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d.c.wraith@bristol.ac.uk

David Wraith is founder and CSO of Apitope International NV


Immune system depends on T cell directed mechanisms for effective immunological tolerance ď‚Ą Ig genes undergo somatic hypermutation in response to foreign antigen - risk of autoantibodies ď‚Ą Immune responses must be governed by T cells, since TCR genes do not undergo somatic hypermutation, through controlled T cell help for B cells and regulatory mechanisms ď‚Ą


 

 

Thymic: positive and negative selection Thymic: generation of FoxP3+ natural regulatory T (nTreg) cells Peripheral: sequestration, privileged site, homeostasis and anergy Peripheral: generation of FoxP3+ inducible regulatory T (iTreg) cells & negative feedback mechanisms


Strength Of Signal

Death by TCR Signalling ‘Negative Selection’

Selection of FoxP3 Treg Pop’n Survival ‘Positive Selection’

Death by neglect MHC + Peptide Antigen

Signal strength is the product of TCR & +ve/-ve costimulatory signals Liu et al. Immunity (1995) 3, 407-415 Verhagen, J., et al. Proc. Natl. Acad. Sci. (USA) (2009) 106, 3306-3311


Natural Regulators

Spleen CD4 cells

Induced Regulators Soluble Peptide 2x Per week

92-95% CD25-ve 5-8% CD25&FoxP3+ve

TCR (Va4,Vb8.2) specific for N-terminal epitope of MBP Ac1-9

Burkhart et al. Int. Immunol. (1999) 11, 1625 Sunstedt et al. J. Immunol. (2003) 170, 1240

• injection of antigen in CFA induces EAE • 5-10 doses of soluble peptide antigen induces tolerance and prevents induction of EAE


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  

Anergy Suppression of inflammatory cytokines Induction of anti-inflammatory cytokine (IL10) Bystander suppression Upregulation of negative costimulatory molecules


Cytokines act on innate and/or adaptive immune cells to control the effector response

CD4+ naïve T cell

Th1 cell T-bet

IFN-g

Th1 cell

T-bet IFN-g & IL-10

Intracellular Pathogens Autoimmunity

Th2 cell GATA-3

X

Regulatory T cell FoxP3

IL-4, IL-5, IL-13, IL-10 Extracellular Pathogens Allergy

None, TGF-b, IL-10 Immune Regulation

Th17 cell ROR-gT

IL-17 IL-10 Bacterial Pathogens Autoimmunity

Gabryšová et al: J. Exp. Med. (2009) 206: 1755-1767


IL-12

DC

Th0

CD28 CD80/86

Th1

IFN-g IFN-g IL-10

TCR signal strength

TCR MHC

IL-10

Is this approach suitable for treatment of allergic and autoimmune diseases? Gabryšová & Wraith Eur. J. Immunol. (2010) 40: 1386-1395


In 1911, Drs John Freeman and Leonard Noon published an account of a novel treatment for hay fever. Their method of desensitisation consisted of injecting increasing doses of an extract of pollen subcutaneously until the hypersensitivity reaction was diminished or abolished “there seems little doubt that there has been a distinct amelioration of symptoms. This improvement took several forms; a greater freedom from attack, the attack not so bad as in former years, and the attack sooner over, the constitutional disturbance not so great”

Noon, L. Prophylactic innoculation against hay fever. Lancet i, 1572-1573. 1911


Intact antigen can activate mast cells and basophils by cross-linking IgE  Intact antigen can stimulate antibody secretion (MOG in EAE)  Intact antigen given orally can stimulate cytotoxic T lymphocytes (Insulin in diabetes)  Use CD4 T cell epitopes* 

*Harrison, L. C. and D. Hafler (2000). "Antigen-specific therapy for autoimmune disease." Current Opinion in Immunology 12: 704-711. Larche, M. and Wraith, D.C. Peptide Vaccines for Allergic and Autoimmune Diseases Nature Medicine (2005) 11: s69-76.


Nature Immunology 3, 175.2002

Not all T cell epitopes induce tolerance Peptides must be designed to mimic naturally processed epitopes Such peptides are defined as antigen processing independent epitopes or apitopes


Journal of Experimental Medicine 178, 1783.

Peptide epitopes induce linked suppression


Disease

Species

Peptide

Dose/animal & route

Reference

MS

Mouse

MBP Ac1-9

100 mg i.n.

Metzler et al 1993 Burkhart et al 1999

MS

Mouse

MBP Ac1-9

100 mg i.p.

Liu et al 1995

MS

Mouse

PLP 139-151

100 mg i.n.

Anderton et al 1998

MS

Rat

MBP 87-99

5 x 120 mg i.n

Liu, et al 1998

Arthritis

Mouse

Collagen II 245-270

3 x 100 mg i.n.

Chu et al 1999

Arthritis

Rat

HSP60 176-190

3 x 100 mg i.n. or s.c.

Prakken et al 1997

Diabetes

Mouse

4 GAD peptides

200 mg i.n.

Tian et al 1996

Diabetes

Mouse

Insulin 9-23

100 mg i.n. or s.c.

Daniel et al 1996

Diabetes

Mouse

HSP60 p277

50 mg i.p.

Elias et al 1991

AIHA

Mouse

Band 3 861-874

100 mg i.n.

Shen et al. 2003

SLE

Mouse

SmD1 83-119

600 mg i.v./month

Riemekasten et al 2004

Myasthenia

Mouse

3 AChR peptides

50 mg i.n.

Karachunski et al 1997

Neuritis

Rat

P0 180-199

10 x 6 mg i.n.

Zou et al 1999


Peptides therapy in MS MOG

MBP

PLP

R. O. Weller


Epitopes in MBP

MS 1 30-44 DQ 6

MS1467

MS 7 83-99 DR 15

MS 4 MS 6 131-145 140-154 DQ 6 DR 15


25% M1

85% M1

PBS treated

Mice express HLA-DR15 and human TCR specific for MBP

Treatment with ATX-MS1467 prevents disease onset and suppresses ongoing disease

Treatment suppresses secretion of inflammatory cytokines (IL-1a, IL-2, IL-6, IL-17, IFN-g, TNF-a, GMCSF)

Secretion of antiinflammatory cytokine (IL10) sustained

ATX-MS1467 treated


Subjects – Patients (6) with secondary progressive multiple sclerosis (SPMS)

Design: – Open-label – Dose-escalation of five doses, plus repeat of highest dose

Posology – Dose frequency: 7 to 14 days apart – Dose Escalation: 25, 50, 100, 400, 800, 800 mg i.d.

Primary objective – Assess safety and tolerability of ATX-MS-1467

Secondary objective – Monitor immunological parameters in response to ATX-MS-1467 – Monitor disease status in the CNS using MRI


Subject No.

HLA DR Type

Disease score

Disease score

Start (V1)

End (V9)

Clinical observations

P2

DRB1*01; DRB1*11

5.0

5.0

P4

DRB1*11; DRB1*15

6.5

6.5

P5

DRB1*04 DRB1*04

6.5

6.5

P6

DRB1*13; DRB1*14

7.5

7.5

Improvement in vision Right eye: 6/24 (V1) to 6/9 (V9) Left eye : 6/9 (V1) to 6/6 (V9)

P7

DRB1*13; DRB1*13

6.0

6.0

Improvement in Gd-enhanced MRI on Visit 8 (1 month follow-up)

P8

DRB1*01; DRB1*07

7.5

7.5


3H.thymidine Incorporation (ccpm)

PPD Response

MBP Response

75000

15000

50000

10000

25000

5000

0

0

Visit 1

Visit 8 P=0.3438

Visit 1: prior to treatment Visit 8: one month after last dose

Visit 1

Visit 8 P=0.0313


3H.thymidine Incorporation (ccpm)

Immune responses 15000

15000

10000

10000

5000

5000

0

0

Visit 1

Visit 8

Visit 1: prior to treatment Visit 8: one month after last dose Visit 9: three months after last dose

Visit 8

Visit 9

Repeated treatment with ATX-MS1467 will be required to maintain suppression of the immune response to myelin antigen


Patterns of MS • A further trial comparing ID and SC routes of ATX-MS1467 is in progress • This second trial is treating patients with relapsing multiple sclerosis Years

ClinicalTrials.gov Identifier: NCT01097668 Dr Jeremy Chataway


J. Clin. Invest. 1998. 102, 98-106

PLA 45-62, 82-92, 113-124

J. Allergy Clin Immunol. 1998. 101, 747-754


“Our results provide, for the first time, in vivo evidence of linked epitope suppression and IL-10 induction in both human allergic disease and a mouse model designed to closely mimic peptide therapy in humans�


Chronic stimulation through infection or repeated dose antigen-specific therapy

IL-12

Th1 Th1 IFN-g

T-bet STAT-4 Na誰ve CD4+ T cell

IL-4 GATA-3 STAT-6

Th2 IL-4/5/13 IL-10

IL-12 (ERK/STAT-4) IL-27 (STATs-1/3) c-MAF/SMAD-4

c-MAF/ERK/JUN GATA-3 STAT-6

Th1 IFN-g IL-10

Th2 IL-4/5/13 IL-10

IL-6 TGF-b, IL-1b STAT3 Rorgt, Rora

Th17 IL-17

IL-21 (STAT-3/c-MAF) IL-6 (STAT-3/c-MAF) IL-27 (STATs-1/3/c-MAF) ERK

Th17 IL-17 IL-10

Sabatos-Peyton, C., Verhagen, J. & Wraith, D.C. Antigen-specific immunotherapy of autoimmune and allergic diseases. Current Opinion in Immunology (2010) 22:609-615


Bristol Collaborators Graham Britton Stephan Strobel Bronwen Burton Immanuel Luescher Leona GabryĹĄovĂĄ Raphael Genolet Elaine Hill Arlene Sharpe Graziella Mazza Graham Anderson Kirsty Nicolson Julian Dyson Srihari Pillai Catherine Sabatos-Peyton Neil Scolding Ella Shepard Heather Streeter Johan Verhagen

Our laboratory is supported by the Wellcome Trust and the Multiple Sclerosis Society of Great Britain and Northern Ireland. The phase I/IIA clinical trial in MS was funded by a Wellcome Trust UTA to Apitope


SIGNAL 1

SIGNAL 1 & 2

SIGNAL 1, 2 & 3

TCR activation in the absence of costimulation

TCR activation with costimulation (TLR)

TCR activation with CD40 ligation, cytokine secretion and co-stimulation

T cell anergy T cell depletion

T cell activation and peripheral tolerance: Expansion of FoxP3+ and FoxP3- regulatory T cells

Activation and polarization of effector cells

David Wraith  
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