Prolonged Diabetes Reversal after intraportal
xenotransplantation of wild-type porcine islets in
immunosuppressed nonhuman primates
Hering et al, Nature Medicine 12:301-303, 2006
• Reversal Diabetes > 100 days Porcine islet
transplants into streptozotocin diabetic
cynomolgus macaques
• Required Rx with toxic regimen including antiCD154, leflunomide, basiliximab, FTY720 and
everolimus
• No Gal-specific antibody mediated hyperacute
rejection
Five-Year Follow-Up After Clinical Islet
Transplantation
Ryan et al, Diabetes 54:2060-2069, 2005.
Percent derived from life Table
100
80
60
40
20
0
0
12
24
% Cpep Positive
36
48
% Insulin Independent
Months of Follow-up
60
Issues in Islet Graft
Transplantation
•Allograft immunity
•Xenograft immunity
•Autoimmunity
Transplant
Immunity
Autoimmunity
Islets
World Experience in Organ / Tissue
Transplantation
Kidney
>500,000
Heart
>50,000
Pancreas
>13,000
Islet
600000
500000
400000
300000
200000
100000
0
<500
Number of transplants
Clinical Experience in Islet Transplantation
Autografts: islets obtained from the recipient to
prevent pancreatectomy-induced diabetes
Allografts: islets obtained from an unrelated
donor to prevent pancreatectomy-induced diabetes
Allografts + IDDM: islets obtained from an unrelated
donor after or at the same time as kidney transplantation
Islet Transplantation Registry
% Insulin-Independence
1990 - 1997
100
90
80
Autografts (n=50, 50%)
70
60
50
40
Allografts (n=15, 40%)
30
20
10
0
Allografts + IDDM (n=200, 8%)
0
1
2
3
4
5
6
7
8
9
Months post-transplantation
10
11
12
Possible Reasons for Islet Graft Failure
Insufficient islet mass
Poor quality of islets
Failure to engraft
Insulin resistance
Islets
Toxicity of antirejection drugs
Disease recurrence
Allograft rejection
`Edmonton’ Protocol
University of Alberta, Edmonton, Alberta
J. Shapiro, M.D.
R. Rajotte, Ph.D.
•
Islet-alone transplantation trial
•
Type 1 diabetic patients received two transplants
of large numbers of high quality islets.
•
Standard immunosuppressive therapy was
replaced with a steroid-free protocol:
Daclizumab (D ZB) (anti-IL2 receptor antibody)
Daily doses of sirolimus and low-dose tacrolimus
Eligibility Criteria
• 18-55 years of
•
age,
have had IDDM for >5 years
Hypoglycemia unawareness requiring medical assistance
•
Uncontrolled blood sugars despite intensive insulin therapy
(“ brittle diabetes”).
•
Evidence of early diabetic nephropathy or other secondary
complications
Exclusion Criteria
•
cardiac disease or psychiatric illness
•
active alcohol or substance abuse
•
previous transplant
•
a history of malignancy or abnormal liver function
•
an active infection (HIV, Hepatitis B or C, TB)
`Edmonton Protocol’
Results
•
13 consecutive cases of insulin-independence with a
duration of (longest > 2.5 years)
•
normalization of HbA1C values (mean of 5.7% at
3 and 6 months post-transplantation)
•
•
no episodes of hypoglycemia
no episodes of acute rejection and minimal toxicity
from anti-rejection drug therapy
Blood glucose (mg/dl)
600
Blood glucose (mg/dl)
600
Pre-transplant
500
400
300
200
100
0
500
Shapiro et al.
N Engl J Med 2000;
343:230-238
Post-transplant
400
300
200
100
0
2
4
6 8 10 12
a.m.
2
4
Time of day
6
8 10 12
p.m.
Islet Transplantation: The NIH Experience
Diabetes Care 2003: 26:3288-95
• Major Procedure Complications
Partial portal vein thrombosis
Intra-abdominal hemorrhage
• Immunosupression Complications
Kidney Toxicity
Sirolimun-induced Pneumonitis
• Three Patients Discontinued Immunotherapy
½ Patients insulin-independent at one year
Decreased Hypoglycemia and less severe Hypoglycemia
Percent 4 Year Survival with Pancreas Transplant
Ventrom et al JAMA 2003; 290: 2817-2823
100
90
80
70
60
50
40
30
20
10
0
Panc Alone
Panc after Kidney
Transplanted
Combined Panc Kidney
Waiting List
Future Directions
• Reduce requirement to single pancreas / recipient
•
Interventions to reduce peri-transplant inflammation
• Progress towards ‘tolerizing’ strategies
Alternative sources of tissue
• insulin-producing cell lines
• stem cells
• xenografts (other species)
Experimental Islet Transplantation
C57Bl/6 mouse (H-2b)
Remove
pancreas
Isolate
islets
Streptozotocin-induced diabetic
BALB/c mouse (H-2d)
Transplant islets
under kidney capsule
Key Components to Islet Allograft
Cellular Rejection
•
Donor-derived APCs
•
Donor MHC class I expression
•
Host CD8 T cells
•
Variable requirement for CD4 T
cell help
Key Components to Islet Xenograft
Cellular Rejection
• Host-derived APCs
• Host MHC class II expression
• Host CD4 T cells
Conclusion / Hypothesis
•
Allograft Rejection --> Predominant CD8-
•
Xenograft Rejection and Autoimmune
pathogenesis --> Predominant CD4-
dependent ‘direct’ recognition
dependent ‘indirect’ recognition
Anti-LFA-1 Therapy Facilitates Long-Term
Islet Allograft Acceptance
(C57Bl/6 --> BALB/c)
% Grafts Functioning
100
80
60
Anti-LFA-1 (n = 20)
Control Ig (n = 10)
40
20
0
0
20
40
60
80
100
Days Post Transplantation
Failure of Anti-LFA-1 to Prevent Disease
Recurrence
(NOD --> NOD)
% Grafts Functioning
100
80
Untreated (n = 10)
60
Anti-LFA-1 (n = 8)
40
Young SZ-NOD (n = 3)
20
0
0
20
40
60
80
Days Post Transplantation
100
% Grafts Functioning
Anti-CD4 but not anti-CD8 therapy prevents
acute disease recurrence in NOD mice
100
80
Untreated (n=8)
Anti-CD8 (116-13.1; n=10)
60
Anti-CD4 (GK1.5; n=9)
40
20
0
0
20
40
60
80
100
Days Post-transplantation
The Stimulator Cell Model
C
(1)
APC
T(C)
C
(2)
T (C)
C
CoS
C
b cell
C
C
T(C)
(1)
No
Response
DIRECT
A
(1)
DONOR
A
APC
(2)
T(A)
T (A)
T(B.X)
T(B.X)
A
Shed Graft
Antigens
INDIRECT
x
(X)
B
HOST
APC
B
x
(1)
B
x
(2)
CD4
T Cell
B Cell
Help
Delayed-Type
Hypersensitivity
GRAFT
CD8 T Cell
Help
'INDIRECT'
Shed graft
antigen (X)
x
II
HOST
APC
II x
CD4
II (x)
II
x
APC-depleted
islet allograft
CD8I
No direct
response
TOLERANCE
Shed graft
antigen (X)
INDIRECT
x
II
HOST
APC
II
x
CD4
II x
II (X)
(
)
DIRECT
I
APC-depleted
islet allograft
CD8 I
DONOR
APC
I
I