definitive mammalian host by penetrating intact skin. The cercariae adhere to the skin surface with the oral sucker and then penetrate the epidermis with the aid of muscular movement and lytic secretions discharged from the acetabular glands, losing their tail in the process and transforming into schistosomula. The schistosomula need 48-96 hr to negotiate the different layers of the stratified epidermis (Wilson, 1987; Sturrock, 1993, 2001). In this context, one wonders about the in vivo relevance of immunological data obtained with the in vitro-favored model of 3and 24-hr schistosomula because in vivo parasites of this age are still in the epidermis, well protected from the effect of blood components and cells. In the blood and lymphatic capillary-free, immunologically privileged environment of the epidermis, schistosomula shed the glycocalyx and undergo metabolic changes that end with replacement of the original, trilaminate tegumental membrane by a heptalaminate, double bilayer. Larvae merge into the dermis after acquiring resistance to the effect of complementand cell-mediated cytotoxicity (Dean, 1977; Samuelson et al., 1980; Dessein et al., 1981; Wilson, 1987). Focal inflammatory reactions elicited in the dermis may impede larval movement within the connective tissue, yet likely facilitate exit into the blood capillaries by increasing wall permeability. Until arrival in the liver, migrating larvae cannot feed as adults do because they lack a functional gut. They depend for their survival on energy obtained through the metabolism of reserve food and glucose and amino acids they obtain from the host via the apical tegument glucose and amino acid transporter, respectively (Skelly et al., 1994, 1999; Skelly and Shoemaker, 1996). Inflammatory cellular foci, induced by inflammatory mediators such as interferon-gamma (IFN-y) may delay or prevent the intravascular migration of larvae. Such impediment of movement is most significant in the lung capillaries, which have thin, unsupported walls that rupture easily, thus allowing extravasation of schistosomula into the air alveoli where they are trapped and die. The cellular foci are accumulations of lymphocytes and activated macrophages and their cytotoxic action is probably due to release of IFN-y, tumor necrosis factor-alpha, and nitric oxide (Crabtree and Wilson, 1986; Wilson et al., 1999). Indeed, IFN-y-dependent cellular immunity has been invoked as an important arm in defense against challenge infection with schistosomes in mice, immunized once or twice with radiation-attenuated larvae. Firm evidence supports the possibility of developing an effective vaccine against human schistosomiasis. Persons classed as endemic normals are continuously exposed to infective cercariae of S. mansoni and yet have no record of previous or current infection and appear uninfected as judged by repeated stool examination. There are numerous examples of lack of reinfection in adult humans that cannot be attributed solely to reduction in exposure to cercaria-infested water or to age-related factors. In such resistant humans, both T-helper 1 (IFN-y) and T-helper 2 (interleukin-4 and interleukin-5)-derived cytokines were found to be associated with the protective immune response to schistosomes (reviewed in McManus, 1999; Dunne and Mountford, 2001). Regarding the antibody arm of immunity, several studies have suggested that immunoglobulin E (IgE) is not required for the protective immune response in mice (Sher et al., 1990; El Ridi, Ragab et al., 2001). In contrast, a build up of IgE antibodies has been correlated with the development of resistance of humans to reinfection in some but not all studies (McManus, 1999; Dunne and Mountford, 2001; El Ridi, Shoemaker et al., 2001). The importance of IgE in protection against human schistosomiasis could be related to its ability to enhance the efficiency of the immune response (Mudde et al., 1990) rather than to its effector role. Indeed, IgE is thought to represent a major defense component against schistosomiasis, presumably by targeting effector cells against invading larvae in antibody-dependent cell-mediated cytotoxicity (ADCC) reactions. But there is limited evidence for ADCC efficacy in vivo because only the young schistosomula (epidermal stage) appear susceptible to the various killing mechanisms, whereas older parasites are almost impervious to ADCC-mediated immune attack. In support, the B-cell-dependent mechanism of protection in the radiation vaccine model, using mice that lack functional FcyRI, FcyRIII, and FceRI, did not appear to require FcR signaling (Jankovic et al., 1999). Yet, th absolute requirement for antibody response in protection against murin and human schistosomiasis has been amply documented (Hoffmann et al., 1999; Jankovic et al., 1999; McManus, 1999; Dunne and Mountford 2001; James and Colley, 2001). The mechanisms by which antibodies might function are unclear. It is worth noting that the antibody may impair larval viability and migration by interaction with critical sites in surface membrane-exposed molecules of importance for the parasite such as the glucose transporter, the amino acid permease and enzymes necessary for the generation of energy and membrane repair. Such neutralizing antibodies might even interfere with the welfare of adult worms in the liver.