Chemochinele si receptorii

-noi tinte terapeutice-

Medic rezident : Mihaela Agache

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Temele abordate
Structura

Rolul

chemochinelor si a receptorilor pentru chemokine

chemochinelor si al receptorilor acestora in PR

Implicatii

terapeutice

Ce sunt??
CHEMOKINE

CITOKINE CHEMOATRACTANTE

Un agent chimic care induce

migrarea catre el a unui organism,
a unei celule

Molecule (proteine,
peptide, glicoproteine) de
semnalizare intercelulara

Din germ. Chemotaktismus

Chemotactism

Gradient

Ligands

Gradient

Ligands

Celula devine
polarizata!

Chemokine
Definitie:

proteine mici 8-10 KDa cu activitate chemotactica pe

celule derivate din MO

Scurt

istoric

Prima descriere a rolului unei chemochine a fost identificarea si caracterizarea

IL-8 in 1987

De atunci au fost descrise aproximativ 50 chemokine si 20 de receptori

Initial denumite dupa functiile indeplinite:

-monocyte chemoattractant protein-1 (MCP-1)

-chemokina derivata din macrofag (MDC)
-factor derivat din celule stromale (SDF1) etc

Clasificarea chemokinelor s-a realizat in anul 2000 tinandu-se cont de structura

acestora

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Ce atrage fiecare familie de CK?

CXC
CC
C

atrage

atrage

atrage

CX3C

atrage

neutrofile, limfocite
monocite, NK, CD, limfocite, bazofile, eozinofile
precursorii limfocitelor T
limfocite T si monocite

fiecare celula leucocitara are un profil individualizat al receptorilor

pentru chemokine
"chemokine receptor profile,"
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Receptor cu 7 domenii TM

Moser, B et al. Ann Rheum Dis 2004;63:ii84-ii89

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Chemotaxisul
leucocitar

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Chemotaxisul
leucocitar
-molecule
implicate-

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von Andrian U and Mackay C. N Engl J Med 2000;343:1020-1034

Cai de semnalizare intracelulara

a
mitogen-a
ctivated
protein k
inase
(MAPK).

15

Chemokinele nu sunt numai chemoatractante!

IF-

Glutamina-leucina -arginina

Non-ELR

ELR

+
Inflamatie cronica

Angiogeneza

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Expansiunea tumorala

Chemokine
Homeostatice

-controleaza traficul limfocitar si compartimentarea la nivelul

organelor limfoide
-maturarea celulelor imune (celule dendritice, celule B)
Inductibile

-induse de TNF, IL1, LPZ

-recruteaza celulele inflamatorii

REDUNDANTA
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Chemokinele in PR

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Expresia receptorilor de
chemokine CCR1, CCR2b,
CCR5, in tesutul sinovial la
pacienti cu PR, OA, AR.

Expressia chemokinelor
CCL2/MCP-1, CCL5/RANTES,
CCL7/MCP-3, in tesutul sinovial
la pacienti cu PR, OA, AR.

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Haringman J, Tak PP et al.

Ann Rheum Dis 2006;65:294-300

Celulele tumorale produc chemokine!

Un avantaj pentru acestea!

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Celulele tumorale produc chemokine!

Un avantaj pentru acestea!

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Intrebare?

Tinand cont de chemokine si de receptorii pentru

chemokine, care ar fi mecanismul prin care tumorile
metastazeaza selectiv in anumite organe?

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Model de metastazare al
neoplasmului de san
Celulele neoplazice
utilizeaza chemokinele
pentru a se mobiliza

Receptorul este CXCR4 pe

celulele neolazice care
migreaza
Ligandul este CXCL12
(plaman, ficat, oase, gg)
Murphy P. N Engl J Med 2001;345:833-835

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CXCR4 important reglator al metastazelor

Tinta terapeutica
Trialuri de faza 2

The Role of Chemokines and their Receptors in Tumor Progression and Invasion: Potential New Targets of
Biological Therapy Paola Allavena; Federica Marchesi,
Current cancer Therapy Reviews, Volume 1, Number 1, January 2005 , pp. 81-92(12)

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Receptorii de chemokine CXCR4 si CCR5

joaca rol de CO-RECEPTORI in infectia HIV

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Tinte terapeutice in poliartrita

reumatoida
Chemochinele??
Sau receptorii??

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CCR1
Prezent

in cantitati mari in infiltatul inflamator din PR

Antagonistii

de receptori au fost eficienti in studiile preclinice

M Amat, C F Benjamim, L M Williams, N Prats, et al
Pharmacological blockade of CCR1 ameliorates murine arthritis and
alters cytokine networks in vivo
Br J Pharmacol. 2006 November; 149(6): 666675

Studii

clinice: un singur studiu dublu-orb, randomozat de faza Ib

care a demonstat la 2 saptamani de tratament oral cu
antagonist de receptor CCR1 scaderea, la nivelul tesutului
sinovial, a numarului de macrofage si de celule CCR+ (16 pac)
Haringman J, Tak PP et al.
Chemokine blockade and chronic inflammatory disease: proof of
concept in patients with rheumatoid arthritis
Ann Rheum Dis 2003;62;715-721

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Expresia
macrofagelor
sinoviale CD68+
inainte si dupa
tratamentul cu
antagonist de
receptor CCR1 la
pacient cu placebo
(A,B) sau cu
tratament activ
(C,D)

Haringman, J J, Tak PP et al. Ann Rheum Dis 2003;62:715-721

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MCP 1-CCL2/CCR2
Abundenta
Implicata

in sinoviala pacientilor cu PR atrage LT si NK

si in ateroscleroza
Martinovic I, Abegunewardene N, et al.
Elevated monocyte chemoattractant protein1 serum levels in patients at risk for coronary
artery disease. Circ J (2005) 69:14849

Boring L, Gosling J, Cleary M, Charo IF.

Decreased lesion formation in CCR2-/- mice
reveals a role for chemokines in the
initiation of atherosclerosis. Nature (1998)

Tinta

terapeutica :

Joner M, Farb A, Cheng Q, et al. Pioglitazone inhibits instent restenosis in atherosclerotic rabbits by targeting
transforming growth factor-beta and MCP-1.
Arterioscler Thromb Vasc Biol (2007) 27:1829.

Ac anti MCP 1(CCL2)/Ac anti CCR2

Haringman JJ, Gerlag DM, Tak PP, et al.

A randomized controlled trial with an anti-CCL2 (anti-monocyte
chemotactic protein 1) monoclonal antibody in patients with
rheumatoid arthritis.
Arthritis Rheum (2006) 54:238792

Schepers A, Eefting D, Bonta PI, et al. Anti-MCP-1 gene

therapy inhibits vascular smooth muscle cells
proliferation and attenuates vein graft thickening both in
vitro and in vivo. Arterioscler Thromb Vasc Biol (2006)
26:20639

Vergunst CE, Gerlag DM, Tak PP, et al.

Modulation of CCR2 in rheumatoid arthritis: a double-blind,
randomized, placebo-controlled clinical trial.
Arthritis Rheum (2008) 58:19319.

Fara imbunatatire clinica sau imunohistologica in PR

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Fractalkina-CX3CL1
Stimulate
FKN

de TNF sinoviocitele-FB like produc FKL.

pp raspunzatoare pentru extravazarea leucocitelor

Determina

proliferarea sinoviocitelor prin MAPK

Volin MV, HuynhN, Chong K et all
Fractalkine is a novel chemoattractant for rheumatoid arthritis
fibroblast-like synoviocyte signaling through MAP kinases and Akt.
Arthritis Rheum. 2007 Aug;56(8):2512-22.

Molecula

agiogenetica

Chemokina

mai putin redundanta, CX3CR1-FKN mare afinitate

mare aviditate
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Fractalkina-CX3CL1

Implicarea si in ateroscleroza! (cantitati mari in placa aterosclerotica

unde recruteaza monocite si Lf T)

Rheumatology 2009 48(1):11-22; REVIEWS

Common inflammatory mediators orchestrate pathophysiological
processes in rheumatoid arthritis and atherosclerosis
F. Montecucco1 and F. Mach1

Circulation (2003) 107:100916

Decreased atherosclerotic lesion formation in
CX3CR1/apolipoprotein E double knockout mice.
Combadire C, Potteaux S, Gao J, et al.

Tinta

terapeutica : Ac monoclonal anti FKN, in artritele colagen

induse la soareci au aratat reducerea semnificativa a infiltratului
inflamator si a eroziunilor osoase
The Journal of Immunology, 2004, 173: 7010-7016.
Inhibition of Fractalkine Ameliorates Murine Collagen-Induced Arthritis1
Toshihiro Nanki2,*, Yasuyo Urasaki*, , Toshio Imai , Miyuki Nishimura

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Chemokinele si receptorii lor in PR

Studii preclinice, pe
animale in care
antagonistii de
chemokine sau
receptori si-au dovedit
eficacitatea in artritele
induse

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Compusi disponibili 2009

Fara eficacitate

Maraviroc
antagonists co-receptor CCR5

2007
Plerixafor
antagonist CXCR4

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2008

Concluzii
Seturile

diferite de chemokine si receptori sunt responsabile

pentru recrutarea diferitelor populatii de leucocite la nivelul
zonelor de inflamatie.

Chemokinele

au multiple implicatii si in angiogeneza si

ploriferarea celulara

Chemokine

sau receptori lor par a fi o tinta terapeutica nu

numai in PR dar si in astm bronsic, psoriazis, neoplazii

Antagonostii

de receptori au eficacitate clinica dovedita in

studiile pe animale dar nu si in trialuri clinice de faza II/III (cu
exceptia compusilor aprobati recent in infectia HIV si TMO)

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Referinte
1)

Haringman JJ, Gerlag DM, Tak PP, et al.A randomized controlled trial with an
anti-CCL2 (anti-monocyte chemotactic protein 1) monoclonal antibody in
patients with rheumatoid arthritis. Arthritis Rheum (2006) 54:238792

2)

Vergunst CE, Gerlag DM, Tak PP, et al.Modulation of CCR2 in rheumatoid

arthritis: a double-blind, randomized, placebo-controlled clinical trial.
Arthritis Rheum (2008) 58:19319

3)

Haringman J, Tak PP et al. Chemokine and chemokine receptor expression in

paired peripheral blood mononuclear cells and synovial tissue of patients
with rheumatoid arthritis, osteoarthritis, and reactive arthritis Ann Rheum Dis
2006; 65:294-300

4)

Haringman J, Tak PP et al. Chemokine blockade and chronic inflammatory

disease: proof of concept in patients with rheumatoid arthritis Ann Rheum
Dis 2003;62;715-721

5)

F. Montecucco1 and F. Mach1 REVIEWSCommon inflammatory mediators

orchestrate pathophysiological processes in rheumatoid arthritis and
atherosclerosis Rheumatology 2009 48(1):11-22.

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