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Biomedical subjects

A Sher

Publications and source records attributed to A Sher.

At least 217 records · Page 12Linked to original sources
PubMed1988

Developmentally regulated expression by Trypanosoma cruzi of molecules that accelerate the decay of complement C3 convertases.

We recently showed that culture-derived metacyclic trypomastigotes (CMT), but not epimastigotes (Epi), of the Miranda 88 strain of Trypanosoma cruzi evade lysis by the human alternative complement pathway because of inefficient binding of factor B to complement component C3b on the parasite surface. These results suggested that CMT and tissue-culture-derived trypomastigotes (TCT), which also activate the alternative pathway poorly, might produce a molecule capable of interfering with factor B binding to C3b. We now demonstrate that CMT and TCT lysates, as well as molecules spontaneously shed from CMT and TCT but not Epi, accelerate decay of 125I-labeled factor Bb from the alternative-pathway C3 convertase (C3bBb) assembled on zymosan or Epi and also accelerate decay of the classical-pathway C3 convertase (C4b2a) on sheep erythrocytes. Parasites metabolically labeled with [35S]methionine spontaneously shed a limited number of radioactive components ranging in molecular mass from 86 to 155 kDa for trypomastigotes and 25 to 80 kDa for Epi. Decay-accelerating activity within supernatants is inactivated by papain and is coeluted with 35S-containing polypeptides on FPLC anion-exchange chromatography, suggesting that the active constituents are protein molecules. Molecules with decay-accelerating activity may explain the developmentally regulated resistance to complement-mediated lysis in infective and vertebrate stages of the T. cruzi life cycle.

Animals↗
PubMed1988

Induction of protective immunity against Schistosoma mansoni by vaccination with schistosome paramyosin (Sm97), a nonsurface parasite antigen.

Paramyosin (Sm97), a 97-kDa myofibrillar protein identified by the unusually monospecific antibody response induced by intradermal vaccination of mice with a complex soluble worm antigen preparation (SWAP) of adult Schistosoma mansoni administered with bacillus Calmette-Guérin (BCG), was purified and tested for its capacity to protect mice against challenge infection. When administered intradermally with BCG at total doses of only 4-40 micrograms per mouse, both the native molecule and a recombinant expression product containing approximately 50% of the whole protein were found to confer significant resistance (26-33%) against challenge infection, while 2 mg of unfractionated SWAP was required to induce similar levels of protection. In addition, paramyosin was shown to stimulate T lymphocytes from vaccinated mice to produce lymphokines [e.g., gamma interferon (IFN-gamma)] that activate macrophages to kill schistosomula. Neither schistosome myosin nor a heterologous paramyosin from a different invertebrate genus were protective, indicating a requirement for specific epitopes in the immunization. That the protection induced by paramyosin involves a T-cell-mediated mechanism was supported by the failure of anti-paramyosin antibodies to passively transfer significant resistance to infection to recipient mice. Lymphocytes from mice vaccinated with paramyosin were found to produce IFN-gamma in response to living schistosomula, suggesting that during challenge infection of vaccinated hosts, paramyosin (a nonsurface antigen) may elicit a protective T-cell response as a consequence of its release from migrating parasite larvae. Paramyosin-depleted SWAP was also found to be protective as well as stimulatory for T lymphocytes from SWAP-vaccinated mice, indicating that other antigens in this preparation may have immunoprophylactic potential. In summary, these results (i) suggest that the induction of T-cell-dependent cell-mediated immunity against soluble nonsurface antigens may be an effective strategy for immunization against multicellular parasites and (ii) in the case of schistosomes, identify paramyosin as a candidate vaccine immunogen in this category.

Animals↗
PubMed1988

Genetic complementation of defects in vaccine-induced immunity against Schistosoma mansoni in P- and A-strain inbred mice.

Inbred P- and A-strain mice are deficient in their capacity to develop resistance to challenge infection in response to vaccination with irradiated cercariae of Schistosoma mansoni and are also defective in their cell-mediated response as assessed by the activity of antigen-elicited macrophages in killing schistosome larvae in vitro. In contrast, vaccinated (P x A)F1 mice displayed high levels of both immunity to challenge and macrophage larvicidal activity, indicating that the P- and A-strain defects in the vaccine-induced response are controlled by distinct genetic loci.

Animals↗
PubMed1987

Vaccination against cutaneous leishmaniasis in a murine model. II. Immunologic properties of protective and nonprotective subfractions of soluble promastigote extract.

We have previously demonstrated that BALB/c mice can be protected against a fatal infection with Leishmania major by i.p. immunization with a soluble leishmanial antigen (SLA) preparation in conjunction with the adjuvant, Corynebacterium parvum (CP). In this study, SLA was separated into nine distinct fractions by anion exchange liquid chromatography, and the fractions were analyzed for their ability to stimulate T cells obtained from immunized mice, to be recognized by vaccine-induced antibodies, and to induce protective immunity. While all but one of the fractions were recognized by antibodies from SLA + CP immunized mice, only two fractions (fractions 1 and 9) stimulated lymphocytes to produce macrophage-activating factor and elicited significant delayed-type hypersensitivity in vivo. When mice were immunized with the fractions, only fraction 9 stimulated significant immunity (76% protection in seven experiments). Proteins (accounting for 1.3% of the total in SLA) appear to be responsible for the protection elicited with fraction 9, since protease treatment of this fraction destroyed its immunogenicity. Thus, a partially purified protective protein antigen fraction has been obtained and protection with this fraction correlated with cell-mediated immune responses. However, these results also demonstrate that the ability of leishmanial antigens to be recognized by T cells and produce macrophage-activating factor does not in itself predict whether such molecules will induce immunity, suggesting that protective leishmanial antigens may have additional unique properties.

Animals↗
PubMed1987

The chemotherapeutic effect of praziquantel against Schistosoma mansoni is dependent on host antibody response.

To assess the role of host humoral immune responses in the mechanism of action of praziquantel (PZQ) against Schistosoma mansoni, the efficacy of the drug was compared in infected B cell-depleted (mu-suppressed) vs immunologically intact C3H/HeN mice. We found that PZQ was on the average only 20% as effective in eliminating adult schistosomes from mu-suppressed as compared with control animals. Indeed, in three of four experiments performed, the drug failed to significantly reduce adult worm burdens in the mu-suppressed mice. These results were not due to a delay in parasite death in the infected B cell-depleted animals, because adult worms recovered from these mice as late as 7 wk after chemotherapy were indistinguishable in number and appearance from those recovered from non-drug-treated animals. The efficacy of PZQ against schistosomes in mu-suppressed mice was completely restored by passive transfer of immune serum from donor mice infected for 6 wk and partially restored with IgG purified from the same sera. Moreover, IgG as well as IgM antibodies were detected by immunofluorescence on the surface of adult worms recovered from intact mice as early as 1 hr after administration of the drug in vivo. The tubercles of the male worms appeared to be a major site for antibody binding. These results formally demonstrate that the mechanism of action of PZQ, the most important anti-schistosomal compound in current use, involves a synergy between the drug and the humoral immune response of the host, and suggest that the relevant effector antibodies act directly against parasite antigens which become exposed on the surface of the worms as a consequence of interaction with the drug.

Animals↗
PubMed1987

Vaccination against cutaneous leishmaniasis in a murine model. I. Induction of protective immunity with a soluble extract of promastigotes.

BALB/c mice can be protected against a fatal Leishmania major infection by immunization with whole radio-attenuated promastigotes; however, neither the antigens responsible for protection nor the protective immunologic mechanisms have been defined. In this study, the ability of promastigote fractions to elicit similar immunity to that obtained with whole organisms, and the immune responses associated with such protection were analyzed. Intraperitoneal immunization with a soluble, membrane-free parasite extract was found to induce protection against L. major challenge equal to that obtained with whole organisms. Induction of immunity (89% protection in seven experiments) was most effective with 100 micrograms of the soluble leishmanial antigen (SLA) and required concomitant injection of the bacterial adjuvant, Corynebacterium parvum (CP), followed by an i.p. boost of SLA alone 1 wk later. Vaccinated animals exhibited Leishmania-specific cell-mediated immunity, as assessed both by lymphocyte transformation and the production of macrophage-activating factors (MAF). In addition, although SLA + CP-immunized mice failed to exhibit delayed-type hypersensitivity (DTH) before challenge, splenic lymphocytes from these mice could transfer a local DTH reaction to naive recipients. Immunization also induced the production of antibodies against two major metabolically labeled proteins of m.w. 30,000 and 53,000, but failed to stimulate a detectable humoral response against promastigote surface antigens. Thus, these experiments demonstrate that vaccine-induced immunity against cutaneous leishmaniasis is strongly associated with the induction of cell-mediated immunity, but does not require the development of an antibody response to promastigote surface antigens. In addition, these studies establish the feasibility of employing soluble, nonmembrane-derived parasite material as a source of protective immunogens.

Adjuvants, Immunologic↗
PubMed1987

Genetic association of defects in macrophage larvicidal activity and vaccine-induced resistance to Schistosoma mansoni in P strain mice.

In contrast to most inbred strains, P mice fail to develop significant resistance to Schistosoma mansoni infection as a result of vaccination with irradiated cercariae. Vaccinated P mice also exhibit a defect in macrophage activation for killing of larval schistosomes upon specific-antigen challenge in vivo. To examine the genetic basis of these defects in vaccine-induced immunity, inheritance of the two traits was examined in (C57BL/6 X P)F1, F2, and reciprocal backcross generations. The defect in macrophage function which characterizes the P strain parent was found to be inherited in a fully recessive manner and to be controlled by only one or two major genetic loci. Moreover, a highly significant correlation (P less than 0.0025) was observed between the level of macrophage larvicidal activity and the level of resistance to challenge infection in segregating generations. Such an association is consistent with a cause-and-effect relationship, providing strong in vivo evidence implicating activated macrophages as immune effector cells of resistance to S. mansoni in the mouse-irradiated-vaccine model.

Animals↗