OPTIMIZATION OF PANCREAS FOR TRANSPLANTATION

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Insulin-dependent diabetes mellitus (IDDM) is a disease that affects 1.4 million patients in the United States with an estimated health care cost of $14 billion annually. To date the only method which successfully frees the IDDM patient from insulin therapy and stabilizes or reverses the secondary complications of IDDM is vascularized pancreas transplantation. Because of the extreme shortage of donor organs, only 600 to 700 pancreas transplants are performed yearly. Transplantation with human fetal pancreas (HFP) is a technically simple procedure which offers many advantages for the treatment of IDDM including the potential for further growth and differentiation and readily available tissue. The objective of this proposal is to develop the standardized methods required to establish clinical HFP transplantation. This objective is defined as seven specific aims listed below. 1. development of standardized methods for the procurement and short-term storage of HFP. We will examine the media used for transplant and storage and determine the time constraints involved in HFP processing. 2. development of standardized methods for detecting bacterial, fungal, and viral contaminants of HFP. We will identify bacterial and fungal contaminants using standard techniques and identify viral contaminants with PCR. 3. Determination of the optimum method for HFP cryopreservation. We will examine several parameters of cryopreservation and determine the optimum post-processing stage for freezing. 4. Correlation of HFP in vitro function with in vivo function. We propose experiments to correlate in vitro function with in vivo function to successfully predict the ability of HFP to reverse diabetes. 5. Development of techniques to accelerate HFP maturation and in vivo function. We will use both cell culture and gene therapy approaches to assess the effects of insulin-like growth factors on the maturation of HFP. 6. Determination of the optimum HFP transplant site. We will compare the renal subcapsular site with other sites that provide portal drainage and are surgically simple. 7. Development of standardized methods for HLA typing of HFP. We propose experiments to adapt serological techniques to type for class I and PCR techniques to type for class II.