Host defense against multicellular, extracellular pathogens such as nematode parasites is believed to be mediated largely, if not exclusively, by T lymphocytes. During our investigations into the course of Brugia malayi and Brugia pahangi infections in immunodeficient mouse models, we found that mice lacking B lymphocytes were permissive for Brugian infections, whereas immunocompetent mice were uniformly resistant. Mice bearing the Btkxid mutation were as permissive as those lacking all B cells, suggesting that the B1 subset may be responsible for host protection. Reconstitution of immunodeficient recombination activating gene (Rag)-1−/− mice with B1 B cells conferred resistance, even in the absence of conventional B2 lymphocytes and most T cells. These results suggest that B1 B cells are necessary to mediate host resistance to Brugian infection. Our data are consistent with a model wherein early resistance to B. malayi is mediated by humoral immune response, with a significant attrition of the incoming infectious larval load. Sterile clearance of the remaining parasite burden appears to require cell-mediated immunity. These data raise the possibility that the identification of molecule(s) recognized by humoral immune mechanisms might help generate prophylactic vaccines.

Abstra ct. Hyperglycemia has been shown to induce arterial hypoxemia in the chronically catheterized fetal sheep. To investigate the mechanism behind this glucose-induced hypoxemia, eight pregnant ewes and their fetuses were studied. Fetal glucose infusion (1 1.9±0.6 mg glucose/kg per min) was associated with a doubling of the fetal plasma glucose concentration with concomitant elevation of the umbilical vein-distal arterial 02 content difference by 24 h of infusion (P < 0.01). Calculated fetal 02 consumption increased from 8.1±0.4 ml/kg per min in the control period to a maximum value of 10.6±0.3 ml/kg per min by third infusion day (P < 0.01), which is an increase of -30%. The degree of stimulation of fetal 02 consumption was related to the degree of fetal hyperglycemia but not to the degree of fetal hyperinsulinemia. The increase in fetal 02 consumption was accompanied by a significant increase in fetal 02 extraction with no change in either fetal 02 delivery or fetal blood 02 affinity. In addition, fetal hypercapnea with a mild fetal respiratory acidosis was induced by fetal hyperglycemia. The increase in fetal arterial Pco2 was linearly related (P < 0.001) to the magnitude of increase in fetal 02 consumption. These studies suggest that chronic fetal hyperglycemia induces a state ofaccelerated fetal oxidative metabolism and may be important in explaining the etiology behind certain unusual findings in human infants of diabetic mothers.

The mechanisms by which mammalian hosts eliminate microparasites such as bacteria and viruses are well established. In viral infections, these mechanisms include the interferons, neutralizing and opsonizing antibodies, and cytotoxic T lymphocytes. In bacterial infections, polymorphonuclear leukocytes and macrophages, often facilitated by opsonizing antibodies, ingest the infectious agent and mediate host defense. In addition, complement, in the presence of specific antibodies directed against surface antigens, can lyse certain bacterial pathogens. In contrast, our understanding of the host defenses against metazoan, extracellular parasites is less well grounded. We obtained data by two different approaches to document the role of nitric oxide (NO) as a mediator of host defense against a human nematode parasite. First, treatment of immunocompetent, nonpermissive mice with an inhibitor of NO synthase abrogated resistance to Brugia malayi, one of the causative agents of human lymphatic filariasis. Second, treatment of permissive, immunodeficient mice with a compound that releases NO conferred resistance to infection. These data reinforce studies by James and her coworkers (I. P.

The attenuation of eosinophilia by the administration of monoclonal antibodies to CCR3 consistently correlates with impairment in worm elimination following primary intraperitoneal Brugia pahangi infections in mice. Host protection was unimpaired in mice deficient in eosinophil peroxidase (EPO) or major basic protein 1 (MBP-1), suggesting that eosinophils are essential in host protection but that neither EPO nor MBP-1 alone is.Despite the consistent association of eosinophilia with parasitic infections, evidence supporting a host-protective role in vivo remains elusive (1-4, 16, 22). The function of eosinophils has been studied by modulating their numbers by manipulating interleukin-5 levels (5) (13) or depleting them selectively with a monoclonal antibody against the eotaxin receptor CCR3 (8). Eosinophilia correlates with improved host protection in Angiostrongylus cantonensis (19), Strongyloides ratti (17), Strongyloides stercoralis (12), Onchocerca volvulus (14), and Litomosoides sigmodontis (15) infections. In contrast, the depletion of eosinophils did not alter the course of Schistosoma mansoni (20), Mesocestoides corti (13), and Trichuris muris (3) infections. In the case of filarial parasites, eotaxin and eosinophils have been shown to play a role in host protection (21).The role of eosinophil granule constituents in host protection is also unclear. Purified eosinophil granule proteins have been shown to effectively kill Brugia microfilariae (11), schistosomulae (2), and Trichinella spiralis newborn larvae (10) in vitro. have shown that the death of onchocercal microfilariae following amocarzine treatment was associated with eosinophil degranulation. Electron microscopy analyses showed apposition of eosinophil granule material on the microfilarial surface. However, the requirement of eosinophil granule protein for in vivo host protection has not been studied extensively. In a recent study, EPO Ϫ/Ϫ and wild-type (WT) mice challenged with O. volvulus manifested similar parasite recoveries, suggesting that eosinophil peroxidase (EPO) is not required for host protection in this model (1). In order to investigate the role of the eosinophil granule proteins in host protection, we have now examined the course of Brugia pahangi infection in mice that have undergone targeted mutations in the genes encoding two of the major proteins in the eosinophil granules.C57BL/6 (hereafter WT) mice were obtained from the Jackson Laboratory (Bar Harbor, Maine). EPO Ϫ/Ϫ and MBP-1 Ϫ/Ϫ mice (6, 7) were transferred from the Mayo Clinic, Scottsdale, Arizona, where they were generated and backcrossed with C57BL/6 mice for six generations at the UCHC AAALACaccredited facility. Brugia pahangi third-stage larvae (L3) were provided by one of the following sources: TRS Inc. Monoclonal antibodies against rat RT 6.1 (DS4.23) and 6.2 (6A5) were obtained from Dale Greiner, UMass Medical Center, Worcester, MA. Antibodies were enriched from hybridoma ascites fluid by 50% ammonium sulfate precipitation. The precipitate was dialyzed against phos...

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