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We have investigated the roles of gamma interferon (IFN-␥) and interleukin-4 (IL-4) in host defense against Brugia malayi. Our data suggest that the lack of either IFN-␥ or IL-4 prolongs the time required to achieve sterile immunity, suggesting that both canonical type 1 and type 2 responses are involved in the clearance of infection.Lymphatic filariasis afflicts over 120 million people worldwide (2). Despite decades of work, many details of host-parasite interactions in this disease remain obscure. Mice bearing targeted mutations in various genes that encode immunologically relevant proteins are powerful tools used to analyze these interactions. Many of these mutations were initially engineered in embryonic stem cells of the 129/SvJ strain and bred into the segregating (C57BL/6J ϫ 129/SvJ [hereafter, B6,129S]) background. In order to study the effect of background genes on parasite resistance in these mice, we examined Brugia malayi larval development in B6,129S and C57BL/6J mice in the absence of T and B cells. Our results prompted us to examine the impact of critical cytokines, gamma interferon (IFN-␥) and interleukin-4 (IL-4), on the growth of B. malayi using BALB background mice bearing homozygous disruptions of the genes encoding these two cytokines.B6,129S-Rag1tm2Nmt (hereafter, IL-4 KO), and BALB/c-Ifng tmITS (hereafter, GKO) mice were obtained from Leonard Shultz (The Jackson Laboratory, Bar Harbor, Maine) and housed under specific-pathogen-free conditions in micro-isolator cages. All of the mice used in this study were males between 4 and 8 weeks of age. L3 larvae of B. malayi were obtained from the insectarium of Thomas Klei (Louisiana State University, Baton Rouge) and injected at a dose of 50 L3 larvae per mouse intraperitoneally (4). Mice were necropsied at the different time points indicated. Peritoneal lavages from individual mice were examined under a dissecting microscope to quantitate adult worms and to determine the presence of microfilariae (MF). Mouse carcasses were further soaked with their peritoneal cavities open in Tris-buffered saline for collection and counting of the remaining worms.We infected B6,129S-Rag1 and B6-Rag1 mice with B. malayi L3 larvae and examined L4 larval yields 2 weeks following infection. B6,129S-Rag1 mice exhibited consistently smaller larval burdens than B6-Rag1 mice (Table 1), ranging from 25 to 50% of those of B6-Rag1 mice (Table 1). These data suggest that the segregating B6,129S background is poorly permissive for B. malayi, even in the complete absence of adaptive immunity, and may therefore be an inappropriate background in which to study the impact of various components of adaptive immunity on host resistance to B. malayi. In view of these results, we decided to examine the role of IFN-␥ and IL-4 in resistance to infection using knockout mice in the more permissive BALB background.To examine the role of IFN-␥ in host resistance, we infected cohorts of ϩ/ϩ, SCID, and GKO mice with 50 B. malayi L3 larvae. Cohorts of mice from each group were necropsied at var...

MK-801, a noncompetitive antagonist of the NMDA (N-methyl-D-aspartate) receptor, has protective effects against excitotoxicity and ethanol withdrawal seizures. We have determined membrane/buffer partition coefficients (Kp[mem]) of MK-801 and its rates of association with and dissociation from membranes. Kp[mem] (+/- SD) = 1137 (+/- 320) in DOPC membranes and 485 (+/- 99) in synaptoneurosomal (SNM) lipid membranes from rat cerebral cortex (unilamellar vesicles). In multilamellar vesicles, Kp[mem] was higher: 3374 (+/- 253) in DOPC and 6879 (+/- 947) in SNM. In cholesterol/DOPC membranes, Kp[mem] decreased as the cholesterol content increased. MK-801 associated with and dissociated from membranes rapidly. Addition of ethanol to SNM did not affect Kp[mem]. MK-801 decreased the cooperative unit size of DMPC membranes. The decrease was smaller than that caused by 1,4-dihydropyridine drugs, indicating a weaker interaction with the hydrocarbon core. Small angle x-ray diffraction, with multilayer autocorrelation difference function modeling, indicated that MK-801 in a cholesterol/DOPC membrane (mole ratio = 0.6) causes a perturbation at approximately 16.0 A from the bilayer center. In bilayers of cholesterol/DOPC = 0.15 (mole ratio) or pure DOPC, the perturbation caused by MK-801 was more complex. The physical chemical interactions of MK-801 with membranes in vitro are consistent with a fast onset and short duration of action in vivo.

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