The goal of this proposal is to determine the potential of immunobarrier technology to protect transplanted islets. We hypothesize that there are important differences in what is required for protection against autoimmunity, allorejection and xenorejection. It is expected that genetic manipulation of the encapsulated islets can further reduce damage from these processes.
Aim 1. To define the immunobarrier requirements for protection against the separate processes of autoimmunity, allorejection and xenorejection. Alginate microcapsules with and without polylysine coating will be tested for their ability to protect against these different immune mechanisms in mouse recipients. NOD mice will be used to study autoimrnunity. For xenorejection studies, rat islets and porcine neonatal pancreatic cell clusters will be used as a donor source.
Aim 2. To improve the outcomes of encapsulated islets with gene transfer approaches. One strategy is to make encapsulated islets better able to resist hypoxic and irnmune injury through the use of the antiapoptotic genes A20 and Bc1-2. The other is to engineer the islets to secrete peptides, in particular CTLA4 and TGF-p, that may modulate the immune attack surrounding the capsules.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK050657-06
Application #
6498105
Study Section
Surgery and Bioengineering Study Section (SB)
Program Officer
Appel, Michael C
Project Start
1996-02-10
Project End
2005-01-31
Budget Start
2002-02-01
Budget End
2003-01-31
Support Year
6
Fiscal Year
2002
Total Cost
$291,375
Indirect Cost
Name
Joslin Diabetes Center
Department
Type
DUNS #
071723084
City
Boston
State
MA
Country
United States
Zip Code
02215
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Fernandes, Justin R; Duvivier-Kali, Valerie F; Keegan, Mitchell et al. (2004) Transplantation of islets transduced with CTLA4-Ig and TGFbeta using adenovirus and lentivirus vectors. Transpl Immunol 13:191-200

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