Development of Immunosuppression Regimens to Facilitate Single Donor Islet Transplantation Using Abatacept

More than 1 million North Americans have type 1 diabetes. Each year, approximately 30,000 new cases of type 1 diabetes are diagnosed in the United States. Type 1 diabetes destroys islets, a cluster of cells within the pancreas that produce insulin. Insulin is a hormone with many effects. However, the most important effect of insulin is to control the level of sugar in the blood. People with Type 1 diabetes no longer produce insulin and must take insulin injections to live. Despite steady improvements in the management of this disease, its victims remain at increased risk for stroke, heart attack, kidney failure, amputation, blindness, nerve damage and premature death. The life expectancy of a teenager is reduced by thirty years from the time of onset of the disease [1]. Unfortunately, many type 1 diabetics cannot control their blood sugars in spite of very careful monitoring and the frequent injection of insulin. This group of patients is considered to have labile or "brittle" diabetes. These "brittle" diabetics can often have wide swings in their blood sugar levels that can be life threatening. Hypoglycemia, or low blood sugars occur when too much insulin is in the bloodstream. When this occurs, it is vital that patients eat or drink something right away that will increase their blood sugars. Many diabetics lose the ability to recognize when their blood sugars are getting dangerously low. These episodes of hypoglycemia can lead to coma, and possibly death, if not recognized and treated right away. Patients can also experience extreme increases in blood sugars, or hyperglycemia, as a result of emotional or physical stress. Hyperglycemia can result in dehydration, confusion, and a condition called ketoacidosis, which can lead to death. When this happens, insulin must be given as soon as possible.

Islet transplantation can restore the body's ability to make insulin and, in turn, restore normal blood sugar levels.

Since the 1960's, doctors and scientists have attempted to replace this islet function by performing whole organ pancreas transplantation. While the results of pancreas transplantation have improved dramatically in recent years, this approach has largely been limited to patients with kidney disease who have also needed a kidney transplant. This is because of the risks associated with the surgical procedure and the immunosuppressive drugs required to prevent rejection or the destruction of the transplanted pancreas by the body's immune system [2]. Transplantation of a whole pancreas requires a major operation that is done through an incision in the abdomen. The patient must be under general anesthesia, or asleep, for the entire procedure. Recent clinical experience suggests that islet transplantation may be a useful approach to correct diabetes in humans [3].

Islet transplantation offers a direct approach to the treatment of type 1 diabetes. A large number of experimental studies carried out in many laboratories over the last decade have documented the beneficial effects of islet transplants in experimental animals. These experiments have confirmed both the efficiency and safety of islet transplantation [4,5].

The inability to isolate enough islets from a single pancreas has been one obstacle to successful islet transplantation. A certain number of islets must be isolated, or separated, from a single pancreas in order to use them for transplant. If this minimum number of islets is not obtained, then the islets do not effectively reverse diabetes. Progress in isolating the islets from a human pancreas has been dramatic in the last several years. Advances in equipment and technology have lead to increases in the number of islets that can be isolated from a single pancreas.