Sel Abnormal FASL

Memory Cells

ADCC

4Prof DR Dr Ariyantto Harsosno SpA(K)

ProbioticTreg

TGF

• Prebiotik yang banyak dikenal dan digunakan adalah oligosakarida kedelai (yang terdiri atas rafinosa dan stakiosa), frukto-oligosakarida (disebut juga oligofruktosa), Inulin, Laktulosa dan Laktosukrosa. Inulin dan oligofruktosa memiliki fungsi penting sebagai penyeimbang fungsi gastrointestinal (menyeimbangkan mikroflora kolon).

5Prof DR Dr Ariyantto Harsosno SpA(K)

Metabolisme Prebiotik--> Short Chain Fatty Acid

6Prof DR Dr Ariyantto Harsosno SpA(K)

Prebiotik membantu mengatasi kerusakan barier mukosa usus

• Prebiotik fructooligosaccharides (FOS) dan inulin merupakan substrat untuk fermentasi mikrobiota usus proximal dan distal

• Fermentasi FOS dan inulin di kolon menghasilkan short-chain fatty acids (SCFA)¹

• SCFAs merupakan pelumas untuk epitel ileum dan kolon, yang membantu memelihara integritas dinding kolon²

7Prof DR Dr Ariyantto Harsosno SpA(K)

Prebiotik membantu pertumbuhan flora normal usus:

• Fermentasi FOS dan inulin menghasilkan lactic acid4

• Lactic acid membantu menurunkan pH kolon, menyebabkan kolon kurang baik untuk pertumbuhan pathogenic bacteria2,4

• FOS dan inulin secara selektif mempermudah pertumbuhan bacteria yang baik dengan dosis 8 gram per hari2-4,5

• Lactate membantu menurunkan pH kolon untuk mengontrol pertumbuhan bacteria patogen

8Prof DR Dr Ariyantto Harsosno SpA(K)

Meta analisis kegunaan Synbiotik

9Prof DR Dr Ariyantto Harsosno SpA(K)

PROBIOTIKNON PATOGENIK

• Probiotik adalah mikroorganisme hidup yang berasal dari tumbuhan. Mereka pada dasarnya adalah ganggang. Bakteri probiotik hadir di usus sejak manusia lahir. Bakteri ini terus menerus mengalahkan mikroba lain dalam tubuh, dan hal ini dapat dapat mengancam populasinya. Selain itu, pengobatan antibiotik dapat membunuh semua bakteri dalam tubuh, termasuk bakteri probiotik.

10Prof DR Dr Ariyantto Harsosno SpA(K)

Mikroflora Usus

11Prof DR Dr Ariyantto Harsosno SpA(K)

Non Pathogenic bacteria Pathogenic bacteria

12Prof DR Dr Ariyantto Harsosno SpA(K)

13Prof DR Dr Ariyantto Harsosno SpA(K)

Bagaimana bacteria intra luminal membangkitkan respons imun sistemik?:

• (A) Fluoresensi di Peyer's patches usus halus

• (B) Fluoresensi di lamina propria usus halus

• (C) Fluoresensi di nodule dan crypta usus besar

14Prof DR Dr Ariyantto Harsosno SpA(K)

Internalisasi bacteria kedalam GI

Sebagian mikrobiota difagosit dan dimusnahakan. Sebagian epitopnya dibantu dengan IL6 menimbulkan clonal IgA B lymphocytes, meningkatkan jumlah IgA-producing cells dan transfer ke plasma sel usus. IL-6 bersama dengan IL-4 dan TGF-ß dapat menginduksi T-independent switch dari IgM ke IgA dipermukaan sel B. (EC, intestinal epithelial cells; MQ, macrophages; TL, T lymphocytes; BL, B lymphocytes; MS, mast cells; PC, plasma cells).

15Prof DR Dr Ariyantto Harsosno SpA(K)

Prof DR Dr Ariyantto Harsosno SpA(K) 16

Prof DR Dr Ariyantto Harsosno SpA(K) 17

Schematic representation of the multiple consequences of the cross-talk between the probiotic bacteria and the intestinal mucosa.

Corthésy B et al. J. Nutr. 2007;137:781S-790S

©2007 by American Society for Nutrition18Prof DR Dr Ariyantto Harsosno SpA(K)

Treg

19Prof DR Dr Ariyantto Harsosno SpA(K)

20Prof DR Dr Ariyantto Harsosno SpA(K)

IgA

TReg

TGF

21Prof DR Dr Ariyantto Harsosno SpA(K)

Cara kerja antibodi yang di-induksi Probiotik

22Prof DR Dr Ariyantto Harsosno SpA(K)

Orihara et. al. WAO Journal 2008, 9-14

The profiles of immune response in healthy subject

23Prof DR Dr Ariyantto Harsosno SpA(K)

The balancing

square model.

The 4 T-cell types (Th1, Th2, Th17, and Treg) antagonize each other.

Proinflammatory T-cell subsets, that is, Th17 cells and Th2 cells that are capable of

producing high levels of TNF-> (iTh2 cells) are upregulated

Th2 cells that are capable of producing IL-10 (rTh2 cells) may be up-regulated, and

Th17 cells may be inactivated

Orihara et. al. WAO Journal 2008, 9-14

The profiles of immune response in symptomatic & asymptomatic

atopy

24Prof DR Dr Ariyantto Harsosno SpA(K)

25Prof DR Dr Ariyantto Harsosno SpA(K)

WHAT ARE IMMUNOMODULATION INDUCED BY PROBIOTICS?

Organism days No. of cells producingb:

CytokinesIgA

TNF- a IFN- g IL-2 IL-12 IL-4 IL-10

L. casei CRL 431

2 90 ± 8* 124 ± 15* 24 ± 6 13 ± 3 86 ± 23* 40 ± 2* 99 ± 21

L. delbrueckii subsp. bulgaricus CRL 423

2 79 ± 6* 59 ± 22* 40 ± 8 23 ± 11 67 ± 4* 85 ± 9* 135 ± 23*

L. acidophilus CRL 724

7 Strains

2

2

52 ± 7

98+/-8

51 ± 25*

165+/-34

27 ± 8

50+/-23

30 ± 16*

45+/-60

44 ± 11

30+/-46

30 ± 7

90+/-54

173 ± 24*

199+/-76

Control 2 24 ± 4 17 ± 6 31 ± 12 11 ± 2 27 ± 7 18 ± 6 98 ± 17

26Prof DR Dr Ariyantto Harsosno SpA(K)

Probiotic modulation of humoral immunity

Bifidobacterium bifidus, (live)

Human Total IgA and response to polio virus

Increased sIgA

27Prof DR Dr Ariyantto Harsosno SpA(K)

Effects of probiotics on nonspecific immunity

Probacteria Species Assessment Effect

Lactobacillus casei Shirota, intravenous

Rodent Peritoneal macrophages Increased phagocytosis

L. acidophilus or Bifidobacterium bifidum, oral (live)

Rodent Peritoneal or peripheral blood macrophages

Enhanced phagocytosis

L. acidophilus or casei, oral (live)

Rodent Resident peritoneal macrophages

Enhanced phagocytosis

L. casei Shirota

7 strains oral (live)

HumanPeripheral blood No effect on natural killer

cell cytolysis in vitro

Enhanced phagocytosis28Prof DR Dr Ariyantto Harsosno SpA(K)

Effect of probiotics on select human disease1

Disease Probiotic Assessment Effect

Asthma Lactobacillus acidophilus, oral (live)

Serum IgE and IL-4 Lymphocyte proliferation

No alterations

Rotavirus infection 7 starins, oral (live) Diarrhea Serum total IgA and IgM and anti-rotavirus IgM and IgG

Duration of diarrhea decreased; Increased anti-rotavirus IgA

Atopic Dermatitis L. casei, oral (live) Anti-ß-lactoglobulin IgA- secreting cells

Number increasedClinical improvement 29Prof DR Dr Ariyantto Harsosno SpA(K)

Synbiotic dalam pencegahan Asthma

• Bayi dengan Dermatitis Atopika lebih sering menderita Asthma.

• Pemberian Synbiotic pada bayi-bayi Dermatitis Atopika mencegah terjadinya Asthma pada masa naka-anak.

(van der Aa LB, Synbiotics prevent asthma-like symptoms in infants with atopic dermatitis, Allergy, 2011:68:170-7)

30Prof DR Dr Ariyantto Harsosno SpA(K)

Regulator Treg

• Probiotic untuk penderita alergi, Inflammatory Bowel Disease, auto imun membangkitkan keseimbangan kearah Treg melalui resptor TLR2, TLR4, TLR6.

(Rook GAW: microbes, immunoregulation, and

Gut.accessed from www.gutjnl,com)

Prof DR Dr Ariyantto Harsosno SpA(K) 31

PROBIOTIC

IgA

Menurunkan kejadian penyakit alergi

• Probiotic Menyebabkan Keseimbangan intestinal dan sistem imun menurunkan kejadian penyakit alergi.

(Hormannsperger G: Gut matters: microbe-host interactions in allergic

disease. J Allergy clin Immunol 2012;129:1452-9)

32Prof DR Dr Ariyantto Harsosno SpA(K)

Meningkatkan CD4 T limfosit

• Probiotic merangsang klonal CD4 T limfosit berperan dalam perbaikan penyakit alergi.

(Mazmanian SK: The love–hate relationship between bacterial

polysaccharides and the host immune system. Nature Reviews Immunology, 2006: 6, 849-858)

Prof DR Dr Ariyantto Harsosno SpA(K) 33

Kegunaan Probiotik

34Prof DR Dr Ariyantto Harsosno SpA(K)

35Prof DR Dr Ariyantto Harsosno SpA(K)

36Prof DR Dr Ariyantto Harsosno SpA(K)

Dasar pemilihan Probiotik

37Prof DR Dr Ariyantto Harsosno SpA(K)

TH1<Treg <TH2

TH1 > Treg > TH2

TH1, Treg and TH2 immunoregulation through TLR2 and TLR4 by Lactobacillus plantarum IS-10506 probiotics in reducing allergic reaction. Experimental Study in Mice Subjects

Alle

rgic

Re

ac

tion

Adaptive

Imm

unity

InnateIm

munity

Control group LIS probiotics group

(Endaryanto A, et.al., 2006)Study on animal model

38Prof DR Dr Ariyantto Harsosno SpA(K)

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Probiotics compared with SLIT in influencing the Treg–mediated balance

shift of TH1-TH2 in children with allergic-asthma.

Fig 1. FEV1 reversibility in % of predicted normal value, total IgE, eosinophil count, IFN-, IL-2, IL10, TGF-, IL-4, and IL-5

in the post-treatment condition with SLIT

Fig 2. FEV1 reversibility in % of predicted normal value, total IgE, eosinophil count, IFN-, IL-2, IL10, TGF-, IL-4, and IL-5

in the post-treatment with probiotics 39Prof DR Dr Ariyantto Harsosno SpA(K)

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(Endaryanto A, Harsono A, 2006)Study on pediatric subjects

The different of probiotics and SLIT in influencing the Treg–mediated balance

shift of TH1-TH2 in children with allergic-asthma.

40Prof DR Dr Ariyantto Harsosno SpA(K)

Thank You41Prof DR Dr Ariyantto Harsosno SpA(K)