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Indian Journal of Pharmacology, Vol. 43, No. 4, July-August, 2011, pp. 485 Letter to the Editor Vaccines for type 1 diabetes in the late stage of clinical development Sandeep K Gupta Clinical Pharmacologist, J-1044, First Floor, Palam Vihar, Gurgaon, Haryana, India Correspondence Address: Sandeep K Gupta Clinical Pharmacologist, J-1044, First Floor, Palam Vihar, Gurgaon, Haryana India drsandeep_gupta@rediffmail.com Code Number: ph11132 DOI: 10.4103/0253-7613.83130 Sir, Type 1 diabetes results from autoimmune destruction of insulin-producing beta cells in the pancreatic islets of Langerhans. Recent advances in the understanding of the autoimmune process leading to diabetes have generated interest in the potential use of vaccines to prevent type 1 diabetes. Vaccines may act by various ways, including changing the immune response from proinflammatory T-helper-1 (Th1) phenotype to an anti-inflammatory T-helper-2 (Th2) phenotype. This Th1-Th2 shift occurs via a change in the type of cytokine signaling molecules being released by regulatory T-cells. Instead of pro-inflammatory cytokines, the regulatory T-cells begin to release cytokines that inhibit inflammation. This phenomenon is known as "acquired immune tolerance". Autoantigens are being tried to induce immunologic tolerance. Several autoantigens have been identified in patients with type 1 diabetes such as glutamic acid decarboxylase (GAD) 65 and heat shock protein (HSP) 60. [1] Promising vaccination intervention based on GAD65 and HSP60 autoantigens are in late stage of clinical development. Vaccine based on GAD65 GAD65 vaccine comprises alum-formulated glutamic acid decarboxylase (GAD-65), a major auto-antigen in Type 1 diabetes. Studies on non obese diabetic (NOD) mice have indicated that GAD65 prevents type 1 diabetes. Prevention of the diabetes was mediated by the induction of GAD65-specific CD4+ regulatory T-cells and it was found that these CD4+ regulatory T-cells had a T-helper 2 phenotype. [2] The efficacy and safety of alum-formulated GAD65 (GAD65-alum) to reverse recent-onset type 1 diabetes in children and adolescents was assessed in a randomized, placebo-controlled phase II study. Seventy patients with recent-onset type 1 diabetes who had fasting C-peptide levels above 0.1 nmol per liter (0.3 ng per milliliter) and GAD autoantibodies were randomly assigned to receive subcutaneous injections of 20 μg of GAD-alum (35 patients) or placebo (alum alone, 35 patients) on study days 1 and 30. At day 1 and months 3, 9, 15, 21, and 30, patients underwent a mixed-meal tolerance test to stimulate residual insulin secretion (measured as the C-peptide level). The effect of GAD-alum on the immune system was also studied. After the GAD65 vaccination, residual insulin secretion was significantly preserved and there were very clear GAD65-specific effects on the immune system. Adverse events appeared to be mild and similar in frequency between the two groups. GAD65 vaccination induces specific T-cells that may rebalance the immune system resulting in the protective effect seen on beta cell function. Upon in vitro stimulation with GAD65, 15 months after vaccination, the immune system of GAD65-treated patients showed a highly statistically significant increase in the secretion of several immunomodulatory substances, dominated by regulatory cytokines, including IL 5, IL13, IL10, IL17, IFN-γ, and TNF-α. Currently, Phase III trials of GAD65 vaccination are under way in patients with early onset type 1 diabetes in Europe and the US. [3] Vaccine based on HSP60 A synthetic immunomodulatory peptide derived from human heat shock protein 60 (Hsp60), is also undergoing Phase III trials in Type I diabetes. Hsp60 was found to be useful as a therapeutic agent to arrest the autoimmune process responsible for diabetes in NOD mice. [4] A randomised, placebo-controlled, double-blind, phase II study of Hsp60 vaccine was done in patients with newly diagnosed type 1 diabetes. The patients in the placebo group showed a fall in their ability to produce C-peptide and an increasing need for exogenous insulin over the period of 10 months after treatment whereas, the patients assigned to Hsp60 vaccine, maintained their ability to produce C-peptide and needed significantly less insulin to control their blood glucose concentrations. Both the maintenance of C-peptide production and the lesser need for exogenous insulin were explained by the arrest of autoimmune beta-cell destruction. Hsp60 vaccine was associated with modulation of the autoimmune response from a Th1 type to Th2 type. The positive correlation between the concentration of C-peptide at10 months and the numbers of T cells secreting interleukin 13 in response to hsp60 further supported this. [5] References
Copyright 2011 - Indian Journal of Pharmacology |
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