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Nick Giannoukakis

Publications and source records attributed to Nick Giannoukakis.

At least 19 recordsLinked to original sources
PubMed2006

Prospective and challenges of islet transplantation for the therapy of autoimmune diabetes.

Pancreatic islet cell transplantation is an attractive treatment of type 1 diabetes (T1D). The success enhanced by the Edmonton protocol has fostered phenomenal progress in the field of clinical islet transplantation in the past 5 years, with 1-year rates of insulin independence after transplantation near 80%. Long-term function of the transplanted islets, however, even under the Edmonton protocol, seems difficult to accomplish, with only 10% of patients maintaining insulin independence 5 years after transplantation. These results differ from the higher metabolic performance achieved by whole pancreas allotransplantation, and autologous islet cell transplantation, and form the basis for a limited applicability of islet allografts to selected adult patients. Candidate problems in islet allotransplantation deal with alloimmunity, autoimmunity, and the need for larger islet cell masses. Employment of animal islets and stem cells, as alternative sources of insulin production, will be considered to face the problem of human tissue shortage. Emerging evidence of the ability to reestablish endogenous insulin production in the pancreas even after the diabetic damage occurs envisions the exogenous supplementation of islets to patients also as a temporary therapeutic aid, useful to buy time toward a possible self-healing process of the pancreatic islets. All together, islet cell transplantation is moving forward.

Autoimmunity↗
PubMed2006

Interleukin-7 is a survival factor for CD4+ CD25+ T-cells and is expressed by diabetes-suppressive dendritic cells.

Dendritic cells can facilitate allograft survival and prevent autoimmunity via direct and indirect cell-mediated mechanisms. Recent studies demonstrate that immunoregulatory dendritic cells (iDCs) confer immune hyporesponsiveness in part through CD4(+) CD25(+) T regulatory cells (Tregs). Herein, we provide evidence to support the hypothesis that dendritic cells derived from NOD mice and engineered ex vivo to exhibit suppressed expression of the CD40, CD80, and CD86 costimulatory molecules motivate an increase in the prevalence of regulatory CD4(+) CD25(+) T-cells via interleukin (IL)-7. Unlike control dendritic cells, these dendritic cells expressed significant levels of IL-7. Exogenous addition of IL-7 to NOD T-cells did not promote expansion or proliferation, but instead selectively maintained the number of CD4(+) CD25(+) T-cells by inhibiting activation of apoptosis in these cells. In vitro, IL-7 receptor alpha-chain (IL-7Ralpha) was expressed at significantly higher levels on CD4(+) CD25(+) T-cells compared with CD4(+) CD25(-) T-cells irrespective of resting or stimulated state. In vivo, CD4(+) CD25(+) T-cells obtained from NOD-scid mice reconstituted with ex vivo engineered iDCs and NOD splenocytes expressed significantly higher levels of IL-7Ralpha compared with levels in the CD4(+) CD25(-) subset, especially in diabetes-suppressive dendritic cell-administered NOD-scid recipients. Taken together, our data suggest a novel mechanism by which iDCs delay autoimmunity through the CD4(+) CD25(+) Treg pathway and suggest IL-7 as a survival factor for these putative Tregs, which express the alpha-chain of its receptor at considerably higher levels than CD4(+) CD25(-) T-cells.

Animals↗
PubMed2006

Drug evaluation: ranirestat--an aldose reductase inhibitor for the potential treatment of diabetic complications.

Ranirestat is an orally available aldose reductase inhibitor under development by Dainippon Sumitomo Pharma Co Ltd (formerly Dainippon Pharmaceutical Co Ltd), Kyorin Pharmaceutical Co Ltd and Eisai Co Ltd for the potential treatment of diabetic complications, such as neuropathy, cataracts, retinopathy and nephropathy. Phase III trials were ongoing in February 2006.

Aldehyde Reductase↗
PubMed2005

Footer: a quantitative comparative genomics method for efficient recognition of cis-regulatory elements.

The search for mammalian DNA regulatory regions poses a challenging problem in computational biology. The short length of the DNA patterns compared with the size of the promoter regions and the degeneracy of the patterns makes their identification difficult. One way to overcome this problem is to use evolutionary information to reduce the number of false-positive predictions. We developed a novel method for pattern identification that compares a pair of putative binding sites in two species (e.g., human and mouse) and assigns two probability scores based on the relative position of the sites in the promoter and their agreement with a known model of binding preferences. We tested the algorithm's ability to predict known binding sites on various promoters. Overall, it exhibited 83% sensitivity and the specificity was 72%, which is a clear improvement over existing methods. Our algorithm also successfully predicted two novel NF-kappaB binding sites in the promoter region of the mouse autotaxin gene (ATX, ENPP2), which we were able to verify by using chromatin immunoprecipitation assay coupled with quantitative real-time PCR.

Algorithms↗
PubMed2005

Pyridoxamine (BioStratum).

BioStratum is developing pyridoxamine (Pyridorin), an advanced glycation end-product (AGE) inhibitor, for the potential prevention of diabetic nephropathy. By January 2004, phase II trials had been completed.

Animals↗
PubMed2005

Gene therapy for type 1 diabetes: a proposal to move to the next level.

A number of studies have confirmed that gene therapy can be successfully applied to prevent type 1 diabetes mellitus and to facilitate the transplantation of replacement insulin-producing cells as allografts of the islets of Langerhans or in the form of enriched and homogeneous surrogate cells. However, these successes have remained restricted to a few rodent models and have not progressed past this stage into larger animals. Newer technology has also emerged that offers exciting alternatives or complementary methods to achieve the same results, including therapeutic cloning. A synopsis of the strategies and tools used successfully in vivo is provided and a proposal to motivate a step-up of these approaches to larger animals, if not outright to safety trials in humans, is outlined. Additionally, newer emerging technologies that can, in the future, complement those that are currently readily adaptable to clinical implementation are suggested.

Animals↗
PubMed2005

DiaPep277 (DeveloGen).

DiaPep277, a 24-amino acid peptide based on residues 437 to 460 of heat shock protein 60, is undergoing phase II clinical trials by DeveloGen for the potential treatment and prevention of established and newly diagnosed type 1 diabetes symptoms of the prediabetic state and of latent autoimmune diabetes of the adult.

Animals↗
PubMed2004

Antisense oligonucleotides down-regulating costimulation confer diabetes-preventive properties to nonobese diabetic mouse dendritic cells.

Phenotypically "immature" dendritic cells (DCs), defined by low cell surface CD40, CD80, and CD86 can elicit host immune suppression in allotransplantation and autoimmunity. Herein, we report the most direct means of achieving phenotypic immaturity in NOD bone marrow-derived DCs aiming at preventing diabetes in syngeneic recipients. CD40, CD80, and CD86 cell surface molecules were specifically down-regulated by treating NOD DCs ex vivo with a mixture of antisense oligonucleotides targeting the CD40, CD80, and CD86 primary transcripts. The incidence of diabetes was significantly delayed by a single injection of the engineered NOD DCs into syngeneic recipients. Insulitis was absent in diabetes-free recipients and their splenic T cells proliferated in response to alloantigen. Engineered DC promoted an increased prevalence of CD4(+)CD25(+) T cells in NOD recipients at all ages examined and diabetes-free recipients exhibited significantly greater numbers of CD4(+)CD25(+) T cells compared with untreated NOD mice. In NOD-scid recipients, antisense-treated NOD DC promoted an increased prevalence of these putative regulatory T cells. Collectively, these data demonstrate that direct interference of cell surface expression of the major costimulatory molecules at the transcriptional level confers diabetes protection by promoting, in part, the proliferation and/or survival of regulatory T cells. This approach is a useful tool by which DC-mediated activation of regulatory T cells can be studied as well as a potential therapeutic option for type 1 diabetes.

Adoptive Transfer↗
PubMed2003

Gene therapy technology applied to disorders of glucose metabolism: promise, achievements, and prospects.

Gene transfer technology has spawned an entire realm of clinical investigation, collectively referred to as "gene therapy." The feasibility and achievements of gene therapy to prevent and treat glucose homeostasis disorders, with particular emphasis on diabetes mellitus, are evaluated in this review. While a considerable amount of effort has yielded gene delivery vectors based on adenoviral, retroviral, and herpes simplex virus DNA, the number of successful clinical applications has not been as impressive. Despite the number of successes in vitro and in animal models, preliminary safety trials in humans have not yet been attempted. The current state of this science, outlined here, underlines the necessity of marrying gene transfer technology with cell therapy. The ex vivo transfer of gene combinations into a variety of cell types will likely prove more therapeutically feasible than direct in vivo vector transfer. Current efforts aimed at assessing the future of gene therapy for diabetes must, at the very least, take into account the importance of moving successful methods into human safety trials.

Diabetes Mellitus↗
PubMed2003

Prevention of diabetes in NOD mice by administration of dendritic cells deficient in nuclear transcription factor-kappaB activity.

Abnormalities of dendritic cells (DCs) have been identified in type 1 diabetic patients and in nonobese diabetic (NOD) mice that are associated with augmented nuclear transcription factor (NF)-kappaB activity. An imbalance that favors development of the immunogenic DCs may predispose to the disease, and restoration of the balance by administration of DCs deficient in NF-kappaB activity may prevent diabetes. DCs propagated from NOD mouse bone marrow and treated with NF-kappaB-specific oligodeoxyribonucleotide (ODN) in vitro (NF-kappaB ODN DC) were assessed for efficacy in prevention of diabetes development in vivo. Gel shift assay with DC nuclear extracts confirmed specific inhibition of NF-kappaB DNA binding by NF-kappaB ODN. The costimulatory molecule expression, interleukin (IL)-12 production, and immunostimulatory capacity in presenting allo- and islet-associated antigens by NF-kappaB ODN DC were significantly suppressed. NF-kappaB ODN renders DCs resistant to lipopolysaccharide stimulation. Administration of 2 x 10(6) NF-kappaB ODN DCs into NOD mice aged 6-7 weeks effectively prevented the onset of diabetes. T-cells from pancreatic lymph nodes of NF-kappaB ODN DC-treated animals exhibited hyporesponsiveness to islet antigens with low production of interferon-gamma and IL-2. These findings provide novel insights into the mechanisms of autoimmune diabetes and may lead to development of novel preventive strategies.

Animals↗
PubMed2003

Exenatide. Amylin/Eli Lilly.

Amylin Pharmaceuticals Inc and Eli Lilly & Co are co-developing exenatide (AC-2993; synthetic exendin-4), a 39-amino acid, glucagon-like peptide-1 agonist derived from the venom of the Gila monster lizard (Heloderma suspectum) as a potential injectable treatment for type 2 diabetes. The first phase III trial (exenatide as a monotherapy) was initiated in December 2001. In January 2002 the second phase III trial, of exenatide in conjunction with sulfonylureas, was initiated and in March 2002, Amylin initiated the third phase III trial, of exenatide in combination with metformin and sulfonylureas.

Animals↗
PubMed2003

Fidarestat. Sanwa Kagaku/NC Curex/Sankyo.

Fidarestat is an aldose reductase inhibitor being co-developed by Sanwa Kagaku, NC Curex (a joint venture company created by Japan Energy and Kaken) and Sankyo, for the potential treatment of diabetic neuropathy.

Aldehyde Reductase↗
PubMed2003

CJC-1131. ConjuChem.

ConjuChem is developing CJC-1131, a drug affinity complex conjugate of glucagon-like peptide 1 for the potential treatment of type 2 diabetes. In August 2003, a phase I/II trial was completed and a phase II trial was expected to begin in October.

Clinical Trials, Phase I as Topic↗
PubMed2002

Immunosuppressive effects of glucosamine.

Glucosamine is a naturally occurring derivative of glucose and is an essential component of glycoproteins and proteoglycans, important constituents of many eukaryotic proteins. In cells, glucosamine is produced enzymatically by the amidation of glucose 6-phosphate and can then be further modified by acetylation to result in N-acetylglucosamine. Commercially, glucosamine is sold over-the-counter to relieve arthritis. Although there is evidence in favor of the beneficial effects of glucosamine, the mechanism is unknown. Our data demonstrate that glucosamine suppresses the activation of T-lymphoblasts and dendritic cells in vitro as well as allogeneic mixed leukocyte reactivity in a dose-dependent manner. There was no inherent cellular toxicity involved in the inhibition, and the activity was not reproducible with other amine sugars. More importantly, glucosamine administration prolonged allogeneic cardiac allograft survival in vivo. We conclude that, despite its documented effects on insulin sensitivity, glucosamine possesses immunosuppressive activity and could be beneficial as an immunosuppressive agent.

Adenosine Triphosphate↗
PubMed2002

Islet/pancreas transplantation: challenges for pediatrics.

Beta cell replacement is a valid alternative to exogenous insulin injections to treat type 1 diabetic patients. The rate of success obtained after whole-pancreas transplantation, performed alone or in combination with kidney, and, as shown recently, by islet transplantation, justifies optimism and sets the stage for a larger clinical application of these approaches. Lifetime immunosuppression, however, required to protect the graft against recurrent autoimmune destruction and allorejection, raises serious doubts about the safety of its employment in children. While it is evident that children may be helped even more than adults by the possibility to correct diabetic metabolic disorders without exogenous insulin, and to lower in a more effective way the chance to develop secondary complications, the drawbacks of the currently used immunosuppressive drugs largely overcome the potential benefits. A great step forward for immediate applicability of transplantation to children involves the optimization of tolerogenic protocols and a better understanding of the concept of immune ignorance. Functional tolerance should be sufficient to entail the absence of immune reactivity against self- and graft antigens, while maintaining immune reactivity against other non-self, non-donor antigens. In addition, novel strategies aimed at utilizing surrogate beta cells obtained from non-islet cells, or by genetic manipulation of beta-cell precursors merit consideration as the use of xenogeneic donors. However, much work is still needed for their safe clinical implementation.

Journal Article↗
PubMed2002

Gene and cell therapies for diabetes mellitus: strategies and clinical potential.

The last 5 years have witnessed an explosion in the use of genes and cells as biomedicines. While primarily aimed at cancer, gene engineering and cell therapy strategies have additionally been used for Mendelian, neurodegenerative and metabolic disorders. The main focus of gene and cell therapy strategies in metabolism has been diabetes mellitus. This disease is a disorder of glucose homeostasis, either due to the immune-mediated eradication of pancreatic beta cells in the islets of Langerhans (type 1 diabetes) or resulting from insulin resistance and obesity syndromes where the insulin-producing capability of the beta cell is ultimately exhausted in the face of insensitivity to the effects of insulin in the peripheral glucose-utilising tissues (type 2 diabetes). A significant number of animal studies have demonstrated the potential in restoring normoglycaemia by islet transplantation in the context of immunoregulation achieved by gene transfer of immunoregulatory genes to allo- and xenogeneic islets ex vivo. Additionally, gene and cell therapy has also been used to induce tolerance to auto- and alloantigens and to generate the tolerant state in autoimmune rodent animal models of type 1 diabetes or rodent recipients of allogeneic/xenogeneic islet transplants. The achievements of gene and cell therapy in type 2 diabetes are less evident, but seminal studies promise that this modality can be relevant to treat and perhaps prevent the underlying causes of the disease. Here we present an overview of the current status of gene and cell therapy for type 1 and 2 diabetes and we propose potential therapeutic options that could be clinically useful. For type 1 diabetes, transplantation of islets engineered to evade or suppress the recipient immune response is the most readily-available technology today. A number of gene delivery vectors encoding proteins that impair a variety of immune cells have already been examined and proven versatile. More challenging but, nonetheless, just over the horizon are attempts to promote tolerance to islet allografts. Type 2 diabetes will likely require a better understanding of the processes that determine insulin sensitivity in the periphery. Targeting tissues such as muscle and fat with vectors encoding genes whose products promote insulin sensitivity and glucose uptake is an approach that does not carry with it the side-effects often associated with pharmacologic agents currently in use. In the end, progress in vector design, elucidation of antigen-specific immunity and insulin sensitivity will provide the framework for gene drug use in the treatment of type 1 and type 2 diabetes.

Animals↗