Download 1. Islet 2. Pancreatic lymph node

Who gets the
autoimmune disease
Type 1 diabetes, and
why?
Mark Peakman
King’s College London
•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
Type 1 diabetes
•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)
1922
“Western Europe:
•15,000 new cases in 2005
Best
Banting
•24,400 in 2020
•Incidence to double in children <5 years…”
•No known cure or spontaneous remission
Marjorie
Background I: pathology
Insulin
T lymphocytes (CD3)
At diagnosis >80% of islets destroyed
Background II: Large genome-wide studies
John Todd and Linda Wicker,
Cambridge
•Pinpoint variants of normal genes that are more frequent in
diabetes
Type 1 diabetes: immune pathogenesis
DC
Proinflammatory
cytokines
3. Via blood
THelper
α
TCytotoxic
β cells
HLA II
THelper
TCytotoxic
CTL
DC
1. Islet
HLA I
Epitope discovery
DC
Insulin
2. Pancreatic
lymph node
Type 1 diabetes: immune pathogenesis
DC
Proinflammatory
cytokines
3. Via blood
THelper
α
TCytotoxic
β cells
HLA II
TCytotoxic
CTL
DC
1. Islet
HLA I
THelper
GENE SET 1: Ag
presentation to
T cells
Epitope discovery
DC
Insulin
2. Pancreatic
lymph node
Type 1 diabetes: immune pathogenesis
Antiinflammatory
cytokines
DC
IL-10
3. Via blood
TH
TRegulatory
α
TCytotoxic
β cells
HLA II
TCytotoxic
CTL
DC
1. Islet
HLA I
DC
Insulin
2. Pancreatic
lymph node
THelper
GENE SET 2:
Immune
regulation
Type 1 diabetes: immune pathogenesis
GENE SET 3:
Pathogen
susceptibility
DC
IL-10
3. Via blood
TH
TRegulatory
α
TCytotoxic
β cells
HLA II
TCytotoxic
CTL
DC
1. Islet
HLA I
DC
Insulin
2. Pancreatic
lymph node
THelper
Type 1 diabetes: immune pathogenesis
GENE SET 3:
Pathogen
susceptibility
DC
IL-10
3. Via blood
TH
TR
α
TCytotoxic
β cells
HLA II
TCytotoxic
CTL
DC
1. Islet
HLA I
THelper
GENE SET 2:
Immune
regulation
GENE SET 1: Ag
presentation to
T cells
DC
Insulin
2. Pancreatic
lymph node
GENE SET 1: Ag
presentation to
T cells
Epitope discovery
β cell
TCytotoxic
DC
30
% Specific lysis
HLA
HLA-A2+ human
islets with 1E6
clone
20
Tcytotoxic cells targeting
insulin kill human β-cells.
10
A2+ islets/control clone
A2- islets/1E6 clone
0
1
3
6
12
25
Number of Effectors per Target
Are these cells in the
islets where β-cells are
killed?
In situ
staining for
antigenspecific T cells
Insulinspecific
T cells
Coppieters et al, JEM, 2012
GENE SET 1: Ag
presentation to
T cells
Crystal
β cell
TCytotoxic
DC
A2+ human islets
with 1E6 clone
% Specific lysis
30
20
Tcytotoxic cells targeting
insulin kill human β-cells.
10
A2+ islets/control clone
A2- islets/1E6 clone
0
1
3
6
12
25
Number of Effectors per Target
How does this
interaction look at the
molecular level?
CTL
β cell
Dissociation constant Kd ~250μM
(ie ultra-low vs tumour antigens
(~50 μM) or virus (~5 μM))
In press
Killer T cell
α-chain
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-chain
TcR
insulin peptide
HLA-A2 (*0201)
β-cell
•Bulek et al, Nat Imm 2012
•Major opportunities for cross-reactivity
•The antigenic peptide that primed killer T cells may not be
from insulin originally
GENE SET 2:
Immune
regulation
GENE SET 2:
Immune
regulation
7.5y
No IL-10
response
IL-10
response
Balance of islet-specific TH
cells in peripheral blood in
Type 1 diabetes is abnormal
•Candidate genes: CD25,
CTLA4, IL-10
GENE SET 3:
Pathogen
susceptibility
GENE SET 3:
Pathogen
susceptibility
Candidate
genes:
IFIH1
EBI2
TLR7/TLR8
BACH2
FUT2
Sense pathogens:
Set “response rheostat”
3. Via blood
α
TCytotoxic
β cells
HLA II
TCytotoxic
CTL
DC
1. Islet
HLA I
DC
Insulin
2. Pancreatic
lymph node
THelper
Type 1 diabetes: the model
GENE SET 3:
Pathogen
susceptibility
DC
IL-10
3. Via blood
TH
TR
α
TCytotoxic
β cells
THelper
HLA II
GENE SET 2:
Immune
regulation
TCytotoxic
CTL
DC
1. Islet
HLA I
DC
Insulin
2. Pancreatic
lymph node
B
GENE SET 1: Ag
presentation to
T cells
Islet cell AAbs
Therapeutic options in T1D:
“immune suppression”
• Anti-CD3, transient depletion of T cells
• Rituximab, anti-CD20, depletes B cells
• Abatacept, CTLA4-Ig, co-stimulation blockade
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
5
IL-10 (SI)
4
3
* **
2
5µM
10µM
•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
1
0
0 3 6 0 3 6
month of study
10g
placebo
•No pro-inflammatory cytokine
induction
•Improved glycaemic control
Phase Ib
(New T1D)
Monthly
Peptide
administration
Bi-weekly
0
3
Month of study
Developmental
programme
(Phase I in 2014)
•Multiple peptides from >1 β-cell antigen
6
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