Immunoglobulin E and Eosinophil-Dependent Protective Immunity to LarvalOnchocerca volvulusin Mice Immunized with Irradiated Larvae

Abstract

Mice immunized with irradiated Onchocerca volvulus third-stage larvae developed protective immunity. Eosinophil levels were elevated in the parasite microenvironment at the time of larval killing, and measurements of total serum antibody levels revealed an increase in the immunoglobulin E (IgE) level in immunized mice. The goal of the present study was to identify the role of granulocytes and antibodies in the protective immune response to the larval stages of O. volvulus in mice immunized with irradiated larvae. Immunity did not develop in mice if granulocytes, including both neutrophils and eosinophils, were eliminated, nor did it develop if only eosinophils were eliminated. Moreover, larvae were killed in naïve interleukin-5 transgenic mice, and the killing coincided with an increase in the number of eosinophils and the eosinophil peroxidase (EPO) level in the animals. To determine if EPO was required for protective immunity, mice that were genetically deficient in EPO were immunized, and there were no differences in the rates of parasite recovery in EPO-deficient mice and wild-type mice. Two mouse strains were used to study B-cell function; MT mice lacked all mature B cells, and Xid mice had deficiencies in the B-1 cell population. Immunity did not develop in the MT mice but did develop in the Xid mice. Finally, protective immunity was abolished in mice treated to eliminate IgE from the blood. We therefore concluded that IgE and eosinophils are required for adaptive protective immunity to larval O. volvulus in mice.Infection of humans with the filarial worm Onchocerca volvulus results in a spectrum of disease states ranging from mild to hyperreactive disease. In addition, there are individuals who are considered immunologically resistant to the infection, based on the fact that they live in an endemic area and are free of infection and disease. Individual immune responses appear to be responsible for the different disease states, and roles have been attributed to Th1 cells, Th2 cells, antibodies, and granulocytes in the different disease presentations (24). Specific mechanisms of protective immunity have been identified in vitro with human cells and serum, and it has been shown that eosinophils and neutrophils adhere to and kill larval O. volvulus in the presence of serum or complement (9,27,41).O. volvulus has a very limited host range, infecting only humans and chimpanzees; therefore, other animal models have been utilized to study immunity to this infection. It has been observed that cattle immunized with irradiated Onchocerca ochengi third-stage larvae (L3) were protected against challenge infection, based on greatly reduced burdens of adult worms in the immunized animals (1). In order to generate a more practical way to study immunity to the larval stages of O. volvulus, a mouse model was developed. L3 were implanted subcutaneously in diffusion chambers to allow efficient recovery of parasites and to permit analysis of the parasite's microenvironment. Larvae survived and grew at the same rate when they ...

In a bovine model of onchocerciasis, protective immunity exists naturally, is absent in drug-cured hosts, and is induced by vaccination

“…The fact that during a primary infection, the majority of L 3 are rapidly killed by innate inflammatory processes [probably involving neutrophils (33)] is commonly overlooked. In contrast, a clear consensus has emerged that immunity induced by irradiated L 3 is mediated by activated eosinophils (29,34,35) and that killing of challenge larvae occurs rapidly, with a major reduction in survival before the molt to the fourth stage (27,29). The immune responses in PI that prevent or ameliorate infection are similarly assumed to operate against the infective L 3 , and indeed, there is evidence that human PI recognize a specific subset of larval antigens (9,36).…”

Role of Eosinophils and Neutrophils in Innate and Adaptive Protective Immunity to LarvalStrongyloides stercoralisin Mice

“…An anti-CCR3 MAb (6S2-19-4) has been shown to specifically reduce the number of eosinophils in the peripheral blood of mice infected with Nippostrongylus brasiliensis to levels below those in naïve mice, without affecting other cell populations (24). Furthermore, treatment of mice with the anti-CCR3 MAb significantly reduced protective immunity to the filarial worms Onchocerca volvulus (1) and Brugia pahangi (49). A similar observation was made in a study of resistance to Trichinella spiralis using CCR3 Ϫ/Ϫ mice, where there was an absence of eosinophil recruitment along with a concomitant increase in larval parasite survival (25).…”

Protective Immunity to the Larval Stages ofOnchocerca volvulusIs Dependent on Toll-Like Receptor 4

“…Elimination of eosinophils with monoclonal antibody (MAb) treatment at the time of the challenge infection resulted in loss of protection (2). Additionally, the development of an antibody response was required for protective immunity, and immunoglobulin E (IgE) was demonstrated to be a protective antibody isotype (2). Thus, protective immunity against O. volvulus is dependent on a Th2 immune response and is mediated by eosinophils and IgE.…”

“…Protective immunity was induced with irradiated L3, and the cytokines interleukin-4 (IL-4) and IL-5 were both required, thus demonstrating a dependency on a Th2 response (22). Elimination of eosinophils with monoclonal antibody (MAb) treatment at the time of the challenge infection resulted in loss of protection (2). Additionally, the development of an antibody response was required for protective immunity, and immunoglobulin E (IgE) was demonstrated to be a protective antibody isotype (2).…”