Biologic therapy in autoimmune disease

Klara Morsley

Contents

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

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

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

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

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

TNF-αTNF-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!!

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

IL-15???

Neutralising IL-15

Reduced inflammation and destruction in CIA Improvement in psoriasis Prevents rejection Improves RA

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 IIL-1R II

Any

P50/65

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

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

IFNβ

JAK

Tyk2

Downregulated by SHP-1

IFN

R1

IFN

R2

IFN

STAT 1& 2

NUCLEUS

Effects

IFNβ reduces active lesions on MRI scan

↓ relapse number and severity

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.

Peptide therapy

Promising results in animals Altered peptide ligand – T cell antagonist

Protected mice from EAE No clinical effects in humans Th2 → hypersensitivity?

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

How? Oral tolerance

Stimulation of regulatory T cells

Active suppression

Mucosal tolerance Regulatory T cells Bystander suppression Immune deviation

Adverse effects

Infection Malignancy Autoantibodies Treatment antibodies Demyelinating disease The unexpected

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

Conclusion

Only a small sample of current/possible biologic therapy

Potential for specific modulation of immune system

Potential for serious adverse effects