Inhibition of apoptosis by survivin improves transplantation of pancreatic islets for treatment of diabetes in mice.

Survivin is a cancer gene implicated in inhibition of apoptosis and regulation of mitosis, but its function in normal cells has remained elusive. Here, we show that transgenic mice expressing survivin in pancreatic islet beta-cells show no changes in cell proliferation, as determined by islet size or islet number. Transplantation of survivin transgenic islets in diabetic recipient mice affords long-term engraftment and stable correction of hyperglycaemia.

Antigen exposure during enhanced CTLA-4 expression promotes allograft tolerance in vivo.

The role of CTLA-4 in tolerance is primarily inferred from knockout and blocking studies. Anti-CD45RB mediates allograft tolerance in mice by inducing CTLA-4 expression on CD4 cells, providing a novel opportunity to determine how therapeutic enhancement of CTLA-4 promotes tolerance. We now show that induced CTLA-4 expression normally resolves by day 17.

Gene silencing in the endocrine pancreas mediated by short-interfering RNA.

Objectives: RNA interference as mediated by short-interfering RNA (siRNA) offers a nonviral means to silence genes in tissue; however, few data exist about gene therapy using siRNA in pancreas tissue. To determine if siRNA treatment could silence an endogenous gene in pancreatic islets, we developed a murine model using the endocrine pancreas.

Methods: The insulin 2 (Ins2) gene was targeted with siRNA, and quantitative RT-PCR, fluorescent microscopy, and FACS were used to measure transcript levels and siRNA cellular uptake and transfection efficiency.

Requirements for induction and maintenance of peripheral tolerance in stringent allograft models.

Peripheral tolerance can be achieved in many but not all murine allograft models. The requirements for controlling more aggressive immune responsiveness and generating peripheral tolerance in stringent allograft models are unknown. Understanding these requirements will provide insight toward ultimately achieving tolerance in humans, which are also resistant.

Renal transplant recipients over aged 60 have diminished immune activity and a low risk of rejection.

Strict consideration of the renal transplant candidate's chronologic age is generally supplanted by more subjective reflection on his (her) physiologic state. In the US, patients over 64 years old represented 9.0% of renal transplant recipients in the year 2000, yet little prior experience is available with which to guide the management of geriatric patients.

Cutting edge: transplantation tolerance through enhanced CTLA-4 expression.

Knockout and blocking studies have shown a critical role for CTLA-4 in peripheral tolerance, however, it is unknown whether augmenting CTLA-4 expression actually promotes tolerance. Here we demonstrate a specific and requisite role for CTLA-4 and its up-regulation in tolerance through anti-CD45RB. First, long-term murine islet allograft survival induced by anti-CD45RB is prevented by CTLA4-Ig, which interferes with B7:CTLA-4 interactions.

Prolonged islet allograft survival in diabetic NOD mice by targeting CD45RB and CD154.

Clinical islet transplantation is a successful procedure that can improve the quality of life in recipients with diabetes. A drawback of the procedure is the need for chronic administration of immunosuppressive drugs that, among other side effects, are potentially diabetogenic. Definition of immunosuppressive protocols that utilize nondiabetogenic compounds could further improve islet transplantation outcome.

Islet filtration: a simple and rapid new purification procedure that avoids ficoll and improves islet mass and function.

Islet isolation is a time-consuming process. Islet yields vary, and previous in vitro studies suggest that Ficoll may be an islet toxin. Here, we describe an alternative, Ficoll-free method to purify murine islets by filtration through a cell strainer.

Treatment of osteoporosis and osteopenia in long-term renal transplant patients with alendronate.

Bone mineral density (BMD) and biochemical markers of bone-turnover were evaluated in a 2-year study in 58 long-term renal transplant recipients with good renal function. In the first year of study, data were collected and patients with osteoporosis and parameters of high bone turnover were classified as being at high risk for on-going bone loss (Group A; n = 29). Patients with lesser degrees of bone loss or without biochemical parameters of high bone turnover were followed longitudinally (Group B; n = 29).