LES 6 TOLERANCE AND COSTIMULATION DENDRITIC CELLS
- Dendritic cells
o Apc
Micropinocytosis and phagocytosis by tissue dc viral infection
Mhc expression is low on tissue dc
High on dc in lymphoid tissues
Co stimulator delivery
niet-fagocyterende lymfoïde dendritische cellen continu co-stimulatoire
signalen leveren, zonder dat een externe trigger nodig is, om immuuncellen,
zoals T-cellen, te activeren en een immuunrespons te ondersteunen.Antigen
presented
Peptide, viral antigen, allergens
Location
Ubiquitous throughout the body
o Dc – dynamically interacting with environment
Moving trough lymph node stretching out dendrites to make contact with other cells
o Ralph Steinman demonstrate cross talk between DC and naïve t cell occur with 3
signals (TCR with MHC class, costimulation, cytokines
o Linking innate and adaptive
DC communicate with t cell and activates t cel with three signals
On DC pathogen or pamp on PRR or Toll
TCR to fe MHC class 2
Costimualtion CD80/86 from dc with CD28 from T cel
o Cd80/86: cd28 facilitates t cell activation, proliferation,
survival and cytokine production
Cytokine
Il 12 th1
Il 4 th2
Il 23 and TGF beta and il 6 Th17
,
- Application
o Costimulation blockade
Rheumatoid artritis (more female)
Polyartritis, symmetric, hand and feet and large joint, destructive,
extra articular
DCs activate T cells, which then produce inflammatory cytokines and
signals that cause inflammation and tissue destruction.
o Activated macrophages
o Ifn gamma
o Il2
o Tnf alfa chondrocyt
o RANK-L activates osteoclasts, leading to bone erosion.
o B cells produce autoantibodies and cytokines like IL-6 and
rheumatoid factor, contributing to inflammation.
Blocking interactions between DCs and T cells can dampen this
inflammatory cascade, potentially reducing damage to tissues and
bone.
CTLA 4 downregulation CD28 mediated t cell activation
Bigger affinity for cd80/86 co inhibitory signals
Abatacept CTLA-4ig recombinant fusion protein treatment for RA
Fc domain from igG and bovenste= CTLA-4
ctla-4ig bind to CD80/86 -> no t cel activation
downstream effect no activation of pro inflammatory cytokine
and chondrocyte and osteoclast
This treatment does not deplete t cells or leukocytes, allowing the
immune system to still function against infections = specific target
therapy
Treat with abatacept ACR response 20, 50, 70 20% decrease or
50% or 70%
You get dubble blind patient do not know which drug
Open label extension all patient get drug
80% ACR20 response
- Dendritic cells
o Apc
Micropinocytosis and phagocytosis by tissue dc viral infection
Mhc expression is low on tissue dc
High on dc in lymphoid tissues
Co stimulator delivery
niet-fagocyterende lymfoïde dendritische cellen continu co-stimulatoire
signalen leveren, zonder dat een externe trigger nodig is, om immuuncellen,
zoals T-cellen, te activeren en een immuunrespons te ondersteunen.Antigen
presented
Peptide, viral antigen, allergens
Location
Ubiquitous throughout the body
o Dc – dynamically interacting with environment
Moving trough lymph node stretching out dendrites to make contact with other cells
o Ralph Steinman demonstrate cross talk between DC and naïve t cell occur with 3
signals (TCR with MHC class, costimulation, cytokines
o Linking innate and adaptive
DC communicate with t cell and activates t cel with three signals
On DC pathogen or pamp on PRR or Toll
TCR to fe MHC class 2
Costimualtion CD80/86 from dc with CD28 from T cel
o Cd80/86: cd28 facilitates t cell activation, proliferation,
survival and cytokine production
Cytokine
Il 12 th1
Il 4 th2
Il 23 and TGF beta and il 6 Th17
,
- Application
o Costimulation blockade
Rheumatoid artritis (more female)
Polyartritis, symmetric, hand and feet and large joint, destructive,
extra articular
DCs activate T cells, which then produce inflammatory cytokines and
signals that cause inflammation and tissue destruction.
o Activated macrophages
o Ifn gamma
o Il2
o Tnf alfa chondrocyt
o RANK-L activates osteoclasts, leading to bone erosion.
o B cells produce autoantibodies and cytokines like IL-6 and
rheumatoid factor, contributing to inflammation.
Blocking interactions between DCs and T cells can dampen this
inflammatory cascade, potentially reducing damage to tissues and
bone.
CTLA 4 downregulation CD28 mediated t cell activation
Bigger affinity for cd80/86 co inhibitory signals
Abatacept CTLA-4ig recombinant fusion protein treatment for RA
Fc domain from igG and bovenste= CTLA-4
ctla-4ig bind to CD80/86 -> no t cel activation
downstream effect no activation of pro inflammatory cytokine
and chondrocyte and osteoclast
This treatment does not deplete t cells or leukocytes, allowing the
immune system to still function against infections = specific target
therapy
Treat with abatacept ACR response 20, 50, 70 20% decrease or
50% or 70%
You get dubble blind patient do not know which drug
Open label extension all patient get drug
80% ACR20 response
