Through the skin to the target

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Human skin is an organ having total surface area of approximately 1.8 m2 and which constitutes a barrier protecting an organism from physical and chemical factors. Weighing in at roughly 4 kg, human skin plays an important role processes such as thermoregulation and immune mechanisms. The latter issue is the focus of research conducted by scientists from the Department of Medical Biology of the Faculty of Health Sciences.

For many years, skin has been treated as a place in which it is relatively easy to evoke an immune response, yet scant attention has been paid to the possibilities to use this organ to block immunity.

Research carried out for over 10 years by a team supervised by Professor Marian Szczepanik from the Department of Medical Biology of the Jagiellonian University has proven that treatment of the skin with an antigen (a substance which causes immune response in normal circumstances) enables the suppression of undesirable inflammatory responses, not necessarily connected to the skin itself. Such inflammatory responses occur, for example, in mice suffering from contact dermatitis and autoimmune diseases such as autoimmune encephalomyelitis, collagen-induced arthritis, and ulcerative colitis, i.e. diseases in which the body attacks its own tissue as a result of the incorrect functioning of the immune system.

Observations made during tests on animals became a starting point for initiating clinical trials in a group of patients suffering from multiple sclerosis (MS). The frequency of incidence of MS in Europe and in the United States is approximately 40–150 cases per 100,000 inhabitants. Most cases occur in young people aged 20–40 years. These two prerequisites and the lack of a fully effective MS therapy led to the attempt to develop a new method of treatment of this illness. Test results confirmed the efficacy of the new, needle-free therapy.

To respond or to remain silent?

In order to better understand the nature of this discovery, one has to realize that when our body comes in contact with microorganisms, the task of the immune system is to create mechanisms that will enable it to fight off the invader's attack. However, it is worth noting that the immune system is programmed in such a way that prevents it from responding to own antigens and neutral antigens, e.g., those present in food or constituting an element of own bacterial flora. Such a situation of ignoring neutral antigens was observed for the first time on the mucous membranes layering the inside of the gastrointestinal tract. It was noticed that administering the antigen orally, apart from evoking a local immune response on the mucous membranes, caused a state of inhibiting the immune response in peripheral parts of the body, such as the skin and the nervous system. The observed phenomenon was tested, for example, in models of autoimmune diseases. Unfortunately, the results of tests on animals did not translate into practical applications when the efficiency of blocking immune reaction was tested in humans.

Immunosuppressants, the aim of which is to block the harmful reaction of the immune system to own antigens, are widely used in the therapy of autoimmune diseases originating from the improper reactions of the immune system. The disadvantage of therapeutic means currently used is their non-specific influence on the immune system. This results in the fact that, in addition to blocking the response to own antigens, the immunity to other antigens, such as antigens of microorganisms, is also depressed, which may lead to the development of serious infection. It is also worth noting that patients treated with such immunosuppressants are more prone not only to infection, but also to cancer. Thus, the development of a new, efficient, and at the same time specific (targeted only against harmful immune response to own antigens) method of treatment of autoimmune diseases is an essential challenge for modern medicine.

Photo Jan Zych

Cheating the immune system

"The possibility to block the immune response through administering the antigen to mucous membranes suggested that, due to the functional similarity of the skin and mucous membranes, it is also likely that it will be possible to block the immune response by applying the antigen onto the skin. This gave me hope to "cheat" the immune system," Professor Marian Szczepanik explains.

Tests involving a non-invasive method of blocking the immune response to own antigens and allergenic substances were started by a team led by Professor Szczepanik at the beginning of 1999. The results of studies on the model of contact dermatitis in mice proved that the application of antigen onto the skin (administered in form of a gauze dressing, also called a patch) strongly blocks the undesirable inflammatory reaction. Specialized immune cells – T lymphocytes – play the key role in this type of inflammatory reactions. These immune cells are also responsible for inflammatory reactions in autoimmune diseases. "This is why, in further stages of our research, we attempted to evaluate the efficiency of the method of counteracting harmful inflammatory reaction in models of autoimmune disorders in animals, such as multiple sclerosis, rheumatoid arthritis and ulcerative colitis. Promising results of tests on animals encouraged us to take attempts aimed at analyzing the efficiency of this method in a group of patients suffering from the diseases listed above," explains the head of the Department of Medical Biology.

Drug in a patch

Professor Szczepanik has been cooperating with Professor Krzysztof Selmaj of the Clinic of Neurology of the Medical University in Lodz for many years, so they both started working together on the application of the results of tests on animals in clinical practice. Clinical trials were conducted with a group of patients suffering from MS, which is a chronic disease of the central nervous system, the brain, and the spinal cord. The exact cause of this disease remains unknown, although it is known that the underlying basis for MS is the improper response of the immune system to myelin proteins. This substance is produced by cells surrounding neural axons. Damage to the myelin which insulates the neural cells causes disorders in neural conductivity, which in turn leads to neurological symptoms including balance problems, visual impairment, numbness, and stiffness of muscles.

Clinical trials consisted of the application of myelin antigens on the skin in the form of a gauze dressing. The substance was administered for a period of one year. This led to a significant improvement in the patients' health. A decrease in the number of exacerbations was observed, which was confirmed by clinical tests and magnetic resonance imaging (MRI). It is worth noting that this method of counteracting an undesired immune response does not lead to any adverse effects.

The antigen applied on the skin in the form of a gauze patch is captured by specialized cells present in the epidermis, the socalled Langerhans cells. These cells transport the antigen to the lymph nodes, where the immune response develops. In the case analyzed by the scientists, it turned out that, instead of T cells that are able to destroy myelin, T-cells were created that were capable of blocking the undesired immune response in the central nervous system. The application of an antigen in the form of a patch has a very selective effect, i.e., it refers only to T lymphocytes responsible for the disorder, yet it does not affect other cells performing defensive functions in the body.

The developed method met with great interest in scientific circles throughout the world. It was called the "magic bullet" thanks to its unique ability to precisely destroy undesired immune response without affecting the remaining parts of correctly functioning immune systems. This was confirmed by the publication of the test results in the prestigious journals "Annals of Neurology" in 2010 and "JAMA Neurology" in 2013. Clinical trials will be continued after obtaining necessary funding.

Research team (employees of the Department of Medical Biology): Professor Marian Szczepanik; Monika Majewska-Szczepanik, PhD; Katarzyna Marcińska, PhD Former team members: Professor Włodzimierz Ptak; Maria Ptak, PhD; Krzysztof Bryniarski, PhD; Monika Tutaj, PhD; Magdalena Zemelka-Wiącek, PhD