Current Advances and Travails in Islet Transplantation

The successful demonstration that insulin-producing -cells can be isolated (in the form of cell clusters called islets containing and other endocrine and nonendocrine cells) from a recently deceased donor’s pancreas, then transplanted into subjects with type 1 diabetes, and thereby restore, at least temporarily, insulin-independent normoglycemia has firmly established the important “proof of concept.” Even so, worldwide efforts to advance the therapy for widespread applicability have served to focus attention on the hurdles yet to clear. This review will briefly describe the present state of the art and succinctly define the research problems being attacked along with some recent advances that demonstrate significant progress. Since Paul Lacy’s early rodent experiments in the 1960s established that pancreatic islets could be isolated from one animal and transplanted into a diabetic recipient to restore normoglycemia (1), investigators have pursued efforts to develop the therapy for clinical use. After years of development in various animal models and efforts to improve human islet isolation techniques (see [2–4] for reviews with a historical perspective), the first patient achieving short-term insulin independence was reported by the group at Washington University in St. Louis. That advance was based on new islet isolation technology utilizing islets pooled from several donors, intensive insulin treatment in the peritransplant period, and induction immunosuppression with antithymocyte globulin (ATG) to avoid glucocorticoid therapy (5). The development of new immunosuppressive drugs that allowed patients to remain off glucocorticoid therapy while awaiting subsequent islet infusions (because most recipients require islets from two or more donors) enabled the group in Edmonton to optimize the clinical islet transplantation procedure (6). The approach allowed the group to conclude that about 12,000 islet equivalents per recipient body weight (in kilograms) was required to restore insulin-independent normoglycemia (6) and sparked intense international interest and effort. Current estimates are that 400 individuals have received allogeneic isolated islets since 1999 (7), with 40 centers actively engaged in further developing the therapy. The Edmonton case series remains the world’s largest, and its data demonstrate that approximately two-thirds of the recipients enjoy insulin independence 1 year after receiving their final islet infusion (again, most recipients require islets from two or more donors). Unfortunately, islet function decreases over time such that by 5 years posttransplant, less than 10% remain insulin independent (8). On the other hand, the majority continues to display islet allograft function and, with it, decreased insulin requirements, less frequent hypoglycemia, and overall improved blood glucose control. While other groups have reported incremental advances (i.e., predictable insulin independence using islets from a single donor, although typically from an ideal donor into a small recipient) (9), the Immune Tolerance Network multicenter trial results were as follows: less than half achieved insulin independence at 1 year and 15% remained insulin independent at 2 years (10). Further, recipients required (on average) islets from 2.1 donors, less than half of the pancreases donated for islet isolation yielded a product suitable for transplant, and for those recipients classified as insulin independent, blood glucose control was not normal for many using the American Diabetes Association criteria (10). Aside from the imperfect success, islet recipients experienced a small number of procedure-related complications (e.g., intraperitoneal bleeding, portal vein thrombosis, and gallbladder puncture). Islets, though only small cell clusters, obey the same immunological laws that govern solid organ transplantation, i.e., allogeneic islets trigger immune-mediated rejection that must be controlled with immunosuppressive drugs, which are associated with an increased risk for declining kidney function, hyperlipidemia, infectious complications, and risk for malignancies. Also, if immunosuppression is stopped, recipients become immunologically sensitized against islet donor tissue antigens, and because islets from multiple donors are typically required, finding a suitable donor for subsequently required transplant therapy may prove difficult (e.g., should the patient develop kidney failure) (11,12). Although islets sharing HLA antigens with a recipient’s previous kidney allotransplant may weaken the anti-islet donor immune response (13), repeatedly administering islet-associated alloantigens to recipients of previous allogeneic islets can jeopardize -cell survival (14). Clearly, experience has identified problems to overcome (15), including the need to develop better assays for monitoring both anti-islet autoimmune and alloimmune responses (Table 1). Assays for immunological monitoring. T-cell assays now can, with reasonable accuracy, identify anti– -cell immune responses in individuals with type 1 diabetes compared with nondiabetic control subjects (16). The best validated assays measure T-cell proliferation in response to diabetes-related antigens. One such assay uses predefined diabetes-related peptide or protein antigens and From the National Institute of Diabetes and Digestive and Kidney Diseases/ National Institutes of Health, Diabetes Branch, Bethesda, Maryland; the Diabetes Research Institute, Miami, Florida; the Department of Clinical Immunology, Rudbeck Laboratory, CII, Uppsala, Sweden; and Leiden University Medical Center IHB, Leiden, the Netherlands. Corresponding author: David M. Harlan, [email protected]. Received 31 March 2009 and accepted 22 July 2009. DOI: 10.2337/db09-0476 © 2009 by the American Diabetes Association. 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