Pancreatic islet transplantation is an attractive approach for the treatment of diabetes. Loss of graft function, however, remains a major problem, and limits application of this promising therapy. Non-specific inflammatory responses induced by the transplant procedure contribute to the early loss of functional islet mass. This response is mediated mainly by infiltrating macrophages and monocytes, which release a variety of cytotoxic mediators that can inhibit insulin secretion and destroy beta cells. A promising strategy is to genetically engineer """"""""designer"""""""" islets that could inhibit macrophage activity within the islet microenvironment. Recent studies indicate that the molecule CD200 is capable of down-regulating cells from the macrophage lineage, which express the CD200 receptor (designated CD200R). Importantly, CD200:CD200R interactions have been shown to block development of a variety of inflammatory processes mediated by macrophages. In addition, studies from our laboratory have also shown that CD200 down-regulates adaptive immune responses, and prolong the survival of allografts and xenografts. We hypothesize that increasing the level of CD200 expression in isolated islets will improve their functional outcome and survival after transplantation. We have produced an adenoviral vector containing the cDNA for CD200. Preliminary experiments indicate that high levels of CD200 can be achieved in islets with no apparent deleterious effect on insulin secretory function or in their ability to restore euglycemia in diabetic mice.
The aims of the proposed study are: 1) To determine whether augmented expression of CD200 in pancreatic islets can attenuate non-specific inflammation and improve islet function after transplantation; and 2) To determine the effect of augmented expression of CD200 on allo-immune responses. For the proposed studies the required probes and reagents have been obtained or generated. The combination of molecular biological, immunological, adenoviral vector construction and transfection, and islet transplantation methods are in place.
