Down Regulation of Macrophage Activation inBrugia pahangi-Infected Jirds (Meriones unguiculatus)

Abstract

The macrophage is a major component of the inflammatory response induced by lymphatic tissue-dwelling filariae. Intraperitoneal (i.p.) infections with Brugia pahangi in Mongolian gerbils, or jirds (Meriones unguiculatus), induce a peritoneal inflammatory response characterized by accumulation of numerous macrophages and fewer eosinophils. This inflammatory response is associated with the release of microfilariae by female worms. The aim of this study was to investigate the activation state of the peritoneal macrophages during the course of i.p. infections with either male or female worms. Activation was determined by a toxoplasmacidal assay and assays which measured the production of tumor necrosis factor (TNF)-like activity and nitric oxide (NO) production. The development of these assays with jirds was initially conducted in parallel with the mouse system, which served as a positive control. Jird macrophages became activated to kill Toxoplasma gondii by in vivo immunization with Mycobacterium bovis BCG in a pattern similar to that of mouse macrophages. However, unlike the mouse system, supernatants from purified protein derivative- or concanavalin A-stimulated jird splenocytes plus lipopolysaccharide failed to activate jird macrophages in vitro or induce NO production. These results indicate that factors involved in jird macrophage activation may differ from those demonstrated in the mouse system and other systems. i.p. infections of 15 days in duration with either male or female worms induced macrophage activation as measured byToxoplasma killing and TNF production. These responses decreased as the infection progressed to the chronic period on a time course that parallels the down regulation of experimentalB. pahangi granulomas. There was no evidence of NO production by activated jird macrophages. These data indicate that macrophage function is down modulated during filarial infection and suggest that mechanisms involved in macrophage deactivation are related to those that induce down modulation of the systemic granulomatous inflammatory response in the jird. This response is not dependent on the microfilarial stage of the parasite and is also independent of mechanisms which induce peritoneal accumulations of macrophages.

Modulation of B-Cell Proliferative Response by a Soluble Extract of Nippostrongylus brasiliensis

“…It is therefore not surprising that they appear to be primary targets for factors modulating lymphocyte function. A number of reports have demonstrated the effects of parasite factors on macrophage activities (2,6,15,27,28,35,36). The data presented in this study show that macrophages are involved in the inhibitory activity of AWH on LPS-stimulated B cells.…”

“…Part of this accommodation is the ability to modulate host immune responsiveness (25). Modulation of lymphocyte function has been widely reported among nematodes (2,3,19,21,22,28) and other parasites (6,15,27,36). For example, we have previously shown a dramatic potentiation of antibody responses to third party antigens by treatment with a body fluid extract of Ascaris suum (19).…”

“…The prevailing evidence supports a significant role for accessory cells in the activation of T and B cells both in vivo and in vitro (7,41). This has prompted numerous investigations into the role of macrophages in helminth-mediated immunomodulation of lymphocyte function (2,15,17,22,27,28,36). These studies have demonstrated a significant role for macrophages in the effects of helminths on developing immune responses.…”

“…Moreover, N. brasiliensis larvae activate alveolar macrophages to produce cytokines postulated to contribute to the robust type 2 immune response associated with nematode infection (12). Other studies have reported parasite factors that either alter accessory cell costimulation or cause accessory cells to produce factors (such as prostaglandins, nitric oxide, hydrogen peroxide, and superoxide anion), which mediate a change in lymphocyte function (2,15,17,27,28,36). These effects of parasites on accessory cell function are likely to have a significant effect on the outcome of infections experienced concurrently.…”

Defect of protective immunity to Schistosoma mansoni infection in Mongolian gerbils involves limited recruitment of dendritic cells in the vaccinated skin

“…The mechanism of this phenomenon in A/J and P/J mice is ascribed to dysfunction of T‐cells and macrophages, particularly the latter, along with the lack of a delayed‐type hypersensitivity (DTH) response. Gerbil macrophages have some impaired functions, such as lower phagocytic activity compared to mouse cells (6), lower filariacidal activity compared to rat cells (7) and no evidence of nitric oxide (NO) production by activated cells (8). NO produced by activated macrophages or endothelial cells has been incriminated as a major factor, or at least one of several major factors, in the elimination of challenge parasites in the lungs of vaccinated mice (9–11).…”