Vaccination of inbred jirds (Meriones unguiculatus) with 60cobalt radiation-attenuated Brugia malayi infective stage larvae (L3) protected against homologous challenge given either subcutaneously (sc) or by the intraperitoneal (ip) route. Groups of jirds vaccinated once sc with 75, 15 Krad L3 showed from 69% to 91% reduction in recovered worms after ip challenge infection compared to infection in non-vaccinated control jirds, while 75% reduction in mean worm burden was seen in jirds receiving sc challenge infection. A single sc vaccination with 75, 10 or 20 Krad L3 produced no protection (10 Krad) and 64% reduction in recovered worms (20 Krad). Therefore the 15 Krad dose appeared to be best. A marked increase in anti-B. malayi antibody in vaccinated jirds was seen (by ELISA) immediately after challenge infection and an immunofluorescence assay showed that L3 incubated in serum from vaccinated jirds were completely and uniformly covered with specific antibody. Eosinophil-rich granulomas containing dead and moribund L3 were recovered from vaccinated jirds. This model of protective immunity in a Brugia-susceptible small rodent may provide a useful system for identification of molecularly defined filarial-protective immunogens.

A s bstract. Various arachidonic acid (AA) metabolites are known to regulate immune cell function(s) and dictate the progression of both acute and chronic inflammatory reactions. Using a model of Schistosoma mansoni egg-induced hypersensitivity granulomas, we have delineated the in vivo effects of inhibitors of cyclooxygenase (CO) and lipoxygenase (LO) pathways on granuloma development and granuloma macrophage I-region-associated (Ia) antigen expression. In addition, by high performance liquid chromatography (HPLC) we have profiled the metabolism ofAA by macrophages that are isolated from granulomatous foci, and have biochemically characterized the in vitro specificity and activity of selected CO and LO inhibitors. The development of hypersensitivity-type pulmonary granulomas in mice was dramatically suppressed by inhibitors with anti-LO activity (nordihydroguairetic acid (NDGA), nafazatrom, and BW755c) in a dose-dependent manner, while indomethacin, which is primarily CO-selective, had no significant effect. Furthermore, NDGA and nafazatrom profoundly arrested the normal progression of preformed granulomatous lesions. The inhibitors of the LO pathway also suppressed the in vivo kinetics of Ia antigen expression by granuloma macrophages. In contrast, indomethacin augmented Ia-antigen expression. The major AA metabolites that were synthesized by the granuloma macrophages were shown to be leukotriene C4 and mono-hydroxyeicosatetraenoic acids. HPLC analysis of AA metabolites from granuloma macrophages that were treated with the various inhibitors confirmed that indomethacin was most CO-selective and NDGA most LO-selective. Nafazatrom and BW755c inhibited AA metabolism by both pathways. Notably, high concentrations ofthe compounds (5 X l0-5 M) tended to suppress all products. Our results suggest that LO products may be important in the generation and maintenance of immune granulomatous inflammatory responses.

The parasite-parasite interaction of Salmonella and Schistosoma was studied. Salmonella typhimurium LT2 was found to associate in vitro with three human species of Schistosoma: Schistosoma mansoni, Schistosoma haematobium, and Schistosoma japonicum. Genetic mutants of S. typhimurium were allowed to interact with ligatured and unligatured worms of S. mansoni in vitro. These studies were undertaken to elucidate the mechanism(s) of the parasite-parasite interaction of Salmonella on the surface of Schistosoma. The ga/E and fla mutants showed 100% association with male schistosomes, but a reduced interaction with female worms. The rough A and pili mutants showed a significant reduction in the ability to associate with both male and female S. mansoni. Observations with the scanning electron microscope revealed that pili function in adhesion of Salmonella to the surface tegument of S. mansoni and S. haematobium. The association of Salmonella and Schistosoma may contribute to persistence of salmonella infection.

Infestation with organisms causing lymphatic filariasis (i.e. Wuchereria bancrofti and Brugia malayi) results in a variety of clinical presentations. It is possible that some of the variation is due to differences in host response to parasite. To determine whether individuals who live in an endemic area but differ in their clinical manifestations respond to different filarial antigens, we screened Onchocerca volvulus expression libraries with sera from a number of individuals belonging to different clinical groups. The results of the study demonstrate that there are indeed differences in the recognition of three cloned filarial antigens and that this differential recognition is related to clinical symptomatology. The most striking finding is that an Onchocerca volvulus protein homologous to the 70 kDa Xenopus laevis heat shock protein is primarily recognized by individuals who are amicrofilaremic. Further analysis is required to determine whether these antigens play any role in the pathogenesis of filarial infection or have any potential value in protective immunity.