Priority Research Area Chronic Lung Diseases

Mucosal Immunology and Diagnostic

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The mucous membranes constitute the largest surface of the human body that is in contact with the environment and nearly all pathogenic substances and microorganisms invade the body via this route. Nevertheless, the immune defense mechanisms at this site are still poorly investigated. One of the central unsolved questions in mucosal immunology is how mucosal immune reactions are controlled. In contrast to the systemic immune system which may eliminate all foreign antigens indiscriminately, the situation at the mucous membranes is more complex. On one hand benign foreign antigens such as food and the oral, intestinal and genital flora must be tolerated. On the other hand bacterial toxins and hostile microorganisms must be identified and their uptake or active intrusion must be prevented. Misclassification of benign antigens as hostile or of maleficient ones as friendly can result in severe disorders such as chronic inflammatory intestinal or pulmonary diseases, food allergies, autoimmune diseases or in attenuated defense against mucosal pathogens.

Elucidating these antigen classification mechanisms and gaining insight into the pathogenesis of disorders that are caused by antigen misclassification are the main goals of our efforts in basic research.

In accordance with our institution's commitment to translational research we not only aim to understand mucosal immune regulation. We also want to exploit these mechanisms for the good of the patients, that is, for diagnosing mucosal diseases and assessing the risk of acquiring such disorders, for the prevention and therapy of allergic asthma and food allergies or for the development of vaccines against mucosal pathogens. Manipulating a mucosal immune reaction, however, is considerably more difficult than intervening in a systemic one because the mucosal immune system is compartmented so that the immunological microenvironment at the site of antigen/allergen contact tends to govern the type, extent and strength of a mucosal immune reaction. Prophylactic and therapeutic interventions must therefore be carried out with high cell type or tissue specificity. Such a site selective drug delivery requires targeting systems. Usually such systems are target seeking bioconjugates that consist of a ligand which mediates binding to the desired biomarker and a drug molecule or a drug container like a supramolecular complex or a nanoparticle.

The development and evaluation of supramolecular and nanoparticulate targeting systems for the delivery of drugs and diagnostics to certain mucosal sites is a cornerstone of our efforts in applied research.

Uptake and classification of antigens at mucosal surfaces

The prevalence of allergies and allergic asthma has been on the rise for decades in affluent countries so that about 25% of the population are affected by those diseases by now. Allergies and asthma are T-helper-2 (Th2)-cell driven immune defense reactions against food and environmental antigens. Generally, such antigens are either tolerated by the host’s immune system (immune tolerance) or completely ignored (immune ignorance). Immune tolerance is thought to be induced at sites where most antigens enter the body, i.e. the skin and the mucosa, particularly at the gastrointestinal mucosa. In our project we want to investigate why and how tolerance or ignorance founder for certain apathogenic antigens and allergens and whether this failure can be ascribed to erroneous mucosal antigen classification mechanisms.

Analysis of antigen stability in mucosal secretions

The absence of an immune defense reaction as well as the induction of an adverse immune reaction may be due to an early degradation of MHC epitopes in the digestive tract or a formation of certain MHC epitopes due to individual predisposition. Our in-house developed experimental repertoire enables us to determine stabilities of proteinaceous as well as of poly- or oligopeptidic antigens in mucosal secretions under in vivo-like conditions. Hence, we can determine and compare half-lifes and fragmentation patterns of antigens in mucosal secretions. This way, we want to address the question whether intestinal epitope stability affects the decision on ignorance, tolerance or immunity.

Development of ligands for cell-type specific targeting of drugs and molecular imaging agents to distinct mucosal sites

The mucosa is safeguarded by various protective means such as mucus, immunoglobulin A, a glycocalyx and digestive enzymes. Thus, mucosally administered drugs or molecular imaging agents must first overcome these obstacles in order to reach their target cells and exert their desired function. Mucus and immunoglobulin A act as traps by crosslinking, engulfing or adsorbing hazardous agents. The glycocalyx presents a porous filter that prevents pathogens or particulate noxae to access the cell membranes. And digestive enzymes directly attack hazardous invaders aiming to destroy them. For mastering these hurdles mucosal targeting systems should be "mucophobic" and free of immunogenic structures in order to escape the mucus and not to induce an immunoglobulin trap. They should be scalable in size in order to penetrate the glyxocalyx filter or to exploit it as a barrier. And finally they should be degradation resistant in order to escape premature destruction. Classical targeting ligands such as monoclonal antibodies, lectins or microbial toxoids do not meet these requirements satisfactorily as they are susceptible to proteolysis, immunogenic and difficult to size. In order to realize drug targeting and molecular imaging at mucosal surfaces we are establishing a technology for the identification of peptidic or peptoid ligands in the 2 kDa range. The technology allows peptidic or peptidomimetic ligands to be tailored such that they evade the abovementioned barriers of mucosal surfaces. Once fully operational, we want to use our platform for the design of peptide-based mucosal targeting systems.

Interactions of nanoparticles with mucosal secretions and surfaces

Actual and envisioned fields of application for nanoparticles range from semiconductors over dirt repellant coatings to suntan lotions and new drugs. With such an omnipresence, involuntary exposure to engineered nanoscale particles is inevitable. This calls for exposure assessments and a thorough investigation of the medical consequences of nanoparticle incorporation. The mucosa represents the first site of contact for ingested or inhaled nanoparticles. Here, it is decided whether, in which form and via which route nanoparticles enter the body. In this project we investigate to which extent nanoparticles are modified by mucosal secretions and how nanoparticles interact with or cross the mucosal surface.

The intestinal glycocalyx as a biomarker

Apart from the mucus layer the glycocalyx – a complex coat of carbohydrates that is linked to the epithelial cell surface – represents an outer barrier of the mucosa. Displaying a height of several nanometers, this carbohydrate fleece is important for the protection of the mucosa but also for nutrient uptake. Food components as well as intestinal proteases can adsorb to and deeply penetrate into this network. Physical or chemical impacts can easily impair the glycocalyx’ integrity, which may lead to a loss of mucosal protection and impaired nutrient uptake. In this project, we want to use electron microscopic techniques in order to investigate whether – in addition to exogenous factors – pathological factors such as cancer or ischemia can lead to alterations in the glycocalyx.