Lecture 30 - Rheumatoid Arthritis - TNF Flashcards
Which cells synthesise TNF-α?
Describe its synthesis
Activated macrophages
(as well as synovial fibroblasts and T cells)
Production:
• Initially transmembrane
• Cytoplasmic tail cleaved
• Soluble TNF-alpha released
When was TNF-alpha first discovered?
What was it called then?
What were the observed features?
1975
Called cachexin
Observed features:
• Lysis of tumour cells
• Wasting
What are the TNF-alpha receptors?
- TNFR1 + p55 (constitutive)
- TNFR2 + p75 (induced)
Both membrane bound
Describe the TNF-dependent cytokine cascade in RA
TNF-alpha release
Proinflammatory: i.e. stimulates the release of other pro-inflammatory cytokines:
• IL-1
• IL-6
• GM-CSF
Anti-inflammatory: stimulates the release of suppressive cytokines
• IL-10
• IL-1ra
• sTNF-R
What was present in human rheumatoid synovium studies early on?
Cells:
• T cells
• Macrophages
Factors:
• Cytokines
• Destructive enzymes
• Prostaglandins
What were the observations in vitro of TNF-alpha neutralising antibody?
What is the conclusion that can thus be made?
- Cells from RA synovium in culture
- Treatment with TNFi
- Observations:
• Decreased IL-1
• Decreased IL-6
• Decreased GM-CSF
However, also decreased:
• IL-10, sTNF-R and IL-1Ra
Conclusion:
TNF-alpha is pro-inflammatory and leads to the release of other pro-inflammatory cytokines (as well as the release of some anti-inflammatory cytokines)
What is the inhibitory effect of TNF-alpha?
TNF-alpha stimulates the release of suppressive cytokines (IL-10, IL-1Ra, sTNF-R)
What is sTNF-R?
Soluble TNF receptor
It is a decoy receptor that binds TNF in the extracellular space so that it can’t bind the membrane bound receptor
What were the worries with TNF blockade?
- TNF has anti-inflammatory effects
* TNF leads to death of tumour cells
Which animal models are used to study TNF-alpha?
Describe the studies
– DBA/1 mice –
1. Genetically susceptible to RA were injected with collagen which induced arthritis (CIA)
2. TNFi administered to mice
3. Observations:
• Decreased joint inflammation
• Protection of joint architecture (cartilage and bone)
compared to the control group
NB In lower doses of anti-TNF mAb there was no significant improvement. Higher doses were required
Conclusion:
TNF-alpha drives disease in arthritis
– h.TNF.Tg mice –
- Mice over-expressing human TNF-alpha
- Treatment with TNFi
- Similar results to CIA mice
Furthermore, these mice also experienced • Polyarthritis • Colitis • Skin pathology i.e. not just RA
With anti-TNF therapy:
• Lead to improvements in these diseases
Conclusion:
Anti-TNF therapy may be effective in other inflammatory disorders
When was the first human trial for anti-TNF therapy?
Describe the trial and the results
1992, Charing Cross Hospital
20 patients
Long-standing RA
Weren’t responding to all other therapy
Given anti-TNF mAbs
Outcomes:
• Improvement in symptoms
• Reduced signs of inflammation
• No alarming adverse events
Describe the histological changes seen in synovial tissue with and without anti-TNF therapy
W/o therapy: many macrophages present (which are producing TNF)
With therapy: absence of most of the macrophages
Which was the first TNFi?
When was it introduced
Infliximab, late 90’s
What is Anakinra?
Recombinant IL-1Ra
Competitive antagonist
What is Tocilizumab?
Humanised Anti-IL-6R mAb
IgG1
What is Abatacept?
Recombinant CTLA4 on IgG1 frame
Through blocking T cell co-stimulation from APCs, the T cell experiences anergy
What is Rituximab?
B cell depletion
Chimaeric mAb against CD20
What is Infliximab?
Describe these features:
• Structure
• Administration
Chimeric mAb against TNF
Chimeric:
• Mouse: variable regions
• Human: constant regions
Administration:
• Every 8 weeks
What is Etanercept?
Describe these features:
• Structure
• Administration
Fusion protein:
• Two p75 TNF-alpha receptors
• Human: constant region
Weekly injection