Islet of Langerhans Transplantation
Islet of Langerhans transplantation appears as a valid method for the treatment of type 1 diabetes. The publication in the year 2000 of the results of the Edmonton protocol showed that it was possible to achieve rates of insulin-independence of 80% at 1 year in transplanted patients, thanks to a steroid-free, islet-sparing immunosuppressive regimen and an increased implanted islet mass, by the utilization of 2-4 donors for each recipient. Nonetheless, several questions remain and several issues have to be addressed in order to improve this method. These constitute the topics of basic and clinical research of the group.
- Islet engraftment is clearly suboptimal (as indicated by the need for multiple donors), as a result od pro-apoptotic and pro-inflammatory stimuli sustained during islet isolation and at the site of implantation. The group is developing a model of cell interaction between beta-cells and macrophages in order to study and prevent these phenomena. Moreover, the role of the pro-inflammatory MIF and anti-inflammatory IL-1Ra molecules is studied in murine models of islet transplantation using knock-out and transgenic animals. Finally, the role played by alpha-1-antitrypsine and cadherins on beta-cell apoptosis and destruction is studied in rodent models and on human islets in vitro.
- Long-term islet graft function must be improved, since the rate of insulin-independence drops to 15% at 5 years post transplant, using the Edmonton protocol. Reasons for this progressive loss of islet graft function are not known and probably of multifactorial origin. Methods designed to monitor islet graft mass and/or function are critical tools that must be developed to better understand these phenomena. The group is developing techniques of islet graft imaging, using PET and MRI technology, in models of islet transplantation in the rat, in human islets in vitro, and in clinical protocols. Molecular monitoring of islet grafts, by measuring circulating levels of insulin mRNA as a marker of islet cell damage, are also developed in collaboration with Prof. Jacques Philippe's group.
- The immunosuppressive regimen currently used in clinical islet transplantation has several drawbacks in terms of side effects, notably kidney toxicity. New clinical immunosuppression protocols are being developed in collaboration with French University centers participating to the Swiss-French GRAGIL network (Grenoble, Lyon, Strasbourg, Besançon, Montpellier) and with other European Universities (Milan, Giessen, Uppsala, Brussels). The possibility of inducing immune tolerance by blockade of T-cell co-stimulatory signals (CD154, TRANCE) is studied on murine models of islet transplantation.