This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.The prevalence of type I diabetes in the United States is estimated to be about 800,000 individuals, and the incidence is approximately 30,000 new cases yearly. To date, there are no thoroughly preventative or curative measures available. The closest has been the Diabetes Control and Complications Trial that demonstrated intensive therapy effectively delays the onset and slows the progression of diabetic retinopathy (worsening eye sight), nephropathy (kidney damage), and neuropathy (decreased sensation/changing sensation in hands/feet/arms/legs). The modality of beta cell (insulin producing cells in the pancreas) replacement by transplantation of the whole pancreas is the most successful method to control glycemia. Transplantation of the islets as free grafts extends the concept of beta cell replacement therapy for patients with type I diabetes. The attraction of islet transplantation compared to conventional pancreas transplantation is its minimal morbidity (severe side-effects) and relative little use of hospital resources. Beta cell replacement therapy by means of islet cell transplantation, when successful, reverses hyperglycemia and the need for exogenous insulin (insulin not produced by the person taking it).The primary barrier to successful human islet transplantation is rejection. The study of islet transplant rejection has revealed the importance of T-cells. However, T-cell mediated islet rejection is not the sole mechanism of islet graft injury post-transplantation. Non-specific host immune responses involving macrophages and macrophage-generated by-products are also detrimental to islet engraftment and function. Beta cell replacement therapy by means of islet cell transplantation, when successful, reverses hyperglycemia and the need for exogenous insulin therapy. Unfortunately, it is not routinely effective. Between January 1, 1990 and December 31, 1998, 267 cases of islet transplantation in type I diabetic recipients have been reported to the International Transplant Registry. Of these cases 245 were reported with one year follow-up and only 20 patients (8%) were insulin independent at one year. The vast majority (95%) of islet transplants have been performed in patients who are either simultaneously receiving a kidney transplant or who have already received one and thus are committed to receiving systemic immunosuppressive therapy. The goal of islet transplantation is to be able to apply it early enough in the course of the disease so that these secondary vascular complications are prevented. For this to occur, anti-rejection regimens must be devised that minimize organ specific side effects while providing substantial protection from rejection.
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