Furthermore, a better understanding of the mechanisms through which microbes contribute to CeD development can provide further rationale and a more targeted approach for microbiota-modulating preventative strategies. For example, results are affected by the number of samples collected and how the biopsies are oriented and reported — Improvement in the quality of serological testing for CeD and the requirement for specific HLA genotypes for CeD to develop has meant that a serogenetic approach to CeD diagnosis is appealing and may be sufficient for diagnosis in the right clinical situations 2 , As expeditious treatment of CeD may avoid or reduce the risk of many CeD-associated complications such as impaired bone density and stunted growth in children, improving early diagnosis remains a clinical and research priority.
In recent years the high rate of community adoption of the GFD, including in children , has compounded the challenge of CeD diagnosis as the accuracy of current serological and histological approaches depend on active gluten intake. In order to make a CeD diagnosis reintroduction of dietary gluten, generally for several weeks to months, is recommended prior to testing but patients are often reluctant to undertake this and for those that do many fail to tolerate it.
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As the serologic and histologic response to gluten challenge is highly heterogeneous the optimal duration of gluten challenge required for definitive diagnosis of CeD remains uncertain — Immune diagnostics that measure the gluten-specific immune response target a fundamental component of CeD and may overcome the limitations of current diagnostics. The use of tetramers or cytokine release assays to identify gluten-specific T cells induced in blood after short-term oral gluten challenge is highly sensitive and specific for CeD Diagnostics that are accurate with limited or even no gluten exposure such as tetramer-based detection of gluten-specfic T cells are particularly appealing to clinicians and patients as they may avoid the need for prolonged gluten challenge prior to testing with serology and histology.
Large multi-center validation studies to confirm the accuracy of assessing disease-specific T cells as a CeD diagnostic are required, and if successful, may force a re-think of how CeD should be classified. Arguably, CeD may be better defined by the HLA-linked, T cell mediated systemic response to gluten rather than histologic changes in the proximal small intestine or circulating antibodies that indirectly reflect disease activity. While adherence to a strict and lifelong GFD still remains the single proven and available treatment for CeD, it is for many patients complicated, onerous, and expensive.
Several longitudinal studies in adults with CeD indicate that failure to achieve mucosal healing is common even in those appearing to maintain good dietary adherence over many years — Assuming enough time has elapsed on the GFD, persistent mucosal activity may be driven by ongoing, potentially intermittent, gluten exposure , such as that inadvertently consumed in contaminated meals when eating out The challenge in maintaining adequately strict gluten exclusion and persistent disease activity is a major driver for research into new therapeutic approaches.
While several therapies are under development it is notable that none of them have yet been evaluated in children. Clinical trials of novel therapies for CeD have increased substantially in recent years but compared to other illnesses such as inflammatory bowel disease the field is still in its infancy.
No therapeutic approach for CeD has yet completed Phase 3 clinical trials. An understanding of the optimal goals of treatment and the methods to assess efficacy are an evolving area and have been shaped by the requirements of regulatory bodies such as the FDA. Symptom improvement is now regarded as a key outcome measure and this has driven interest in validating patient reported outcome measures and understanding the basis for gluten-induced symptoms in CeD.
A standardized approach to reporting small intestinal histology based on quantitative assessment of morphology villus height, crypt depth and their ratio and inflammation density of intraepithelial lymphocytes is now commonly employed in CeD clinical trials Confirming adequate dietary gluten exclusion during studies is a major challenge as symptom records, serology, histology, and dietary history are indirect measures of GFD adherence In addition to a role in the clinic, it may be a promising tool for evaluating and selecting patients for CeD clinical trials where controlling for inadvertent gluten exposure is important, such as therapies designed to prevent symptoms due to inadvertent gluten exposure Insight into the molecular mechanisms underpinning CeD pathogenesis provide several opportunities for novel therapeutics development and a range of pharmaceuticals are currently being assessed in pre-clinical and clinical trials Table 3.
These can be broadly classified into luminal approaches that aim to quantitatively reduce the load of gluten available to trigger the immune response and qualitative approaches that aim to induce gluten tolerance. A third category, not discussed in this review, encompass immunomodulators e. Table 3. Experimental therapies for celiac disease in pre-clinical or clinical development.
Quantitative approaches include the use of i endopeptidase enzymes glutenases derived from plants, bacteria or fungi that have a gluten degrading effect, such as latiglutenase ALV , and AN-PEP ii agents to reduce paracellular passage of gluten i. Supplements to the GFD which render small amounts of dietary gluten harmless could substantially improve the quality of life of patients by allowing them to dine out with less fear of adverse effects resulting from contamination by small amounts of gluten.
Enzymatic approaches could also be applied during the baking process to reduce gluten immunogenicity Genetic modification of wheat with a variety of targeted techniques such as RNA interference and CRISPR can reduce gluten T cell epitope content and immunogenicity however clinical feeding trials are awaited. The recent publication of the first fully annotated reference wheat genome is an important advance that may help guide targeted approaches Use of protease inhibitors, such as elafin, which is decreased in the mucosa of patients with active CeD has been proposed as it has barrier enhancing and anti-inflammatory effects in gluten-sensitive mice A phase 2 RCT of latiglutenase taken orally showed it could attenuate small intestinal mucosal injury in CeD patients induced by 2 g of ingested gluten In symptomatic CeD patients following a GFD, latiglutenase reduced symptoms in the subgroup who were seropositive , suggesting that gluten exposure was necessary in order to demonstrate a positive effect of the enzyme.
More studies are required to establish the efficacy of these approaches and how they can be safely used by patients. A controlled gluten challenge will be an important component of the study design in order to demonstrate efficacy and establish the amount of ingested gluten patients can be protected from.
Qualitative approaches aim to establish durable immune tolerance to gluten. One way this might be achieved is by targeting the long-lived population of gluten-specific T cells and deleting or rendering them functionally unresponsive anergic and inducing suppressive Tregs As the target T cell population is stable in established CeD , , , it is anticipated these approaches will apply similarly to children as they do in adults with CeD.
Phase 1 studies of Nexvax2, a therapeutic vaccine composed of three gluten peptides encompassing immunodominant HLA-DQ2.
The recall immune response to gluten was modified in people with CeD receiving Nexvax2. A phase 2 clinical trial of infection with the hookworm Necator Americanus combined with a micro-gluten challenge in 12 CeD patients showed immune modifying effects and clinical protection against gluten and a larger controlled study is underway.
Aside from the fact it is driven by an exogenous, dietary antigen, the genetic and immunologic basis for CeD overlaps with that of traditional autoimmune diseases.
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While HLA susceptibility and wheat consumption and are major determinants of disease development it is apparent that non-HLA genes and a range of environmental factors are important for disease development. Prospective studies have established that the timing of gluten introduction and breastfeeding do not impact the development of CeD. More results from multicenter, prospective longitudinal studies are needed to understand the long-term effects of a high amount of gluten intake and to identify if other environmental exposures might trigger the disease. Furthermore, although in vitro and in vivo studies suggests there are host-microbe or gluten-microbe interactions that promote gluten-specific immune responses, larger clinical trials where both the composition and function of the microbiota is studied in at-risk individuals and followed over time are needed to help understand gene-microbe interactions in CeD development.
These kinds of studies may provide insight into the microbial events leading to CeD development that could be targeted as preventative or therapeutic strategies. Finally, understanding how tolerance to gluten is lost in CeD is a fundamental question that needs more study. Insights into disease relevant pathways may come from analysis of the genome and gene expression in CeD, and epigenetic studies are needed to examine the impact of environment on gene expression and disease development. While novel therapies for CeD have not yet been tested in children, emerging studies on the role of environmental factors and the microbiome and how they might impact gluten immunity and tolerance may one day make disease prevention possible.
For now, as primary prevention of CeD is a highly attractive, but as yet unrealized goal, the focus must be on driving expeditious diagnosis and treatment in symptomatic children and adults. JT-D wrote the first draft of the manuscript. DA and HG wrote sections of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.http://say.dev3.develag.com/549.php
Nexpep Pty. DA has served as principal investigator for probiotic studies in collaboration with Probi AB, Lund, Sweden, and is the co-inventor of patents pertaining to the use of L. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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