Vaccine Immunotherapy for Celiac Disease

Abstract

Autoimmune and allergic disorders are highly prevalent conditions in which an altered or abnormal immune response is mounted against self- or environmental antigens, respectively. Antigen-based immunotherapy is a therapeutic option aimed at restoring the specific immune tolerance toward pathogenic antigens while leaving the rest of the immune system unaffected. This strategy proved efficacy especially in allergic diseases, including asthma, allergic rhinitis, and food allergies, but still has shortcomings for the treatment of autoimmune diseases. However, there are no available therapies, currently, in clinical practice for restoring the physiological tolerance that is typically lost in autoimmune diseases. In celiac disease, which is a common immune-mediated enteropathy triggered by the ingestion of gluten in genetically susceptible individuals, antigen-based immunotherapy could be a feasible option thanks to our deep understanding of the pathogenic mechanisms underpinning this condition. In fact, the immunodominant gluten epitopes are well-characterized and are recognized by pathogenic CD4+ T-cells that could be desensitized with immunotherapy. Moreover, the intestinal damage occurring in celiac disease (i.e., villous atrophy) is reversible upon gluten withdrawal. Only recently the results of a phase I trial of an intradermal, adjuvant-free, formulation of three specific gluten peptides (Nexvax2) showed a good safety profile, albeit its efficacy still needs to be demonstrated. More results are awaited, as they may radically change patients' quality of life that is constrained by the lifelong gluten-free diet and by the potential onset of life-threatening complications.

Controlling Gut Inflammation by Restoring Anti-Inflammatory Pathways in Inflammatory Bowel Disease

“…Immunotherapy represents an intriguing therapeutic option that has the aim of restoring the physiological T cell tolerance towards specific antigens, while leaving the rest of the immune system unaffected. Antigen- and epitope-based immunotherapy has rapidly developed over the last decade, especially for oncologic and allergic disorders, in which immunodominant disease triggers are increasingly recognized, and therefore can be targeted [89]. The development of immunotherapy is more complex for autoimmune and immune-mediated diseases, given that many different antigens play a role in disease onset, as in the case of CD.…”

Genistein antagonizes gliadin-induced CFTR malfunction in models of celiac disease

“…At present the therapy of CD is exclusively based on a gluten-free diet or the still experimental ingestion of enzymes that degrade pathogenic gliadin peptides within the gut lumen [49–51]. Other experimental strategies are emerging, such as tolerogenic vaccines to desensitize celiac individuals or strategies to prevent intestinal permeabilization [52–56]. In this perspective, targeting the initial pro-inflammatory reactions might represent an interesting option to prevent or treat CD.…”

Defective proteostasis in celiac disease as a new therapeutic target

“…Beyond the obvious solution to prevent antigen exposure (by means of a gluten-free diet or the still experimental provision of enzymes that degrade pathogenic gliadin-derived peptides in the gut lumen) 47,48 a number of distinct strategies can be envisaged. Several biotech companies are working on the concept of tolerogenic vaccines to “desensitize“ patients vis-à-vis of gliadin, thus switching the immunogenic/autoimmune reaction into a response that reinforces immunosuppressive circuitries to assure permanent tolerance of the xenogenic antigen 49,50 . Others are developing agents designed to prevent the leaky gut syndrome that participates to CD pathogenesis, for instance by providing synthetic peptides that improve the maintenance of tight junction by enterocytes 51–53 .…”