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“A targeted switch off of only the disease-enhancing memory cells would be desirable“
Professor Max Löhning©J.Hirscher/
However, to this day the entire mechanism of the immunological memory has not been completely decoded.
MEDICA. de spoke with Lichtenberg-Professor Dr. Max Löhning, who at the Department of Rheumatology and Clinical Immunology at the Charité – University Medicine Berlin and the German Rheumatism Research Center (DRFZ) is researching the cellular and molecular fundamentals of the immunological memory and its functional characteristics.
MEDICA.de: Professor Löhning, there are two inter-connected main areas of the immune system, the innate and the adaptive one. How do these “systems“ differ in their functionality?
Max Löhning: First of all, time is a deciding factor in controlling pathogens, since many of them can quickly proliferate in the body. That’s why there is an early innate immune response, which is based on a relatively broad recognition of pathogen groups. It roughly distinguishes whether these pathogens are for instance bacteria, viruses or fungi. The defense cells of the innate immune system, like for instance granulocytes or macrophages, identify general structures here which are frequently observed as universal patterns in these pathogens. This way, a comparatively broad first immune response can be immediately triggered. Fortunately, a good portion of pathogens can already be controlled at this stage.
However, some pathogens manage to outwit and bypass the early defense. This then requires and activates a specific adaptive immune response. It is a specific identification of very individual structures of single pathogens via adapted receptors on T cells or B cells. The soluble receptors of the B cells are the antibodies.
MEDICA.de: Different cells in the body are responsible for blocking foreign substances. Among others, the B- and T cells of the adaptive immune system are involved in this. How and when do these cells become active?
Löhning: T-and B cells have similar basic patterns. Each of these cells carries a unique receptor on their cell surface, whose physical structure is determined by random genetic programming. If this receptor docks onto a virus, the selected T- or B cell that carries this receptor is activated, proliferates heavily and can then proceed against the virus. Although we have a large number of B- or T cells in our bodies, only a few of them are coincidentally equipped with the receptor that fits the pathogen. Only those few cells that carry such a matching receptor are selectively activated, then go through many cell divisions and finally supply a large, effective number of pathogen-specific defense cells. That’s the basic principle.
Since these cell divisions depict a time-consuming process though, you need the already set-up innate immune system to be able to respond quickly. The specific response normally takes effect after several days. This makes it too slow to protect against bacterial and viral infections by itself, since these often have a very high reproduction rate. So the innate immune defense is essential here to limit an early dissemination of pathogens in the body.
MEDICA.de: What do you generally mean by “the immune system’s memory“ and how is it built?
Löhning: The immune system’s memory is a memory of specific adaptive immune responses that have already taken place. This memory is retained for a long time, even if the pathogenic agent that originally triggered the immune response is no longer detectable in the body. The memory consists of long-lived T- and B memory cells and the antibody-producing types of B cells, the so-called plasma cells. Plasma cells constantly secrete large amounts of antibodies that can achieve protective antibody titers in the body. Memory T- and B cells are maintained in larger number in the body and can react quickly and more vigorously than their initial naïve T- and B-cell precursors upon re-infection with the same pathogen. In clinical practice the immune system’s memory serves as the basis for vaccinations via induction of protective antibody titers, and it provides protection against already survived infections.
MEDICA.de: B- and T cells are also known as the memory cells of the immune system. How do they develop this function and how is it regulated by the body?
Löhning: This is a question that is currently strongly researched. We know that after completion of the immune response against the pathogens, some of the activated T- or B cells which were activated through their specific receptor, develop a long-lived type of memory and can enter a dormant memory state. How the memory development functions exactly is not fully understood. A lot supports the view that the length of the infection with the presence of the pathogen in the body and the localization of pathogen-specific T- or B-cells in body tissues, especially the bone marrow, has a large bearing. These factors can contribute to selection processes of pathogen-specific T- or B cells during their development into long-lived memory cells. For long-lived antibody producing plasma cells and also memory T cells, the bone marrow can provide very specific ”survival niches“.
MEDICA.de: There is the so-called horror of self-destruction, the “horror autotoxicus“, a term coined in 1899 by Paul Ehrlich, scientist and founder of immunology. This is the case when the immune system attacks the body’s own tissue. In what way does this have to do with the immune system’s memory?
Löhning: The immunological memory in some instances can also turn against the body’s own tissues and cause autoimmune diseases and their chronic progression. Usually selection processes and regulatory mechanisms prevent the activation of those T-and B cells that are equipped with receptors against structures of our own body. However, in some cases these preventive mechanisms fail. Also immune pathologies are damages to the body, which develop during an immune response. In most cases they primarily turn against pathogens.
Some of these pathogens, viruses for example, mainly linger in body cells. To proceed against them, the infected cells need to be killed off. That is to say, the body’s own cells are being destroyed to fight the pathogenic germ. If this gets out of hand, it results in a massive immune pathology – damage to the body through its very own immune response.
Something similar happens in autoimmune diseases. Here "by mistake", T-and B cells recognizing the body's own tissues have been activated. The immunological memory can contribute especially to the chronic course of the disease, since in autoimmune diseases also memory cells are generated directed against the body’s own structures.
MEDICA.de: How do regulatory cells normally prevent an autoimmune attack in the body?
Löhning: The regulatory cells are able to restrict activation of non-active resting T cells or to completely inhibit them. How this takes place at a molecular level is currently the subject of intensive research. Several possible mechanisms are being discussed. Among them are the competition for growth factors or also the application of direct negative signals for the T cells that need to be slowed down. It is being researched whether there are molecular “switches“, which lead to the switching off of T cells that need to be slowed down and which are served by regulatory T cells.
MEDICA.de: Is an increased susceptibility to infection, maybe triggered by an immune deficiency, also linked to a disorder of the immunological memory?
Löhning: There could be a connection, but it does not have to be the case. The immunological memory can only protect against those pathogens, with which the body already sparred with previously. That is to say, in the case of generally increased susceptibility to infection to an array of different and in each case new pathogens for the body, one perhaps might rather look for defects in the innate immune system, which forms the first early stage of defense.
MEDICA.de: So far relatively little is known about the immunological memory of the body. You have been researching for some time how this memory can be used to prevent diseases. How does this already work or how could it work in the future?
Löhning: One possibility that we are researching are “tailored“ memory cells, which can make an ideal immune response in a short amount of time possible. We are working towards having these tailored cells quickly trigger an immune defense that’s as effective as possible, but at the same time also having this accompanied by as little immunopathological “collateral damage“as possible. Already the immunological memory is now routinely used to prevent infectious diseases in the area of vaccinations, which trigger protective antibody responses.
MEDICA.de: For which other areas is the development of targeted and tailored memory T cells of interest?
Löhning: Generally, these cells lend themselves to be applied in cell therapeutic situations. There already are clinical trials to selectively transfer for example virus-specific cells to the patient. These cells should have optimal characteristics to contain or completely eliminate the viral infection which the patient contracted. Cell therapy with tailored memory T cells could also be relevant in situations where the pathogen is highly variable. These are for instance specific viruses that can significantly alter their surface structure, like the HIV. In this case, the antibody response, the classic response, which has thus far been induced with common vaccination strategies, is not sufficient in most cases, because the pathogens’ structures change too quickly.
The antibody response usually lags behind. In contrast, the T cell response can identify the more fundamental principles of the pathogen’s makeup, which the virus has a harder time altering. Optimized memory T cells could present an additional method to proceed more aggressively against variable pathogens.
MEDICA.de: Can the immune memory also be permanently erased to combat rheumatic illnesses for instance?
Löhning: In some individual cases there already is clinical evidence - also here at the Berlin Charité - that it could work this way. In carefully chosen and so far only the most severe forms of rheumatic illnesses, so-called immune ablations combined with autologous stem cell transplantations are being performed. This is an intense intervention, which also involves a high risk of infection for the patients during a restricted time period after the treatment. This is why the deletion of the immunological memory by means of a temporary elimination of all the immune system are so far only performed in extremely severe and otherwise barely treatable advanced cases. After the intervention the immune system regenerates itself anew from stem cells. Hence it gets a second chance to avoid the generation of autoimmunity.
In individual patients a treatment-free remission could be achieved this way, either durable or over longer period of time, which suggests the driving force of the immunological memory in maintaining autoimmune diseases. Unfortunately, up to now this is intervention not successful in every patient. Considering the risks which at this time are still associated with this treatment, the hospital very carefully deliberates when to suggest it.
MEDICA.de: Does the principle of eliminating the immune system resemble the stage when cancer patients are undergoing radiation treatments or chemotherapy?
Löhning: For cancer patients who receive a radiation treatment or chemotherapy, there also can be more or less intense immunosuppressed stages. However, the goal of these treatments is not an elimination of immunological memory, but rather the destruction of cancer cells. During this time, patients can be very susceptible to infectious diseases. If necessary, the hospital takes appropriate preventive measures, like for example a preventative treatment with broadly-acting substances against bacterial and viral infections and mycosis.
It is desirable to accomplish a targeted and selective switch-off of precisely those memory cells - and clinical research is developing towards this – which chronically perpetuate autoimmune diseases and wrongly attack the body’s own structures. However, the protective immunological memory should be affected as little as possible. Our team and colleagues in Berlin and elsewhere research how the illness-perpetuating memory cells can be switched off, meaning how they can be killed off or “re-programmed”. We try to change the programming of these cells, to where they won’t cause inflammation or illness, but instead act in an anti-inflammatory way. The immune response against the body’s own tissue should be slowed down this way and stalled. This is a central goal of our research.
The interview was conducted by Diana Posth
(Translated by Elena O'Meara)