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"Two substantial limitations, however, impede broad application of these therapies. First and foremost, the side effect profile associated with these therapies is generally unacceptable given the current high standard of care with exogenous insulin therapy [14,15]. Second, the effect of C-peptide preservation is not lasting, meaning that treatment should be administered chronically which, in view of the aforementioned side effects, is not an option. "
[Show abstract][Hide abstract]ABSTRACT: Up to 25 per cent of the world׳s adult population may have the metabolic syndrome, a condition closely associated with central obesity. The metabolic syndrome is a major risk factor for cardiovascular disease and type 2 diabetes and therefore represents an important worldwide health problem. In addition to metabolic abnormalities such as raised fasting plasma glucose, high cholesterol and high blood pressure, there is consensus that obese subjects develop a state of low-grade chronic immune activation. This sustained pro-inflammatory response in fat tissue is thought to worsen insulin resistance and dyslipidemia. Likewise, the immune system contributes to the detrimental cascade of events leading to plaque formation in atherosclerosis. It has long been assumed that the innate arm of the immune system was the only key player, but emerging evidence suggests that there is in fact a sizeable adaptive immune component to obesity and cardiovascular disease. From a therapeutic perspective, it could be envisioned that immune modulation drugs such as cytokine inhibitors, co-stimulation blockers or anti-T cell agents could offer benefit. It is questionable, however, whether chronic treatment with for instance biologicals will have a favorable risk/benefit profile in a silent condition such as the metabolic syndrome. An attractive alternative could be the development of antigen-specific T cell therapies, not unlike those currently in various phases of development for type 1 diabetes. In this article, we will give an overview of antigen-specific treatment modalities in type 1 diabetes, followed by a review of the evidence for T cell involvement in obesity and atherosclerosis.
Full-text · Article · Jun 2014 · Molecular Metabolism
"Clinical studies involving transient immunoablation to " reset " the immune system, followed by reconstitution with autologous hematopoietic stem cells, have demonstrated some positive results, even after multiyear follow-up, for patients with type 1 diabetes (Burt et al. 2002; Couri et al. 2009; Diabetes Research Group 1998; Milanetti et al. 2010 Snarski winter 2012 winter @BULLET volume 55, number 1et al. 2011Voltarelli et al. 2007). However, there are lingering nontrivial concerns, such as the common occurrence of adverse effects, efficacy that is restricted to the new-onset period, and concerns about study design (Couri et al. 2009; Rosengren et al. 2009; Ross and Philipson 2007;Voltarelli et al. 2007). Mechanisms of action behind the observed positive results of autologous hematopoietic stem cell transplantation have yet to be clearly elucidated, but results suggest the immune tolerance may be achieved through reduced autoantibody titers, cytokine effects, and cellular alterations (Voltarelli et al. 2008). "
[Show abstract][Hide abstract]ABSTRACT: Stem cell research has entered the public consciousness through the media. Proponents and opponents of all such research, or of human embryonic stem cell research specifically, engage in heated exchanges in the modern public forum where stakeholders negotiate, the agora. One common claim that emerges from the fray is that a particular type of stem cell research should be pursued as the most promising path toward the reduction of suffering and untimely death for all of humanity. Upon evaluation, experimental data regarding the potential role of stem cells in regenerative therapies for three conditions-spinal cord injury, type 1 diabetes, and cardiovascular disease-tell distinct, complex, and inconclusive stories. Further analyses in this article incorporate realistic considerations of a broad range of relevant factors: limited funding for biomedical research, media motives, the discordance hypothesis of evolutionary medicine, the relationship between religion and science, medical care in developing nations, and culture wars over abortion. Holistic investigation inspired by the current agora conversation supports the need to drastically change interactions regarding stem cell research so that its potential to benefit humanity may be more fully realized.
Preview · Article · Dec 2012 · Perspectives in Biology and Medicine
"Treatment-related toxicity was low, with no mortality. Limitations of the study included the short follow-up time, as well as a lack of convincing C-peptide data to confirm a treatment effect rather than a prolonged honeymoon period resulting from dietary and exercise changes associated with close posttransplantation medical observation [41,42]. Updated results for the extended group of 23 patients followed for 7-58 months posttreatment were presented by Couri et al. . "
[Show abstract][Hide abstract]ABSTRACT: The pathology of type 1 diabetes mellitus (T1D) involves the autoimmune destruction or malfunction of pancreatic β cells, leading to a lack of insulin. The absence of insulin is life-threatening, necessitating daily hormone injections from an exogenous source. Insulin injections do not adequately mimic the precise regulation of β cells on glucose homeostasis, however, eventually leading to complications in diabetic patients. There currently is no definitive cure for T1D. Pancreas transplantation, although quite successful, is an invasive intervention that is restricted to patients with advanced complications, requires constant immunosuppression, and is severely limited by donor availability. Recent progress in human islet cell isolation and immunosuppressive protocols has restored euglycemia in patients who received islet cells from 2 or 3 pancreas donors. However, because of the scarcity of cadaver pancreata and the low yield of islet cells obtained by the procedure, not all patients have access to this surgical intervention. Thus, other therapeutic approaches are needed to arrest immune aggression, preserve β cell mass, and provide efficient replacement. In this sense, bone marrow and umbilical cord blood transplantation are promising possibilities that merit exploration. In this review, we summarize multiple strategies that have been proposed and tested for potential therapeutic benefit in patients with T1D.
Full-text · Article · Apr 2011 · Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation