Range of Progress Presented at Annual Conference
The DRI is tackling diabetes from many angles as evidenced by our scientists' research updates on more than a dozen initiatives that were presented at the American Diabetes Association's 70th Scientific Sessions in June. Presentations ranged from new uses for bioengineered devices that protect islets to newly-observed behavior of toxic T-cells, and demonstrate how we're coordinating efforts across many disciplines to discover a biological cure for diabetes.
Where We Stand
The DRI's Scientific Director Dr. Camillo Ricordi provided an overview on our progress in islet transplantation. Among the highlights of his presentation:
• Islet transplant success rates are rising and, in some cases, are approaching the success rate of pancreas transplants.
• The long-term survival of transplanted islets appears to be aided, in part, by new immunosuppressive drugs as well as the administration of a powerful anti-rejection agent given to patients prior to transplantation. The drugs are designed to deplete the recipient's killer T-cells, giving the transplanted cells an opportunity to establish themselves before the immune system can attack them. The findings are the result of studies conducted by the Clinical Islet Transplant Consortium, which was established in 2004. Dr. Ricordi is one of the Consortium's principal investigators.
• New sites for islet transplants are being tested and are showing promise. In collaboration with scientists in Sweden, islets are being transplanted into the muscle of the patient's arm. And in Italy, islets are being transplanted directly into a patient's bone marrow. The intra-bone transplants can be done under local anesthesia in as few as 10 minutes and both studies are encouraging as scientists search for sites other than the liver where transplanted islets can flourish.
In addition to the progress reported by Dr. Ricordi, the following research was presented by DRI scientists:
Improving Islet Transplant Technology
Much of today’s research at the DRI is aimed at achieving long-term islet function and making the transplant procedure available for every child and adult who can benefit from it. To increase transplant viability, our scientists are merging cellular therapies with emerging technologies and reported the following updates at the conference:
• Small, bio-engineered mesh cylinders, designed to house and protect transplanted islets, can also be used to deliver tiny amounts of anti-rejection drugs precisely where the cells are located, eliminating the systemic drugs used today which cause so many unwanted side effects. The DRI's Dr. Antonello Pileggi reported that as a result of using this localized procedure, just 1/100th of the amount of anti-rejection drugs was required in experimental models, minimizing side effects for the transplant recipient.
• Mesenchymal Stem Cells, which are found naturally in our body's own bone marrow and other tissues, have a beneficial effect on transplanted islets and may enhance the use of cell-based therapies for the treatment of diabetes. Dr. Cherie Stabler reported that in the latest DRI study in which MSCs were co-transplanted with insulin-producing cells into a bio-engineered scaffold, one recipient became insulin independent and two others are currently being followed to determine if they will also achieve insulin independence.
• Toxic T-cells may be destroying insulin-producing islets at a rate far greater than previously thought. The observation was made using the DRI's revolutionary technique that allows our scientists to view, in real time, how transplanted insulin-producing cells function when they are inside a living organism. The findings were presented by Midhat Abdulreda, post-doctoral fellow in our Cell Biology and Signal Transduction Program, who is part of the DRI team that transplanted islets into the anterior chamber of a mouse eye, enabling them to view the the cells through the cornea as if it was a "living window. " Using this model, DRI researchers made the T-cell observation.
• A master gene regulator, MiRNA 29, appears to be involved in the cascade of events that leads to the destruction of transplanted cells by inflammation. Dagmar Klein, DRI scientist in molecular biology, reported that by learning more about the mechanics of how MiRNA 29 works, we can develop strategies to limit its influence and reduce inflammation.
• It has long been known that tumor cells express and secrete proteins to evade immune attack and prevent rejection of the tumor. Identifying the potency of their effect and developing methods for harnessing these proteins could provide a novel means to protect transplanted islets from immune attack. Dr. Jeffrey Hubbell, adjunct professor of surgery at the DRI, reported on a study exploring how CCL21, a protein recently discovered to be highly expressed by cells in aggressive tumors, can create a localized immunoprotective environment for transplanted cells. In this study, it was found that cells genetically engineered to over express CCL21 recruited regulatory cells to the implant site, which prevented the rejection of the cellular implant. Cells not engineered to express CCL21, on the other hand, were promptly rejected. Future studies are now exploring how to translate these results to transplanted islets.
Cell Sources and Cell Biology
One of the most critical challenges we face in our commitment to cure diabetes is to develop new sources of insulin-producing cells. Donor tissue is in short supply and, as a result, we must develop alternative sources that are viable and abundant. In this area of research, DRI scientists reported the following updates:
• Recent observations indicate inflammation may trigger the pancreas to try to regenerate or remodel the insulin-producing cells. Interestingly, we know that inflammation is harmful to transplanted tissue and, in the case of islets, is a significant reason for islet loss during and after transplantation. However, our scientists have observed a beneficial effect by studying pancreases transplanted into patients with type 1 diabetes where autoimmunity recurred and destroyed the insulin-producing cells in the transplanted organ. The researchers found that the inflammation associated with the recurrent autoimmunity might actually trigger the formation of new insulin-producing cells. According to Dr. Alberto Pugliese, head of the Immunogenetics Program at the DRI, once we have a better understanding of this area of study, it could ultimately help us develop strategies to induce the formation of new beta cells to restore the body's ability to produce insulin.
• We've shed new light on the pathway responsible for insulin release. Dr. Alessia Fornoni, assistant professor of clinical medicine in the Division of Nephrology and Hypertension and the Diabetes Research Institute, reported on recent findings involving nephrin, a molecule vital for beta cells to secrete insulin in response to blood sugar, and the role it plays in insulin secretion. By learning more about this key molecule and its role in insulin release, we can better assess beta cell function.
At the Diabetes Research Institute, we house all three phases of research (basic, pre-clinical and clinical) under one roof. In the area of clinical or patient-based research, our scientists presenteded the following findings:
• The DRI evaluated a new tool used to measure postprandial, or after-meal, blood glucose in islet transplant recipients. According to Dr. Rodolfo Alejandro, who leads the Clinical Cell Transplant Program at the Diabetes Research Institute, the tool, called 1,5-AG, could be used in conjunction with existing methods of measurement to more accurately assess after-meal glucose control - which is a good predictor of islet graft loss.
• As part of an NIH-sponsored, Type 1 Diabetes TrialNet study, we identified a test to better predict the progression of diabetes in the children and relatives of persons with type 1 diabetes. The results of the study were presented by Dr. Jay Sosenko of the Diabetes Research Institute.
• In a 10-year follow up of the Diabetes Prevention Program Studies of Type 2 diabetes, Dr. Ronald Goldberg, director of the Lipid Disorders Unit, presented new information on identifying predictive markers for type 2 diabetes in "at risk" populations.
• We reported on the results of a recent study which suggests diabetes patients who participate in focused, insulin-management group education are able to improve control over their blood sugar levels. The findings were presented by Dr. Luigi F. Meneghini, director of the Kosow Diabetes Treatment Center at the Diabetes Research Institute.