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Biomedical subjects

A Sher

Publications and source records attributed to A Sher.

At least 235 records · Page 13Linked to original sources
PubMed1987

Prospects for a nonliving vaccine against schistosomiasis based on cell-mediated immune resistance mechanisms.

We have designed a vaccine model based on induction of cell-mediated immunity and shown that it protects mice against Schistosoma mansoni infection. Mice are immunized by intradermal injection with schistosome antigens plus BCG. Resistance is dependent on the route of antigen presentation and the adjuvant chosen. The pattern of resistance correlates with sensitization of T lymphocytes for production of gamma interferon, a macrophage activating lymphokine that stimulates the cellular effector mechanism of protection. Purified schistosome paramyosin, a muscle cell component present in soluble parasite antigenic preparations, is immunogenic for T lymphocytes and induces resistance when given intradermally with BCG. It is likely that this protein, and possibly other soluble molecules that are released by the parasites of a challenge infection, induce a cellular inflammatory response resulting in larval trapping and/or killing by activated macrophages. These results verify the feasibility of a vaccine against schistosomiasis based on induction of cell-mediated immune resistance mechanisms.

Adjuvants, Immunologic↗
PubMed1987

Anti-schistosomal drugs: observations on the mechanism of drug resistance to hycanthone, and on the involvement of host antibodies in the mode of action of praziquantel.

This paper reports recent observations from our laboratory dealing with the anti-schistosome drugs hycanthone (HC) and praziquantel (PZQ). In particular, we discuss a laboratory model of drug resistance to HC in Schistosoma mansoni and show that drug sensitive and resistant lines of the parasite can be differentiated on the basis of restriction fragment length polymorphisms using homologous ribosomal gene probes. In addition, we summarize data demonstrating that effective chemotherapy of S. mansoni infection with PZQ in mice requires the presence of host anti-parasite antibodies. These antibodies bind to PZQ treated worms and may be involved in an antibody-dependent cellular cytotoxicity reactions which result in the clearance of worms from the vasculature.

Animals↗
PubMed1987

Mechanisms of immune evasion in schistosomiasis.

An unusual property of schistosomes is their capacity to survive intravascularly for many years in the face of an ongoing antiparasite immune response by the infected host. This ability to evade the immune system appears to be due to several unusual parasite adaptations occurring soon after infection is initiated. Foremost amongst these are processes which result in reduced surface antigenicity and the development of a tegument intrinsically resistant to immune damage. The unusual ability of the schistosome surface membrane to escape immune recognition and damage suggests that attempts to vaccinate against this important parasite either should be directed against very early schistosomula which have yet to achieve the refractory state, or involve stimulation of effector mechanisms, such as killing by activated macrophages, which do not require recognition or interaction with parasite surface antigens.

Animals↗
PubMed1987

Sjögren's syndrome: severe upper airways obstruction due to primary malignant tracheal lymphoma developing during successful treatment of lymphocytic interstitial pneumonitis.

A wide spectrum of respiratory tract involvement may be seen in Sjögren's syndrome, however, multiple manifestations in one patient are unusual. A 65-year-old woman with a 5-year history of Sjögren's syndrome presented with hoarseness and pulmonary infiltrates. Lymphocytic interstitial pneumonitis, tracheobronchitis with subglottic edema and obstructive small airways disease were initially documented. Dramatic radiographic improvement of the lymphocytic interstitial pneumonitis occurred during 14 months of corticosteroid therapy. However, a rare primary malignant lymphoma of the trachea developed and presented with steroid refractory, upper airways obstruction. Subsequent patient management and the dichotomous behavior of the lymphoid infiltrates are discussed.

Aged↗
PubMed1986

Immunochemical characterization and purification of Sm-97, a Schistosoma mansoni antigen monospecifically recognized by antibodies from mice protectively immunized with a nonliving vaccine.

Mice protected against Schistosoma mansoni infection by intradermal (i.d.) vaccination with nonliving schistosomula or soluble extracts of larval or adult schistosomes (SCHLAP and SWAP, respectively) produce antibodies that react by Western blot analysis with one antigen of Mr (X 10(-3)) 97 in SWAP prepared in the presence of protease inhibitors and two antigens of Mr (X 10(-3)) 95 and 78 in SWAP prepared in their absence. Vaccine antibodies also immunoprecipitated a single 97k molecule, with a pI of 5.5, from detergent extracts of [35S] methionine-labeled schistosomes. Three hybridomas, produced from spleen cells of i.d. immunized mice, all recognized both the 95k/78k doublet and the 97k antigen, indicating that the two lower Mr components are degradation products of the same 97k molecule. The 97k/95k/78k complex (Sm-97) was purified by affinity chromatography and found to constitute 0.5% of the total protein in SWAP. 125I-concanavalin A bound weakly to purified Sm-97, indicating that this antigen is minimally glycosylated. By indirect immunofluorescence, Sm-97 was localized to regions just below the tegumental and gut syncitia of adult worms. Mice protected by i.d. vaccination produced high titers (1:10,240) of anti-Sm-97 antibodies, whereas chronically infected mice responded at a much lower level (titer 1:640). In contrast, mice protectively immunized with irradiated cercariae and mice nonprophylactically inoculated by the i.v. route failed to produce detectable anti-Sm-97 antibodies. Competitive radioimmunoassays performed with 125I-labeled monoclonal antibodies and purified antigen defined at least two distinct epitopes on Sm-97. Antibodies from i.d. vaccinated mice recognized both monoclonal antibody-defined epitopes, whereas anti-Sm-97 antibodies in chronic infection sera recognized neither. Finally, purified Sm-97 was shown to elicit delayed-type hypersensitivity in i.d. vaccinated mice, suggesting that this molecule is also capable of evoking cell-mediated responses, a finding consistent with its proposed function as a vaccine immunogen.

Animals↗
PubMed1986

Evasion of the alternative complement pathway by metacyclic trypomastigotes of Trypanosoma cruzi: dependence on the developmentally regulated synthesis of surface protein and N-linked carbohydrate.

Epimastigotes (EPI) of Trypanosoma cruzi are highly sensitive to lysis in fresh normal human serum by the alternative complement pathway (ACP). In contrast, metacyclic trypomastigotes (CMT) derived from EPI in stationary culture fail to activate the ACP and are thus resistant to serum-mediated lysis. To investigate the nature of the parasitic surface molecules which enable infective metacyclic trypomastigotes to evade the ACP, CMT were treated with a variety of different proteolytic and glycosidic enzymes, and their sensitivity to ACP-dependent lysis was tested. Pretreatment with pronase was found to cause a near complete reversal in the resistance of CMT to serum lysis, whereas trypsin or chymotrypsin induced smaller increases in complement sensitivity. Similarly, pretreatment with N-glycanase or neuraminidase also partially abrogated the resistance of CMT to ACP-dependent lysis. The effect of these enzymes on susceptibility to complement-mediated lysis was paralleled in increased C3 and C9 deposition on the organism. In addition, electrophoretic analysis of parasite-bound C3 indicated that the hemolytically inactive fragment, iC3b, was the major form of the molecule on CMT, while the hemolytically active fragment, C3b, predominated on pronase-treated CMT. Furthermore, when C3 was deposited on the parasite surface by means of purified ACP components, 80% of C3b on pronase-pretreated CMT but only 14% of the C3b on CMT bound the amplification protein factor B with high affinity, a prerequisite for efficient ACP activation. When cultured at 37 degrees C after pronase treatment, CMT gradually regained their resistance to ACP-mediated lysis. This process was blocked if puromycin, cycloheximide, or tunicamycin were included in the culture medium. The above findings suggest that evasion of the ACP by CMT is dependent on the developmentally regulated synthesis of protein as well as N-linked carbohydrate chains. A stage-specific 90,000 to 115,000 m.w. glycoprotein doublet present on the surface of CMT was shown to be uniquely sensitive to pronase digestion. Thus, this complex, which is also recognized by a CMT-specific monoclonal antibody, may be the glycoprotein component responsible for control of ACP activation

Animals↗
PubMed1986

Identification of paramyosin as schistosome antigen recognized by intradermally vaccinated mice.

Mice immunized intradermally with extracts of Schistosoma mansoni in combination with the adjuvant BCG are significantly protected against subsequent infection with living larval forms of the parasite. Remarkably, these vaccinated animals produce antibodies predominantly against a single parasite protein of molecular weight 97 kilodaltons (Sm-97). A complementary DNA that encodes about half of the Sm-97 molecule has now been cloned and sequenced. Analysis of the deduced amino acid sequence reveals a protein containing periodic repeats of hydrophobic amino acids characteristic of an alpha-helical coiled-coil structure. The deduced amino acid composition of the cloned gene and several properties of the native protein are similar to that of paramyosin, an alpha-helical protein that forms the core for myosin filaments in invertebrate muscle. Paramyosin was isolated from Schistosoma mansoni adult worms and antibodies to Sm-97 were shown to react with this molecule as well as with a known paramyosin from molluscan muscle.

Amino Acid Sequence↗
PubMed1986

Identification of a genetic locus, Rsm-1, controlling protective immunity against Schistosoma mansoni.

Mice of most inbred strains develop moderate to high levels of resistance to challenge infection on vaccination with radiation-attenuated cercariae of Schistosoma mansoni. P strain mice, however, fail to display significant protective immunity after exposure to the same vaccine. To examine the genetic basis of this polymorphism in host immunity, vaccine-induced resistance was examined in (C57/BL6J X P/N)F1, F2, and reciprocal backcross generations. The defective immunity which characterizes the P strain parent was found to be inherited in a fully recessive manner and to be controlled by a single genetic locus, which we have designated Rsm-1. Linkage analyses revealed that Rsm-1 is not genetically associated with the major histocompatibility complex (chromosome 17), the immunoglobulin heavy chain locus (chromosome 12), or a single locus influencing defective anti-schistosomulum IgM antibody responses in the P parental stock. These data provide the first example of single gene control of vaccine-induced immunity against a helminth infection. Because P mice are also defective in their capacity to develop tumoricidal macrophages and in their immunity to Leishmania major, genes encoded by the Rsm-1 locus may play a general role in resistance to infection and malignancy.

Animals↗
PubMed1986

B lymphocytes are required for the generation of T cells that mediate healing of cutaneous leishmaniasis.

The role that B lymphocytes and/or antibodies play in the healing of Leishmania major infections in genetically resistant C3H/HeN mice was investigated by monitoring the course of infection in animals that had been B cell depleted by treatment from birth with anti-IgM sera (mu-suppressed). L. major infection of mu-suppressed C3H/HeN mice produced lesions that were significantly larger than those induced in control animals, and failed to heal. Moreover, vaccinated mu-suppressed mice also developed chronic nonhealing infections, although their lesions were initially smaller than those developed by nonvaccinated mu-suppressed controls. The enhanced susceptibility of mu-suppressed mice could be completely overcome by adoptive transfer of T lymphocytes from mice that had spontaneously healed their lesions, and to a lesser extent by T lymphocytes from normal animals. Anti-leishmanial antibody responses were completely absent in mu-suppressed mice, regardless of whether they were lymphocyte reconstituted, whereas delayed type hypersensitivity (DTH) to leishmanial antigens was present in normal and mu-suppressed animals. The ability of immune T cells to protect mu-suppressed mice without restoring humoral responsiveness clearly indicates that antibodies are not necessary for healing leishmanial infections. Instead, the observed effect of mu-suppression argues that B lymphocytes are required for the generation of an effector T cell population, apparently unrelated to DTH, which mediates the healing of cutaneous lesions. These results thus provide the first evidence for the B cell and/or Ig dependency of a T cell population that is critical for the development of immunity against a microbial agent.

Animals↗
PubMed1986

Induction of protective immunity against Schistosoma mansoni by a nonliving vaccine. IV. Fractionation and antigenic properties of a soluble adult worm immunoprophylactic activity.

An aqueous buffer-soluble, nonparticulate fraction of adult Schistosoma mansoni worms (SWAP) was separated by gel filtration on Ultragel AcA-34, and portions of the eluate were tested for their capacity to induce protective immunity against cercarial challenge when administered intradermally to mice in combination with the adjuvant BCG. All of the immunogenic activity was found in a single peak of protein excluded in the void volume of the column. This same fraction was determined by SDS-PAGE and Western immunoblotting to be unique in that it contained a component of Mr (X 10(-3) 97 (97,000) recognized monospecifically by antibodies from mice vaccinated with unseparated SWAP plus BCG. Similarly, the protective fraction was unique in possessing the capacity to elicit 24 hr delayed footpad swelling responses, as well as lymphokine production, in SWAP-BCG-immunized mice. These results suggest that the immunogenic activity of SWAP resides in a restricted population of molecules, and possibly in the 97,000 antigen detected with antibodies from vaccinated animals. Because both the protective capacity of unfractionated SWAP and the serologic reactivity of the 97,000 antigen are sensitive to digestion with protease, it is likely that the immunologic activity of these molecules is dependent on peptide-bonded structural elements.

Animals↗
PubMed1986

A spectrum in the susceptibility of leishmanial strains to intracellular killing by murine macrophages.

The susceptibility of 26 strains and clones of Leishmania to in vitro killing by lymphokine (LK)-activated macrophages was determined. A spectrum in the susceptibility of Leishmania to macrophage killing was observed. Some leishmanias were completely resistant to killing, including some but not all of the L. mexicana strains studied. This resistance was expressed in amastigotes and stationary growth-phase promastigotes, but not in logarithmic promastigotes. In contrast, some L. braziliensis parasites failed to survive within either activated or nonactivated macrophages. Between these two extremes were strains that survived within nonactivated macrophages, but were readily killed within activated macrophages. These included L. donovani, L. major, and some L. mexicana strains. Finally, one L. mexicana strain (WR357) was found to be susceptible to killing at high LK concentrations, but was relatively resistant at lower LK concentrations or at cutaneous temperatures. The observed differences in susceptibility to macrophage-mediated microbicidal activity may explain, in part, the variable pathogenesis of leishmanial infections.

Animals↗
PubMed1986

Kinetic correlation of the acquisition of resistance to immune attack in schistosomula of Schistosoma mansoni with a developmental change in membrane potential.

When Schistosoma mansoni cercariae penetrate the skin of the mammalian host they rapidly pass from fresh water to a high salt physiologic environment and transform into schistosomula. Following this transition, the parasites migrate from the skin to the lungs during which time they change from being highly susceptible to immune attack to being refractory, as measured by in vitro cytotoxicity assays. In this study, in vivo or in vitro schistosomula of different ages were examined for developmentally linked changes in membrane function which might correlate with the attainment of the resistant state. In particular, alterations in the distribution of tetraphenylphosphonium (TPP+), a synthetic lipophilic cation which shows a potential dependent partition across membranes, were followed. Three-hour-old schistosomula, which are greater than 75% susceptible to antibody-dependent complement-mediated attack or lymphokine-activated macrophage-mediated cytotoxicity, acquired TPP+ at a similar rate and steady state level to 5-day-old lung worms, which were completely resistant to both these effector mechanisms. The addition of ouabain, a Na+/K+-ATPase inhibitor, caused a 50% decrease in both the rate and steady state of TPP+ uptake by 3 h parasites but had little effect on these parameters in lung worms. Valinomycin, a K+-ionophore, completely inhibited TPP+ influx in both stages. The characteristics of TPP+ efflux from 3-h and 5-day-old parasites preloaded with the cation were found to be dissimilar. Whereas 30% of acquired TPP+ was lost from lung worms within 2 h, only 10% of acquired cation was released from 3-h schistosomula during the same period.(ABSTRACT TRUNCATED AT 250 WORDS)

Adaptation, Physiological↗
PubMed1986

Evasion of alternative complement pathway by Trypanosoma cruzi results from inefficient binding of factor B.

During its differentiation in the insect vector to a stage infective for the mammalian host, Trypanosoma cruzi becomes resistant to lysis by the alternative pathway of complement. To elucidate the mechanism of complement evasion, we studied control of complement activation on the surface of the noninfective epimastigote and the infective culture-derived metacyclic trypomastigote stages (CMT) of T. cruzi. It was found that the predominant form of complement component C3 on epimastigotes is C3b, whereas the majority of C3 on CMT is in the form of the hemolytically inactive fragment iC3b, which cannot participate in C5 convertase formation or lead to deposition of the lytic C5b-9 complex. Our results also showed that C3 binds by a covalent ester linkage to surface molecules of different molecular weight in the epimastigote stage and CMT. Binding studies with purified complement components indicated that CMT do not support efficient formation of an alternative pathway C3 convertase. C3b on the parasite surface fails to bind the amplification component, factor B, rather than showing enhanced binding of the control component, factor H. These results identify the biochemical basis for evasion of complement-mediated killing in T. cruzi and reveal a mechanism for developmental regulation of complement activation.

Animals↗
PubMed1986

Evidence that the reduced surface antigenicity of developing Schistosoma mansoni schistosomula is due to antigen shedding rather than host molecule acquisition.

Antibody and lectin binding characteristics of Schistosoma mansoni schistosomula maturing in vivo and in vitro were quantitatively assessed and compared in order to investigate the basis of the reduced surface antigenicity of host derived larval schistosomes. Quantitative indirect immunofluorescence assays showed that schistosomula recovered from mice at 24 h and 5-10 days post infection bound low or insignificant amounts of a variety of anti-schistosome antibodies including those from chronically infected and radiation attenuated cercariae-vaccinated mice, a vaccinated rabbit and rabbits hyper-immunized with non-living larval and adult schistosome antigen preparations. In contrast, parasites maturing in vitro continued to bind highly significant levels of each of these antibody preparations until at least 10 days post transformation. To investigate the basis of the decreased surface antigenicity of parasites maturing in vivo, 6-day-cultured parasites were injected intravenously into mice and recovered from the lungs at various times thereafter and examined for their ability to bind both anti-parasite and anti-host antibodies. After 30 min in vivo, cultured schistosomula exhibited a significantly decreased capacity to bind anti-parasite antibodies and concanavalin A (Con A), and by 16 h had lost their binding sites for fucose binding protein (FBP) as well. That this reduction in antigenicity was due to shedding of surface antigens was suggested by the observation that the reduced ability of these parasites to bind anti-parasite antibodies coincided closely with the loss of 125I-labelled surface proteins. Furthermore unlike 6 day schistosomula which had developed wholly in vivo, 6-day-cultured parasites recovered after 30 min in vivo failed to bind anti-host antibodies suggesting that in these organisms parasite antigens were not masked by host molecules. These data argue that surface antigen shedding may explain the reduced surface antigenicity of schistosomula developing in vivo. While this surface modulation apparently occurs independently of host antigen uptake, it is dependent upon an as yet unidentified host factor.

Animals↗