An IL-12-based vaccination method for preventing fibrosis induced by schistosome infection

Abstract

The harmful fibrosis which often occurs in the context of infectious disease involves the excessive deposition of connective tissue matrix, particularly collagen, and is mostly resistant to pharmacological and immunological intervention. In schistosomiasis, fibrosis is associated with the granulomatous response to parasite eggs trapped in the liver. We have previously shown that interleukin (IL)-12 administered peritoneally with eggs prevents subsequent pulmonary granuloma formation on intravenous challenge with eggs. Here we show that sensitization with eggs plus IL-12 partly inhibits granuloma formation and dramatically reduces the tissue fibrosis induced by natural infection with Schistosoma mansoni worms. These results are an example of a vaccine against parasites which acts by preventing pathology rather than infection. IL-12 is known to favour the priming of TH1 rather than Th2 cells, and the effects on fibrosis are accompanied by replacement of the Th2-dominated pattern of cytokine expression characteristic of S. mansoni infection with one dominated by Th1 cytokines. Elevated Th2 cytokine expression and fibrosis are common manifestations of a wide variety of infectious diseases and atopic disorders which might be ameliorated by vaccination with antigen and IL-12.

Interleukin-13 Fusion Cytotoxin Arrests Schistosoma mansoni Egg-Induced Pulmonary Granuloma Formation in Mice

“…This finding is particularly interesting in light of the potent downregulatory effect of IL-12 on the development of S. mansoni egg-induced granulomatous responses. 49,68,69 However, these findings are somewhat tempered by recent findings from Stat-4Ϫ/Ϫ mice, which lack IL-12-mediated immune responses, 70 in which pulmonary granuloma formation was modestly inhibited during S. mansoni infection. 16 Regardless of the precise role invoked by Th1-type cytokines during S. mansoni egg granuloma formation, it was apparent from the present study that IL13-PE treatment did not appear to promote an aggressive Th1 cytokine response as a result of its diminution of the Th2 cytokine response.…”

Experimental models of Schistosoma mansoni infection

“…Stat4 deficient mice showed a minimal Th1 response but normal hepatic granulomas. Wynn et al (1995a) found that immunization with SEA and IL-12 produced immune deviation toward Th-1 type reactions with reduction of granuloma sized. All of these effects are consistent with the concept of the granuloma as a Th2 dominant reaction, but under some conditions Th1 granulomatous responses may be predominant and damaging , Chen & Boros 1999, Hoffmann et al 2000, Rutitzkky et al 2001.…”

Lack of antigen-specific Th1 response alters granuloma formation and composition inSchistosoma mansoni-infected MyD88-/- mice

“…Immunological studies of the adaptive immune response in the mouse have focused on the prevalent CD4 + T cell activity and revealed that, initially, the host develops a Th1 response, which is characterized by the production of IFN-c. However, as the infection progresses, this Th1 response gradually succumbs to a dominant Th2 response, and is indicated by the secretion of IL-4, IL-5, IL-13 and IL-10 [2][3][4][5]. The host factors that are responsible for the initial Ag-specific Th1 response remain unclear.…”