Clinical islet transplantation at the University of California, San Francisco.
ABSTRACT The UCSF clinical islet transplant program has evolved to utilize immunosuppressive strategies that do not rely on CNIs or other nephro- and beta-cell-toxic immunosuppressive agents. These novel strategies depend on lymphocyte-depleting induction immunotherapy and maintenance immunosuppression with novel agents that focus on co-stimulation and/or lymphocyte migration blockade. These drugs are well tolerated, frequently allow establishment of insulin independence after single islet infusions, and minimize allosensitization. Our early results suggest these regimens will be attractive immunosuppressive agents for future protocols in allogeneic islet transplantation as well as protocols utilizing stem-cell-derived beta cells.
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ABSTRACT: Islet transplantation has proven to be a successful strategy to restore normoglycemia in patients with type 1 diabetes (T1D). However, the dearth of cadaveric islets available for transplantation hampers the widespread application of this treatment option. Although human embryonic stem cells and induced pluripotent stem cells are capable of generating insulin-producing cells in vitro when provided with the appropriate inductive cues, the insulin-expressing cells that develop behave more like immature β-cells with minimal sensitivity to glucose stimulation. Here, we identify a set of signaling factors expressed in mouse embryonic mesenchyme during the time when foregut and pancreatic progenitors are specified and test their activities during in vitro differentiation of human embryonic stem cells. Several of the identified factors work in concert to expand the pancreatic progenitor pool. Interestingly, transforming growth factor (TGF)-β ligands, most potent in inducing pancreatic progenitors, display strong inhibitory effects on subsequent endocrine cell differentiation. Treatment with TGF-β ligands, followed by the addition of a TGF-β receptor antagonist, dramatically increased the number of insulin-producing cells in vitro, demonstrating the need for dynamic temporal regulation of TGF-β signaling during in vitro differentiation. These studies illustrate the need to precisely mimic the in vivo conditions to fully recapitulate pancreatic lineage specification in vitro.Diabetes 01/2013; 62(5). DOI:10.2337/db12-0167 · 8.47 Impact Factor
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ABSTRACT: Remarkable progress has been made in islet transplantation over a span of 40 years. Once just an experimental curiosity in mice, this therapy has moved forward, and can now provide robust therapy for highly selected patients with type 1 diabetes (T1D), refractory to stabilization by other means. This progress could not have occurred without extensive dynamic international collaboration. Currently, 1,085 patients have undergone islet transplantation at 40 international sites since the Edmonton Protocol was reported in 2000 (752 allografts, 333 autografts), according to the Collaborative Islet Transplant Registry. The long-term results of islet transplantation in selected centers now match registry data of pancreas-alone transplantation, with 6 sites reporting five-year insulin independence rates ≥50%. Islet transplantation has been criticized for the use of multiple donor pancreas organs, but progress has also occurred in single-donor success, with 10 sites reporting increased single-donor engraftment. The next wave of innovative clinical trial interventions will address instant blood-mediated inflammatory reaction (IBMIR), apoptosis, and inflammation, and will translate into further marked improvements in single-donor success. Effective control of auto- and alloimmunity is the key to long-term islet function, and high-resolution cellular and antibody-based assays will add considerable precision to this process. Advances in immunosuppression, with new antibody-based targeting of costimulatory blockade and other T-B cellular signaling, will have further profound impact on the safety record of immunotherapy. Clinical trials will move forward shortly to test out new human stem cell derived islets, and in parallel trials will move forward, testing pig islets for compatibility in patients. Induction of immunological tolerance to self-islet antigens and to allografts is a difficult challenge, but potentially within our grasp.The Review of Diabetic Studies 01/2012; 9(4):385-406. DOI:10.1900/RDS.2012.9.385
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ABSTRACT: Type 1 diabetes mellitus is an autoimmune disease that is characterized by the destruction of the islets of Langerhans cells which produce insulin. The current gold standard treatment is exogenous insulin injection, but this is onerous for the patients, and can lead to severe complications. Another approach involves transplanting pancreatic islet cells in order to restore endogenous insulin production under physiologic regulation. Although there has been some success with this treatment plan, there have been several hurdles. The largest hurdle is improving the 5 year survival of the graft, which is currently at 10%. In order to do so, there has been research into better locations for the graft, better isolation techniques, alternate immune suppression regimens, and novel transplantation methodologies utilizing encapsulated grafts. Another hurdle for pancreatic islet transplantation is that current methodologies require islets from several pancreata in order to create one successful graft, which leads to difficulties since there is a limited supply. However, there has been research looking into single donor transplants and porcine xenografts to increase the supply and address this problem. In this article, we review the current state of research regarding pancreatic islet transplantation.Current diabetes reviews 05/2013; DOI:10.2174/15733998113099990063