From Insulin therapy to immunotherapy
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Despite our advancing knowledge in medical science there is still no cure for type I diabetes. Insulin production made possible by DNA recombinant technology and the invention of insulin pump have revolutionised the treatment of insulin-dependent diabetes. Yet, insulin replacement therapy is merely a symptomatic treatment for diabetes which does not modify the disease process.
Repeated intravenous injections of insulin daily is highly inconvenient for the patients and can significantly affect patients’ quality of life. People with diabetes receiving insulin replacement therapy continue to have a markedly decreased life span. Insulin pump, though shown to be more effective at controlling plasma glucose levels than injections, poses a great risk of infection at the infusion site. In addition, rates of complication remain high even with appropriate treatment and aggressive approaches aimed to minimise complications are associated with higher mortality owing to hypoglycemia.
Presently, the treatment of autoimmune diseases is based on non-antigen-specific immunosuppression which works by interfering with the production of cytokines and proliferations of cytotoxic T cells. However, such intervention is frequently ineffective in the long-term owing to high relapse rate following withdrawal of treatment and the risk of generalised immunosuppression predisposing patients to secondary infections and tumours. The discovery of monoclonal antibodies has allowed us to generate induction of specific immune tolerance by suppressing the pathogenic processes involved in a particular autoimmune disease.
Previous studies (1997 - 2011) have attempted to induce specific beta-cell self-tolerance by using CD3 specific antibodies that has been altered to prevent binding to Fc receptor. CD3 is a protein complex on the surface of T-cells. It associates with T-cell receptors (TCR) to form TCR complex which is crucial in the generation of activation signal in T-lymphocytes. Anti-CD3 antibodies have been shown to induce remission of recent-onset diabetes in non-obese diabetic (NOD) mice to varying degrees through the induction of population by CD4+ CD25+ regulatory T-cells (formerly known as suppressor T-cells) that involves transforming growth factor-β (TGF-β). In addition, studies in recent-onset diabetic patients showed improved insulin secretions and better metabolic control in the group of patients that were treated with monoclonal anti-CD3 antibodies. However, these protective effects were shown to be transient. Normal glucose levels were not achieved and patient still had to remain on insulin therapy, although with lower doses of insulin. Despite the fact that the anti-CD3 antibodies have been modified to become non-Fc binding (NFB), binding of antibodies to T-cell may induce apoptosis under the proinflammatory conditions found in the pancreas, resulting in a decreased systemic T-cell number which may compromise normal protective immunity. Furthermore, the anti-CD3 antibodies treatment appeared to produce a cytokine-related syndrome which manifested itself as flu-like symptoms experienced by most patients. As more studies have begun to demonstrate the direct involvement of CD4 and CD8 T-cells in β-cell autoimmunity, it becomes more relevant to prevent such event through directly suppressing CD4 and C8 T-cells with anti-CD4 and anti-CD-8 antibodies.
Repeated intravenous injections of insulin daily is highly inconvenient for the patients and can significantly affect patients’ quality of life. People with diabetes receiving insulin replacement therapy continue to have a markedly decreased life span. Insulin pump, though shown to be more effective at controlling plasma glucose levels than injections, poses a great risk of infection at the infusion site. In addition, rates of complication remain high even with appropriate treatment and aggressive approaches aimed to minimise complications are associated with higher mortality owing to hypoglycemia.
Presently, the treatment of autoimmune diseases is based on non-antigen-specific immunosuppression which works by interfering with the production of cytokines and proliferations of cytotoxic T cells. However, such intervention is frequently ineffective in the long-term owing to high relapse rate following withdrawal of treatment and the risk of generalised immunosuppression predisposing patients to secondary infections and tumours. The discovery of monoclonal antibodies has allowed us to generate induction of specific immune tolerance by suppressing the pathogenic processes involved in a particular autoimmune disease.
Previous studies (1997 - 2011) have attempted to induce specific beta-cell self-tolerance by using CD3 specific antibodies that has been altered to prevent binding to Fc receptor. CD3 is a protein complex on the surface of T-cells. It associates with T-cell receptors (TCR) to form TCR complex which is crucial in the generation of activation signal in T-lymphocytes. Anti-CD3 antibodies have been shown to induce remission of recent-onset diabetes in non-obese diabetic (NOD) mice to varying degrees through the induction of population by CD4+ CD25+ regulatory T-cells (formerly known as suppressor T-cells) that involves transforming growth factor-β (TGF-β). In addition, studies in recent-onset diabetic patients showed improved insulin secretions and better metabolic control in the group of patients that were treated with monoclonal anti-CD3 antibodies. However, these protective effects were shown to be transient. Normal glucose levels were not achieved and patient still had to remain on insulin therapy, although with lower doses of insulin. Despite the fact that the anti-CD3 antibodies have been modified to become non-Fc binding (NFB), binding of antibodies to T-cell may induce apoptosis under the proinflammatory conditions found in the pancreas, resulting in a decreased systemic T-cell number which may compromise normal protective immunity. Furthermore, the anti-CD3 antibodies treatment appeared to produce a cytokine-related syndrome which manifested itself as flu-like symptoms experienced by most patients. As more studies have begun to demonstrate the direct involvement of CD4 and CD8 T-cells in β-cell autoimmunity, it becomes more relevant to prevent such event through directly suppressing CD4 and C8 T-cells with anti-CD4 and anti-CD-8 antibodies.
T.N. Budi A.N. Khuong C. April | Copyright ©2012