Targeting GSK-3 in antigen-specific immunotherapy

点击翻译按钮获取中文摘要

In 1911, Noon and Freeman published their account of the treatment of a hay fever sufferer with pollen extract. This was one of the first documented descriptions of specific immunotherapy (SIT) in which the agent causing the allergic condition was used to 'desensitise' the patient. While the value of SIT has been widely accepted, the approach still carries the risk of severe side effects including anaphylactic shock. The investigation of SIT for treatment of autoimmune diseases has lagged behind that of SIT in allergy and has also been hampered by aberrant events. For example, administration of a brain protein exacerbated a disease resembling MS in primates. Similarly, administration of an artificial islet antigen, via the lung or gut, induced T lymphocytes that exacerbated autoimmune diabetes in an animal model. The complications associated with intact antigen have led opinion leaders in the field to recommend the use of fragments of proteins called 'synthetic peptides' for SIT. Our laboratory studies the design and mode of action of peptides that are able to suppress immune responses. Effective induction of suppression depends on the solubility of the peptide. Previously we had shown that some peptides failed to mediate SIT even when administered in a highly soluble form. This proved to be because the peptides could bind to their receptor, an immune molecule called MHC, to produce the wrong shape or conformation. Peptides can be designed, however, to fit the MHC appropriately and these then induce tolerance to the native protein. Effective SIT with peptides leads to the induction of a subset of lymphocytes, known as CD4 T-cells, and they secrete a protein called IL-10. IL-10 is a hormone-like substance, known as a cytokine, that suppresses activation of neighbouring T cells in the body via a negative feedback loop mechanism. It was recently shown that peptide SIT in allergic asthma also generates IL-10-dependent suppression thus revealing a similar role for IL-10 in SIT for both allergy and autoimmune disease.The overall aim of this current proposal is to improve the efficacy of peptide-induced SIT by enhancing the conversion of lymphocytes capable of causing disease into IL-10 secreting disease suppressor cells. Recently we showed that the addition of drugs that block the activity of the enzyme GSK-3 to cultures of lymphocytes in vitro greatly enhanced their production of IL-10. The specific aims of this project are, therefore, to:i. identify the most suitable GSK-3 inhibitor from a panel previously characterised by GSK ii. investigate the ability of GSK-3 inhibitors to enhance the in vivo generation of IL-10 secreting suppressor cells in conjunction with SIT in a relevant animal model of autoimmune diseaseiii. confirm the activity of the selected inhibitor/s on human lymphocytesiv. assess the stability of the IL-10 phenotype in both mouse and human cellsThere are no patents relating to these compounds and, as a result, no 'freedom to operate' issues associated with them. We propose a novel application for these compounds, as adjunct treatments, in conjunction with SIT, for immunotherapy of autoimmune diseases and allergies. We have conducted patent searches relating to this application of the drugs and have not found prior art. The enhancement of IL-10 production during SIT will greatly improve the efficacy of this therapeutic approach. As such, the use of GSK-3 inhibitors as adjunct therapy will be applicable to any allergic condition currently treated by SIT or equally to any autoimmune condition for which the target antigens are known. The improvement of SIT provided by co-administration of GSK-3 inhibitors will allow health care providers to move away from the use of non-specific therapies for allergic and autoimmune diseases since these are often ineffective and can cause severe side effects. This improvement will be of considerable benefit to both patients and the health care system.