Pancreatic Islet Cell Transplantation

Transplantation of isolated pancreatic islets offers the advantage of a minimally invasive procedure associated with very low incidence of adverse effects (Hering and Ricordi, 1999). Following islet infusion a dramatic reduction of insulin requirement is generally observed, and insulin independence can be achieved when an optimal islet mass has been implanted (Shapiro et al, 2000 and 2003; Goss et al, 2002; Markmann et al, 2003).

Transplantation of islets of Langerhans consists in the implantation of different degrees of purified endocrine pancreatic tissue into diabetic recipients. The protocols for the isolation and purification of islets of Langerhans are not yet completely standardized and differ slightly between centers. The islet isolation procedure consists of a mechanically enhanced enzymatic digestion of the pancreatic tissue that frees the islets from the surrounding connective and acinar tissue without destroying islet integrity (Ricordi, 1995). The subsequent purification step addresses the need to physically separate the islet tissue, which constitutes < 2% of the digest, from nonendocrine tissue (exocrine fragments, ductal and vascular tissues, and lymph nodes) (Ricordi, 1995). Islets are transplanted in the portal system and minimization of the volume of implanted tissue can prevent excessive ischemic insult to the liver and elevation of portal pressure, thereby decreasing the potential for procedure-related complications. After purification, islets can be transplanted immediately or cultured for a short period of time (usually 2 to 3 days) prior to implantation. Pretransplantation culture allows for the assessment of sterility and in vitro function of the islet preparation. Also, the culture period may provide a window of opportunity for manipulation of islets prior to implantation by means of emerging interventional approaches (modulation of immunogenicity, induction of cytoprotective molecules, gene therapy, immunoisolation, etc), and/or preconditioning the recipient (immunomodulation, immunosup-pression, reduction of inflammation) to maximize both engraftment of the islets and their survival. Thanks to the availability of minimally invasive interventional radiology techniques, implantation of an islet graft consists in the can-nulation of the portal vein via a transhepatic percutaneous access under ultrasound and angiographic guidance (Froud et al, 2004). This approach is associated with minimal surgical risk and low incidence of complications, it is quicker and less expensive than surgery, it is well tolerated by the patients (conscious sedation protocol), can be performed as outpatient procedure, and can be repeated in different occasions. The minimally invasive approach is generally offered to patients receiving solitary allogeneic islet grafts subsequent to a kidney transplant (islets after kidney, IAK), or to patients receiving islet transplantation alone (ITA).

The surgical approach consists of the cannulation of a tributary of the portal vein (omental vein, branch of the middle colic vein, or inferior mesenteric vein) that requires laparotomy. This approach is preferred during a simultaneous islet and kidney (SIK) transplantation, when access to the portal system can be obtained during an open surgical procedure (Alejandro et al, 1997) or in selected cases (IAK and ITA) in which the percutaneous procedure may be contraindicated, including patients at high risk of bleedings, patients with hepatic hemangiomas, lack of an experienced interventional radiologist, or patient preference after inform consent. Alternative less invasive surgical procedures under evaluation include the use of laparoscopic access to infuse islets in the umbilical vein or islets implantation within the omental layers.

The main indication for allogeneic islet transplantation is T1DM (Brendel et al, 2001; Hering and Ricordi, 1999). Transplantation of islets of Langerhans can be performed in uremic patients as either SIK or IAK procedure, since chronic immunosuppression therapy is already implemented to sustain the function of the kidney graft. More recently, ITA has been introduced for the treatment of selected patients with brittle T1DM associated with hypoglycemic unawareness (absence of autonomic symptoms at glycemic levels < 54 mg/dL), severe metabolic lability (mean amplitude of glucose excursions > 11.1 mmol/L or 200 mg/dL), progressive secondary diabetes complications, and failure of intensive insulin therapy despite strict compliance (Robertson et al, 2003; Shapiro et al, 2000; Shapiro and Ricordi, 2004). In these patients the risk associated with metabolic lability and hypoglycemic unawareness (often life threatening) justifies that related to the transplantation procedure and chronic immunosuppression. A number of clinical trials of allogeneic ITA for patients with T1DM ongoing worldwide have shown that sustained insulin independence can be reproducibly achieved after islet transplantation in experienced centers (Shapiro et al, 2003; Shapiro and Ricordi, 2004). This is generally achieved after sequential infusion (Shapiro et al, 2000; Goss et al, 2002) or single infusion of pooled islet preparations (Markmann et al, 2003) obtained from more than one gland, and, in some cases, after the infusion of a single islet preparation (Hering et al, 2004; Shapiro and Ricordi, 2004). Insulin requirements are generally dramatically reduced after single islet transplantation, and improved glycemic metabolic control, with normalization of glycated hemoglobin and absence of hypoglycemic episodes is always observed even when exogenous insulin treatment is still required (such as in the case a suboptimal graft mass is implanted, or when partial loss of function is observed) (Brendel et al, 2001; Shapiro et al, 2003; Shapiro and

Ricordi, 2004) Success rates of ITA using a steroid-free immunosuppressive protocol are close to 90% insulin independence at 1 year, and approximately 80% at 2 years (Shapiro et al, 2003; Shapiro and Ricordi, 2004).

The need to transplant a large number of islets (> 12,000 islet equivalents per kg of body weight, in the recent successful clinical trials) to attain insulin independence may be consequent to multiple factors all contributing to the loss of viable insulin-producing cells (Pileggi et al, 2001). Brain death, donor characteristics, and isolation and purification procedures may dramatically influence both yield and quality of islets obtained from a cadaveric pancreas. Additionally, culture conditions, and nonspecific inflammation generated at the site of implant may affect the actual number of islets that will engraft and function after transplantation. Although the need for more than one islet preparation (therefore > 1 pancreatic gland per recipient) to restore normoglycemia may represent a drawback due to the shortage of organs for transplant, it is noteworthy that most centers performing islet isolations worldwide have mainly used "sub-optimal" pancreata that had been "discarded" by the pancreas transplantation surgeons for a number of reasons (fatty pancreas, technical problems, damaged glands, long ischemia, etc). Implementing fair allocation rules for cadaveric pancreata between whole pancreas and isolated islet programs may allow for the availability of optimal tissue for the isolation of islets for transplantation, which may render possible achieving insulin independence from a single islet preparation per recipient. Moreover, at the present time the use of pancreata for transplantation (either as whole organ or for islets) is still poor, and a large number of glands are, unfortunately, not used (Krieger et al, 2003).

Other indications for the transplantation of allogeneic islets include selected cases of pancreatectomy-induced diabetes (Hering and Ricordi, 1999). Patients with "insulin-requiring diabetes" secondary to cystic fibrosis (Cretin et al, 1998) and hemochromatosis (Brunicardi et al, 1995) may benefit of an islet graft combined with lung or liver transplantation. Islet transplantation for type 2 diabetes has been attempted in very few cases in pilot trials (Ricordi et al, 1997). Successful transplantation of allogeneic islets isolated from pancreatic grafts explanted for technical complications has been reported as a "rescue" procedure (Leone et al, 1998).

Transplantation of islets obtained from autologous pancreas (islet autotransplantation) removed for benign conditions has been performed for several years to prevent iatrogenic diabetes (Hering and Ricordi, 1999; Robertson et al, 2003). This procedure is mainly performed in patients undergoing total pancreatectomy to relive the pain associated with chronic pancreatitis, offering the perspective of a better quality of life and prevention of the occurrence of diabetes and its complications. Indeed, normoglycemia and insulin independence are observed in about 70% of the patients after intrahepatic islet autotransplantation when > 250,000 islets are implanted.

Increasing interest has been focused on islet isolation and transplantation in the recent years, following the unprecedented results of clinical trials (Brendel et al, 2001; Shapiro et al, 2003). The Food and Drug Administration regulates islet cell transplantation at the present time under the category of investigational new drug (Weber et al, 2002). Emerging evidence from the ongoing clinical trials supports the relevance of multidisciplinary expertise at the islet isolation and transplantation center (Shapiro et al, 2003; Shapiro and Ricordi, 2004). This includes the availability of adequate infrastructures and highly qualified personnel (endocrinology, transplant surgery, radiology, cell biology, immunology, administrative, and current Good Manufacturing Practice human islet cell processing facility and personnel). These important premises have been associated with the best results, not only in obtaining adequate islets from the donor pancreata, but also in assuring appropriate posttransplantation management (ie, metabolic and immunosuppression) of the recipients. Using specialized, experienced islet cell processing centers that distribute islet cell products to remote islet transplantation centers has also been demonstrated an effective strategy (Goss et al, 2002; Leone et al, 1998; Robertson et al, 2001). The possibility of having "regional centers" may improve the efficiency of use of cadaveric pancreata and may be of assistance to improve the success rate of clinical islet transplantation, while lowering the costs for islet preparation.

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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