The goal of this project is to improve the performance and survival of insulin producing cells so they can be transplanted into people with diabetes. The focus is upon porcine islets which will be genetically modified to resist xenograft rejection.
The aims are: 1. To use porcine neonatal pancreatic cell clusters (NPCCs) to learn more about how precursor and protodifferentiated pancreatic cells develop into mature endocrine cells. 2. To manipulate replication and differentiation with various growth and differentiation factors to both optimize the tissue source for the transplantation and enhance gene transfer maneuvers. 3. To examine populations of porcine neonatal cells transplanted into nude mice to understand their growth capacity, differentiation and function in vivo 4. To study the characteristics of adenovirus vector-mediated gene transfer and expression in transplanted islets and to establish and characterize a lentivirus-based gene transfer system for islets. Experiments performed with rat islets represent a prelude to experiments with adult and neonatal porcine islets. 5. To determine the extent to which rat islets engineered to express either CTLA4Ig or FasL show enhanced graft survival in a xenogeneic mouse diabetes model and to characterize the requirements for transgene expression and the immune mechanisms involved in graft survival. 6. To establish conditions for the efficient transduction of neonatal porcine islet cells so they can be studied in xenogeneic models.

Project Start
1999-12-15
Project End
2000-11-30
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
3
Fiscal Year
2000
Total Cost
$120,062
Indirect Cost
Name
Joslin Diabetes Center
Department
Type
DUNS #
071723084
City
Boston
State
MA
Country
United States
Zip Code
02215
Koulmanda, M; Qipo, A; Fan, Z et al. (2012) Prolonged survival of allogeneic islets in cynomolgus monkeys after short-term triple therapy. Am J Transplant 12:1296-302
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
Koulmanda, M; Smith, R N; Qipo, A et al. (2006) Prolonged survival of allogeneic islets in cynomolgus monkeys after short-term anti-CD154-based therapy: nonimmunologic graft failure? Am J Transplant 6:687-96
Koulmanda, Maria; Laufer, Terri M; Auchincloss Jr, Hugh et al. (2004) Prolonged survival of fetal pig islet xenografts in mice lacking the capacity for an indirect response. Xenotransplantation 11:525-30
Omer, Abdulkadir; Duvivier-Kali, Valerie F; Trivedi, Nitin et al. (2003) Survival and maturation of microencapsulated porcine neonatal pancreatic cell clusters transplanted into immunocompetent diabetic mice. Diabetes 52:69-75
Koulmanda, M; Qipo, A; Auchincloss Jr, H et al. (2003) Effects of streptozotocin on autoimmune diabetes in NOD mice. Clin Exp Immunol 134:210-6
Koulmanda, M; Qipo, A; Chebrolu, S et al. (2003) The effect of low versus high dose of streptozotocin in cynomolgus monkeys (Macaca fascilularis). Am J Transplant 3:267-72
Omer, Abdulkadir; Keegan, Mitchell; Czismadia, Eva et al. (2003) Macrophage depletion improves survival of porcine neonatal pancreatic cell clusters contained in alginate macrocapsules transplanted into rats. Xenotransplantation 10:240-51
Koulmanda, Maria; Qipo, Andi; Smith, R Neal et al. (2003) Pig islet xenografts are resistant to autoimmune destruction by non-obese diabetic recipients after anti-CD4 treatment. Xenotransplantation 10:178-84
Grey, Shane T; Longo, Christopher; Shukri, Tala et al. (2003) Genetic engineering of a suboptimal islet graft with A20 preserves beta cell mass and function. J Immunol 170:6250-6

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