Abstract

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK050657-05A1
Application #
6286618
Study Section
Surgery and Bioengineering Study Section (SB)
Program Officer
Eggerman, Thomas L
Project Start
1996-02-10
Project End
2005-01-31
Budget Start
2001-02-15
Budget End
2002-01-31
Support Year
5
Fiscal Year
2001
Total Cost
$291,375
Indirect Cost

  Institution

Name
Joslin Diabetes Center
Department
Type
DUNS #
071723084
City
Boston
State
MA
Country
United States
Zip Code
02215

  Publications

Weir, Gordon C; Bonner-Weir, Susan (2013) Islet ýý cell mass in diabetes and how it relates to function, birth, and death. Ann N Y Acad Sci 1281:92-105
O'Sullivan, Esther S; Vegas, Arturo; Anderson, Daniel G et al. (2011) Islets transplanted in immunoisolation devices: a review of the progress and the challenges that remain. Endocr Rev 32:827-44
Johnson, Amy S; O'Sullivan, Esther; D'Aoust, Laura N et al. (2011) Quantitative assessment of islets of Langerhans encapsulated in alginate. Tissue Eng Part C Methods 17:435-49
O'Sullivan, E S; Johnson, A S; Omer, A et al. (2010) Rat islet cell aggregates are superior to islets for transplantation in microcapsules. Diabetologia 53:937-945
Laybutt, D R; Hawkins, Y C; Lock, J et al. (2007) Influence of diabetes on the loss of beta cell differentiation after islet transplantation in rats. Diabetologia 50:2117-25
Ahn, Y B; Xu, G; Marselli, L et al. (2007) Changes in gene expression in beta cells after islet isolation and transplantation using laser-capture microdissection. Diabetologia 50:334-42
Omer, Abdulkadir; Duvivier-Kali, Valerie; Fernandes, Justin et al. (2005) Long-term normoglycemia in rats receiving transplants with encapsulated islets. Transplantation 79:52-8
King, A; Lock, J; Xu, G et al. (2005) Islet transplantation outcomes in mice are better with fresh islets and exendin-4 treatment. Diabetologia 48:2074-9
Duvivier-Kali, Valerie F; Omer, Abdulkadir; Lopez-Avalos, Maria D et al. (2004) Survival of microencapsulated adult pig islets in mice in spite of an antibody response. Am J Transplant 4:1991-2000
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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