T regulatory cells as therapeutic targets of rheumatoid arthritis

1. Treg Cells:
therapeutic targets of
rheumatoid arthritis
Submitted By: Sanjana Badwal
M.Sc Molecular biology
and Biochemistry Sem IV1

2. What is RA?
Causes
Symptoms
Risk factors
Diagnosis
Drugs
New marker of RA
Treg as therapeutic targets
CONTENTS:
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3. What is RA?
 It is an autoimmune disease where body’s
own immune system attacks the joints
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4. Causes:
 There are many theories about what
triggers autoimmune diseases,
including:
 bacteria or virus
 drugs
 chemical irritants
 environmental irritants
 family history
4

5. Symptoms:
 Swelling,pain,heat in joints
 Joint stiffness
 Sleeping difficulties because of pain
 Weak muscles
 Reference:medicalnewstoday
5

6. Risk Factors:
 Gender: more common in
women
 Age: more likely to begin in
people aged between 40 and 60
years
 Genetics: people having family
history of RA are more likely to
develop this disease
 Smoking: regular smokers have
significantly higher risk of 6

7. Cont….
 Obesity: obese people are
more prone to RA
 Bacterial infection: some
bacteria produce toxins as a self
defense strategy that can induce
hypercitrullination of proteins
thus changing structure and
function of proteins.
Eg: A.
actinomycetemcomitans
7

8. Diagnosis:
• Anaemia
• C-Reactive protein(liver)
• Erythrocyte sedimentation rate
• X-ray
• MRI(Magnetic resonance
imaging)
• Rheumatoid factor
8

9. Drugs:
Drug treatment includes:
 NSAIDs: They dampen the
inflammation but have side
effects.
 Corticosteroids: they suppress
the immune response.
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10. New Marker Of RA:
 Citrullinated proteins have been
found as specific marker of RA
 Enzyme involved: Peptidylarginine
deaminase(PAD)
 Rheumatoid factor is non specific
thus not good marker
 Citrullinated antigens such as
vimentin and fibrin are candidate
targets in RA
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11. Tregs as Therapeutic
Targets:
 Involved in active supression of T cell
responses
 Belong to CD4+ CD25+
 FOXp3 is the transcription factor(genetic
defects can lead to abnormalities in
functioning of Tregs)
 Tregs suppress the production of TNF and
IFN-y by effector T cells
 Many drugs have been approved for RA
that work by promoting the function or
increasing the no. of Tregs
11

12. Cont.….
 Ultimate goal of this therapy is to restore normal
immune function rather than achieving broad
immunosupression.
 Cytokine based therapies like IL-2 orTNF and
IL-6 Blockers may restore the regulatory
capacity of Tregs
 TLR Antagonists(IRS-954) may restore the
regulatory capacity of Tregs by decreasing the
production of inflammatory cytokines from
APCs.
 Produce TGF-Beta and IL-10-anti inflammatory
molecules.
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13. 1) TNF Inhibitors:
 TNF is produced by effector T cells(TH Cells)
and macrophages: cause inflammation and
block immunosupressive functions of Tregs
when present in high concentration.
 TNF inhibitors interact with TNF Receptors on
target cells and prevent inflammation.
 Anti-TNF drugs bind TNF in circulation and
prevent their interaction with TNF receptors
thus reducing inflammation and progression
of disease.
 Examples: Infliximab, adalimumab
13

14. 2) T Cell Costimulaory
Blocking Agent:
 They bind CD80/86(B7-1& B7-2) present
on APCs and prevent the interaction of
CD28 on T cell with CD80/86.
 It reduces T cell activation and further
production of inflammatory molecules.
 Example: Abatacept (CTLA4-Ig fusion
protein)-Fc region of IgG1 fused to
extracellular domain of CTLA-4.It blocks
secondary signal without which T cell cant
be activated. 14

15. Cont.….
CTLA-4 is member of immunoglobulin
superfamily expressed by activated T
cells.
Homologous to CD28 and binds
CD80/86.
CTLA-4 transmitts an inhibitory signal
to T cells whereas CD28 transmitts
stimulatory signal.
15

16. Structure Of Abatacept
16

17. Mode Of Action Of Abatacept
17

18. 3) TLR Antagonists:
 TLRs present on dendritic
cells,macrophages,NK cells, T Cells.
 Upon activation recruit adapter
proteins within cytosol of immune cell
to propagate antigen-induced signal
transduction pathway.
 TLR antagonists block TLR Signalling.
 TLR Antagonists bind TLRs. Eg: IRS
954
18

19. 4) HDAC(Histone Deacetylation
Inhibitors)
 Inhibit deacetylation and promote
acetylation of Histones.
 This in turn induces FOX P3
expression and immunosupressive
capacity of Tregs.
 Eg: Trichostatin
19

20. 5) Interleukin-2:
 It is principal survival factor for Treg and its
absence contributes to defective Tregs.
 Administration of IL-2 can boost the activity
of Tregs and can increase the no. of Tregs.
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21. CONCLUSION:
 Ultimate goal of this therapy is to restore the
normal immune function rather than
achieving broad immunosupression.
 Therefore use of Tregs as therapeutic
targets is of great importance in
understanding the pathogenesis of
autoimmunity.
 Moreover, the ability to control such
regulatory mechanisms might provide novel
therapeutic opportunities in autoimmune
diseases like RA.
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22. References
 Jonathan H.Esensten,David Wofsy and Jeffrey
A.Bluestone(2009),Regulatory T cells as therapeutic
targets in rheumatoid arthritis,Nature
reviews,Rheumatology;560-565
 Leipe J,Skapenko A(2007),Regulatory T cells in
rheumatoid arthritis,Arthritis research and
therapy,biomed central;93-99
 Snanoudj R,Frangie C,(2007),The blockade T Cell
costimulation as therapeutic stratagem for
immunosupression,Biologics:Targets and
Therapy;203-212
 Walter J van venrooij and Ger J M
Pruijn(2000),Citrullination:a small change for protein
with great consequences for rheumatoid
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23. THANKYOU
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