2010 - TTS International Congress


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Islet and Pancreas Transplantation I

103.5 - A novel approach to prevent early loss of transplanted islets by targeting donor islets with a PPARγ agonist prior to transplantation

Presenter: Toshiyuki, Mera, Fukuoka, Japan
Authors: Mera T., Kojima D., Itoh T., Matsuoka N., Ono J., Kodama S., Yasunami Y.

A NOVEL APPROACH TO PREVENT EARLY LOSS OF TRANSPLANTED ISLETS BY TARGETING DONOR ISLETS WITH A PPAR? AGONIST PRIOR TO TRANSPLANTATION

ISLET AND PANCREAS TRANSPLANTATION I

T. Mera1, D. Kojima1, T. Itoh2, N. Matsuoka1, J. Ono3, S. Kodama1, Y. Yasunami4
1Regenerative Medicine And Transplantation, Fukuoka University, Fukuoka/JAPAN, 2, Baylor Research Institute, Dallas/UNITED STATES OF AMERICA, 3, Murakami Karindoh Hospital, Fukuoka/JAPAN, 4Department Of Regenerative Medicine And Transplantation, Fukuoka University, Fukuoka/JAPAN

Body:
Introduction: The limited success in achieving insulin-independence of IDDM recipients from a single donor hampers clinical application of islet transplantation. A major reason for this includesearly loss of transplanted islets in the liver, the site of transplantation, in association with engraftments. Previously, we have shown that NKT cell-dependent IFN-γ production ofGr-1+CD11b+ cells in the liver triggered by HMGB1 released from islets themselves plays an essential role in early loss of transplanted islets in mice (JEM 2005, JCI 2010). Here we demonstrate thatHMGB1 release from islets is induced by hypoxia and that the in vitro pretreatment of islets with a PPARγ agonist (pioglitazone; Pio) alleviates islet cell damage in hypoxia facilitatingto prevent early loss of transplanted islets. Methods and Results: we first confirmed the expression of PPARγ on pancreatic islet β cells immunohistochemically. Islet celldamage was assessed by fluorescent microscopy to evaluate islet cell damage with PI and HO342 stain. To examine the effect of hypoxia on islet cell damage , isolated mouse islets (C57BL/6) wereplaced in a chamber at 37C filled with hypoxic gas (1%O2+5%CO2+94%N2) in which O2 concentration dropped to 20mmHg within 30 min and maintained the same level for more than 24 hours. Islets culturedin CO2 incubator (5%CO2+95% air) served as controls in which O2 concentration was 130-150mmHg (normoxia). When islets were cultured in normoxia, islets remained intact morphologically by 24 hours. Incontrast, islets became degenerated with central necrosis when cultured in hypoxia for more than 6 hours. Importantly, the central necrosis at 6 hrs was not seen in islets pretreated with Pio(10μM, 3hrs) prior to the hypoxic culture. The beneficial effect of Pio was abolished when anti-PPARγ was added to the culture medium with Pio. The amount of HMGB1 (ng/ml)in the medium of islets in hypoxia was increased with time, which was significantly decreased in the culture medium of islets pretreated with Pio at 12 and 24 hours (6 hrs; 2.1+-0.7 (n=5) vs2.0+-1.1, 12 hrs; 7.5+-2.7 vs 4.5+-0.9*, 24hrs; 10.6+-1.6 vs 7.5+-1.2*). The amount of HMGB1 in the culture medium of islets in normoxia remained low by 24 hours (6hrs; 0.5+-0.4 (n=5), 12hrs;1.1+-0.4, 24hrs; 0.1+-0.2). When 200 syngenic islets, the number of islets from one donor, were grafted into the liver of STZ-diabetic mice (C57BL/6), recipient mice remained hyperglycemic aftertransplantation. In contrast, diabetic mice became normoglycemic when donor islets were pretreated with Pio prior to transplantation and grafted into the liver. Diabetic mice receiving 200 isletspretreated with pio and anti-PPARγ antibody remained hyperglycemic and those receiving islets pretreated with Pio and control ab became normoglycemic after transplantation. Conclusions:These findings clearly demonstrate that hypoxic islet cell death is alleviated by the pretreatment of islets with Pio and afford a novel approach to prevent early loss of transplanted islets bytargeting donor islets prior to transplantation. The molecular mechanism involved in the effect by PPAR-γ on hypoxic islet cell death is currently under investigation.

Disclosure: All authors have declared no conflicts of interest.


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