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JDRF Funded Research

JDRF-Funded Research: Lay Abstract

Name: Dolca Thomas ,MD
Weill Medical College of Cornell University, USA
Lab Website:

Project duration: 01-JUL-2006 to 30-JUN-2008
Innovative Grant

Project grant award: $110,000.00*

* Total Grant award amount may vary depending on budget adjustments and it is contingent upon research progress and availability of JDRF research funds.

File No: 5-2006-361

(Abstract Dt: 01-JUL-2006)

Therapeutic Area: Beta Cell Therapies

Grant Status: Inactive

Project Title

Nanomolecular TGF-b1 DNA-hydrogels to block autoimmunity and alloimmunity.

Objective

Type 1 diabetes mellitus is the result of immune mediated targeted islet destruction (autoimmunity). Islet cell transplantation is an excellent therapy for type 1 diabetes. Effective inhibition of autoimmunity and alloimmunity (the immune destructive forces against foreign cells) is essential for the long-term survival and maintenance of transplanted islets. This translates to life-long treatment with immunosuppressive medications that are often associated with toxic side effects such as increased risk of cancer, infections, high cholesterol and diabetes. Many of these side effects are the direct result of nonspecific systemic administration of these medications. Therapeutic strategies aimed at localized inhibition of immune mediated islet destruction can potentially obliviate the need for immunosuppressive medication. We propose to evaluate, with the use of mouse islet cell transplant models, the efficacy of a novel TGF-¿1 DNA-hydrogel system in facilitating permanent islet graft survival without the use of immunosuppressive medication.

Background/Rationale

Autoimmunity and alloimmunity are twin barriers to successful islet transplantation. These immune processes lead to the progressive destruction of transplanted islets. Transforming growth factor-¿1 (TGF- ¿1) is a potent suppressor of multiple immune cells including T cells, B cells, macrophages and natural killer cells, and has been shown to prolong the survival of transplanted organs in multiple animal models. Transgenic non-obese diabetic (NOD) mice generated to express porcine TGF- ¿1 within the ¿ cells of islets were protected from the development of diabetes. These mice, in a similar fashion to patients with type 1 diabetes, develop diabetes on their own. TGF- ¿1 has also been shown to constrain alloimmunity and promote tolerance (lack of immune destruction of foreign islet cells) in a number of animal experimental models.

Description of Project

We have developed a novel drug/protein delivery system that is specific and devoid of intracellular genetic manipulation or use of viral vectors. DNA is used for the production of hydrogels that are non-toxic, biodegradable, water-soluble and inexpensive. These gels have been shown to result in sustained protein release over time. We will evaluate, with the use of a mouse islet cell transplant model, the efficacy of a TGF-b1 DNA-hydrogel system to result in localized TGF-b1 protein delivery and facilitate permanent islet graft survival.

Anticipated Outcome

It is our expectation that co-implantation of islets with a TGF-¿1 DNA-hydrogel will result in localized TGF-¿1 protein delivery, inhibit autoimmune and alloimmune islet graft destruction with avoidance of toxicities that result from systemic immunosuppression.

Relevance to Type I Diabetes

Therapeutic strategies that result in long term islet function without the use of toxic immunosuppressive medication would effectively transform islet transplantation from a treatment to a cure for type I diabetes.