A New Home for Pancreatic Islet Transplants: The Bone Marrow

Transplantation of pancreatic islets represents a clinical therapeutic option to preserve and/or restore b-cell function in patients with diabetes (1,2). The source of the islets is the patient’s own pancreas (autologous, islet autotransplantation [IAT]) when the goal is preserving pancreatic endocrine function in pediatric and adult individuals undergoing total pancreatectomy due to pancreatitis (3,4) or trauma (5,6). Recently, IAT has been also proposed for enucleable benign (7) and malignant (8) pancreatic neoplasms. Transplantation of deceased-donor (allogeneic) islets is performed for patients with brittle type 1 diabetes and hypoglycemia unawareness as islet transplant alone (ITA) if nonuremic and as simultaneous islet–kidney (SIK) or sequential islet after kidney (IAK) transplantation procedures if uremic (endstage renal disease) requiring kidney transplantation. Allogeneic islets can be part of cluster organ transplantation (Table 1). In recognition of the excellent metabolic control obtained after islet transplantation even when exogenous insulin treatment is required, reimbursement has been approved in several countries (e.g., Australia, Canada, France, Italy, Switzerland, U.K., Sweden, and the Nordic Network). In the U.S., only IAT is currently reimbursed, while biological licensure by the U.S. Food and Drug Administration should be imminent after recent completion of the Clinical Islet Transplant Consortium registration trials (www .citisletstudy.org). Since the 1970s, islets have been embolized into the hepatic portal system by a minimally invasive technique consisting of transhepatic cannulation of the portal vein under ultrasound and fluoroscopy guidance followed by sealing of the tract with thrombostatic treatment (2). Alternatively, in patients at risk for bleeding, the transplant is performed by cannulation of a tributary of the portal vein using open surgery (minilaparotomy) or laparoscopic approach. An instant blood-mediated inflammatory reaction occurring after intraportal islet infusion may activate the coagulation cascade and the endothelium of the hepatic sinusoids, triggering adhesion of platelets and leukocytes and generation of thrombi and ischemia, contributing to the loss of a conspicuous mass of transplanted tissue. Nonspecific inflammation generated at the time of transplant may heighten the intensity of subsequent adaptive immune responses. In organ transplantation, these responses are responsible for higher incidence of acute and chronic rejection episodes, and in type 1 diabetes they also promote the recurrence of autoimmunity. Other disadvantages of the hepatic site include the relatively hyperglycemic environment and the elevated concentration of immunosuppressants (first-pass) that are toxic to islets. Definition of extrahepatic transplantation sites is recognized as a research priority. Ongoing investigations (Table 2) aimed at identifying a microenvironment that could provide prompt engraftment and minimize early inflammation and islet cell death while achieving sustained function are of particular interest. Engraftment of islet grafts in several extrahepatic sites with or without bioengineering strategies has been demonstrated in experimental models (2,9–11), although clinical translation for some remains arguable (Table 2). An ideal new “home” for islet grafts should accommodate relatively large volumes of tissue (e.g., low purity, or pooled donor islet preparations, and/or retransplantation), rely on minimally invasive transplant procedures, and allow for noninvasive longitudinal monitoring and easy access for biopsy. Portal blood drainage may be preferable to reproduce physiological metabolic responses. Confinement and retrievability of the graft is desirable, particularly for bioengineering approaches to optimize the site. Extrahepatic sites already tested in humans include muscle (12,13) and