Future Therapeutic Options for Celiac Disease

Ludvig M Sollid; Chaitan Khosla

Disclosures

Nat Clin Pract Gastroenterol Hepatol. 2005;2(3):140-147. 

In This Article

Summary and Introduction

Celiac disease is a disorder of the small intestine caused by an inappropriate immune response to wheat gluten and similar proteins of barley and rye. At present, the only available treatment is a strict gluten-exclusion diet; hence the need for alternative treatments. Recent advances have improved our understanding of the molecular basis for this disorder and there are several attractive targets for new treatments. Oral enzyme supplementation is designed to accelerate gastrointestinal degradation of proline-rich gluten, especially its proteolytically stable antigenic peptides. Complementary strategies aiming to interfere with activation of gluten-reactive T cells include the inhibition of intestinal tissue transglutaminase activity to prevent selective deamidation of gluten peptides, and blocking the binding of gluten peptides to the HLA-DQ2 or HLA-DQ8 molecules. Other possible treatments include cytokine therapy, and selective adhesion molecule inhibitors that interfere with inflammatory reactions, some of which are already showing promise in the clinic for other gastrointestinal diseases.

Celiac disease -- also known as celiac sprue and GLUTEN-sensitive enteropathy -- is a prevalent (~1:100) food hypersensitivity disorder caused by an inflammatory response to wheat gluten and similar proteins of barley and rye.[1] The resulting intestinal inflammation often causes symptoms related to malabsorption, but in many patients extra-intestinal symptoms dominate, and in others the disease is clinically silent. Genes encoding HLA-DQ2 and HLA-DQ8 molecules are the single most important predisposing genetic factor; however, although these polymorphisms are necessary, they are not sufficient for disease development. HLA-DQ2 and HLA-DQ8 predispose to disease development by preferential presentation to mucosal CD4+ T cells of proline-rich gluten peptides that have undergone deamidation by the enzyme tissue transglutaminase (Transglutaminase 2; TG2). Fewer details are known about the effector mechanisms that lead to the development of the typical celiac lesion -- villous atrophy, crypt hyperplasia and infiltration of inflammatory cells (Figure 1) -- but, once activated, gluten-reactive CD4+ T cells produce cytokines and are likely to control the inflammatory reactions that produce the celiac lesion. This notion is based on the nature of the HLA association and the unique presentation of gluten antigens to T cells by HLA-DQ2 or HLA-DQ8 in the intestine. Recent advances have improved our understanding of the molecular basis for this disorder,[2] and new targets for rational therapy have been identified. This paper reviews concepts for new treatments and their current status.

The small-intestinal lesion in patients with celiac disease. Factors that contribute to the development of celiac disease and that can be targeted for new therapies are depicted. Proline-rich fragments of gluten that are resistant to processing by luminal and brush-border enzymes survive digestion[5] and can be transported across the mucosal epithelium as polypeptides. CD4+ T cells in the lamina propria recognize predominantly deamidated gluten peptides[37] in the context of HLA-DQ2 or HLA-DQ8 molecules on the cell surface of antigen-presenting cells (APCs).[38] The deamidation of gluten peptides is mediated by tissue transglutaminase (TG2).[39-41] The gluten-reactive CD4+ T cells produce interferon (IFN)-γ on activation.[27] IFN-γ is also produced by T cells in the epithelium.[42] Interleukin (IL)-15, produced by either mononuclear cells in the lamina propria or by enterocytes,[30,31] stimulates T cells to migrate to the epithelium and facilitate killing of enterocytes by upregulated expression of MIC by enterocytes and NKG2D by intraepithelial T cells.[29,32] IL-15 production is stimulated by gluten.[28,29] Gluten can also induce production of the intestinal peptide zonulin, which acts on tight junctions and increases epithelial permeability.[43] Adapted with permission from[2] ©(2002) Macmillan Publishers Ltd.

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