”Traditionell” inflammationsmodulerande farmakoterpi
Thomas Skogh
Avdelningen för Reumatologi
IMK
Autoimmunitet & Immunreglering
”Traditionell” inflammationsmodulerande farmakoterpi
Kolchicin
’NSAID’ (COX-hämmare )
”Antimetaboliter”
- metotrexat
- azatioprin
Glukokortikosteroider
Cytokiner
- IFN-α
- IFN-β
- IL1-Ra
IVIG
Riktad ”biologisk” terapi mot
• cytokiner
- TNF (etanercept, Infliximab, adalimumab)
- IL-1 (kineret)
- IL-6
• adhesionsmolekyler
- β1 integrinet VLA-4 (natalizumab)
• Celler
- B-celler (rituximab)
- T-celler (t.ex. abatacept)
”Icke-traditionell” inflammationsmodulerande farmakoterapi ?
- antimikrobiella läkemedel
- könshormoner (P-piller, HRT, testosteron)
- andra steroidpreparat (spironolakton)
- beta-blockare
- adrenalin
- statiner
- heparin
inflammationsmodulering - livsstil
-
stress ? (sympatikus; parasympatikus)
motion ?
sömn
kost ?
fetma ?
svält ?
koffein ?
alkohol ?
rökning ? nikotin?
TS
”Traditionell” inflammationsmodulerande farmakoterpi
Kolchicin
’NSAID’ (COX-hämmare )
Jan Bergman (artros)
”Antimetaboliter”
- metotrexat
- azatioprin
Glukokortikosteroider
Cytokiner
- IFN-α
- IFN-β
- IL1-Ra
IVIG
Riktad ”biologisk” terapi mot
• cytokiner
- TNF (etanercept, Infliximab, adalimumab)
- IL-1 (anakinra)
- IL-6
• adhesionsmolekyler
- β1 integrinet VLA-4 (natalizumab)
• Celler
- B-celler (rituximab)
- T-celler (t.ex. abatacept)
TS
”Traditionell” inflammationsmodulerande farmakoterpi
Kolchicin
’NSAID’ (COX-hämmare )
Jan Bergman (artros)
”Antimetaboliter”
- metotrexat
- azatioprin
Maria Ekbäck (psoriasis)
Glukokortikosteroider
Cytokiner
- IFN-α
- IFN-β
- IL1-Ra
IVIG
Riktad ”biologisk” terapi mot
• cytokiner
- TNF (etanercept, Infliximab, adalimumab)
- IL-1 (anakinra)
- IL-6
• adhesionsmolekyler
- β1 integrinet VLA-4 (natalizumab)
• Celler
- B-celler (rituximab)
- T-celler (t.ex. abatacept)
TS
”Traditionell” inflammationsmodulerande farmakoterpi
Kolchicin
’NSAID’ (COX-hämmare )
Jan Bergman (artros)
”Antimetaboliter”
- metotrexat
- azatioprin
Maria Ekbäck (psoriasis)
Curt Tysk (ulcerös kolit)
Glukokortikosteroider
Cytokiner
- IFN-α
- IFN-β
- IL1-Ra
IVIG
Riktad ”biologisk” terapi mot
• cytokiner
- TNF (etanercept, Infliximab, adalimumab)
- IL-1 (anakinra)
- IL-6
• adhesionsmolekyler
- β1 integrinet VLA-4 (natalizumab)
• Celler
- B-celler (rituximab)
- T-celler (t.ex. abatacept)
TS
”Traditionell” inflammationsmodulerande farmakoterpi
Kolchicin
’NSAID’ (COX-hämmare )
Jan Bergman (artros)
”Antimetaboliter”
- metotrexat
- azatioprin
Maria Ekbäck (psoriasis)
Curt Tysk (ulcerös kolit)
Glukokortikosteroider
Marit Eliasson (astma)
Cytokiner
- IFN-α
- IFN-β
- IL1-Ra
IVIG
Riktad ”biologisk” terapi mot
• cytokiner
- TNF (etanercept, Infliximab, adalimumab)
- IL-1 (anakinra)
- IL-6
• adhesionsmolekyler
- β1 integrinet VLA-4 (natalizumab)
• Celler
- B-celler (rituximab)
- T-celler (t.ex. abatacept)
TS
”Traditionell” inflammationsmodulerande farmakoterpi
Kolchicin
’NSAID’ (COX-hämmare )
Jan Bergman (artros)
”Antimetaboliter”
- metotrexat
- azatioprin
Maria Ekbäck (psoriasis)
Curt Tysk (ulcerös kolit)
Glukokortikosteroider
Marit Eliasson (astma)
Cytokiner
- IFN-α
- IFN-β
- IL1-Ra
IVIG
Riktad ”biologisk” terapi mot
• cytokiner
- TNF (etanercept, Infliximab, adalimumab)
- IL-1 (anakinra)
- IL-6
• adhesionsmolekyler
- β1 integrinet VLA-4 (natalizumab)
Finn Akre (reumatoid artrit)
• Celler
- B-celler (rituximab)
- T-celler (t.ex. abatacept)
TS
”Traditionell” inflammationsmodulerande farmakoterpi
TS
”Traditionell” inflammationsmodulerande farmakoterpi
Granulocyt
CD62L
TS
CD62L
kemokiner
TS
CD62L
kemokiner
TS
CD62L
kemokiner
TS
CD62L
kemokiner
TS
CD62L
CD11b
ICAM-1 VCAM-1
kemokiner
TS
CD11b
kemokiner
TS
CD11b
kemokiner
TS
CD11b
kemokiner
TS
kemokiner
TS
CD62L
CD11b-CD18, CD11a
Selektiner ---------------------- Integriner --------------------- Ig superfamilj
kontakt
rullning
aktivering
fast vidhäftning
transmigration
ICAM-1
O2
’metabolic burst’
VCAM-1
kemokiner
kemotaxis
proteaser
AA-metaboliter
Fagocytos
cytokiner , m.m.
TS
Mi
k ro
HM
GB
-
ICx
/ CR
P
kom
plem
ent
PL
S
LP
bie
llt
DN
A/
RN
A
CD14
TLR
arakidonsyra
COX-1
1
RAGE
fosfolipas A2
COX-2
FcR
Prostaglandiner
LOX
Leukotriener
CR
O2
NADPHoxidas
.O2
H2O2
arginas
NOS
Fe2+
.OH
.
NO
L-Arg
L-Citr
NFκB
ONOOTS
PL
fosfolipas A2
arakidonsyra
COX-1
COX-2
Prostaglandiner
LOX
Leukotriener
O2
NADPHoxisdas
.O2
H2O2
arginas
NOS
Fe2+
.OH
.
NO
L-Arg
L-Citr
NFκB
Vane J. Aspirin
and other anti-inflammatory drugs.
ONOO
Thorax 2000;55:3-9
TS
Metotrexat
+ folyra
folsyrasyntes ↓ – kvävebassyntes ↓
polyaminer↑ - T-cellshämning?
Adenosinutsöndring ↑
Etanol liknande effekt !
Koffein motverkar (?)
Prostaglandiner
Glukokortikoider
PL
Purin-antagonist
Prodrog till 6-merkaptopurin
fosfolipas A2
TPMT
XO
arakidonsyra
COX-1
COX-2
NADPHoxisdas
Azatioprin
AO
LOX
Leukotriener
6-MMP
oxiderade
metaboliter
arginas
NFκB
Anti-inflammatoriska
mediatorer
TS
PL
fosfolipas A2
arakidonsyra
COX-1
COX-2
Prostaglandiner
LOX
Leukotriener
Antiinflammatorisk
reaktion
NADPHarginas
inflammation
oxisdas
NFκB
TS
inflammation
immunreglering
Antiinflammatorisk
reaktion
TS
TS
inflammatorisk
reaktion
Antiinflammatorisk
reaktion
TS
Immunreaktioner
IL-1β
Inflammation
TNF-α
cytokiner
-
IL-10
TGF-β
Antiinflammatorisk
reaktion
TS
Immunreaktioner
cytokiner
autokrina effekter
parakrina effekter
endokrina effekter
lever
CNS
Trötthet
Feber
aptitlöshet
CRP
TS
IFNα
TNFα
IL-18
IL-13
Immunreaktioner
TGF-β
IL-6
IL-1β
IL-5
cytokiner
IFNγ
IL-12
IL-8
IL-12
IFNβ
autokrina effekter
parakrina effekter
endokrina effekter
Pleiotropa effekter
IL-17
IL-4
IL-10
TS
Immunreaktioner
TNFα
cytokiner
TNF
TNF
Anti-TNF
TNF
TS
TNFα
Anti-TNF
Anti-TNF
TNF
TNF
TNF
Anti-TNF
cytokiner
TNF
TS
TNFα
cytokiner
TNF
Anti-TNF
TNF
FcγR
Rituximab
CD20
CD20
B-cell
TS
High Mobility Group Box 1 protein
TNFα
CR
Anti-TNF
TNF
Anti-TNF
C
TNF
TNF
Anti-TNF
cytokiner
TNF
TS
HMGB-1
High Mobility Group Box 1 protein
TS
HMGB-1
+
+
+
Box A
+
+
+
+
+
Box B
-------------------
acidic tail
DNA
Knapp et al. The long acidic tail of high mobility group box 1 (HMGB1)
protein forms an extended and flexible structure that interacts with specific
residues within and between the HMG boxes. Biochemistry 2004;43:11992-7
TS
HMGB-1
Box A
Box B
HE Q et al. Intercalating residues determine the mode of
HMG1 domains A and B binding to cisplatin-modified DNA.
Biochemistry 2000;39:14426-35
TS
HMGB-1
H1
DNA
H1
Nucleosome
H
M
G
B
1
H1 CH3CO
TS
HMGB-1
H
M
G
B
1
H1
CH3CO
DNA
H1
Nucleosome
H1
TS
HMGB-1
TS
HMGB-1
TNF-α
Amfoterin
Utväxt av nervändar
Cellrörlighet
Tumör-metastasering/invasion
UU U
U
TS
HMGB-1
apoptos
inflammation
TS
HMGB-1
receptorer
RAGE
RNA
DNA (CpG)
LPS
TLR
NFκB
pro-inflammatoriskt
TS
Str
es
s
ä r ta
Sm
Hypotalamus
CRH
GnRH
Hypofys
ryggmärg
ANS
LH/FSH
ACTH
Prolaktin
CRH
Testis
binjure
PNS
DHEA
Äggstock
Katekolaminer
Kortisol
Substans P
Placenta
Th1
Östrogen
Progesteron
Testosteron
Th2
IFN-γ, IL-12, IL-17, IL-18, IL-2,IL-10, TGF-β, IL-6, IL-5, IL-13, IL-4
TNF-α, IL-1β,
IFN-α,
TS
TS
Tiopuriner
Coulthard S, Hogarth L. Thiopurines. An update. Inv New Drugs 205;23:523-532
TS
