Pediatric Clinics of North America
Volume 52 • Number 6 • December 2005 - Весь номер посвящен DM
A Look to the Future: Prediction, Prevention, and Cure Including Islet Transplantation and Stem Cell Therapy
Anna Casu, MD
Massimo Trucco, MD
Massimo Pietropaolo, MD
PANCREAS AND ISLET TRANSPLANTATION
A major goal of clinical investigation in T1DM is to restore a physiologic insulin secretion after engrafting the pancreas or the pancreatic islets into T1DM diabetic recipients. Although ectopancreatic transplantation of donor pancreas has proved fairly effective in normalizing blood glucose levels with partial to complete restoration of C-peptide production in selected groups of patients, islet transplantation gave less promising results [116]. It should be noted that pancreas and islet transplantation cannot be considered as life-saving procedures, and the benefit and risk of these procedures must be thoroughly weighed, particularly if one is dealing with pediatric patients that need long-lasting chronic immunosuppressant therapy to prevent allorejection of the graft. The improvement of new immunosuppressive regimens is an important objective to achieve before considering pancreas and islet transplantation as the standard of care for T1DM [117].
Over the past few years, Shapiro and coworkers [118] have been able to reverse T1DM following islet implantation and the success of the Edmonton protocol has again sparked interest for islet transplantation. Shapiro and coworkers [118] administered a steroid-free immunosuppression regimen along with a larger number of transplanted islets compared with previous islet transplantation protocols; sirolimus (0.2 mg/kg/d orally, followed by 0.1 mg/kg/d); low-dose tacrolimus (<2 mg/d orally); and daclizumab (1 mg/kg intravenously every 14 days), an anti interleukin-2 receptor antibody [118]. Side effects were those related to transhepatic puncture and intrahepatic infusion and those related to immunosuppression, such as ulceration of the buccal mucosa, nausea and vomiting, arthralgias, diarrhea, and anemia. Some of the patients had low white blood cell count and a rise in serum creatinine. After a median follow-up of 20 months, 11 transplanted patients were off insulin. According to the American Diabetes Association criteria for diagnosis of diabetes after oral glucose tolerance test, however, only two subjects met the criteria for normal glucose tolerance and the remainder had diabetes [119]. The Edmonton protocol has been widely adopted; however, data on long-term follow-up are not yet available.
STEM CELL THERAPY, GENE THERAPY, AND OTHER THERAPIES
With the initial success of the Edmonton protocol and increased interest for islet transplantation [118], a number of concerns have arisen, including the insufficient number of donors to yield a sufficient number of implantable islets and the need for a life-long immunosuppressive therapy to prevent both allograft rejection and autoimmunity recurrence. These major obstacles have shifted the interest to alternative approaches to create less immunoreactive and potentially endless alternative sources of islet cells, or to regenerate pancreatic β-cells (reviewed in [120]). The shortage of implantable islets could be overcome by a number of new approaches, including transformed insulin-producing cell lines, transfection of different cell types enabled to produce insulin, in vivo transdifferentiation of liver cells, and isolation of xenogeneic porcine islets [117], [120], [121].
It has been hypothesized that newly formed islets derive from the duct epithelium [122], or alternatively from the islet cells themselves [123] or from islet neogenesis, a precursor that may be able to compensate for islet loss. Islet neogenesis may be the end result of a dedifferentiation of pancreatic epithelial cells, or newly formed islets might originate from common endocrine, multipotent progenitors. These islet progenitors seem also to be present within the pancreatic islet microenvironment [124]. It might be easier to derive precursor cells from stem cells, adult or embryonic, and use them to regenerate the damaged endocrine pancreas. Embryonic stem cell lines might give rise to a potentially unlimited source of insulin-producing cells. Even if embryonic stem cells were soon made available for the scientific community, however, their differentiation toward insulin-producing cells would still remain very difficult to direct. In contrast, achieving transdifferentiation into β-cells from adult stem cells obtained from tissues that belong to other lineages might be a more feasible task. The latter could be an attractive approach to avoid the serious problems related to allorejection because adult tissues can be obtained from an autologous living donor. Nevertheless, this approach is not likely to prevent the recurrence of autoimmunity if it is not combined with immunotherapy.
A similar strategy is based on converting the patient's nonislet cells of different lineages into insulin-producing cells. This has been accomplished using gene-engineered hepatocytes that were able to produce insulin after transfecting them with pdx1 under the control of the rat insulin 1 promoter [125]. Although not yet confirmed, this observation suggests that engineered surrogate β-cells or insulin-producing cells obtained from cells of different lineages could be exploited to restore insulin secretion.
Other alternative sources of insulin-producing cells include xenogeneic donor manipulated cells that could provide an indefinite supply of β-cells for transplantation. In an elegant set of experiments, the generation of a transgenic pig that was deficient for α(1,3)-galactosyltransferase resulted in the dissipation of the hyperacute xenograft rejection response. This was a major advance that might set the stage toward the attainment of the first clinical trial in humans using xenogeneic islet donors [126], [127], [128], [129].
Although many of these approaches seem to hold great promise as alternative strategies to cure T1DM, it is unlikely that the recurrence of islet autoimmunity can be prevented without an appropriate immunotherapeutic treatment. In T1DM patients, the autoimmune process not only damages the pancreatic β-cells, leading to the clinical onset of the disease, but also limits the regeneration of newly formed β-cells that will eventually replace those cells that are lost. The recurrence of autoimmunity in combination with allorejection is probably what differentiates transplanted patients with T1DM from patients who received islet autotransplantation and were able to maintain long-lasting glucose homeostasis [117], [130]. Strategies aimed at blocking this autoimmune process, or at manipulating potentially less immunoreactive transplanted cells, should yield more encouraging results. These strategies include patient's own cells of different lineages converted into insulin-producing cells; xenogeneic donor manipulated cells; and other manipulated insulin-producing cells, which are likely less immunoreactive. Furthermore, the autoimmune process is successfully averted by blocking the autoreactive T cells with an anti–T-cell antibody (antilymphocyte serum) and by inducing a mixed allogeneic chimerism by transplanting bone marrow from a diabetes-resistant donor [131]. Hematopoietic precursors do not directly participate in islet cell regeneration, although they might be necessary to promote an effective regenerative process, which is independent of the ability to block the autoimmune process [132]. A better understanding of the autoimmune process and the ability to restrain this process not only could prevent the disease, but also help restore residual islet function following islet transplantation or regeneration.