Autologous Hsct In Recentonset Autoimmune Type 1 Diabetes Mellitus

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Loss of islet p cells occurs over a time span of 3-5 years and is initially balanced by regeneration; however, persistent autoimmunity eventually exhausts or overwhelms the regenerative capacity of pancreatic stem cells (27). Clinical symptoms manifest when the number of islet p cells falls below the threshold necessary to maintain glycemic control, but before complete ablation of islet p cells. Patients with residual islet p cells have better metabolic control, are less likely to experience acute hypoglycemic or ketotic episodes, and are less likely to develop chronic complications (28). Therapeutic intervention designed to control autoimmunity in patients with recent onset type 1 diabetes may preserve remaining islets and thus improve disease management.

Autologous HSCT has the potential to restore self tolerance to islet p cells, and thus preserve remaining pancreatic islets. The rationale for autologous HSCT is based on the observations that (1) development of type 1 diabetes in genetically susceptible individuals is dependent on environmental or stochastic immune-triggering events and (2) type 1 diabetes is responsive to immunosuppressive therapy. Although autologous HSCT would not alter genetic susceptibility to the development of type 1 diabetes, genetic susceptibility alone does not induce type 1 diabetes in susceptible individuals. Therefore, restoration of self-tolerance may result in durable disease remission. Likewise, type 1 diabetes is transiently responsive to immunosuppressive therapy, which suggests that dose-escalation of immunosuppressive therapies, although requiring stem cell rescue, may result in greater therapeutic benefit.

In patients with recent-onset type 1 diabetes, immunosuppressive therapy with corticosteroids or cyclosporine delays the onset of insulin-dependency; nevertheless, chronic immunosuppressive therapy slows but does not halt autoimmune disease progression (29-33). Lack of long-term benefits of chronic immu-nosuppressive therapy in patients with recent-onset type 1 diabetes may be due to inadequate immunosuppression resulting in low-level, persistent autoimmune reactivity or cumulative diabetogenic effects of immunosuppressive agents. Both cyclosporine and corticosteroids are associated with the development of insulin resistance and inhibition of insulin secretion by pancreatic islet p cells (34-37). Nevertheless, dose reduction or withdrawal of corticosteroids or cyclosporine may reverse impaired insulin secretion (38); therefore, intensive, short-term therapy with immunosuppressive agents may minimize toxic effects. Dose escalation of immunosuppressive therapies followed by stem cell rescue (autologous HSCT) might overcome the limitations of low-dose, chronic immunosuppressive therapies and restore self-tolerance to islet p cells. Relief from autoimmunity would preserve remaining islet p cells and potentially allow for complete restoration of glycemic control as a result of islet p-cell regeneration. Nevertheless, the likelihood of autoimmune relapse or recurrence after autologous HSCT may outweigh the possible benefits of short-term remission or extended insulin-independence.

Autologous HSCT does not correct genetic predisposition to development of autoimmunity, and thus the mechanisms that trigger autoimmunity in type 1 diabetes profoundly affect whether autologous HSCT can provide therapeutic benefit (durable disease remission). For example, if autoimmunity is triggered by exposure to specific pathogens, then autologous HSCT could provide therapeutic benefit in the absence of reexposure to the inducing pathogen. Alternatively, in the event that autoimmunity develops as a consequence of nonspecific immune processes such as inflammation or pancreatic damage, then autologous HSCT might accelerate recurrent type 1 diabetes because of both preexisting autoimmune-mediated damage as well as the diabetogenic effects of many of the available immunosuppressive drugs. Although autologous HCT followed by chronic immunosuppressive therapy to prevent disease recurrence may be more effective than immunosuppressive therapy alone, the necessity for chronic immu-nosuppressive therapy negates many of the benefits to autologous versus alloge-neic HSCT.

One of the more compelling arguments for autologous HSCT in the treatment of type 1 diabetes is the number of monozygotic twins that do not share type 1 diabetes. Concordance among identical twins is typically estimated at 30-50% (39,40); however, long-term studies show that lifetime concordance rates may be as high as 50-70% (41,42). Moreover, in a long-term study of diabetes concordance of monozygotic twins, 8 of 12 nondiabetic twins tested showed evidence of damage to pancreatic p cells or autoimmunity in the absence of diabetes (based on the presence of autoantibodies or functional insulin release tests (41)). The genetic influence toward development of type 1 diabetes thus may be higher than previously assumed; moreover, susceptibility toward (re)development of autoimmunity may be higher in patients with preexisting pancreatic endocrine damage than in nondiabetic twins.

The possibility of autoimmune disease relapse or recurrence and benefit of relief from hyperglycemia must be balanced against the risks of autologous HSCT. The acute risk of mortality resulting from induction toxicity and infections after autologous HSCT is approximately 1-2% (43). Although the potential for durable disease remission in patients with debilitating autoimmune disease favors autologous HSCT in spite of the risk of acute mortality, recent-onset type 1 diabetes can be controlled with exogenous insulin therapy in the majority of patients. The potential benefit of autologous HSCT thus does not balance the risk of HSCT in patients with recent-onset type 1 diabetes because (1) high probabil ity of disease recurrence after autologous HSCT, (2) toxicity of induction therapies, and (3) acute risk of mortality from infection after HSCT.

The benefit-to-risk ratio of autologous HSCT would favor autologous HSCT, however, with the development of gene therapy or successful pre-autoimmune vaccination protocols. If autologous HSCT could correct genetic predisposition to the development of type 1 diabetes, then the potential for long-term disease remission (or cure) would negate the necessity for chronic post-HSCT immuno-suppressive therapies and offset the acute risk of mortality.

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