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

IL-1 TNF-  GM-CSF IL-6 IFN-  IL-2 IL-4 IL-6 IgG VCAM-1ICAM-1 effector T-cells Collagenase MMP PGs

IL-1 TNF-  GM-CSF IL-6 IFN-  IL-2 IL-4 IL-6 IgG VCAM-1ICAM-1 effector T-cells Collagenase MMP PGs avoid Ag exposure antimicrobial

IL-1 TNF-  GM-CSF IL-6 IFN-  IL-2 IL-4 IL-6 IgG VCAM-1ICAM-1 effector T-cells Collagenase MMP PGs

Antimalarial drug change pH in phagosome

IL-1 TNF-  GM-CSF IL-6 IFN-  IL-2 IL-4 IL-6 IgG VCAM-1ICAM-1 effector T-cells Collagenase MMP PGs

HLA-DR TcR  TcR CD3 CD4 CD2 LFA-3 ICAM-1 Ag TRIMOLECULAR COMPLEX & COSTIMULATORY PATHWAY APC THTH CD80/86 (B7) CD28 CTLA4 (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) CD40L azathioprine

B CD40 HLA-DR TcR  TcR CD3 CD4 CD2 LFA-3 ICAM-1 Ag APC THTH CD80/86 (B7) CD28 CTLA4 (CD154) CTLA4 (CD154) CD40 CD40L CD40L TRIMOLECULAR COMPLEX & COSTIMULATORY PATHWAY Anti CD40L mAb ( IDEC-131, hu5c8, BG9588, Biogen ) Anti CD40L mAb ( IDEC-131, hu5c8, BG9588, Biogen ) RA T B CD40 SLE B CD40 B B LFA-1 (CD11a/CD18)  thrombosis ! CD40 on platelets??

HLA-DR TcR  TcR CD3 CD4 CD2 LFA-3 ICAM-1 Ag APC THTH CD80/86 (B7) CD28 CTLA4 (CD154) CTLA4 (CD154) CD40 TRIMOLECULAR COMPLEX & COSTIMULATORY PATHWAY efalizumab : humanized mAb CD11a psoriasis LFA-1 (CD11a/CD18) LFA-1 (CD11a/CD18) CD40L CD40L

HLA-DR TcR  TcR CD3 CD3 CD4 CD2 LFA-3 ICAM-1 Ag APC THTH CD80/86 (B7) CD28 CTLA4 (CD154) CTLA4 (CD154) CD40 TRIMOLECULAR COMPLEX & COSTIMULATORY PATHWAY LFA-1 (CD11a/CD18) CD40L Anti-CD3 : HuOKT3  1 (Ala-Ala)

HLA-DR TcR  TcR CD3 CD4 CD2 CD2 LFA-3 ICAM-1 Ag APC THTH CD80/86 (B7) CD28 CTLA4 (CD154) CTLA4 (CD154) CD40 TRIMOLECULAR COMPLEX & COSTIMULATORY PATHWAY LFA-1 (CD11a/CD18) CD40L CD2 antagonist : Alefacept (Biogen Idec, phase II)

Signal Transduction

HLA-DR stimulus specific receptor signal transductiontranscription translation proteins Receptor associating proteins Protein kinease pathways Translocation of transcription factors mRNA post- transcription

HLA-DR stimulus specific receptor signal transductiontranscription translation proteins Receptor associating proteins Protein kinease pathways Translocation of transcription factors mRNA 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 siRNA TNF blockade mouse model siRNA TNF blockade mouse model Calcineurin inhibitor Calcineurin inhibitor JNK inhibitor TRAF inhibitor

IL-1 TNF-  GM-CSF IL-6 IFN-  IL-2 IL-4 IL-6 IgG VCAM-1ICAM-1 effector T-cells Collagenase MMP PGs CAMPATH-1H Profound peripheral lymphopenia

IL-1 TNF-  GM-CSF IL-6 IFN-  IL-2 IL-4 IL-6 IgG VCAM-1ICAM-1 effector T-cells Collagenase MMP PGs IL-2 DAB IL-2

IL-1 TNF-  GM-CSF IL-6 IFN-  IL-2 IL-4 IL-6 IgG VCAM-1ICAM-1 effector T-cells Collagenase MMP PGs Rituximeb anti-CD20 Rituximeb anti-CD20

B CD20 immature mature naive B CD20 memory B CD20 P Plasma cell Rituximeb anti-CD20 Rituximeb anti-CD20 B-cell depletion Autoimmune with antibody production refractory Wegener granulomatosis, SLE with AIHA, ITP essential mixed cryoglobulinemia, RA (? RF+ve) B CD20 CD40 CD80 B-cell repair

IL-1 TNF-  GM-CSF IL-6 IFN-  IL-2 IL-4 IL-6 IgG VCAM-1ICAM-1 effector T-cells Collagenase MMP PGs IVIG

IL-1 TNF-  GM-CSF IL-6 IFN-  IL-2 IL-4 IL-6 IgG VCAM-1ICAM-1 effector T-cells Collagenase MMP PGs Biologic response modifier

IL-1 TNF-  GM-CSF IL-6 IFN-  IL-2 IL-4 IL-6 IgG VCAM-1ICAM-1 effector T-cells Collagenase MMP PGs ET-1® TGF- 

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 , Isis Pharma, phase II) - oral TNF inhibitor (AGIX4207, AtheroGenics, phas II) Biologic response modifier

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) IFN   recombinant 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

Chemokines & Growth factors IL-18 recombinant human IL-18 binding protein IL-8humanized CXCL8 / IL-8 Ab CCR1oral 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

IL-1 TNF-  GM-CSF IL-6 IFN-  IL-2 IL-4 IL-6 IgG VCAM-1ICAM-1 effector T-cells Collagenase MMP PGs block adhesion molecules

HLA DR+ CD 44 LFA-1 CLA P & E Selectin (CD62) ICAM-1 ICAM-2 VCAM-1 ( CD106) VLA-4 (CD49/29) Anti-human-ICAM-1 Ab (enlimomab) ADHESION MOLECULES mAb E-selectin humanized anti–  v  3 (integrin mAb) humanized anti–  v  3 (integrin mAb) Humanized 4-1, 4-7 mAb (Natalizumab) 2ME2 (2 methoxyextradiol) antiangiogenesis anti VCAM-1

IL-1 TNF-  GM-CSF IL-6 IFN-  IL-2 IL-4 IL-6 IgG VCAM-1ICAM-1 effector T-cells Collagenase MMP PGs Anti-inflammatory agents NO synthetase Superoxide dismutase

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