Biomedical subjects
Publications and source records attributed to S L James.
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The purpose of this study was to investigate the pragmatic function of preschool children's spontaneously produced questions. Twenty-four normal children between the age of 2 and 5 years were observed in a variety of situations at their day-care centers. Questions produced during these observation periods were categorized by pragmatic function. The three functional categories were information seeking, conversational, and directive. The distribution of the questions among the three pragmatic functions differed with age. The major function of the questions produced by the 2- and 3-year-old subjects was clearly information seeking, but the 4- and 5-year-olds' questions were more evenly distributed among the functional categories. The 4-year-olds used a high percentage of conversational questions in comparison to the other age groups. The children's question use appeared to follow the principle of using new forms for old functions and old forms for new functions.
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For an exploration of the effects of interferon-inducible resistance mechanisms in acute American trypanosomiasis, the synthetic interferon inducer tilerone hydrochloride was administered to mice of the C57BL/6J strain, which is highly resistant to Trypanosoma cruzi, 18 to 24 h before infection with a potentially lethal dose of bloodstream trypomastigotes. Although all of the control mice died within 30 days of the acute infection, approximately 50% of the tilerone-treated animals were able to survive indefinitely (P less than 0.05). The tilerone-treated mice demonstrated significant levels of serum interferon and splenic natural killer cells at the time of infection. Macrophages isolated from the peritoneal cavities of tilerone-treated C57BL/6J mice appeared to kill significant numbers of trypanosomes during 2 to 3 days of in vitro culture, indicating that activated macrophages may contribute to the enhanced resistance to T. cruzi infection in these mice. Beige mice treated with tilerone did not survive T. cruzi infection as well as tilerone-treated heterozygotes did, suggesting a role for natural killer cells in interferon-induced resistance. These results suggest that interferon or effector mechanisms enhanced by interferon induction can play a significant role in influencing resistance to T. cruzi infection.
Laboratory mice with genetic or induced immunodeficiencies were vaccinated with irradiated cercariae of Schistosoma mansoni and assayed 4 wk later for their resistance to challenge infection. Athymic nude mice failed to develop immunity to challenge or detectable antibody responses to schistosomula, whereas heterozygote (nu/+) controls and nude mice with thymus grafts displayed highly significant levels of resistance and anti-schistosomulum antibody. Similarly, no resistance or antibody production as observed in vaccinated mice that had been made deficient in B lymphocytes by the injection of anti-mu-chain antisera from birth. In contrast, normal levels of vaccine-induced resistance were observed in mice genetically deficient in the fifth component of complement (C5) and in mice decomplemented before challenge by treatment with cobra venom factor. These results indicate that the resistance to challenge infection induced by irradiated cercariae is both thymus and B lymphocyte dependent and therefore is likely to result from specific immune responses directed against schistosome worms. The data also argue against a role for complement in the effector mechanism of vaccine-induced immunity.
Plastic adherent peritoneal cells from Schistosoma mansoni-infected mice have previously been shown to exhibit nonspecific tumoricidal activity in vitro. In this report we show that these same cell populations kill significant numbers of skin-stage schistosomula in vitro in the absence of added antibody. Larval killing by these activated cells could be enhanced by the use of suspension rather than monolayer cultures and by addition of heat-inactivated immune mouse serum to the cultures. Adherence of cells to schistosomula was also enhanced under the same conditions, suggesting that cell binding to the larvae might be critical in the development or expression of microbicidal activity. In support of this hypothesis, the same level of enhancement of cell binding and larval damage was observed upon substitution of concanavalin A for immune mouse serum. Killing of schistosomula appeared to be mediated solely by activated macrophages in the peritoneal cell suspensions from S. mansoni-infected mice, because partially purified preparations of eosinophils were virtually inactive in these assays. Likewise, inflammatory macrophages from uninfected mice were unable to kill schistosomula under the same conditions, emphasizing the importance of activation in the development of killing capability. The finding that macrophages activated as a consequence of S. mansoni infection are able to kill larval schistosomes in vitro suggests that these cells may play a role in concomitant immunity to schistosomiasis in vivo.
Newly transformed skin-stage and lung-stage schistosomula were compared in terms of their susceptibility to killing mediated by activated mouse macrophages in vitro. Although skin-stage schistosomula were readily killed by macrophages activated as a consequence of either BCG or Schistosoma mansoni infection and used either as cell monolayers or in suspension, lung-stage larvae appeared to be totally resistant to this effector mechanism and survived normally when reinjected into mice. Resistance of schistosomula to in vitro damage by macrophages was evident as early as 18 hr after host infection and was complete in worms recovered at 42 hr. The insusceptibility of lung-stage larvae is apparently not due to a defect in effector cell-target contact, because the induction of extensive macrophage adherence to the worms by the addition of anti-mouse red blood cell antisera to the cultures had no effect on parasite viability. These findings provide additional support for the concept that schistosomula during their development to the lung stage undergo a generalized change affecting their susceptibility to a variety of different immunologic effector mechanisms.
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The addition of a small peptide can significantly increase the rate at which pepsin cleaves a substrate at pH 4.5. Why? In order to find out, we have determined spectrophotometrically the relative ability of over a dozen peptides to speed the initial rate of disappearance of Phe-Trp-NH2 and Leu-Trp-Met-Arg. Here are some of the criteria which establish the reliability of the acquired kinetic data: (1) rates depend linearly on [E] and , to a good approximation, on [activator], (2) measurements with both substrates yield the same ranking for the activators tested; (3) high-pressure liquid chromatographic investigations independently confirm conclusions derived from the spectrophotometric studies. The best activators found were Z-Ala-Phe and Ala-Leu. At 3.2 mM they are respectively 60 and 30 times more effective than an equal concentration of A-(Ala)2. The two-step mechanism given below (for Phe-Trp-NH2) best explains the structural specificity found, as well as other observations on the nature of these activated cleavages. It assumes that reaction commences when pepsin catalyzes synthesis of a peptide bond between activator and substrate. The polypeptide so formed subsequently undergoes scission at a different bond. The modified activator liberated, here designated Z-AA2-AA1-Phe, can eventually provide a variety of reaction products, as the succeeding paper demonstrates.
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Selective suppression of the total IgE antibody response has been achieved in rats by injection of rabbit anti-rat epsilon-chain antibodies. This IgE-specific suppression was maintained during the course of a natural infection by the nematode Trichinella spiralis. Depletion of the IgE antibody response resulted in a marked reduction of the number of eosinophils attracted to the T. spiralis larvae encysted in striated muscle. Blood eosinophilia following T. spiralis infection, although reaching normal peak levels, was abbreviated in IgE-suppressed animals. Moreover, IgE-depleted animals were more susceptible to the infection; they harbored two to three times more larvae encysted in their muscles than their control litter mates.
The development of T cell reactivity toward schistosomula during murine Schistosoma mansoni infection has been studied using an adaptation of the in vitro lymphocyte proliferation assay in which the response is elicited by exposure to living schistosomula. The reactivity measured in this system was shown to be a T lymphocyte function and to require the presence of adherent cells. This assay may therefore provide a new method for analysis of basic interactions between host cells and schistosomula. Lymph node cell responses were observed in two phases, the first of which appeared during the second week after infection, reflecting the immunogenicity of schistosome larval forms. A later, more pronounced response appeared during the chronic stage of infection, where sensitization appeared to be stimulated primarily by ongoing exposure to adult worms, rather than eggs. Lung-stage and skin-stage larvae elicited a similar degree of thymidine uptake by cells from chronically infected mice. Intact skin-stage larvae and particulate fractions provoked greater proliferation than soluble larval constituents, indicating that the lymphocyte response is directed in large part toward determinants which remain associated with the schistosomula during culture. However, the presence of major histocompatibility complex products on the membrane of lung-stage schistosomula did not influence the presentation of larval antigens to sensitized lymphocytes. The implications of these findings in immunity to schistosomiasis are discussed.
Skin-stage schistosomula of Schistosoma mansoni modified with 2,4,6-trinitrophenyl (TNP) induce primary anti-TNP plaque-forming cell (PFC) responses in normal mouse spleen cells in vitro. The PFC are TNP-specific, and the response is dependent on adherent cells and T lymphocytes. In contrast, comparably haptenated lung stage larvae are weakly or nonimmunogenic in this system, and their inability to stimulate anti-TNP PFC cannot be attributed to a toxic or suppressive effect. These observations suggest that maturation of schistosomula in vivo is accompanied by a decline in their immunogenicity, which, along with other adaptive mechanisms, may promote the survival of parasites in the host environment.
Mouse mononuclear cells, neutrophils, and eosinophils were tested for their capacity to mediate antibody-dependent cytotoxicity against bloodstream trypomastigotes of Trypanosoma cruzi. Granulocyte populations were found to be far more effective than nonadherent mononuclear cells in an in vitro assay in which the number of motile parasites was measured. Eosinophils and neutrophils were observed to be equally efficient on a cell-per-cell basis in killing the trypomastigotes. These results were verified in parallel experiments in which trypomastigotes, after incubation with antibody and effector cells, were reinjected into susceptible mice and the survival of the animals was determined.