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Human Islet Cell and Bone Marrow Transplantation Trials

The Diabetes Research Institute's Cell Transplantation Center has initiated a new clinical trial involving the transplantation of human islet cells and high dose donor bone marrow infusions from the same donor source. Recent clinical studies conducted by the DRI and the Division of Transplan-tation at the University of Miami, showed that high dose donor bone marrow infusions greatly enhance graft acceptance in organ transplant patients. Based on these encouraging results, along with the evidence of long-term function of transplanted islet cells in patients requiring immunosup-pression, the DRI received approval from the University of Miami's Institutional Review Board (IRB) and the Food and Drug Administration (FDA) to begin this clinical trial. For the first time, islets will be transplanted into patients that do not require an organ transplant and therefore, long-term immunosuppression. Previously, islet transplantation was only performed in patients requiring continuous immunosuppressive drugs to prevent rejection of a transplanted organ such as a kidney and/or liver. In this trial, all patients will have their immunosuppression discontinued after one year. This study will be initially conducted in a limited group of patients with labile (brittle) insulin dependent diabetes, as well as those who are unable to sense hypoglycemia (low blood sugar) and who meet the age and duration of diabetes requirements and other approved criteria.


In the early 1980's, when DRI researchers cured diabetic dogs through islet transplantation, our hope was to quickly transfer that technology into humans. The initial patients selected for the first clinical trials were those who received kidney transplants and required immunosuppressive drugs to prevent rejection of their new organs. In 1985, the first clinical islet transplant was conducted in a young woman. The transplanted islets greatly improved her blood sugar control, and insulin requirement was reduced by almost 75 percent. However, the islet graft failed after one year. This failure was attributed to two factors: the insufficient number of islets isolated and transplanted; and the possible destruction of the "foreign" cells by the recipient's immune system. These two obstacles impeded the progress of human clinical trials until 1990, when Dr. Camillo Ricordi developed the automated method for islet isolation and purification, now used by researchers worldwide.

With the ability to transplant greater numbers of purified islets, numerous new clinical trials were initiated. Drs. Mintz and Alejandro from the Diabetes Research Institute and Drs. Ricordi and Andreas Tzakis, then at the University of Pittsburgh, combined their efforts in a unique clinical trial. Patients with extensive abdominal cancer underwent multiple organ transplants to replace their affected organs. In each case, the pancreas had to be removed and, since earlier efforts to transplant the entire pancreas failed, the surgical team turned to islet transplantation to prevent diabetes from occurring in these pancreatectomized patients.

Using the new isolation techniques and modified protocols for immunosuppression, eight patients underwent the "cluster" organ transplants. Each received islet cells which were infused into the portal vein leading to the newly transplanted liver. In all eight cases, islet function was achieved. Sadly, most of these patients eventually succumbed to their primary disease, cancer. However, the first patient, a 15 year old girl, survived for five years and never once needed an insulin injection.

Upon her recent death, an autopsy revealed that the transplanted islets were still healthy and producing insulin. This case proved that islet cells could be isolated from a pancreas, transplanted into a liver and successfully produce enough insulin to normalize blood sugars for at least five years.

While these trials and subsequent clinical trials have been limited to patients requiring organ trans-plants and, therefore, immunosuppressive therapy, there is evidence that the drugs used to prevent rejection may adversely effect transplanted islets. The DRI is studying this and other potential factors which may help protect newly transplanted islets and enhance engraftment (the establishment of a blood supply to cells). In addition, our transplant immunology team is conducting research to identify bone marrow cells responsible for enhancing donor specific tolerance and those cells which activate the rejection process.

The recently concluded Diabetes Control and Complication Trial (DCCT), funded by the National Institutes of Health, determined that sustained normalization of blood glucose levels can greatly reduce the risk of long-term complications. However, the intensive management required to improve diabetes control increased the likelihood of severe hypoglycemia. At the International Pancreas and Islet Transplantation Association (IPITA) meetings held in Miami in June, scientists from five centers presented data on the glucose control of their patients after islet transplantation. The data revealed that even partially successful islet transplants, in which patients remained on minimal doses of insulin, achieved better hemoglobin A1c results without episodes of hypoglycemia.

Tolerance Induction

The goal of islet transplantation has always been to provide this technology to patients early in their course of diabetes and to do so without long-term immunosuppressive therapy. In an effort to enhance transplant acceptance and allow the recipient's immune system to become tolerant of a "foreign" tissue, the DRI and the Division of Transplantation has been involved in an extensive clinical trial using donor bone marrow infusions to trick or re-educate the recipient's immune system to accept specific donor tissue. This study, under the direction of Drs. Ricordi and Tzakis, who were recruited to Miami, determined the effectiveness and safety of single, double or multiple donor bone marrow infusions in organ transplant recipients, compared to a control group receiving no donor bone marrow. The double or multiple infusions had a dramatic impact on graft acceptance. When two or more donor bone marrow infusions were given, there was > 95 percent graft acceptance, while in the control group the acceptance rate was 76 percent. Transplant survival was significantly improved by the addition of donor bone marrow infusions.

It is important to note that while bone marrow infusions for leukemia require radiation of the recipient, no radiation is necessary for these protocols. The bone marrow is given through a routine intravenous drip (like a blood transfusion).

The goal of the new islet cell and bone marrow infusion trial is to test whether high dose multiple infusions of donor bone marrow will help make the recipient tolerant to the "foreign" islet cells. In addition, we will test these patients to see if a state of chimerism (co-existence of donor and recipient cells) has been achieved. Immunosuppression will be withdrawn in all patients within the first year post transplant.

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Last Updated: Thursday February 27, 2014 19:28:21
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