Baylor Annette C. and Harold C. Simmons Transplant Institute,
Baylor University Medical Center, Dallas
Baylor All Saints Medical Center, Ft. Worth
Disclosures
• No commercial disclosures
• Off-label use: Kineret, Enbrel
• Grant Support
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–
–
–
–
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National Institutes of Health (2)
Juvenile Diabetes Research Foundation (5)
Baylor Health Care System Foundation
All Saints Health Foundation
TikoMed
Dompé
Pancreas and Islets
Dithizone staining islets
Maintenance normal glucose
Trucco M. J Clin Invest. 2005;115:5
Insulin/Glucagon
Production
Glucose sensor
Release
insulin/glucagon
Bashoo Naziruddin, PhD
Director, Islet Cell Research/Islet Cell Processing Laboratory
Michael Lawrence, PhD
Assistant Investigator
Baylor Research Institute
Morihito Takita, MD, PhD
Assistant Investigator
Baylor Research Institute
Allogeneic Islet Transplantation
PLoS Med. 2004;1(3):e58
Autologous Islet Transplantation
Major Characteristics of Allogeneic versus
Autologous Islet Transplantation
Allogeneic
Autologous
Pancreas
Acute inflammation due to cytokine
storm related to brain death
Chronic inflammation due to disease
process
Disease
Immunosuppression
“Brittle” type 1 diabetes
Refractory chronic pancreatitis
Induction and maintenance
immunosuppression required
None
Autoimmune response
Patients inherently have
autoimmune response to islet
antigens
Due to multiple infusions of islets
isolated from different donors and
transplant HLA mis-matching, HLA
sensitization is an issue
Most patients do not have
autoimmune response to islet
antigens
None
Long-term islet survival is unclear,
with 15% to 50% insulin
independence at 5 years
After patients attain insulin
independence, sustenance of islet
function is better compared to
allogenic transplants
Alloimmune response
Outcome
Baylor Progress
March 2005 Started islet allo-transplant for type 1
diabetes
August 2006 Started islet isolation at Baylor
November 2006 Started islet auto-transplant for
chronic pancreatitis
So far total 111 islet transplants: 27 allo-transplants
and 86 auto-transplants performed
Auto Vs Allo - Graft Function
Sutherland et al, Transplantation 2008;86:1799-1802.
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pblsurgeryny.com
Yamauchi F I et al. Radiographics 2012;32:743-764
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AIT Centers
Leicester
Minneapolis
Geneva
Baylor
South Carolina
Alabama
Samsung
Indication for Autologous Islet Transplantation following
Total Pancreatectomy—Baylor University Medical Center
• Diagnosed with Chronic Pancreatitis by a treating Gastroenterologist or Pancreatologist
or other indications as jointly agreed upon by Islet Transplant Surgeon and
Pancreatologist
• Narcotic dependence for chronic pain of pancreatitis
• Prior procedures (celiac block or pancreatic duct stents) which have failed or only
provided temporary pain relief
• Self-reported poor quality of life with use of a formal scale
• Ability to understand/give informed consent
Contraindications
•
•
•
•
•
•
•
•
Known or suspected pancreatic malignancy
Portal hypertension or significant hepatic fibrosis
Cardiac contraindication to major abdominal operation
Pulmonary contraindication to major abdominal operation
Ongoing non-prescribed substance abuse, including alcohol
Profound uncorrected malnutrition
C-peptide negative (Directed for pancreatectomy alone)
Inability to understand/give informed consent
Patient Characteristics before TP-AIT (n=83)
—Baylor University Medical Center at Dallas
• Age (Average ± S.D.): 40.6 ± 11.0 yrs
• Gender: Female— n=57 (69%)
• Body weight and BMI: 74.8 ± 17.7 kg and 26.6 ± 5.6 kg/m2
• Symptom duration: 8.0 ± 7.5 yrs
• Etiology of CP:
8%
6%
4%
5%
Idiopathic
48%
Pancreatic divisum
Hereditary
13%
Alcohol
16%
Autoimmune
Sphincter of Oddi dysfunction
Other
• Smoking: n=21, 25%
• Hypertension: n=30, 36%
33%
BMI<23
BMI≥23
Patient Characteristics before TP-AIT (n=83 in total)
—Baylor University Medical Center at Dallas
Pancreatic endocrine function
20%
• HbA1c (Average ± S.D.): 6.0 ± 1.2 %
50%
30%
• Fasting C-peptide: 2.0 ± 1.2 ng/mL
• Stimulated (by 75g OGTT) C-peptide: 5.8 ± 3.6 ng/mL
• Δ C-peptide: 3.9 ± 2.9 ng/mL
Pain Care
•
•
•
•
5.7 — 6.4
6.5% ≥ HbA1c
D o s e ( IE /k g P a t ie n t w e ig h t )
• Diabetes medication: n=14 (17%)
• Insulin therapy: n=8
• Metformin: n=6
HbA1c<5.7%
Spearman r = 0.52
p < 0.001
Pain score (0 [no pain ] to 10 [worst pain ] ): 7 ± 2
Narcotic dependent: n=77 (93%)
History of endoscopic celiac plexus block: 95% in recent 21 pts, 1 ― 7 times
Morphine equivalent dose: 183 ± 185 mg/day
Patient Characteristics before TP-AIT (n=83)
—Baylor University Medical Center at Dallas
History of pancreatic surgery
• n=10 (12%)
• Puestow procedure (Pancreaticojejunostomy): n=4
• Whipple resection (Pancreaticoduodenectomy): n=4
• Distal pancreatectomy: n=2
History of endoscopic procedure (in recent 20 pts)
• Placement of pancreatic duct stent: 57%
• Sphincterotomy (EST): 45%
Transplantation 2010; 90(4):458
Baylor cGMP Islet Processing
Laboratory
Baylor Institute for
Immunology Research
BUMC Roberts Hospital
Clean Room
Class 100
Class 10,000
Class 100,000
Received FDA Approval in 2006
Islet Transplantation – Regulatory Compliance
 Follow current Good Manufacturing Practices defined by
Food and Drug Administration (FDA)
 Dynamic, ever changing process
 Code of Federal Regulations
 21 CFR Parts 210 and 211 (cGMP)
 21 CFR 610 (product)
 21 CFR 11 (electronic records and signatures)
 21 CFR 1271 (GTP for Cell & Tissue)
 Regulations concern the facilities, controls, recordkeeping,
labeling, reporting, inspections, QC program
Islet Product Release
 Product release tests are
performed before transplant
(except potency test)
 QA verifies the results with
source documents
 QA and Laboratory Director
release the islet product to the
Medical Director
 Medical Director determines the
disposition of the islet product
(Transplant or Research or
Discard)
TP-AIT at Baylor University Medical Center
Total islet yield (IEQ)
1,000,000
800,000
600,000
400,000
200,000
0
Isolation ID
Year
2006 2009
2010
2011
2012
2013
2014
TP-AIT at Baylor University Medical Center
>5,000 IEQ/kg
Islet dose (IEQ/kg of patient body weight)
2,500-5,000 IEQ
20%
47%
<2,500 IEQ/kg
33%
10,000
5,000
0
Isolation ID
Year
2006 2009
2010
2011
2012
2013
2014
TP-AIT at Baylor University Medical Center
Tissue volume post-pancreas digestion (mL)
80
60
40
Purification (n=39, 47%)
20
0
Year
2006 2009
2010
2011
2012
2013
2014
TP-AIT at Baylor University Medical Center
Final tissue volume post-purification (mL)
80
60
40
Purification (n=39, 47%)
20
0
Year
2006 2009
2010
2011
2012
2013
2014
The Outcome
Significant improvement in pain
Pain Score
Before TP-AIT
10
p <0.0001
8
7%
Narcoticsdependent
6
4
Narcoticsfree
2
0
Pre-TP/AIT
1 yr post-TP/AIT
93%
Morphine equivalent dose (mg/day)
Narcotic Medication
250
p <0.0001
200
29%
150
100
50
71%
0
Pre-TP/AIT
1 yr post-TP/AIT
1 yr after TP-AIT
The Outcome
Preservation of pancreatic endocrine function
All Patients (n=81)
Achievement
of Insulin
Independence
32%
Patients followed up over 1yr (n=51)
Achievement
of Insulin
Independence
41%
Insulin
Dependent
59%
Insulin
Dependent
68%
Follow up: 23.7 ± 2.2 months
Follow up: 16.7 ± 1.7 (Avg±SE) months
Glycemic control―Hemoglobin A1c
9.0
p <0.01
8.0
29%
17%
HbA1c<5.7%
5.7 — 6.4
6.5 — 7.0
7.0
7% ≤HbA1c
6.0
12%
42%
5.0
4.0
Pre-TP/AIT
Post-TP/AIT
n=81, Ave ± SE are shown.
71%—HbA1c<7.0
AIT Summary
• Autologous islet transplantation is a viable
treatment option for severe cases of Chronic
Pancreatitis
• cGMP islet isolation facility is required to
perform islet isolation
• The outcomes following islet transplantation
are excellent in terms of freedom from pain
with acceptable glycemic control.
Medians:
A = 16.6 yrs
B = 12.9 yrs
Detection of Instant Blood Mediated
Inflammatory Reaction in Autologous Islet
Transplantation
Islet Transplant Program
Baylor Annette C. and Harold C. Simmons Transplant Institute
Dallas-Fort Worth, Texas
Islet Graft Function post-transplant
Variables
Month 1
Single Blockage group Double Blockage group
p value
(n=28)
(n=36)
Fasting C-peptide (ng/mL)
0.9 ± 0.2
1.1 ± 0.2
0.42
HbA1c (%)
6.2 ± 0.2
5.8 ± 0.2
0.21
(n=18)
(n=22)
Fasting C-peptide (ng/mL)
1.2 ± 0.2
1.9 ± 0.3
0.06
Fasting glucose (mg/dL)
142 ± 13
115 ± 7
0.07
29 ± 6
47 ± 7
0.049
6.6 ± 0.2
6.2 ± 0.1
0.17
Month 3
SUITO index
HbA1c (%)
Average ± S.E. are shown.
Mɸ
DC
Ne
Anakinra
DC
ERK
IL-1β
TNF-α
T cell
Mɸ
WA
function
Etanercept
NFAT
NFκB
IP-10
p38
JNK
apoptosis WA
SB203580
SP600125
BMS-936557
β cell
Targeting NFκB and Nuclear Factor of Activated T-cells signaling to improve islet transplantion
ERK
2. Signal Transduction
3. Gene expression
Anakinra
Etanercept
IL-1β, TNF-α
1. Receptor Signaling
p38
JNK
Co-regulators
NFAT
SB203580
SP600125
NFκB
WA
ITF2357
Proinflammatory genes
Beta-cell
Function
Inflammation
Apoptosis
Acknowledgement
Transplant Services
Goran Klintmalm, MD, PhD
Robert Goldstein, MD
Giuliano Testa , MD
Nicholas Onaca, MD
Peter Kim, MD
Tiffany Anthony MD
Greg McKenna, MD
Richard Ruiz, MD
Sharon Bruer, RN
Endocrinology
Gastroenterology
James S. Burdick, MD
Islet Isolation Team
Bashoo Naziruddin, PhD
Michael Lawrence, PhD
Morihito Takita, MD PhD
Rauf Shahbazov, MD PhD
Faisal Kunnathodi, PhD
Mazhar Kanak, MS
Yoshiko Tamura
Ana Rahman
Nofit Borenstein
Benjamin Thomas
Research
Michelle Acker, RN
Kerri Purcell, RN
Sonnya Coultrup
IT
Jennifer Peattie
Darrell Grimes
Linda Jennings, PhD
Administration
Janice Whitmire
Betsy Stein
Stacie Eglinsdoerfer
Regina Whitaker
QA/QC
Patricia Phipps
Philip Cross
Financial Support by
BHCS Foundation
All Saints Health Foundation
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