Insulin-dependent diabetes mellitus is characterized by specific destruction of the insulin-producing beta-cells of the islet of Langerhans of the pancreas, resulting in insufficient insulin production, eventually leading to hyperglycaemia. Among other factors, the Fas ligand (FasL) as been shown to contribute to the destruction of islets. Since FasL is also expressed at immune privileged sites such as the testis and the eye attempts have been made to genetically transfer FasL into betacells to increase graft survival across allogeneic barriers. This is complicated, however, by the observation that FasL also attracts neutrophils. Recently, we have shown that upon triggering, the Fas/FasL complex internalizes in a caspase-8-dependent manner. One of the functions of the i nternalization may be to remove bound FasL from the cell surface to avoid bystander kill. We hypothesize that modifying tumors or transplants in a way which prevents internalization of Fas may result in accumulation of soluble FasL on noninternalizing Fas receptor at the cell surface and reduced rejection. We further hypothesize that genetic modification of beta-cells that prevents Fas internalization will be beneficial in two ways. It may inhibit the Fas dependent autoimmune destruction by blocking signaling of endogenous Fas and give these cells an immune privileged status by """"""""presenting"""""""" FasL on the cell surface through binding to noninternalizing Fas. We plan to test these hypotheses by establishing a mouse tumor model as well as mouse islet transplantation models. In the first aim we will test the role of internalization of Fas in the growth of a mouse tumor which serves as a transplant model. In the second aim we will determine whether adenoviral transfer of a signaling deficient Fas mutant into human R-cells will inhibit Fas mediated apoptosis and receptor internalization, and in the third aim we will determine the effects of noninternalizing Fas on islet transplant rejection and autoimmune diabetes. The results of this pilot study could lead to a novel concept in tolerizing transplants and treating autoimmune diseases.
| Vijayan, S; Zhou, P; Rajapaksha, T W et al. (2005) Transplanted islets from lpr mice are resistant to autoimmune destruction in a model of streptozotocin-induced type I diabetes. Apoptosis 10:725-30 |
