Top Banner
Basic Immunology II Targeted therapy Ratanavadee Nanagara, M.D. Allergy-Immunology-Rheumatology Unit Department of Medicine KhonKaen University
29

Basic Immunology II Targeted therapy Basic Immunology II Targeted therapy Ratanavadee Nanagara, M.D. Allergy-Immunology-Rheumatology Unit Department of.

Dec 22, 2015

Download

Documents

Ethelbert Craig
Welcome message from author
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
Page 1: Basic Immunology II Targeted therapy Basic Immunology II Targeted therapy Ratanavadee Nanagara, M.D. Allergy-Immunology-Rheumatology Unit Department of.

Basic Immunology IITargeted therapy

Basic Immunology IITargeted therapy

Ratanavadee Nanagara, M.D.

Allergy-Immunology-Rheumatology UnitDepartment of MedicineKhonKaen University

Page 2: Basic Immunology II Targeted therapy Basic Immunology II Targeted therapy Ratanavadee Nanagara, M.D. Allergy-Immunology-Rheumatology Unit Department of.

IL-1TNF-GM-CSFIL-6

IFN-IL-2IL-4IL-6

IgG

VCAM-1 ICAM-1

effectorT-cells

1

2

3

4

CollagenaseMMP

PGs

56

7

8

Page 3: Basic Immunology II Targeted therapy Basic Immunology II Targeted therapy Ratanavadee Nanagara, M.D. Allergy-Immunology-Rheumatology Unit Department of.

IL-1TNF-GM-CSFIL-6

IFN-IL-2IL-4IL-6

IgG

VCAM-1 ICAM-1

effectorT-cells

1

2

3

4

CollagenaseMMP

PGs

56

7

8

avoid Ag exposure antimicrobial

Page 4: Basic Immunology II Targeted therapy Basic Immunology II Targeted therapy Ratanavadee Nanagara, M.D. Allergy-Immunology-Rheumatology Unit Department of.

IL-1TNF-GM-CSFIL-6

IFN-IL-2IL-4IL-6

IgG

VCAM-1 ICAM-1

effectorT-cells

1

2

3

4

CollagenaseMMP

PGs

56

7

8

Page 5: Basic Immunology II Targeted therapy Basic Immunology II Targeted therapy Ratanavadee Nanagara, M.D. Allergy-Immunology-Rheumatology Unit Department of.

Antimalarial drug

change pH in

phagosome

Page 6: Basic Immunology II Targeted therapy Basic Immunology II Targeted therapy Ratanavadee Nanagara, M.D. Allergy-Immunology-Rheumatology Unit Department of.

IL-1TNF-GM-CSFIL-6

IFN-IL-2IL-4IL-6

IgG

VCAM-1 ICAM-1

effectorT-cells

1

2

3

4

CollagenaseMMP

PGs

56

7

8

Page 7: Basic Immunology II Targeted therapy Basic Immunology II Targeted therapy Ratanavadee Nanagara, M.D. Allergy-Immunology-Rheumatology Unit Department of.

HLA-DR

TcR TcRTcR

CD3

CD4CD4CD2LFA-3

ICAM-1

Ag

TRIMOLECULAR COMPLEX

& COSTIMULATORY PATHWAY

APC TH

CD80/86 (B7) CD28CTLA4 (CD154)CTLA4 (CD154)

Cytotoxic T lymphcyte-associated antigen 4= immunoregulatory protein

? RA refractory to TNF- inhibitor? RA subset …. phase III? SLE mice

CD40

CTLA4-Ig - CTLA4-Fc - LEA29Y

CTLA4-Ig - CTLA4-Fc - LEA29Y

LFA-1 (CD11a/CD18)LFA-1 (CD11a/CD18)

CD40LCD40L

azathioprine

Page 8: Basic Immunology II Targeted therapy Basic Immunology II Targeted therapy Ratanavadee Nanagara, M.D. Allergy-Immunology-Rheumatology Unit Department of.

BCD40

HLA-DR

TcR TcRTcR

CD3

CD4CD4

CD2LFA-3

ICAM-1

Ag

APC TH

CD80/86 (B7) CD28CTLA4 (CD154)CTLA4 (CD154)

CD40 CD40LCD40L

TRIMOLECULAR COMPLEX

& COSTIMULATORY PATHWAY

Anti CD40L mAb( IDEC-131, hu5c8, BG9588, Biogen )

Anti CD40L mAb( IDEC-131, hu5c8, BG9588, Biogen )

RA

T

B

CD40

SLEB

CD40

B CD

40 B

CD40

LFA-1 (CD11a/CD18)LFA-1 (CD11a/CD18)

thrombosis !

CD40 on platelets??

Page 9: Basic Immunology II Targeted therapy Basic Immunology II Targeted therapy Ratanavadee Nanagara, M.D. Allergy-Immunology-Rheumatology Unit Department of.

HLA-DR

TcR TcRTcR

CD3

CD4CD4

CD2LFA-3

ICAM-1

Ag

APC TH

CD80/86 (B7) CD28CTLA4 (CD154)CTLA4 (CD154)

CD40

TRIMOLECULAR COMPLEX

& COSTIMULATORY PATHWAY

efalizumabefalizumab: humanized mAb CD11a: humanized mAb CD11a

psoriasis

LFA-1 (CD11a/CD18)LFA-1 (CD11a/CD18)

CD40LCD40L

Page 10: Basic Immunology II Targeted therapy Basic Immunology II Targeted therapy Ratanavadee Nanagara, M.D. Allergy-Immunology-Rheumatology Unit Department of.

HLA-DR

TcR TcRTcR

CD3CD3

CD4CD4

CD2LFA-3

ICAM-1

Ag

APC TH

CD80/86 (B7) CD28CTLA4 (CD154)CTLA4 (CD154)

CD40

TRIMOLECULAR COMPLEX

& COSTIMULATORY PATHWAY

LFA-1 (CD11a/CD18)LFA-1 (CD11a/CD18)

CD40LCD40L

Anti-CD3 : HuOKT31 (Ala-Ala)Anti-CD3 : HuOKT31 (Ala-Ala)

Page 11: Basic Immunology II Targeted therapy Basic Immunology II Targeted therapy Ratanavadee Nanagara, M.D. Allergy-Immunology-Rheumatology Unit Department of.

HLA-DR

TcR TcRTcR

CD3CD3

CD4CD4

CD2CD2LFA-3

ICAM-1

Ag

APC TH

CD80/86 (B7) CD28CTLA4 (CD154)CTLA4 (CD154)

CD40

TRIMOLECULAR COMPLEX

& COSTIMULATORY PATHWAY

LFA-1 (CD11a/CD18)LFA-1 (CD11a/CD18)

CD40LCD40L

CD2 antagonist : Alefacept (Biogen Idec, phase II)CD2 antagonist : Alefacept (Biogen Idec, phase II)

Page 12: Basic Immunology II Targeted therapy Basic Immunology II Targeted therapy Ratanavadee Nanagara, M.D. Allergy-Immunology-Rheumatology Unit Department of.

Signal Transduction

Page 13: Basic Immunology II Targeted therapy Basic Immunology II Targeted therapy Ratanavadee Nanagara, M.D. Allergy-Immunology-Rheumatology Unit Department of.

HLA-DR

stimulusspecificreceptor

signal transduction transcriptiontranslation

proteins

Receptor associating

proteins

Protein kineasepathways

Translocation oftranscription factors

mRNAmRNA

post-transcription

Page 14: Basic Immunology II Targeted therapy Basic Immunology II Targeted therapy Ratanavadee Nanagara, M.D. Allergy-Immunology-Rheumatology Unit Department of.

HLA-DR

stimulusspecificreceptor

signal transduction transcriptiontranslation

proteins

Receptor associating

proteins

Protein kineasepathways

Translocation oftranscription factors

mRNAmRNA

post-transcription

MAPK inhibitor Scio-469 (oral )

phase IIb

MAPK inhibitor Scio-469 (oral )

phase IIb

RANKL

AMG162 Humanized Ab

AMG162 Humanized Ab

Antiresorptive during bone remodeling

siRNATNF blockademouse model

siRNATNF blockademouse model

Calcineurin

inhibitor

Calcineurin

inhibitor

JNK inhibitorJNK inhibitor

TRAF inhibitorTRAF inhibitor

Page 15: Basic Immunology II Targeted therapy Basic Immunology II Targeted therapy Ratanavadee Nanagara, M.D. Allergy-Immunology-Rheumatology Unit Department of.

IL-1TNF-GM-CSFIL-6

IFN-IL-2IL-4IL-6

IgG

VCAM-1 ICAM-1

effectorT-cells

1

2

3

4

CollagenaseMMP

PGs

56

7

8

CAMPATH-1HCAMPATH-1H

Profound peripherallymphopenia

Page 16: Basic Immunology II Targeted therapy Basic Immunology II Targeted therapy Ratanavadee Nanagara, M.D. Allergy-Immunology-Rheumatology Unit Department of.

IL-1TNF-GM-CSFIL-6

IFN-IL-2IL-4IL-6

IgG

VCAM-1 ICAM-1

effectorT-cells

1

2

3

4

CollagenaseMMP

PGs

56

7

8

IL-2 DAB IL-2DAB IL-2

Page 17: Basic Immunology II Targeted therapy Basic Immunology II Targeted therapy Ratanavadee Nanagara, M.D. Allergy-Immunology-Rheumatology Unit Department of.

IL-1TNF-GM-CSFIL-6

IFN-IL-2IL-4IL-6

IgG

VCAM-1 ICAM-1

effectorT-cells

1

2

3

4

CollagenaseMMP

PGs

56

7

8

Rituximebanti-CD20Rituximebanti-CD20

Page 18: Basic Immunology II Targeted therapy Basic Immunology II Targeted therapy Ratanavadee Nanagara, M.D. Allergy-Immunology-Rheumatology Unit Department of.

B

CD20

immaturematurenaive

B

CD20

memory

B

CD20

P

Plasma cell

Rituximebanti-CD20Rituximebanti-CD20

B-cell depletion

Autoimmune with antibody production

refractory Wegener granulomatosis, SLE with AIHA, ITP

essential mixed cryoglobulinemia, RA (? RF+ve)

B

CD20

CD40CD80 B-cell repair

Page 19: Basic Immunology II Targeted therapy Basic Immunology II Targeted therapy Ratanavadee Nanagara, M.D. Allergy-Immunology-Rheumatology Unit Department of.

IL-1TNF-GM-CSFIL-6

IFN-IL-2IL-4IL-6

IgG

VCAM-1 ICAM-1

effectorT-cells

1

2

3

4

CollagenaseMMP

PGs

56

7

8IVIG

Page 20: Basic Immunology II Targeted therapy Basic Immunology II Targeted therapy Ratanavadee Nanagara, M.D. Allergy-Immunology-Rheumatology Unit Department of.

IL-1TNF-GM-CSFIL-6

IFN-IL-2IL-4IL-6

IgG

VCAM-1 ICAM-1

effectorT-cells

1

2

3

4

CollagenaseMMP

PGs

56

7

8

Biologic response modifier

Page 21: Basic Immunology II Targeted therapy Basic Immunology II Targeted therapy Ratanavadee Nanagara, M.D. Allergy-Immunology-Rheumatology Unit Department of.

IL-1TNF-GM-CSFIL-6

IFN-IL-2IL-4IL-6

IgG

VCAM-1 ICAM-1

effectorT-cells

1

2

3

4

CollagenaseMMP

PGs

56

7

8

ET-1®TGF-

Page 22: Basic Immunology II Targeted therapy Basic Immunology II Targeted therapy Ratanavadee Nanagara, M.D. Allergy-Immunology-Rheumatology Unit Department of.

TNF- - soluble p75-TNFR type II (etanercept)

- chimeric human: mouse mAb (infliximab)

- humanized mAb (adalimumab)

- converting enzyme inhibitors (GW3333)

in developing:

- PEGylated anti TNF- Fab’ fragment (CDP-870, UCB, phase III RA)

- PEGylated soluble TNF receptor type I (Pegsunercept, Amgen, phase II)

- TNF- antisense inhibitor (ISIS-104838, Isis Pharma, phase II)

- oral TNF inhibitor (AGIX4207, AtheroGenics, phas II)

Biologic response modifier

Page 23: Basic Immunology II Targeted therapy Basic Immunology II Targeted therapy Ratanavadee Nanagara, M.D. Allergy-Immunology-Rheumatology Unit Department of.

IL-1 recombinant IL-1R antagonist (anakinra)

soluble IL-1R type II

IL-1 Trap (recombinant IL-1R I – IgG Fc)

IL-1 converting enzyme inhibitor (caspase-1)

IFNrecombinant IFN- recombinant IFN-

IL-6 IL-6 mAb soluble IL-6R humanized anti IL-6 R mAb (Atlizumab, MRA,

Roache/Ghugai phase I, II)

IL-12 anti IL-12 mAb (ABT874/J-695, Abbott/Cambridge Ab Tech, phase II)

IL-15 anti IL-15 mAb (HuMAX-IL-15/AMG-714, Immunex/Genmab, phase II)

Biologic response modifier

Page 24: Basic Immunology II Targeted therapy Basic Immunology II Targeted therapy Ratanavadee Nanagara, M.D. Allergy-Immunology-Rheumatology Unit Department of.

Chemokines & Growth factors

IL-18 recombinant human IL-18 binding protein

IL-8 humanized CXCL8 / IL-8 Ab

CCR1 oral CCR1-antagonist

ET-1 ET-1 receptor antagonist (Bosentan)

TGF- anti-TGF-

VEGF soluble VEGFR1-Fc

Signal p38 MAPK pathway inhibitor (vx-745)

transduction c-Jun-N terminal kinase (JNK) inhibitor

calcineurin inhibition (post receptor signaling)

signaling repressor (CIS3/SOCS3)

Alternative targets of cytokine modifying Rx

Page 25: Basic Immunology II Targeted therapy Basic Immunology II Targeted therapy Ratanavadee Nanagara, M.D. Allergy-Immunology-Rheumatology Unit Department of.

IL-1TNF-GM-CSFIL-6

IFN-IL-2IL-4IL-6

IgG

VCAM-1 ICAM-1

effectorT-cells

1

2

3

4

CollagenaseMMP

PGs

56

7

8

block adhesionmolecules

Page 26: Basic Immunology II Targeted therapy Basic Immunology II Targeted therapy Ratanavadee Nanagara, M.D. Allergy-Immunology-Rheumatology Unit Department of.

HLA DR+

CD 44LFA-1

CLA

P & E Selectin (CD62)

ICAM-1

ICAM-2VCAM-1 (CD106)

VLA-4(CD49/29)

Anti-human-ICAM-1 Ab (enlimomab)Anti-human-ICAM-1 Ab (enlimomab)

ADHESION MOLECULES

mAb E-selectinmAb E-selectin

humanized anti–v3

(integrin mAb)

humanized anti–v3

(integrin mAb)

Humanized 4-1, 4-7 mAb (Natalizumab)

2ME2 (2 methoxyextradiol) antiangiogenesis

anti VCAM-1anti VCAM-1

Page 27: Basic Immunology II Targeted therapy Basic Immunology II Targeted therapy Ratanavadee Nanagara, M.D. Allergy-Immunology-Rheumatology Unit Department of.

IL-1TNF-GM-CSFIL-6

IFN-IL-2IL-4IL-6

IgG

VCAM-1 ICAM-1

effectorT-cells

1

2

3

4

CollagenaseMMP

PGs

56

7

8

Anti-inflammatory agents

NO synthetaseSuperoxide dismutase

Page 28: Basic Immunology II Targeted therapy Basic Immunology II Targeted therapy Ratanavadee Nanagara, M.D. Allergy-Immunology-Rheumatology Unit Department of.

Good luck

Page 29: Basic Immunology II Targeted therapy Basic Immunology II Targeted therapy Ratanavadee Nanagara, M.D. Allergy-Immunology-Rheumatology Unit Department of.