who gets the autoimmune disease type 1 diabetes, and why?

Who gets the autoimmune disease Type 1 diabetes, and

why?

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

•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

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 diabetesType 1 diabetes

1922

Banting

Marjorie

Best

Insulin T lymphocytes (CD3)

Background I: pathologyBackground I: pathology

At diagnosis >80% of islets destroyed

John Todd and Linda Wicker, Cambridge

Background II: Large genome-wide studiesBackground II: Large genome-wide studies

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

αα

β cells β cells

1. Islet

2. Pancreatic lymph node

3. Via blood

HLA II

Type 1 diabetes: immune pathogenesisType 1 diabetes: immune pathogenesis

HLA I

Pro-inflammatory

cytokines

CTLTCytotoxic

Epitope discoveryEpitope discovery

Insulin

αα

β cells β cells

1. Islet

2. Pancreatic lymph node

3. Via blood

HLA II

Type 1 diabetes: immune pathogenesisType 1 diabetes: immune pathogenesis

HLA I

Pro-inflammatory

cytokines

CTLTCytotoxic

Epitope discoveryEpitope discovery

GENE SET 1: Ag presentation to T cells

Insulin

αα

β cells β cells

1. Islet

2. Pancreatic lymph node

3. Via blood

HLA II

Type 1 diabetes: immune pathogenesisType 1 diabetes: immune pathogenesis

HLA I

CTL

IL-10IL-10

TCytotoxic GENE SET 2: Immune regulation

Anti-inflammatory

cytokines

Insulin

αα

β cells β cells

1. Islet

2. Pancreatic lymph node

3. Via blood

HLA II

Type 1 diabetes: immune pathogenesisType 1 diabetes: immune pathogenesis

HLA I

CTL

IL-10IL-10

TCytotoxic

GENE SET 3: Pathogen susceptibility

Insulin

αα

β cells β cells

1. Islet

2. Pancreatic lymph node

3. Via blood

HLA II

Type 1 diabetes: immune pathogenesisType 1 diabetes: immune pathogenesis

HLA I

CTL

IL-10IL-10

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

TCytotoxicβ cell 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?

Tcytotoxic cells targeting insulin kill human β-cells.

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

Epitope discoveryEpitope 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

TCytotoxicβ cell 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?

Tcytotoxic cells targeting insulin kill human β-cells.

How does this interaction look at the molecular level?

CrystalCrystal

CTL

β cell 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

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

αα

β cells β cells

1. Islet

2. Pancreatic lymph node

3. Via blood

HLA II

HLA I

CTL

Insulin

TCytotoxic

GENE SET 3: Pathogen susceptibility

Candidate genes: IFIH1 EBI2TLR7/TLR8BACH2FUT2

Candidate genes: IFIH1 EBI2TLR7/TLR8BACH2FUT2

Sense pathogens:Set “response rheostat”Sense pathogens:Set “response rheostat”

αα

β cells β cells

1. Islet

2. Pancreatic lymph node

3. Via blood

HLA II

Type 1 diabetes: the modelType 1 diabetes: the model

HLA I

CTL

IL-10IL-10

TCytotoxic

GENE SET 3: Pathogen susceptibility

GENE SET 1: Ag presentation to T cells

GENE SET 2: Immune regulation

Insulin

B

Islet cell AAbsIslet 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”

Therapeutic options in T1D: “immune suppression”

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

“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

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-10IL-10

Proinsulin peptide immunotherapyProinsulin 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)Phase Ib

(New T1D) Monthly

Bi-weekly

Developmental programme

(Phase I in 2014)

Developmental programme

(Phase I in 2014)

•Multiple peptides from >1 β-cell antigen

Who gets the autoimmune disease Type 1 diabetes, and

why?

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

•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 collaboratorsFunders 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