Our Plan

Administration Core A

Core A is the Administrative Core for the Project and is designed to facilitates efforts of the program investigators to achieve the aims of their respective core and   projects.  Core A maintains budgetary and fiscal oversight of the program, and fosters interaction among core and project investigators, monitors the program's cores and projects and acts as a central repository for data accumulated over the course of   this program.  Core A is also responsible for reports on progress and fiscal status as well as public relations management.

Josephine Sipple ---Finance

Eileen Markmann --- Clinical Coordinator

Paige Oliver      ---Administration

Isolation and Evaluation   Core B

It is our goal to provide the largest number possible of viable and functional cells for transplantation.  Core B has two areas of focus, but it will be primarily responsible for the procurement and isolation of human islet cells.   In conjunction with Penn's already established Human Islet Isolation Core Facility, we will develop a new facility which meets the government good manufacturing practice standards for use in humans and establish a pancreas procurement network to facilitate and optimize islet yield through attention to procurement and preservation detail.  A dedicated team of transplant surgeons will be established and utilized to minimize pancreas graft cold ischemia time following pancreas procurement.  We will also nurture an established tie to the currently largest transplant program in the US, the Gift of Life Donor Program (formerly Delaware Valley Transplant Program) to be sure that we utilize all appropriately available human pancreata for islet transplantation.  This larger availability of suitable pancreas and faster procurement time will help us provide more viable and functional islet cells.  Variables in procurement and isolation such as donor stability, warm ischemia time and procurement time will be compared with the islet cell evaluation to assess any effects on the cells.

Core B will work to define parameters predicting islet viability and function.  To this end we must work to establish strict quality criteria and reliable standard quality test systems.  This evaluation will include islet hormone content, cell viability test by flow cytometry, insulin secretion dynamics, respiration, glucose oxidation, cAMP release, imaging of Ca²⁺ transients and graft survival.  The goal of this evaluation is to develop an Islet Quality Index.  This Islet Quality Index, once established, will be used to assess: 1) Primate and human islets for transplantation  2) Effect of storage condition on transplant outcome, 3) Effect of conditioning on transplant outcome and, 4) Effects of other components of program project on transplant outcome.  Proper testing of this IQI will help maximize graft survival and therapeutic efficacy (blood glucose and serum insulin of recipients) and help make islet transplantation in humans for Type I Diabetes clinically valuable.

Imaging   Project 1

The goals of Project 1 focus on the in vivo imaging of islets in humans.  This project looks at three practical uses for in vivo imaging of islets.   First, the ability to identify islets in vivo would prove a unique opportunity to monitor the chronic loss of b cells following islet transplantation.   Second, in vivo imaging can be used to monitor the evolution of b cells during the onset of type I diabetes that is characterized by a gradual loss of islets resulting in hyperglycemia.  The third and final aim is to demonstrate the value of the imaging technique in evaluating the effectiveness of anti-rejection drugs following islet transplantation.

The first step in imaging islets is choosing a tracer.  A tracer is a chemical that can be viewed by the imaging equipment, and is contained by, or binds only to, the area that you wish to view.  We have chosen to work with Tolbutamide because it has a high affinity to SUR1 (Sulfayl Urea Receptor 1), a receptor that is found specifically in b cells, and has a low affinity to the SUR2 receptor that is found in other tissues.  The first milestone (1) is to synthesize and three different Tolbutamide analogs.  These will be tested for binding ability.  Other milestones include: (2) imaging of islets in healthy and diabetic non-human primates, (3) In vivo imaging of transplanted islets in non-human primates over time to demonstrate a pattern of rejection, (4) In vivo imaging of the effects of immunosuppression on the pattern demonstrated for rejection and, (5) application of the imaging technique to healthy human subjects and patients with Type 1 and Type 2 diabetes.  Aims 2-4 will be accomplish$ in conjunction with Project 2 to limit the total number of animals used in this program.

Non-Human $ Islet Transplantation   Project 2

The goal of Project 2 is successful intrathymic islet transplantation in non-human primates.  Although it is agreed that islet transplantation to achieve euglycemia is an excellent idea, it has been difficult to put into practice.  It has been frustrated by the vulnerability of islet allografts to immune destruction.  This graft rejection is the reason for the failure in the majority of previous clinical trials of islet transplant in humans.  Recognizing that beta cell replacement could only be realized if the patient is spared of immunosuppresive agents, we are targeting our investigations on two complementary areas based on previous work:  1) We have confirmed that islets transplanted into the thymus enjoy permanent survival and more importantly, have the capacity to induce peripheral unresponsiveness to donor alloantigenes and, 2) We have established that intra-islet expression of immunomodulatory molecules block T-cell co-stimulatory signals and reduce the ability of the islet to generate an immune response.  This reduction of immunogenicity renders the islet allografts resistant to autoimmune recurrence and rejection.   We propose to assess the feasibility of these two strategies to promote islet strategies allograft tolerance in non-human primates.

Aim 1: To Achieve euglycemia in insulin-dependant monkeys by intrathyic transplantation in conjunction with a peri-operative therapy to induce tolerance to the transplant.   We plan to use a clinically approved anti-T lymphocyte depletion with Thymoglobulin, anti-IL-2 receptor blockade or an anti-B cell antibody to prevent the development of anti-donor alloantibodies

Aim 2:  To determine the efficacy of adenoviral-mediated CTLA4-Ig transduced islet allografts to restore proper blood sugar levels in diabetic monkeys.  This study also uses a peri-operative immune suppression.

The primates used in this study will also aid in Project 1, thereby limiting the number of animals used in the overall project.  We hope that the information learned from these experiments with non-human primates will lead directly to Project 3-- islet transplants in humans.

Human Islet Transplantation   Project 3

Based on our background of 27 years of research in islet transplantation in rodents and considerable experience during recent years in isolation of large animal and human islets, we now plan to embark on human islet transplantation.  Pancreases will be recovered by experienced Penn transplant surgeons from cadaveric donors, identified by the regional organ procurement agency (see Core B).  Islets will be isolated by the automated technique of Ricordi.  Only islets of the highest quality as determined by the innovative biochemical and metabolic in vitro assays (see Core C) will be utilized.  In each transplant at least 10,000 islet equivalents per kg body weight will be embolized to the liver via percutaneous catheterization of the portal vein.  

Highly selected patients of the following groups will receive islet transplants: 1) type I diabetics receiving a simultaneous kidney transplant (the largest group; currently 40-45 diabetic patients per year receive renal transplants at our hospital); 2) type I diabetics harboring a successful kidney transplant; 3)patients rendered diabetic by total pancreatectomy done for relief of unrelenting pain from chronic pancreatitis; 4) diabetic patients who require a hepatic transplant for liver failure (in these unusual cases, a composite liver/islet graft will be utilized). 

During the initial period (1-2 years), our goal will be a total of 8-10 islet transplants.  Subsequently, we anticipate 10 islet transplants per year.  In the initial period, we will employ a conventional immunosuppressive protocol differing from that which we currently utilize for renal transplants only by the addition of an antilymphocytic antibody for the first 5-7 days.   In later years, we will also evaluate promising novel transplant sites and novel immunosuppressive strategies based on results of the primate studies in Project 2.

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