54: Helminth-induced innate type-2 cytokines protect against autoimmunity

Abstract

Helminth parasites typically establish chronic infections in the mammalian host which can persist for decades. Helminths evade protective host immune responses by promoting innate and adaptive anti-inflammatory networks which can also suppress immune responses to unrelated antigens. Indeed, it has been shown parasitic infection of humans is associated with a lower incidence of allergy and autoimmune disease in rural areas of the developing world. Experimental models of autoimmunity have revealed that helminth-induced protection against disease can be mediated by the action of either Treg or Th2 cells [1] . Here we examined the immunoregulatory effects of the excretory-secretory (ES) products of the helminth parasite, Fasciola hepatica, in the mouse model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE). Administration of ES delayed the onset and attenuated the clinical severity of EAE which was associated with a decreased production of auto antigen-specific IFN- γ and IL-17. Unexpectedly, IL-10, TGF- β , or regulatory T cells did not play a role in the ES-induced attenuation of disease. Moreover, ES-elicited T cells did not suppress EAE and protection from disease was also retained in IL-4-deficient mice, suggesting that Th2 cells do not play a role in ES-induced amelioration of EAE. However adoptive transfer of macrophages or eosinophils, from ES-treated mice transferred protection. Furthermore, IL-5, a cytokine which mediates eosinophilia in vivo, was required for ES-induced protection against EAE. We are currently investigating the role of the epithelial cell-derived ‘alarmin’ cytokine, IL-33, in mediating the regulatory effects of ES. We have determined that IL-33 acts on mast cells to promote the alternative activation of macrophages with regulatory capacity while also promoting eosinophilia in vivo. These findings provide new insights into how helminths target innate immune cells in order to modulate the immune response thereby inhibiting the Th1 and Th17 responses that mediate inflammatory disease.