Islet Transplantation

Summary

Since approximately 25 years islet transplantation as a mean for the treatment of diabetes has been developed from early attempts in rodents to first clinical applications in man in recent years.

The review describes the results obtained in diabetic rats including metabolic effects as well as prevention of late complications. In the syngeneic system (Lewis-rats) the intraportal transplantation of 1,000-2,000 isolated islets may cure streptozotocininduced diabetes for the whole lifespan of the animal. In the allogeneic system (across a major histocompatibility barrier), however, isolated islets are highly immunogeneic. According to present knowledge, mainly class-II antigen bearing cells are responsible while the role of the endocrine cells seems to be less important. By various in vitro methods (e. g. low temperature culture at 24^°C) it was possible to induce immunoalteration of allogeneic islets which was followed by long-term acceptance by the host in rodents. Whether the same technique is effective in larger animals and in man remains open.

New technologies for the isolation of high numbers of pure islets from human pancreatic glands have been the key for the use of islet transplantation in man in several centers. The review describes the details regarding institutions as well as results in patients on the basis of the International Islet Transplant Registry which is located at Giessen University. Although longer lasting insulin independency (longest lasting effect 2 1/2 years) has been observed only in a few patients, islet transplantation has been proven to be a very safe procedure for the patient. It is hoped that with increasing experiences regarding the factors which at present limitate the function as number and quality of islets, immunosuppressive protocols etc. islet transplantation will develop to a definite alternative to whole-organtransplantation.

One of the most important challenges for modern medicine is the fact of a worldwide increase of diabetic long-term complications such as kidney failure, coronary and peripheral vascular disease, blindness and neuropathy. Although intensified insulin treatment in a small percentage of patients may moderate morbidity and mortality, from experimental work there is sufficient evidence suggesting that only the restoration of normoglycemia early in the course of the disease may prevent complications. This, however, can only be achieved by the replacement of the destroyed islets of Langerhans either by transplantation of an intact vascularised pancreas or by isolated islets. It is the purpose of this review to describe the development of early experimental attempts to use isolated islets as a treatment for diabetes in rodents and further to clinical transplantation of human islets in diabetic patients.

Historically, the first attempts of treating diabetes by transplantation of tissue particles instead of the whole organ have been reported by Minkovski already in 1892 (Minkowski, 1892). He described a reduction of glycosuria after subcutaneous implantation of small pieces of the pancreas in pancreatectomized dogs. Definitely, the era of islet transplantation started in 1967 when Lacy and Kostianovsky described a method to isolate large amounts of islets from the rat pancreas (Lacy and Kostianovsky, 1967). Soon after, the first experiments began to treat diabetic rats with streptozotocin-induced diabetes by intra-peritoneal implantation of isolated islets. The first successful results were reported by Ballinger and Lacy (1972). At the same time, the first own results could be reported at the EASD Congress in Madrid (Federlin et al., 1973). During the following two decades there was a continuous development of experimental islet transplantation which led to a vast number of publications regarding the following fields: technologies of islet isolation and purification, studies of the most suitable implantation site, immuno-genicity of isolated islets, cryopresservation and culture of islets, use of fetal islets, effect of immunosuppressive drugs to prevent immune rejection and the technologies for immunoisolation of xenogeneic islets.

In 1977, first attempts were made to transplant diabetic patients with isolated islets (Najarian et al., 1977), but because of lacking success many years passed until clinical islet transplantation had a new beginning at the end of the eighties. A new semiautomated islet isolation and purification technique which will be discussed later opened the door for clinical islet transplantation.

Key words

Experimental islet transplantation - Clinical islet transplantation