Who gets the autoimmune disease Type 1 diabetes, and

why?

•35 years of Type 1 diabetes immunology research – an autoimmune disease model emerges

•How genes and environment may come together in the “perfect storm”

•Devising new immunological approaches for translation into therapies

Mark Peakman

King’s College London

•Type 1 diabetes 1921; universally fatal; discovery of insulin

•Diabetic complications (renal failure, blindness, early cardiovascular disease) due to chronic hyperglycaemia

•Diabetes costs NHS ~£8-10 billion (Type 1 diabetes £2-5b)

“Western Europe: • 15,000 new cases in 2005 • 24,400 in 2020 • Incidence to double in children <5 years…”

•No known cure or spontaneous remission

Type 1 diabetes

1922

Banting

Marjorie

Best

Insulin T lymphocytes (CD3)

Background I: pathology

At diagnosis >80% of islets destroyed

John Todd and Linda Wicker, Cambridge

Background II: Large genome-wide studies

•Pinpoint variants of normal genes that are more frequent in diabetes

DC

α THelper

β cells

DC

1. Islet

2. Pancreatic lymph node

DC

3. Via blood

HLA II

Type 1 diabetes: immune pathogenesis

HLA I

Pro-inflammatory

cytokines

CTLTCytotoxic

THelper

TCytotoxic

Epitope discovery

Insulin

DC

α THelper

β cells

DC

1. Islet

2. Pancreatic lymph node

DC

3. Via blood

HLA II

Type 1 diabetes: immune pathogenesis

HLA I

Pro-inflammatory

cytokines

CTLTCytotoxic

THelper

TCytotoxic

Epitope discovery

GENE SET 1: Ag presentation to T cells

Insulin

DC

α THelper

β cells

DC

1. Islet

2. Pancreatic lymph node

DC

3. Via blood

HLA II

Type 1 diabetes: immune pathogenesis

HLA I

CTLTCytotoxic

TH

IL-10TRegulatory

TCytotoxic GENE SET 2: Immune regulation

Anti-inflammatory

cytokines

Insulin

DC

α THelper

β cells

DC

1. Islet

2. Pancreatic lymph node

DC

3. Via blood

HLA II

Type 1 diabetes: immune pathogenesis

HLA I

CTLTCytotoxic

TH

IL-10TRegulatory

TCytotoxic

GENE SET 3: Pathogen susceptibility

Insulin

DC

α THelper

β cells

DC

1. Islet

2. Pancreatic lymph node

DC

3. Via blood

HLA II

Type 1 diabetes: immune pathogenesis

HLA I

CTLTCytotoxic

TH

IL-10

TR

TCytotoxic

GENE SET 3: Pathogen susceptibility

GENE SET 1: Ag presentation to T cells

GENE SET 2: Immune regulation

Insulin

GENE SET 1: Ag presentation to T cells

TCytotoxic

DC

β cell

0

10

20

30

Number of Effectors per Target

12631 25

% S

peci

fic ly

sis

HLA-A2+ human islets with 1E6 clone

A2+ islets/control clone

A2- islets/1E6 clone

Tcytotoxic cells targeting insulin kill human β-cells.

Are these cells in the islets where β-cells are killed?

Epitope discovery

HLA

Coppieters et al, JEM, 2012

Insulin- specific T cells

In situ staining for antigen-specific T cells

GENE SET 1: Ag presentation to T cells

TCytotoxic

DC

β cell

0

10

20

30

Number of Effectors per Target

12631 25

% S

peci

fic ly

sis

A2+ human islets with 1E6 clone

A2+ islets/control clone

A2- islets/1E6 clone

Tcytotoxic cells targeting insulin kill human β-cells.

How does this interaction look at the molecular level?

Crystal

CTL

β cell Dissociation constant Kd ~250μM

(ie ultra-low vs tumour antigens (~50 μM) or virus (~5 μM))

In press

HLA-A2 (*0201)

TcR

β-chainα-chain

•Bulek et al, Nat Imm 2012

Unique features of insulin-specific TCR:

• Weakest binding affinity to a natural agonist antigen ever described

• highly peptide-centric binding dominated by hotspots focused on just two amino acids in the peptide

β-cell

Killer T cell

insulin peptide

•Major opportunities for cross-reactivity

•The antigenic peptide that primed killer T cells may not be from insulin originally

GENE SET 2: Immune regulation

No IL-10 response

IL-10 response

7.5y Balance of islet-specific TH cells in peripheral blood in Type 1 diabetes is abnormal

•Candidate genes: CD25, CTLA4, IL-10

GENE SET 2: Immune regulation

GENE SET 3: Pathogen susceptibility

α THelper

β cells

DC

1. Islet

2. Pancreatic lymph node

DC

3. Via blood

HLA II

HLA I

CTLTCytotoxic

Insulin

TCytotoxic

GENE SET 3: Pathogen susceptibility

Candidate genes: IFIH1 EBI2TLR7/TLR8BACH2FUT2

Sense pathogens:Set “response rheostat”

DC

α THelper

β cells

DC

1. Islet

2. Pancreatic lymph node

DC

3. Via blood

HLA II

Type 1 diabetes: the model

HLA I

CTLTCytotoxic

TH

IL-10

TR

TCytotoxic

GENE SET 3: Pathogen susceptibility

GENE SET 1: Ag presentation to T cells

GENE SET 2: Immune regulation

Insulin

B

Islet cell AAbs

• Anti-CD3, transient depletion of T cells• Rituximab, anti-CD20, depletes B cells • Abatacept, CTLA4-Ig, co-stimulation blockade

Therapeutic options in T1D: “immune suppression”

Emergence of the concept of Antigen Specific Immunotherapy (ASI) for autoimmune disease

“The administration of auto-antigen in a form or by a route designed to induce or re-establish tolerance to the same antigen or to the target tissues of the autoimmune response”

Lead disease setting: clinical allergy (multiple sclerosis)

Inject whole proteins or peptides from allergens

Good, sustained clinical efficacy

24/11/11

Figure 1

Benefit

IL-10

TR

Proinsulin peptide immunotherapy

•Monthly i.d. injections of proinsulin peptide x 3;•10, 100 and 1000μg per dose

0

1

2

3

4

5

IL-1

0 (S

I) **

10g placebo

0 3 6 0 3 6month of study

*5µM10µM

•Induction of IL-10 response to proinsulin peptide C19-A3 after low dose i.d administration in T1D patients

•No autoantibody increase or induction; no anti-peptide antibodies

•No pro-inflammatory cytokine induction

•Improved glycaemic control

0 3 6

Peptide administration

Month of study

Phase Ib (New T1D) Monthly

Bi-weekly

Developmental programme

(Phase I in 2014)

•Multiple peptides from >1 β-cell antigen

Who gets the autoimmune disease Type 1 diabetes, and

why?

•35 years of Type 1 diabetes immunology research – an autoimmune disease model emerges

•Genes and environment come together in the “perfect storm”

•New immunological approaches for translation into therapies are emerging: an exciting decade ahead

Funders and collaborators•Department of Immunobiology at KCL

•Clinical collaborators, Guy’s and St Thomas’ NHS Foundation Trust & King’s College Hospital

•Cardiff University (Colin Dayan); Cambridge University (Catherine Guy, David Dunger, Linda Wicker, John Todd); University of Bristol (Polly Bingley)

•Funding agencies:

Naimit