Modulation of Specific and Allergy-Related Immune Responses by Helminths

Helminths are master regulators of host immune responses utilising complex mechanisms to dampen host protective Th2-type responses and favour long-term persistence. Such evasion mechanisms ensure mutual survival of both the parasite and the host. In this paper, we present recent findings on the cells that are targeted by helminths and the molecules and mechanisms that are induced during infection. We discuss the impact of these factors on the host response as well as their effect in preventing the development of aberrant allergic inflammation. We also examine recent findings on helminth-derived molecules that can be used as tools to pinpoint the underlying mechanisms of immune regulation or to determine new anti-inflammatory therapeutics

Impact of helminths and helminth products on immune responses

Helmintheninfektionen induzieren in ihren Wirten Typ 2 (Th2) Immunantworten, welche parasitäre Larvenstadien hemmen und/oder zur Abstoßung von intestinalen Würmern führen. Th2-Antworten können auch gegenüber Umweltallergenen ausgebildet werden und allergische Reaktionen vermitteln. Mastzellen (MZ) spielen eine herausragende Rolle für die Wirtsantwort gegen Parasiten. Die Ergebnisse der vorliegenden Arbeit zeigen, dass eine Infektion von MZ-defizienten Mäusen mit Helminthen zu einer reduzierten Produktion von IL-25, IL-33 und TSLP, einer beeinträchtigten Etablierung von Th2 Immunantworten und einer erhöhten Wurmlast führt. Diese Parameter konnten allerdings nach einem erfolgreichen Transfer von Knochenmark aus Wildtypmäusen wiederhergestellt werden. Die vorliegende Arbeit beschreibt somit eine wichtige Funktion von Mastzellen für die Initialisierung von Th2 Immunantworten. Des Weiteren konnte gezeigt werden, dass ein Cystein-Protease-Inhibitor - AvCystatin sowohl Parameter von Atemwegsentzündung und -hyperreaktivität als auch Lieschgraspollen (Phl p 5b)-spezifische Immunantworten in einem klinisch relevanten Mausmodell für Atemwegsentzündung inhibiert. Gleichzeitig führte die Behandlung mit AvCystatin zu einem Anstieg von IL-10 und erhöhten Frequenzen von CD4+CD25+Foxp3+ T Zellen. Die in vivo Effekte von AvCystatin wurden unabhängig von der Protease-inhibitorischen Aktivität des Immunmodulators oder dessen Fähigkeit zur Oligomerisation vermittelt. AvCystatin unterdrückte zudem die Allergen-spezifische Produktion von IL-13 und induzierte in vitro unter Verwendung mononukleärer Zellen aus dem peripheren Blut (PBMCs) von Graspollen allergischen Patienten einen IFN-gamma vermittelten Th1 shift. Zusammenfassend tragen die Ergebnisse der Arbeit zu einem besseren Verständnis für die frühen Ereignisse von Th2 Immunantworten bei und zeigen, dass Helminthenmoleküle Bystandereffekte auf Immunantworten vermitteln können, die gegen andere Antigene gerichtet sind.Helminth infections induce protective type 2 (Th2) immune responses in the host leading to arrested larval development and/or intestinal worm expulsion. Moreover, Th2 immune responses are initiated against harmless environmental allergens and mediate development of allergic disease. Among multiple mechanisms implicated in host responses to parasites and allergens, mast cells (MCs) play a pivotal role. The present study shows that MC-deficient mouse strains following infection with two gastrointestinal helminths had dramatically reduced early production of the tissue-derived cytokines IL-25, IL-33, and TSLP, which resulted in impaired induction of Th2 immune responses as well as increased parasite burden. These parameters were restored after transfer of WT bone marrow. These data reveal an important role for MCs in orchestrating type 2 immune responses. Parasites have developed various strategies to modulate the immune system via induction of a range of regulatory mechanisms. In this study AvCystatin, the filarial cysteine inhibitor, was found to inhibit airway inflammation and hyperreactivity induced by a clinically relevant allergen of timothy grass pollen (Phl p 5b). AvCystatin increased levels of the regulatory cytokine IL-10 and total numbers of CD4+CD25+Foxp3+ T cells. The immunomodulatory effect in vivo was found to be independent of AvCystatin’s protease inhibitor activity or oligomerization. Finally, AvCystatin suppressed allergen-specific production of IL-13 and created a shift towards Th1 immunity by increased levels IFN-gamma of human peripheral blood mononuclear cells (PBMCs) from grass pollen allergic patients. The findings contribute to a better understanding of the early events that dictate the priming of type 2 immune responses. Furthermore, helminth product-induced suppression may also have effects on bystander responses to unrelated antigens, thus, suggesting a promising preventive and therapeutic concept in the treatment of aberrant inflammations

Mast cells orchestrate type 2 immunity to helminths through regulation of tissue-derived cytokines.

Mast cells (MCs) are potent inflammatory cells that are distributed throughout mucosal barrier tissues and respond rapidly to pathogenic stimuli. During helminth infections, MCs play an important role as late-stage effectors. However, it is currently unknown whether MCs contribute to the early innate events that determine the priming of adaptive immunity. MC-deficient mouse strains and mice treated with the MC stabilizing agent cromolyn sodium had dramatically reduced Th2 priming and type 2 cytokine production and harbored increased parasite burdens following infection with gastrointestinal helminths (Heligmosomoides polygyrus bakeri and Trichuris muris). In addition, early production of the tissue-derived cytokines IL-25, IL-33, and thymic stromal lymphopoietin (TSLP) was significantly diminished in MC-deficient mice and resulted in decreased numbers of infection-elicited IL-25–dependent (Lin(−)CD45(−))CD34(+)Sca-1(+) progenitors, which produced type 2 cytokines and could be differentiated into mast cells ex vivo. Finally, repair of MC deficiency increased production of IL-25, IL-33, and TSLP, restored progenitor cell numbers and Th2 priming, and reduced parasite burden. Our data reveal an innate IgE-independent role for MCs in orchestrating type 2 immune responses via the regulation of IL-25, IL-33, and TSLP