1. Biologic therapy in
autoimmune disease
Klara Morsley

2. Contents
 Introduction
 IL-6
 TNFα
 IL-15
 IL-1
 IFNβ
 Peptide therapy
 Adverse effects
 Therapies to come
 Conclusion

3. Introduction
 Therapies for autoimmune disease can have
major side effects
 Current therapies are not always effective
 Biologic therapies have the potential to be
specific and not cause general
immunosuppression

4. IL-6
Macrophages
T cells
Endothelial
cells
IL-6R
Acute phase protein
production
Fever
T + B cell growth and
differentiation
Bone metabolism
Haematopoietic stem
cell growth
IL-6

5. IL-6 and disease
 ↑ IL-6 in synovial fluid of RA patients
 ↑ IL-6 in pleural effusion cells of TB patients
 Produced by cells infiltrating islets of
Langerhans in type 1 diabetes
 Produced by cells from patients with UC
 Levels correlate with disease activity on
Crohn’s

6. Effects
 Mice
 IL-6 deficient mice resistant to EAE
 Onset and severity of CIA delayed
 Partially resistant to colitis
 Anti-IL-6
 Inhibits type 1 diabetes
 Prevents colitis
 Suppresses EAE
 People
 Used in sJIA – 30% improvement
 RA-20% improvement in 50% patients

7. TNF-α
TNF-α
TNFR
•acute phase proteins
•mobilises neutrophils from BM
•induces fever
•activates endothelial cells
•migration of dendritic cells to
lymph nodes and their maturation
elevated
elevated
sTNFR
elevated!!

10. IL-15
T cell memory
maintenance
T cell
recruitment and
activation
Neutrophil
activation
Delays
apoptosis in
endothelial
cells and
synoviocytes
TNF-α and
IL-1β
production

11. IL-15???
Neutralising IL-15
 Reduced inflammation and destruction in CIA
 Improvement in psoriasis
 Prevents rejection
 Improves RA

12. IL-1
Pro-
inflammatory
Receptor
antagonist
Receptors
IL-1α IL-1β IL-1Ra IL-1R I IL-1R II
NO SIGNAL
IL-1a
IL-1b
IL-1ra
IL-1R I
IL-1R II
Any
P50/65

13. Effects
 Inhibition of collagen synthesis
 Stimulating the release of prostaglandin E2 and NO
 Inducing fever
 Activation of T and B cells
 Resorption of bone
 Release of enzymes and chemotactic factors from
macrophages

14. IL-1 and RA
 Elevated levels found in patients with RA
 Correlates with disease activity
 IL-1b injected into joints→arthritis
 IL-1ra deficient →autoimmune disease
 Human trials
 Rapid reduction of disease progression
 BUT short ½life – daily injections
 Combined with anti-TNF-α→serious infection

15. IFNβ
JAK
Tyk2
Downregulated
by SHP-1
IFNR1
IFNR2
IFN
STAT
1& 2
NUCLEUS

16. Effects
 IFNβ reduces
active lesions on
MRI scan
 ↓ relapse number
and severity

17. How?
 Improves BBB function
 Inhibits transmigration of leucocytes
 Inhibits the action of H2O2 and TNF-α to alter the tight
junction molecules between endothelial cells
 Reduces the ability of inflammatory cells to enter the
CNS.

18. Peptide therapy
 Promising results in animals
 Altered peptide ligand – T cell antagonist
 Protected mice from EAE
 No clinical effects in humans
 Th2 → hypersensitivity?

19.  Mice
 (Ac1-9), MBP 68-86 + 87-99 protected against
EAE
 Synergistic effects of MBP 68-86 + 87-99
 B chain of insulin protected against type 1
diabetes
 Humans
 Hsp60 maintained islet cell function
 dnaJ reduced TNFα and IFNγ in RA

20. How?
 Oral tolerance
 Stimulation of regulatory
T cells
 Active suppression
 Mucosal tolerance
 Regulatory T cells
 Bystander suppression
 Immune deviation

21. Adverse effects
 Infection
 Malignancy
 Autoantibodies
 Treatment antibodies
 Demyelinating disease
 The unexpected

22. Therapies to come
 IL-23
 IL-23 deficient mice resistant to EAE, CIA, IBD
 Blockade prevents EAE
 Does not affect ongoing EAE
 Efalizumab
 Blocks LFA-1 + ICAM-1 interaction
 Reduced T cell activation + recruitment
 LymphoStat-B
 Blocks BlyS
 Increased expression associated with autoantibodies
 Required for B cell maturation

23. Conclusion
 Only a small sample of current/possible
biologic therapy
 Potential for specific modulation of immune
system
 Potential for serious adverse effects