Publikationsserver der Universitätsbibliothek Marburg

Titel: Humorale und zelluläre Immunparameter nach Abschluss der allergenspezifischen Immuntherapie bei Patienten mit Hymenopterengiftallergie
Autor: Pickert, Julia Elisabeth
Weitere Beteiligte: Pfützner, Wolfgang (Prof. Dr.)
Veröffentlicht: 2017
URI: https://archiv.ub.uni-marburg.de/diss/z2017/0390
DOI: https://doi.org/10.17192/z2017.0390
URN: urn:nbn:de:hebis:04-z2017-03908
DDC: Medizin, Gesundheit
Titel(trans.): Humoral and cellular immune parameters after finishing allergen-specific immunotherapy in patients with hymenoptera venom allergy
Publikationsdatum: 2017-07-12
Lizenz: https://creativecommons.org/licenses/by-nc-sa/4.0

Dokument

Schlagwörter:
Immunparameter, zellulär, humoral, Spezifische Immuntherapie, Hyposensibilisierung, Insektengiftallergie

Zusammenfassung:
Seit über einem Jahrhundert wird die spezifische Immuntherapie (SIT), auch Hypo- oder Desensibilisierung genannt, zur Behandlung von Soforttypallergien eingesetzt. Bei diesem Allergietyp kommt es durch wiederholten Allergenkontakt zur Quervernetzung der auf der Oberfläche von basophilen und eosinophilen Granulozyten oder Mastzellen gebundenen IgE-Antikörper mit konsekutiver Zellaktivierung und Freisetzung von Histamin bzw. weiterer proinflammatorischer Mediatoren, die letztendlich zu den typischen allergischen Symptomen führen. Insbesondere bei der Insektengiftallergie kann es im Rahmen von Stichreaktionen zu lebensbedrohlichen anaphylaktischen Reaktionen kommen. Die SIT stellt nach wie vor die einzige, kausale Behandlungsform dar, die in der Lage ist, den natürlichen Krankheitsverlauf von Soforttypallergikern positiv zu beeinflussen. In zahlreichen klinischen Studien wurde die kurative Wirksamkeit belegt. Die der SIT zugrunde liegenden immunologischen Mechanismen sind seit Jahrzehnten Gegenstand der Forschung. Während die Veränderungen, die zur Induktion der Allergentoleranz führen, bereits besser erforscht sind, sind die Mechanismen, die der Aufrechterhaltung der Toleranz auch nach Abschluss der SIT dienen, noch weitestgehend ungeklärt. Zwar ist gezeigt, dass bei ca. 90-95% der Insektengiftallergiker während der SIT eine Toleranz erreicht wird, allerdings ist auch bekannt, dass ca. 15% die erworbene Toleranz innerhalb weniger Jahre nach Beendigung der SIT wieder verlieren. Bislang gibt es allerdings keine Laborparameter, welche eine weiterhin bestehende Toleranz bzw. einen drohenden Toleranzverlust, der mit wiederkehrenden lebensgefährlichen Anaphylaxien einhergehen kann, zuverlässig voraussagt. Mit dieser „diagnostischen Lücke“ beschäftigt sich die vorliegende Studie. Es wurden Patienten, die eine SIT mit Bienen- oder Wespengift bereits vor 4-13 Jahren abgeschlossen haben, bezüglich verschiedener zellulärer und humoraler Immunparameter untersucht. Die Patienten wurden, je nach Zeitraum, der seit Beendigung der SIT vergangen war, in Gruppen eingeteilt. Vergleichend wurde diesen Kohorten eine Kontrollpopulation bestehend aus gesunden Probanden ohne Manifestation einer IgE-vermittelten Allergie gegenübergestellt. Die Analysen unterschiedlicher T-Zellpopulationen zeigten bezüglich der allergenspezifischen T-Zellfrequenzen für T-Helfer (Th)2-, Th1- und Typ-1-regulatorischen T (Tr1)-Zellen zwar signifikante Abweichungen in Hinblick auf das Kontrollkollektiv, jedoch bei den Th1- und Tr1-Zellen nicht im Vergleich der einzelnen Patientengruppen nach abgeschlossener SIT untereinander. Für die allergenspezifischen Th2-Zellen hingegen zeigte sich eine (bei einer Subpopulation auch signifikante) Zunahme der allergenspezifischen Th2-Zellen, je länger die SIT zurücklag. Die Frequenz unspezifischer Foxp3+ regulatorischer T-Zellen, ermittelt durch das Expressionsmuster der Oberflächenmarker CD4, CD25 und CD127, zeigte hingegen weder innerhalb der Patientengruppen noch gegenüber dem Kontrollkollektiv Abweichungen. Um die humorale Immunantwort nach Abschluss der SIT zu charakterisieren, wurden für die einzelnen Patientengruppen die Serumkonzentrationen der allergenspezifischen IgE-, IgG- und IgG4-Antikörper und ebenso die quantitativen Verhältnisse der unterschiedlichen Antikörperklassen zueinander ermittelt. Hier zeigten sich wiederum signifikante Unterschiede im Vergleich zum Kontrollkollektiv, jedoch konnten keine signifikanten Abweichungen der Patientengruppen untereinander festgestellt werden. In einer Subgruppenanalyse konnten bezüglich der beschriebenen Parameter zudem keine Unterschiede zwischen den Patienten ermittelt werden, die mehrere Jahre nach Beendigung der SIT mit einer (erneuten) allergischen Reaktion auf einen Feldstich reagierten, und denen mit ausbleibender Stichreaktion (die also nach wie vor tolerant waren). Die im Rahmen dieser Arbeit erhobenen Daten zeigen somit, dass die Aufrechterhaltung von Allergentoleranz bzw. der Toleranzverlust nach SIT nicht nur von den in dieser Studie quantitativ bestimmten, immunologischen Parametern abhängt, sondern maßgeblich auch von anderen, qualitativen Faktoren abzuhängen scheint, wie bspw. der allergenblockierenden Aktivität des Serums.

Summary:
For over a century, specific immunotherapy (SIT), also known as hypo- or desensitization, has been used to treat immediate-type allergies. In this type of allergy, repeated allergen contact results in cross-linking of IgE-antibodies bound to the surface of basophilic and eosinophilic granulocytes or mast cells with consecutive cell activation and release of histamine or other pro-inflammatory mediators ultimately leading to typical allergic symptoms. Particularly, in the case of insect venom allergy stings of e.g. bees or wasps can lead to life-threatening anaphylactic reactions. To date, SIT is still the only causal treatment capable of positively affecting the natural course of the disease in patients suffering from immediate-type allergies. Numerous clinical studies have demonstrated the curative efficacy of SIT. However, the underlying immunological mechanisms of this therapy have been subject of research for decades. While the immune alterations leading to induction of allergen tolerance are already being investigated, the mechanisms responsible for maintenance of tolerance even after SIT remain largely unexplained. Although it has been shown that approximately 90-95% of insect venom allergic patients will gain tolerance during SIT, however, it is also known that approximately 15% will lose the acquired tolerance within a few years after cessation of therapy. So far, there are no laboratory biomarkers which reliably predict either a continuing tolerance or an imminent tolerance loss, which may be associated with recurring life-threatening anaphylaxis. The present study was conducted to fill this "diagnostic gap". Patients allergic to bee or venom who have completed SIT between 4-13 years ago were examined for different cellular and humoral immune parameters. Depending on the time period since termination of SIT, patients were divided into four cohorts. In addition, a control population consisting of healthy subjects without manifestation of an IgE-mediated allergy was compared to the allergic groups. The analysis of different T-cell populations showed significant deviations in allergen-specific T-cell frequencies for T-helper (Th) 2, Th1 and Type 1 regulatory T (Tr1) cells between patients and healthy control subjects. In contrast, there were no significant changes of Th1 or Tr1 cells comparing the patient groups after finishing SIT. Only for allergen-specific Th2 cells an increase by trend could be observed (which was actually significant for a subpopulation of the allergic patients) the longer the SIT dated back. The frequency of non-specific Foxp3+ regulatory T cells, as determined by the expression pattern of the surface markers CD4, CD25 and CD127, remained unchanged in both the patient cohorts and in comparison to the control group. In order to characterize the humoral immune response after completion of SIT, serum concentrations of allergen-specific IgE, IgG and IgG4 antibodies were determined for the individual patient groups as well as the respective ratios of the different antibody classes. Significant differences could be demonstrated for the insect venom-allergic patients in comparison to the healthy controls, however, among the four patient cohorts serum concentrations were constant. In further subgroup analyses between patients who reacted again to a field sting several years after the end of SIT, and those who had no anaphylactic sting reaction after a re-experienced field sting (i.e. patients who were still tolerant), showed no alterations in the investigated parameters. Thus, the data showed that both maintenance and loss of allergen tolerance after SIT is not only dependent on the immunological parameters determined quantitatively in this study, but rather essentially based on other, qualitative factors such as Allergen-blocking serum activity.

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