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Journal of Pediatric Gastroenterology & Nutrition:
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Research Agenda for Pediatric Gastroenterology, Hepatology and Nutrition: Allergy and Immunology: Report of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition for the Children's Digestive Health and Nutrition Foundation

Wershil, Barry; Hoffenberg, Edward J.; Winter, Harland S.

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Brooklyn

Denver

Boston

Address requests for reprints to: Executive Director, Children's Digestive Health and Nutrition Foundation, PO Box 6, Flourtown, PA, 19031, U.S.A. (e-mail: NASPGHAN @naspghan.org).

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RATIONALE

The gastrointestinal (GI) tract is exposed to a vast array of foreign antigens in the form of ingested foods, environmental toxins and microorganisms. The organized immunological system of the GI tract, or gut-associated lymphoid tissue (GALT), is responsible for defending the host from pathogens while simultaneously remaining unresponsive to food antigens. In addition, several other cell types, such as the epithelial cells that line the intestines, perform important immune functions.

Aberrant activity in GALT is associated with a variety of diseases, such as food hypersensitivity reactions, eosinophilic gastroenteritis, eosinophilic esophagitis, celiac disease, autoimmune diseases and inflammatory bowel disease, but the precise pathogenesis of these conditions is not well understood. As many as one in four American households report the perception of a family member with a food allergy. However, the true prevalence of food allergy is much lower. Approximately 6% to 8% of children in the US are affected with food hypersensitivity reactions in the first year of life, a much higher prevalence than in adults. However, controversy still exists over the true prevalence of allergic diseases of the GI tract because of the limited tests available to accurately diagnose this and other immunologically mediated diseases.

An important area for ongoing investigation is the prevention of disease expression. This can be at the level of primary prevention (inhibiting sensitizing antibody production), secondary prevention (inhibiting disease expression after sensitization), or tertiary prevention (suppressing symptoms despite sensitization and disease onset). It is clear that the prevalence of these food-induced reactions is significantly higher in children with atopic dermatitis or asthma. Strategies aimed at primary prevention will be aided by further studies of the genetic factors associated with food hypersensitivity—in particular, the identification of genes or genetic markers that would identify individuals at risk.

Celiac disease is an autoimmune process driven by ingestion of wheat, rye and barley proteins in genetically susceptible individuals. Celiac disease is unique among the autoimmune diseases in that the inciting agent—the cereal protein gliadin—is well known, a genetic marker (DR3 or DQ2) is known, and treatment with a gluten-free diet is effective. The prevalence of celiac disease may be as high as 1:250 based on cross-sectional studies from Italy and Baltimore blood donors, with emerging evidence of 1:100 based on prospective early childhood data. Certain groups are at increased risk of celiac disease, including those with type 1 diabetes (4% to 10%), Down syndrome (7% to 19%), and other autoimmune disorders. Most diabetes programs regularly screen for celiac disease. It is not known why most individuals with a genetic predisposition and similar environmental exposures do not develop celiac disease. In addition, the factors influencing early versus late onset and disease severity are not known.

The majority of affected individuals have no symptoms or mild symptoms, which are usually not concerning enough to seek medical attention. Over the past few decades, a decrease has been noted in the frequency of the “classic” presentation of celiac disease (diarrhea, malabsorption, growth failure, nutritional deficiency). Instead, there has been an increase in the “atypical” presentation, not obviously related to the GI tract (e.g., dental enamel defects, arthritis, iron deficiency anemia, epilepsy with cerebral calcifications and cerebellar ataxia, infertility, osteoporosis). Why celiac disease is associated with multi-systemic involvement is unclear.

The current, albeit inadequate, definition of celiac disease requires the demonstration of characteristic change in the lining of the small-bowel mucosa, which is reversible with treatment with a gluten-free diet. However, lifelong adherence to the diet is achieved primarily by those with severe symptoms on ingestion of offending proteins. Untreated celiac disease is a risk factor for intestinal lymphoma.

A major advance has been the description in 1997 of tissue transglutaminase (TG) as the antigen recognized by the anti-endomysial antibody test. The TG assay detects the major antigen associated with celiac autoimmunity, is now widely commercially available, and lends itself to mass screening. Use of new serologic assays has confirmed that most affected individuals have little or no symptoms and are identifiable only by screening programs.

Although the pathogenesis of GI manifestations of immunoregulatory disorders is not well understood, correction of immune deficiencies often corrects or improves malabsorption. This observation is especially true in human immunodeficiency virus (HIV) disease. On a worldwide scale, HIV is the most devastating of the immunodeficiency disorders. According to the World Health Organization, in the year 2000, approximately 36 million adults and children are living with HIV disease, the great majority (25.3 million) in sub-Saharan Africa. A total of 920,000 adults and children are affected in the US and Canada. Over the past two decades, about 21.8 million people have died, including 3 million in the year 2000. Because heterosexual transmission throughout the world has increased in prevalence, the number of congenitally infected children continues to increase, especially in Africa and Asia. The socioeconomic impact of this disease is measured in billions of dollars.

Breaks in mucosal integrity such as mouth ulcers, surface inflammation such as with oral thrush, and a more permeable mucosal surface may be the entry route for HIV infection in the gut. The presence of virus particles in oropharyngeal and gastric aspirates of newborn infants, along with the observation that premature and low-birth-weight infants have a higher risk of mother-to-child HIV transmission, supports a role for the GI tract in the acquisition of this perinatally acquired infection. In addition to transmission of HIV to children, injury and malabsorption in the GI tract may contribute to morbidity and mortality. Effective antiretroviral therapy may reduce GI dysfunction. A better understanding of the relationship between mucosal immune function and absorption will lead to more effective therapy for both primary and secondary immunodeficiencies.

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AREAS OF EMPHASIS

Elucidate the mechanisms involved in oral tolerance
Research Goals

Oral antigen is known to induce the down-regulation of immune responses at peripheral sites. This property, known as oral tolerance, is not completely understood at a mechanistic level. However, there have been several attempts to use this property of the GI immunological system as a therapeutic modality for multiple myeloma, rheumatoid arthritis and other autoimmune diseases. To date, this approach has been problematic for several reasons, including a lack of understanding of the fundamental mechanisms of oral tolerance and a lack of knowledge of the specific antigen that might be involved in these conditions.

Studies should be directed at elucidating the mechanisms of oral tolerance. The specific issue of how oral tolerance is induced and maintained needs further investigation. The role of antigen processing in the gut also warrants further study as it impacts on this issue.

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Research Strategies

The Immune Tolerance Network (ITN) is an international consortium of clinical researchers dedicated to developing approaches to induce immune “tolerance.” The scope of this organization should be expanded to include pediatric-based immunological disorders such as food hypersensitivity and eosinophilic diseases of the GI system.

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Projected Timetable and Funding Requirements

These questions are amenable to requests for applications (RFAs) to study specific aspects of mucosal immune function. Many of these basic questions will be answered by research in related areas. Investing in the training of pediatric investigators will enhance the transfer of knowledge to problems relevant to pediatric gastroenterology.

Define the role of the intestinal epithelium in immune responses

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Research Goals

Considerable evidence suggests that the intestinal epithelium is not a passive barrier to luminal antigens, but in fact acts as a sensor of the luminal environment and may play a role in initiating immunological responses. For example, intestinal epithelial cells can produce a variety of pro-inflammatory cytokines and chemokines that may influence inflammatory reactions. The intestinal epithelium has also been shown to present antigens in a non-classical, non-major histocompatibility complex (MHC) restricted manner. Most of the research into epithelial immune function has been carried out using transformed tumor cell lines of colonic origin, which may not accurately represent epithelial cell function in vivo. Human and small animal cell lines representative of small-intestinal epithelium must be developed and in vivo approaches to epithelial immune function must be emphasized.

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Research Strategies

The mechanisms of epithelial cell antigen processing must be addressed at the molecular level, using approaches such as confocal microscopy to determine antigen uptake, intracellular trafficking and antigen presentation. The signal transduction pathways involved in epithelial cytokine production need to be elucidated, particularly from the standpoint of ligand/receptor interactions. Development of new cell lines must be a priority to facilitate these studies.

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Projected Timetable and Funding Requirements

This area of research has many investigator-initiated research grants and program projects, but additional projects relating to epithelial function in the developing organism are appropriate.

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Develop new approaches to diagnose and treat food hypersensitivity reactions
Research Goals

The diagnostic approach for suspected food hypersensitivity reactions was recently reviewed, and it is clear that little has changed over the past decade. The radioallergosorbent test (RAST) and properly performed prick/puncture skin testing have a role in patients suspected of having reactions mediated by immunoglobulin E (IgE). In the case of food hypersensitivity reactions thought not to involve IgE-dependent mechanisms, elimination diets and food challenges remain the mainstay of diagnosis, with the double-blinded and placebo-controlled food challenge considered the “gold standard.” While accurate, this approach is costly and can be performed only in a limited number of centers. Similarly, therapy in general remains the avoidance of offending antigens, but this is often difficult when there are reactions to multiple antigens.

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Research Strategies

New diagnostic and therapeutic approaches need to be developed. In vitro analysis of T-cell function and development of Th2 responses must be studied at the molecular level to potentially down-regulate or switch-off aberrant T-cell activity. The genetics of food hypersensitivities must be studied from both a diagnostic and patient counseling standpoint. New therapies for other atopic diseases are on the horizon. For example, administration of humanized monoclonal anti-IgE antibodies has been demonstrated to be efficacious in the treatment of asthma and allergic rhinitis. Such novel therapies should be studied in children with food hypersensitivity reactions. In addition, new genetic approaches aimed at “desensitizing” the patient to reactive proteins warrant intense investigation.

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Projected Timetable and Funding Requirements

Unfortunately, many in the scientific community have considered research in the area of food allergy a “soft” science. Given the large number of patients that research in this area will impact, more investigator-initiated research grants are necessary to understand these problems. The development of a consortium to investigate the genetics of food hypersensitivity and new diagnostic and therapeutic approaches would greatly enhance our understanding, and the treatment, of these conditions. Such a consortium would coordinate clinical research protocols and share patient materials for basic research efforts.

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Clarify the natural history and immunopathogenesis of celiac disease
Research Goals

Develop working definition of celiac disease. The 1990 European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) definition of celiac disease requiring typical alterations of small-bowel mucosa is outdated. A modern definition incorporating newer serologic assays and the extraintestinal manifestations of celiac disease is needed. Many GI societies in Europe and the US have convened expert panels to clarify the diagnostic criteria for celiac disease, and some guidelines have recently been published.

Investigate pathogenesis of celiac disease. The pathway leading to T-cell activation—specifically the interplay between DQ2 and DR3, T cells, gliadin and transglutaminase—is an area of potential importance to understand the immunopathogenesis of celiac disease.

Evaluate screening cost-effectiveness. The cost-effectiveness of mass screening strategies needs to be evaluated. This entails assessing the clinical importance of screening-identified celiac disease and the benefits of early vs. late case ascertainment. The social impact of screening also warrants careful analysis.

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Research Strategies

A number of research strategies are recommended. Increased collaboration with diabetes centers can provide an infrastructure and offer additional resources to evaluate potentially effective screening programs. Collaboration with researchers in related fields, including immunology, preventive medicine and social sciences, also is to be encouraged. Multicenter prospective studies are needed to assess the role of environmental factors and genetics in development of celiac autoimmunity and the clinical significance of celiac autoimmunity. New technologies, such as DQ2 or DQ8 tetramers, need to be applied to study the interplay of T-cell activation mechanisms with gliadin and transglutaminase.

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Projected Timetable and Funding Requirements

These research questions can be addressed in investigator-initiated studies, but such projects also can be integrated into large multicenter studies and program projects evaluating other autoimmune disorders.

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Develop approaches for the prevention and treatment of celiac disease
Research Goals

Develop animal model. The prevention of celiac disease is a tantalizing goal that should be considered within reach. Development of an animal model for celiac disease would provide a critical tool for this endeavor.

Improve compliance with gluten-free diet. Allocation of resources to the development and management of post-diagnosis management of celiac disease would result in programs that improve compliance. Modified grains, whether bioengineered or created through cross-breeding, may possess nontoxic or less toxic or less abundant offending proteins. Genetic engineering of foods is a hotly debated area of research and ethical discussion. Clearly, patients with celiac disease are one group that might benefit from genetically engineered foods from which gluten is eliminated. In addition, a clearer definition of “gluten-free” is needed for international commerce, to increase availability of gluten-free products to the consumer.

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Research Strategies

Collaborative relationships are to be established with the agriculture industry and social science professionals. Development of better treatment options may require novel strategies, such as the alteration of dietary proteins and modification of the intestinal milieu to induce immune tolerance.

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Projected Timetable and Funding Requirements

Collaboration with industry to develop gluten-free foods could be supported through Small Business Initiated Research (SBIR) grants.

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Define the role of the mucosal and systemic immune systems and HIV in malabsorption and growth retardation associated with congenitally acquired HIV disease
Research Goals

The pathogenesis of intestinal dysfunction is a major question in HIV-infected children. The lack of appropriate animal models has resulted in data primarily from human subjects. Basic physiological data in HIV-infected children are lacking that would enable clinicians to understand the role of malabsorption, viral load and immune function on growth and body composition. Clinical trials on the impact of early nutritional therapy in regions with high transmission rates, such as sub-Saharan Africa, may provide data that will guide future research involving effective nutritional therapeutic interventions. In the less-developed world, maternal-child transmission and malnutrition are the most important areas in which to focus research efforts. Research efforts should be prioritized to these areas in which new knowledge is needed.

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Research Strategies

Animal and cellular models should be developed to investigate the potential interrelationships between nutrition, infection, gastric acid production, motility and the effects of the immunological, neurological and endocrine systems on GI tract function as well as mucosal and systemic immunity. In the less-developed world, socioeconomic issues play a central role in the GI and nutritional aspects of HIV disease. Research studies are currently ongoing to evaluate nutritional strategies in HIV-infected children. Integrating studies of intestinal function and mucosal immunity will enhance our knowledge of the pathogenesis of malabsorption.

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Projected Timetable and Funding Requirements

In the US, investigator-initiated research projects may be funded through collaborative RFAs from the National Institute of Child Health and Human Development (NICHD), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and National Institute of Allergy and Infectious Diseases (NIAID). In less-developed countries, agencies such as the World Bank could play a central role in the education of the public and professional sectors of the community.

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© 2002 Lippincott Williams & Wilkins, Inc.

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