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Biomedical subjects

G F Mitchell

Publications and source records attributed to G F Mitchell.

At least 73 records · Page 4Linked to original sources
PubMed1990

Stage-specific immunity to Taenia taeniaeformis infection in mice. A histological study of the course of infection in mice vaccinated with either oncosphere or metacestode antigens.

The course of Taenia taeniaeformis infection in mice previously vaccinated with antigens prepared from either oncosphere (TtO) or metacestode (TtM) was followed by histological examination of livers from mice killed at various times post-infection (p.i.). Distinctly different immune responses occurred in the two groups. Very few cysts were seen at any stage of infection in TtO-vaccinated mice and most of those which were present appeared histologically similar to cysts in control mice. In TtM-vaccinated mice many cysts were present from early in infection but histologically it was apparent that most were dying from 15 days p.i. because the tegument had lost its integrity, and degranulated polymorphonuclear leucocytes were present inside the parasites. These findings support earlier suggestions that stage-specific antigens are expressed in oncospheres and metacestodes. Parasites developing normally were surrounded by a halo of alcian blue staining amorphous acellular material. This material appeared to act as a barrier to attack by host inflammatory cells, and disappearance of this layer signalled death of the parasite. The possibility that the gut acted as a barrier to delay migration of oncospheres to the liver in vaccinated mice was investigated, but no evidence for this could be found.

Animals↗
PubMed1990

Further studies on variable resistance of 129/J and C57BL/6 mice to infection with Schistosoma japonicum and Schistosoma mansoni.

Two mouse strains maintained in this laboratory (WEHI) are variably resistant to infection with Schistosoma japonicum and S. mansoni in that worms cannot be found in the liver and portal system in a high proportion (WEHI 129/J mice) or low proportion (C57BL/6 mice) some weeks after exposure to cercariae. Resistance can be as high as 100% in WEHI 129/J mice and is usually around 20% in C57BL/6 mice. The proportion of resistant mice closely parallels the proportion of mice that demonstrate a shunting of microbeads, injected into a mesenteric vein, from liver to lungs. This applies to F1 x WEHI 129/J backcross mice in which the data suggest oligogenic genetic effects although no evidence for a participation of MHC-linked genes in the phenomenon has emerged. 129/J mice derived from the Jackson Laboratory do not show a shunting of beads from the portal system to the lungs but their progeny bred at WEHI do. Germ-free WEHI 129/J mice resemble conventionally-maintained, SPF-derived WEHI 129/J mice in their variable resistance to schistosome infection. No satisfactory explantation for hepato-portal system peculiarities in WEHI 129/J and C57BL/6 mice can be advanced as yet and a possibility raised in this paper is a contribution from nutritional factors such as hypervitaminosis A superimposed on a genetic predisposition in these two related mouse strains.

Animals↗
PubMed1989

Identification of a multispecific lipoprotein receptor in adult Schistosoma japonicum by ligand blotting analyses.

A 43-kDa putative lipoprotein receptor (Sj43) of adult Schistosoma japonicum worms has been identified using ligand blotting techniques. Single and two dimensional electrophoretic analyses showed that Sj43 consisted of a single acidic polypeptide with multiple lipoprotein specificity. The molecule bound 125I-labelled low-density (apo-B), very low-density or high-density (apo-A and/or apo-C) lipoproteins from different mammalian hosts that are permissive to S. japonicum infection, but did not bind mouse apo-A containing lipoprotein. The binding of 125I-labelled lipoprotein to Sj43 could be inhibited by unlabelled human LDL, EDTA or Suramin, or by chemical modification of lipoprotein lysine or arginine residues. Sj43 was localised at the parasite's tegument and gut lining.

Animals↗
PubMed1989

Monoclonal antibodies reacting with Schistosoma japonicum eggs and their target epitopes.

Ten monoclonal antibodies (McAbs) raised to Schistosoma japonicum eggs could be assigned using several serological and immunochemical techniques to 3 groups. The McAbs, termed A, B and C-McAbs, apparently recognize carbohydrate epitopes that can be located on the same antigen molecule. The antibodies, generally of IgM isotype, are idiotypically related. They are distinct from another IgM McAb (Group D-McAb) the carbohydrate target epitope of which can also be associated with the epitopes of A, B and C-McAbs. The McAbs produce large vacuolated bleb reactions in the circumoval precipitin test (COPT) and target epitopes have different representations in various life cycle stages such as immature and mature eggs, male and female worms (including S. mansoni). Antigens affinity purified on columns containing A, B, C and D-McAbs stimulate proliferation of T cells from egg-sensitized mice and elicit DTH reactions in such mice. This raises the possibility that the target antigens of these carbohydrate-reactive monoclonal antibodies are immunopathologic and involved in egg-induced granuloma formation.

Animals↗
PubMed1989

Effects of induction of anti-embryonation immunity on liver granulomas, spleen weight and portal pressure in mice infected with Schistosoma japonicum.

BALB/c mice sensitized with injections of viable immature Schistosoma japonicum eggs had significantly fewer and smaller granulomas in the liver, lower portal pressure and smaller spleens at D + 75 of infection compared to similarly infected unsensitized controls. The portal pressure and spleen weights of the mice sensitized with immature eggs were not different from uninfected unsensitized mice of similar ages at D + 75 of infection. The results strongly support our hypothesis that it should be possible to prevent serious hepatosplenic disease in schistosomiasis japonica by vaccination to induce anti-embryonation immunity.

Animals↗
PubMed1989

Assessment of the prevalence and titer of antibodies to a candidate schistosomiasis vaccine molecule, Sj26, in several human serum banks.

Using immunoassay and immunoblotting approaches, antibodies to Sj26, a glutathione S-transferase molecule (Mr = 26,000) of Schistosoma japonicum worms that is a vaccine candidate, have been sought in three large human serum banks. For these studies, a near-native recombinant Sj26 molecule produced in Escherichia coli was used, generally in ELISAs. Anti-Sj26 activity was detected readily in a high proportion of the sera at titres below 1:400 and appeared to be largely protein A-binding IgG antibodies. No differences in the prevalence of anti-Sj26 antibodies were noted in sera from entirely normal individuals or those with a variety of parasitic infections, but never exposed to S. japonicum. The stimulus responsible for induction of these low titre, probably low affinity antibodies in humans remains unknown.

Animals↗
PubMed1989

Schistosoma mansoni: evidence that 'non-permissiveness' in 129/Ola mice involves worm relocation and attrition in the lungs.

129/Ola mice resemble WEHI 129J mice in that around 70% of the individuals in any given population resist a primary infection with Schistosoma mansoni. Squashed-organ autoradiographic tracking of [75Se]selenomethionine-labelled parasites has shown that the kinetics of worm migration in 129/Ola mice follows the expected pattern, and that all rodents harbour essentially similar numbers of worms on day 14 post-infection. Combined lung and liver worm recovery techniques have revealed, however, that segregation of mice into 'permissive' and 'non-permissive' individuals can first be detected on day 20. 'Non-permissive' mice are characterized by the absence of schistosome eggs at all times in the liver parenchyma and, in consequence, lack the attendant manifestations of pathology; they do, however, harbour a few stunted worms in the liver and significant numbers of adult schistosomes in the pulmonary vasculature. Histological analysis of sectioned lung tissue from such animals indicates that some lung-located schistosomes feed, pair and lay eggs. Nevertheless, eosinophil-enriched inflammatory reactions develop around such worms and the parasites themselves exhibit various manifestations of trauma, ranging from minor vacuolation to gut herniation and extrusion. The phenomenon of 'non-permissiveness' thus involves retardation of worm development in the liver and, in consequence, relocation of the parasites to the lungs, where they become subject to host effector responses.

Animals↗
PubMed1989

Portal system peculiarities may contribute to resistance against schistosomes in 129/J mice.

Using the technique of latex microsphere injection into a mesenteric vein, evidence has been obtained for a 'leaky' portal system in 129/J mice maintained in this institute (WEHI 129/J) and also in C57BL/6 mice. Thus, 20-microns beads injected into the portal venous system of BALB/c and (BALB/cx129/J)F1 mice are trapped efficiently in the liver whereas in many 129/J and C57BL/6 mice the bulk of the injected beads is found in the lungs. Peculiarities in the hepatic portal system may thus contribute to resistance of WEHI 129/J mice (and to a lesser extent C57BL/6 mice) to infection with Schistosoma mansoni and S. japonicum. The possibility is raised by the data that increased access to, or residency times in, the lungs increases opportunities for expression of anti-schistosome immune responses and, in particular, the effects of recently described T-cell-initiated inflammatory responses in this organ. The variability within groups of WEHI 129/J and C57BL/6 mice in susceptibility to schistosomes as well as hepatic trapping of injected microspheres suggests that an infection of unknown type, proposed by others, contributes to the several peculiarities that have been described in at least 129/J mice.

Animals↗
PubMed1989

Evidence of T-cell recognition in mice of a purified lipophosphoglycan from Leishmania major.

We have previously reported that a Leishmania major lipophosphoglycan (LPG), given with killed Corynebacterium parvum as an adjuvant, can vaccinate mice against cutaneous leishmaniasis. In order to analyze whether T cells are able to recognize this important parasite antigen, we have studied both humoral and cellular immune responses to L. major LPG that had been isolated from promastigotes by sequential solvent extraction and hydrophobic chromatography. The data show that immunization of mice with highly purified LPG induced an increase in frequency of L. major-reactive T cells and the production of immunoglobulin G antibodies to LPG. Furthermore, genetically resistant mice infected with L. major were able to develop a specific delayed-type hypersensitivity response in the ear to L. major LPG. These findings strongly suggest that T cells can recognize and respond to glycolipid antigens, in this case a host-protective Leishmania LPG, even though such antigens appear not to be potent T-cell stimulators in mice.

Animals↗
PubMed1988

Expression of an enzymatically active parasite molecule in Escherichia coli: Schistosoma japonicum glutathione S-transferase.

The NH2-terminal amino acid sequence of the Mr 26 000 glutathione S-transferase (EC 2.5.1.18) of Schistosoma japonicum (Sj26) has been deduced by RNA and protein sequence analysis. Using this information, a bacterial plasmid has been constructed that directs the synthesis of the entire Sj26 molecule in Escherichia coli. Recombinant Sj26 exhibits glutathione S-transferase activity and can be readily purified from bacteria in a one-step procedure under non-denaturing conditions. The availability of recombinant Sj26 in essentially unlimited quantities will aid its assessment as a candidate vaccine molecule in schistosomiasis and could eventually lead to the rational design of a drug targetted on schistosome glutathione S-transferases.

Amino Acid Sequence↗
PubMed1988

Sensitization against the parasite antigen Sj26 is not sufficient for consistent expression of resistance to Schistosoma japonicum in mice.

Mice immunized with purified antigen preparations produced in Escherichia coli and containing the glutathione S-transferase (GST) isoenzyme of Schistosoma japonicum (Sj26) can be partially resistant to infection with this parasite. Maximum resistance was approximately 50% and no protection was obtained in BALB/c mice, known low responders to Sj26. Although only Freund's complete adjuvant has been used, the data obtained indicate that satisfactory levels of resistance to S. japonicum will not be attained by vaccination with Sj26 alone. Other antigens, including the additional GST isoenzyme of S. japonicum Sj28, will probably be required to establish whether Sj26 will be an important component of a defined multivalent vaccine against schistosomiasis japonica.

Animals↗
PubMed1988

Immunoblotting analysis of the major integral membrane protein antigens of Schistosoma japonicum.

Triton X-114 has been employed to isolate integral membrane proteins from Schistosoma japonicum and Schistosoma mansoni adult worms. Suitable marker molecules and antisera directed or raised against schistosome proteins partitioned by Triton X-114 extraction indicated that the phase separation and purification of integral membrane proteins had been successful and this fraction was free of contamination with aqueous (soluble) or secretory antigens. Two dimensional immunoblots further exemplified differences between antigens in the integral membrane protein extract and those of the aqueous fraction. Seven S. japonicum integral membrane proteins have been identified on immunoblots by serum from a hyperimmune and an infected rabbit and by sera from Philippine patients with a history of schistosomiasis japonica. Integral membrane proteins of S. mansoni and S. japonicum had surprisingly little conformity in the molecular weights and electrophoretic mobilities between the two species.

Alkaline Phosphatase↗
PubMed1988

The way ahead for vaccines and vaccination: symposium summary.

In this summary, several biological and non-biological constraints to rapid progress in the molecular vaccine era are highlighted such as genetically-based unresponsiveness, induction of inappropriate immune responses, sustaining protective immunity in the vaccines problems in demonstrating efficacy, and ensuring availability and usage of this class of biologicals throughout the world. Some approaches to increasing immunogenicity are discussed with emphasis on composite antigens. Finally, the eight broad strategies for constructing vaccines outlined by Chanock in 1984 are re-examined.

Adjuvants, Immunologic↗
PubMed1988

Resistance to cutaneous leishmaniasis in nude mice injected with L3T4+ T cells but not with Ly-2+ T cells.

The importance of T cells in resistance to infection with the intracellular protozoan parasite Leishmania major is substantiated by the susceptibility to infection of athymic nude mice of both resistant and susceptible strains. However, the relative roles of different T cell subpopulations remain controversial. In order to address this issue, selected L3T4+ Ly-2- or L3T4- Ly-2+ T cell subpopulations from normal mice were adoptively transferred into athymic nude recipients of the same strain, and their capacity to mediate host-protective immunity against infection with L. major promastigotes was determined. In experiments with mice of different inbred strains, reconstitution with L3T4+ Ly-2- cells rendered the nude mice completely resistant to cutaneous leishmaniasis, whereas L3T4- Ly-2+ cells failed to do so. Partial protection in some recipients of large numbers of Ly-2+ cells could be ascribed to contamination of the transferred inoculum with L3T4+ cells. Thus, resistance to L. major infection in reconstituted nude mice can be promoted by L3T4+ T cells in the absence of detectable Ly-2+ T cells.

Animals↗