β-cell Preservation and Regeneration After Islet Transplantation

Transcription

1 β-cell Preservation and Regeneration After Islet Transplantation Jyuhn-Huarng Juang, MD Division of Endocrinology and Metabolism, Department of Internal Medicine, Chang Gung University and Memorial Hospital, TAIWAN

2 Nature History of Type 1 Diabetes N Engl J Med 1986; 314:

3 Human Islet Transplantation

4 Human Islet Transplantation Insulin independence: at 1 year Year rate patient no % 493 (total) % 237 (type 1)

5 Human Islet Transplantation Insulin independence: at 1 year Year rate patient no % 493 (total) % 237 (type 1) % (SIK) Giessen 27% (IAK)

6 Human Islet Transplantation Insulin independence: at 1 year Year rate patient no % 493 (total) % 237 (type 1) % (SIK) Giessen 27% (IAK) % (ITA) 7 (Edmonton) % (ITA) 33 (Edmonton)

7 Human Islet Transplantation Insulin independence: at 1 year Year rate patient no % 493 (total) % 237 (type 1) % (SIK) 27% (IAK) % (ITA) 7 (Edmonton) % (ITA) 33 (Edmonton) % 36 (9 sites)

8 Edmonton Protocol (Shapiro AMJ et al. N Engl J Med 2000;343:230-8) High quality of human islets Glucocorticoid-free immunosuppressive regimen Repeat transplants

9 Human Islet Transplantation Insulin Independence and Graft Function (Edmonton)

10 Graftβ-Cell Preservation and Regeneration Prevent rejection and autoimmune destruction Enhance islet engraftment Promote beta-cell regeneration

11 Prevention of Rejection and Autoimmune Destruction Immunosuppression Immunomodulation Immunoisolation Tolerance induction

12 Approaches to Prevent Rejection and Autoimmune Destruction Microcapsule Hsu BRS et al. Transplant Proc 1996 Cell Transplant 1999 CTLA4 Ig Lu WT et al. Transplant Proc 2001 FasL/HO-1 Tg Juang JH et al. Transplant Proc 2011 DCR3 Tg Sung HH et al. J Exp Med 2004 Rejection Autoimmune

13 Immunoisolation Microparticle Generator Alginate-Poly-L-Lysine-Alginate (APA) Microcapsule Immunoglobulin Glucose Islet Insulin Hsu BRS et al., J Formos Med Assoc 93:240-5, 1994.

14 APA Microencapsuled Rat Islets IL-1ra 15-DSG fibrosis X Macrophage IL-1β X Islet Hsu BRS et al., Cell Transplant 8:307-15, Hsu BRS et al., Transplant Proc 28:1961-3, 1996.

15 DCR3 Transgenic Islets Prevented Autoimmune Destruction Overexpression of DCR3 Protected NOD from Insulitis NOD Mice (12 wks) DCR3 Transgenic Islet Transplantation in NOD Mice DCR3 Transgenic NOD Mice Sung H-H, Juang J-H et al. J Exp Med 2004;199:

16 Graftβ-Cell Preservation and Regeneration Prevent rejection and autoimmune destruction Enhance islet engraftment Promote beta-cell regeneration

17 Problems Related to Islet Engraftment Hyperglycemia Hypoperfusion Hypoxia Ischemia/Reperfusion Nonspecific inflammatory response

18 Approaches to Enhance the Islet Engraftment Additional Islets Juang JH et al. Insulin Juang JH et al. Transplant Proc HBO Juang JH et al. Cell Transplant Pentoxiphylline Juang JH et al. Transplant Proc NDGA Hsu BRS et al. Cell Transplant DSG Juang JH et al. Transplant Proc Diabetes COPP Fu SH et al. Transplant Proc 2004 Islet Growth and Function Rosiglitazone Hsu BRS et al. Transplant Proc 2005 Outcome of Islet Transplantation

19 Beneficial Influence of Additional Islets on Syngeneic Mouse Islet Transplantation Blood Glucose (mg/dl) Tx with 200 islets (n=22) Tx with 200X2 islets (n=53) P<0.001 vs. data at day Graft Removal (n=16) Nephrectomy (n=6) Sham operation (n=5) p < 0.05, p < 0.01 vs. data at day Days after Transplantation Days after Nephrectomy or Graft Removal Juang JH et al., Diabetes 1994;43:1334-9

20 Beta-Cell Mass and Insulin Content of the Graft Graft Removal P<0.01 vs. 200 islets and day Sham Operation 9 P<0.05 vs. day 14 Beta-Cell Mass (mg) Islets 0 14 Days after Graft Removal or Sham Operation Insulin Content (µg) Islets 0 14 Days after Graft Removal or Sham Operation Juang JH et al., Diabetes 1994;43:1334-9

21 Replication Rate of Islet Grafts Replication Rate (%/4h)1.4 Graft Removal Sham Removal p < 0.02 vs. other groups in graft removal, and p < 0.04 vs. day 3 in sham operation Days after One Graft Removal or Sham Removal Juang JH et al., Diabetes 1994;43:1334-9

22 Effect of Insulin Treatment on Syngeneic Mouse Islet Transplantation Blood Glucose (mg/dl) NS (n=16) UT (n=30) P<0.05, P<0.01, P<0.001 vs. NS Ultratard or NS sc qd Days After Transplantation Juang JH et al., Transplant Proc 1998;30:576-7.

23 Blood Glucose Changes After Transplantation 500 Control (n=16) UT-A (n=30) UT-B (n=7) UT-B+A (n=5) Blood Glucose (mg/dl) P<0.05 vs. NS Days After Transplantation Juang JH et al., Transplant Proc 1998;30:576-7.

24 Beta-Cell Mass of Mouse Islet Grafts At 4 Weeks After Transplantation 0.5 Beta-Cell Mass (mg) P<0.05 vs. Control 0 Control UT-B UT-A UT-B+A Juang JH et al., Transplant Proc 1998;30:576-7.

25 Graftβ-Cell Preservation and Regeneration Prevent rejection and autoimmune destruction Enhance islet engraftment Promote beta-cell regeneration

26 Regeneration Therapy in Islet Recipients β-cell Mass Graft Failure Islet Regeneration Insulin independence threshold Islet Transplant Time

27 Pancreatic Targets for Expansion of β-cell Mass Annu Rev Med 2006;57:265 81

28 GLP-1 on β-cell Mass β-cell Endocrine Reviews 2007;28:

29 Exenatide in Clinical Islet Transplantation 1 EXENATIDE 3 2 ISLETS 1 Exenatide reduces the number of islet infusions to achieve normoglycemia (Am J Transplant 2008;8: ) 2 Exenatide rescues islet recipients with allograft dysfunction (Transplantation 2008;86:36 45) 3 Exenatide improves success rates in recipients with supplemental islet infusions (Transplantation 2008;86: )

30 Exendin-4 Improves Outcome of Syngeneic Mouse Islet Transplantation Blood Glucose Diabetes (%) Blood Glucose (mg/dl) 500 P<0.05 vs. control Control (n=17) Exendin-4 (n=16) Days After Transplantation Diabetes (%) Days After Transplantation Juang JH et al., Cell Transplant 17:641-7, 2008 P=0.012 vs. control Control (47.5%) Exendin-4

31 Exendin-4 Expands Mouse Graft β-cell Mass Mouse Islet Graft at 6 Weeks Insulin Staining Exendin-4 Control β-cell Mass 100 µm 100 µm Juang JH et al., Cell Transplant 17:641-7, 2008

32 Exendin-4 Prevents Mouse Graft β-cell Apoptosis and Preserves Graft β-cell Mass β-cell Area Apoptosis Toyoda K et al. Biochem Biophys Res Commun 367:793-9, 2008

33 Liraglutide Prevents Mouse Graft β-cell Apoptosis But Does Not Promote β-cell Proliferation 48 hr Apoptotic β-cells (%) 2 wk BrdU+ β-cells (%) Merani S et al. Endocrinology 149: , 2008

34 Sitagliptin Prolongs Mouse Islet Graft Survival Islets: infected with rad-tk to allow [ 18 F]FHBG PET imaging Kim S-J et al. Diabetes 57:1331 9, 2008

35 Effects of Dipeptidyl Peptidase-4 Inhibition on Syngeneic Mouse Islet Transplantation Blood Glucose MK-0431 LAF 237 P=0.001 Juang JH et al. Diabetes 61 (suppl 1):A409, 2012

36 Effects of Dipeptidyl Peptidase-4 Inhibition on Syngeneic Mouse Islet Transplantation Body Weight MK-0431 LAF 237 P=0.057 Juang JH et al. Diabetes 61 (suppl 1):A409, 2012

37 Effects of Dipeptidyl Peptidase-4 Inhibition on Syngeneic Mouse Islet Transplantation Insulin Content and β-cell Mass MK-0431 LAF 237 Control MK insulin content (ng) β-cell mass (mg) Juang JH et al. Diabetes 61 (suppl 1):A409, 2012

38 Islet Transplantation Graft β-cell Preservation and Regeneration A Cure for Diabetes

39 CGMH Islet Transplant Team Grant Support National Science Council, Taiwan Industrial Technology Research Institute, Taiwan Chang Gung Memorial Hospital, Taiwan