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  5. Therapy and diagnosis utilising peptides recognised by gluten reactive T cells

Therapy and diagnosis utilising peptides recognised by gluten reactive T cells

 Bob AndersonDr Bob Anderson

Coeliac disease has been the focus of Dr Bob Anderson since 1998 when he commenced post doctoral studies at the University of Oxford, to identify the toxic gluten peptides driving the immune response to gluten. Dr Anderson trained in medicine and completed a PhD in immunology at Otago University in New Zealand before training as a gastroenterologist in Melbourne, Australia. In the late 90s in Oxford, and from 2002 at The Walter and Eliza Hall Institute in Melbourne, blood collected from hundreds of volunteers with coeliac disease undergoing three day oral challenges has provided a detailed molecular map of the peptides in wheat, rye, barley and oats that activate T cells in genetically proven coeliac disease. Since 2006, Dr Anderson’s focus has been on utilising the most dominant peptides recognised by T cells in coeliac disease in diagnostic blood tests and to restore immune tolerance to gluten with Nexvax2®, an adjuvant free “epitope specific immunotherapy”. He was appointed Chief Scientific Officer at ImmusanT Inc. in 2012, where he continues to advance the development of peptide based diagnostics and therapeutics, including Nexvax2®.

   

Abstract

The immune response to gluten is reactivated whenever someone with coeliac disease consumes gluten. In a patient with coeliac disease who follows a strict gluten-free diet, there is a pronounced increase in the number of circulating T cells recognising gluten peptides six days after gluten is consumed [1]. Characterising the gluten derived peptides recognized by CD4+ T cells, circulating after oral gluten challenge in overnight cytokine release tests, using fresh blood, has overcome much of the uncertainty surrounding epitope discovery in coeliac disease. Although the frequency of T cells mobilized in blood varies widely, the hierarchies of gluten derived T cell epitopes, recognised by circulating T cells, are highly reproducible in patients who have the same disease associated HLA-DQA and DQB genotype and consume the same gluten challenge [2, 3, 4]. Identification of the dominant gluten derived epitopes has enabled the design and development of “epitope specific immunotherapy” (Nexvax2®) and a blood based diagnostic test [5, 6].

ImmusanT is developing Nexvax2® to restore immune tolerance to gluten and prevent disease relapse after ingestion of gluten by HLA-DQ2.5+ patients with coeliac disease. Three Phase 1 studies of Nexvax2® have been completed. Multicentre phase two studies of Nexvax2® as well as clinical studies assessing peptide based diagnostic blood tests will be enrolling volunteers in 2015. Effective therapeutics and diagnostics specific for disease causing CD4+ T cells have been a long-awaited development in the management of autoimmune diseases. Clinical studies of Nexvax2® and whole blood cytokine release test, promise to reveal greater understanding of the role of gluten reactive CD4+ T cells in coeliac disease, and offer the prospect of a treatment without a gluten-free diet and highly selective and sensitive blood based diagnostics detecting circulating T cells in coeliac disease.

 [1] Anderson RP et al. (2000) In vivo antigen challenge in celiac disease identifies a single transglutaminase-modified peptide as the dominant A-gliadin T-cell epitope. Nat. Med. Mar; 6 (3): 337-42

[2] Henderson KN et al. (2007) A structural and immunological basis for the role of human leukocyte antigen DQ8 in celiac disease. Immunity Jul; 27 (1): 23-34

[3] Tye-Din JA et al. (2010) Comprehensive, quantitative mapping of T cell epitopes in gluten in celiac disease. Sci. Trans. Med. Jul 21; 2 (41): 41ra51

[4] Hardy MY et al. (2015) Ingestion of oats and barley in patients with celiac disease mobilizes cross-reactive T cells activated by avenin peptides and immuno-dominant hordein peptides. J. Autoimmun. Jan; 56: 56-65

[5] Anderson RP et al. (2013) Vaccine against autoimmune disease: antigen-specific immunotherapy. Curr. Opin. Immunol. Jun; 25 (3): 410-7

[6] Ontiveros N et al. (2014) Ex-vivo whole blood secretion of interferon (IFN) gamma and IFN gamma inducible protein 10 measured by enzyme linked immunosorbent assay are as sensitive as IFN gamma enzyme linked immunospot for the detection of gluten reactive T cells in human leucocyte antigen HLA-DQ2.5+ associated coeliac disease. Clin. Exp. Immunol. Feb; 175 (2): 305 -15

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