Impaired immunity and altered pulmonary responses in mice with a disrupted interferon‐γ receptor gene exposed to the irradiated Schistosoma mansoni vaccine

Abstract

SUMMARYA high level of protection against Schistosoma mansoni is elicited in mice by the irradiated cercaria vaccine and interferon-g (IFN-g) is a key cytokine in the pulmonary effector response. The role of this cytokine has been investigated in mice with a targeted disruption of the IFN-g receptor gene (IFN-gR ÿ /ÿ mice). The level of protection was impaired relative to that elicited in C57BL/6 and 129 wild-type (WT) animals. These two groups developed compact effector foci, of largely mononuclear cell composition, around individual challenge parasites migrating through the lungs. In contrast the IFN-gR ÿ /ÿ mice showed a massive and generalized leucocytic infiltration of the airways and interstitium in which eosinophils were a prominent feature. Cultures of airway leucocytes from C57BL/6 mice produced abundant IFN-g whilst those from IFN-gR ÿ /ÿ mice produced interleukin-4 (IL-4), IL-5 and IL-10, indicating default to the Th2 pathway; the WT animals showed an intermediate response. The pattern of cytokine gene transcripts in whole lung tissue agreed remarkably well with the level of cytokine protein detected in leucocyte cultures, with the exception of substantial IL-4 mRNA but negligible protein in C57BL/6 mice. The loose but intense infiltrate of leucocytes in the lungs of IFN-gR ÿ /ÿ mice was clearly ineffective in eliminating challenge parasites, whereas the level of IFN-g protein and mRNA in the lungs of C57BL/6 and WT mice correlated with the size and compactness of effector foci. On the basis of these and earlier observations, we suggest that a primary role for IFN-g is to promote intercelluar adhesion between the leucocytes in an effector focus, promoting its ability to block parasite migration.

In the Absence of CD154, Administration of Interleukin-12 Restores Th1 Responses but Not Protective Immunity toSchistosoma mansoni

“…Ϫ/Ϫ mice is significant because the absence of many other immune components (e.g., IFN-␥ [20], IFN-␥R [57], IL-4R␣ [35], and IL12p40 [2,16]) only leads to the partial abrogation of resistance. Our studies using CD154 Ϫ/Ϫ mice that do not produce anti- CD154 is important for optimal expression of MHC-II and CD86 by APCs in the skin and their migration from the skin to the sdLN (32), which are important in immune priming against schistosomes (24).…”

“…The absence of antibodies in CD154 Ϫ/Ϫ mice has allowed us to examine the nature of the cell-mediated effector mechanism that was previously thought to be at least partially responsible for conferring protection (1,2,14,16,20,33,53,57,59,60). However, despite recreating the Th1-mediated immune responses in the lungs following the administration of IL-12, we were unable to recreate a protective response against challenge parasites, even to a limited extent.…”

Signaling via Interleukin-4 Receptor α Chain Is Required for Successful Vaccination against Schistosomiasis in BALB/c Mice

“…The established dogma that protective immunity to a single dose of the RA schistosome vaccine in C57BL/6 mice is associated with a strong Th1 cell-mediated immune response involving an inflammatory reaction to challenge parasites in the lungs has been supported in many studies using cytokine ablation treatments (57,59) or cytokine-deficient mice (1,23,64). Therefore, we predicted that in the absence of IL-4R signaling, Th1-type responses would increase and that consequently protective immunity would be greater in IL-4R␣ Ϫ/Ϫ than in WT mice.…”

Cutting Edge: Susceptibility to the Larval Stage of the Helminth ParasiteTaenia crassicepsIs Mediated by Th2 Response Induced Via STAT6 Signaling

“…They also indicate that Th2-type response may be detrimental for cysticercosis. Moreover, others using radiation-attenuated vaccine and IL-12 as an adjuvant against Schistosoma have shown that a Th1-like response can mediate protective immunity in this model (22,23).…”