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
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Who gets the autoimmune disease Type 1 diabetes, and why?
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” - PowerPoint PPT Presentation
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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
“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)