Vaccination and Other Antigen-Specific Immunomodulatory Strategies in Celiac Disease

Abstract

Background: Celiac disease (CD) results from an alteration in the oral tolerance to dietary gluten. The response to gluten is normally tightly regulated and involves the secretion of TGF-β and IL-10 from different subtypes of regulatory T cells (Tregs). Interestingly, in addition to proinflammatory cytokines, the inflamed CD mucosa also contains high levels of T cell-derived IL-10 compared with treated CD patients or normal donors. Furthermore, most studies describe an increase in the number of Foxp3+ Tregs in the small intestinal mucosa in CD patients compared to controls. This paradoxical condition suggests that regulatory mechanisms might operate to counterbalance the abnormal gliadin-triggered immune activation in untreated mucosa. Indeed, addition of exogenous IL-10 to mucosal cultures from treated CD patients can suppress gliadin-induced T cell activation. Considering the central role of adaptive immunity in CD, the development of strategies to stimulate these mechanisms is a primary goal of efforts to restore gluten tolerance. Key Messages: Different immunomodulatory strategies have been explored. NexVax2, a desensitizing vaccine that uses three dominant gluten peptides administered subcutaneously to induce a tolerogenic response in CD patients, is under development. Alternatively, the potential of substituted, cyclic or dimeric peptide analogues as blockers to prevent HLA from binding to the immunodominant gliadin epitopes has been demonstrated in vitro. In line with these results, we recently found that modified (transamidated) gliadins influenced the immune response in intestinal biopsy samples from CD patients with overt disease by drastically reducing the production of IFN-γ. Notably, in a mouse model, transamidated gliadins reverted the phenotype of the gliadin-inducible immune response from an inflammatory phenotype to an anti-inflammatory phenotype. Conclusions: Various approaches are currently under investigation to recover gluten tolerance based on the use of both modified and native antigen molecules. More specific studies are now required to test the efficacy of such strategies for preventing CD.

Neues zur Zöliakie

“…Hieraus leitet sich bereits die erste klinisch verwertbare Schlussfolgerung ab: Erstgradige Verwandte von Zöliakie-Betroffenen haben eine ca. 10 % Wahrscheinlichkeit, auch an einer Zöliakie zu leiden -unabhängig von einer vorhande- der ein Gemisch dreier immundominanter Glutensequenzen enthält, angewendet [9].…”

Development of Vaccines in Celiac Disease Therapies

“…Starting with a small dose of antigen exposure and gradually increasing the dose to gradually build up a tolerance to the specific antigen and reduce the immune response. It is not possible to use natural antigens directly in the treatment of celiac disease, such as consuming foods containing gluten, as this could exacerbate the condition in those who already suffer from it [7].…”

“…One idea is to still use oral administration to deliver gliadin to patients to build tolerance. To avoid exacerbation by direct intestinal exposure to the antigenic protein, gliadin was modified to be nontoxic [8] and delivered via genetically modified non-stereotypic, non-pathogenic bacteria [7,8].…”

Celiac disease: Participation of Cytokines and Other Factors in the Immune Response

“…Over time and due to the global problems of CD, researchers have developed various ways to avoid the adverse effects of gliadin, such as: genetically modified wheat cultivars, transamidated gliadins that revert the inflammatory phenotype by an anti-inflammatory in the gliadin-inducible immune response and a desensitizing vaccine (NexVax2) that have three dominant gluten peptides and induces tolerogenic response in CD patients [30,31] . Also, researchers have demonstrated that anti-wheat gliadin IgY antibody produced in their study has proved to inhibit absorption of gliadin and gliadin-induced inflammatory process in Caco2 cell culture model of CD.…”