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Biomedical subjects

D D McGregor

Publications and source records attributed to D D McGregor.

At least 19 recordsLinked to original sources
PubMed1993

Trichinella spiralis: the effect of specific antibody on muscle larvae in the small intestines of weaned rats.

Weaned rats were passively immunized with rat IgG2c monoclonal antibodies previously shown to protect infant rats against challenge with Trichinella spiralis. Although the antibodies did not protect rats against infection, the course of larval establishment in the intestine was altered in a way that has not been described previously. Specifically, larvae that invaded the epithelium were inhibited from migrating from intestinal tissue into saline during the standard recovery procedure. The inhibition was reversed at a time coincident with the first moult. Whole serum from infected rats had a similar effect. These results show that specific antibodies influence T. spiralis larvae in the intestinal epithelium, yet fail to effect their expulsion from adult rats.

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PubMed1991

Intestinal mucus entrapment of Trichinella spiralis larvae induced by specific antibodies.

Entrapment of muscle larvae (ML) occurred in vitro when antibodies specific for Trichinella spiralis were added directly to intestinal mucus from normal non-immunized rats or when mucus was collected from pups suckling a T. spiralis-infected dam. Normal rat serum immunoglobulins failed to promote mucus entrapment and complement did not appear to play a part in the entrapment process. Differences were not observed in the efficiency of entrapment of ML by mucus harvested from different regions of the small intestine. Employing a panel of monoclonal antibodies (mAb) specific for excretory-secretory antigen (ESA), we attempted to dissociate antibody-mediated protection from mucus entrapment. We assessed mucus entrapment and rapid expulsion by these mAb in vivo, and observed protection in the absence of significant, immediate mucus entrapment in two cases. In addition, we measured mucus entrapment of ML in two in vitro assays. One assay employed intestinal mucus harvested from pups suckling dams that had been injected i.v. with a mAb. Results confirmed those obtained in vivo and indicated that antibodies were present in the intestinal lumina of passively immunized pups. In the second in vitro assay, mAb were added individually to mucus from pups suckling non-immunized dams. Results from these assays suggested that certain antibody isotypes may be processed in vivo in ways that influence, either positively or negatively, their abilities to cause mucus entrapment.

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PubMed1991

The role of the antibody Fc region in rapid expulsion of Trichinella spiralis in suckling rats.

When an IgG2c monoclonal antibody specific for Trichinella spiralis muscle stage larvae was cleaved with pepsin to yield F(ab')2 fragments, the latter retained their capacity to cause mucus entrapment and rapid expulsion of larvae from the intestines of suckling rats. When fed to pups, the F(ab')2 fragments of this antibody and the F(ab')2 fragments of a similarly prepared IgG2a antibody caused mucus entrapment of muscle larvae (ML), demonstrating that trapping is not dependent upon the Fc region of the antibody molecule. Despite the fact that these two antibodies had similar specificities and that their F(ab')2 fragments caused larval entrapment in mucus, F(ab')2 fragments of the IgG2a antibody failed to protect rat pups. Fragments of the IgG2c antibody caused rapid expulsion when injected into pups, but the distribution of larvae was dramatically different from when the fragments were delivered orally. These results indicate that entrapment of T. spiralis in mucus is not in itself the cause of the expulsion. The more likely possibility is that antibody impedes a function of Trichinella spiralis that is related to the capacity of the parasite to reside in its epithelial niche.

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PubMed1990

The role of mucus in antibody-mediated rapid expulsion of Trichinella spiralis in suckling rats.

Rat pups suckling dams parasitized by Trichinella spiralis express rapid expulsion, a protective response that is associated with the entrapment of infectious muscle larvae in intestinal mucus. Immunofluorescent studies revealed that antibodies were bound to the surfaces of the entrapped larvae. Mucus binding and rapid expulsion occurred in normal pups dosed with larvae coated with antibodies prepared from infected rat serum. Subsequent experiments revealed that entrapped larvae escaped from mucus after 2 hr in vitro incubation in saline. Escape correlated with the loss of the surface-bound antibodies, suggesting that mucus entrapment was reversible and dependent on antibody coating. Finally, when protective antibodies were injected 1, 2 or 6 hr after larvae were administered to pups, the parasites were forced to leave their epithelial niche and became enveloped in mucus. The above findings suggest that mucus trapping of T. spiralis larvae is dependent upon the coating of larvae by antibody, but that trapping is reversible, and is not in itself the pivotal event in rapid expulsion. The primary mechanism of rapid expulsion appears to be antibody-mediated inhibition of processes required for the parasite to maintain itself in the epithelium.

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PubMed1988

Rapid expulsion of Trichinella spiralis in suckling rats: mediation by monoclonal antibodies.

Pups born to rats immunized with the excretory/secretory antigens (ESA) of Trichinella spiralis L1 larvae expressed rapid expulsion when challenged orally. Rat monoclonal antibodies specific for ESA were produced and tested for their specificity in Western blots, binding to intact larvae and protective capacity in suckling rats. Eight antibodies had apparently identical specificity in Western blots, each recognizing a polypeptide family that included three molecular weight species sized at 41,000-50,000 MW. These polypeptides formed a series of higher molecular weight aggregates that were also bound by the monoclonal antibodies. Four of eight antibodies were protective when serially transferred to suckling pups. Each protective antibody was able to bind to intact larvae. Antibodies of two subclasses, IgG1 and IgG2c, were strongly protective, delivering to pups the capacity to expel as much as 94% of the challenge dose.

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PubMed1987

Characterization of the immune mediator of rapid expulsion of Trichinella spiralis in suckling rats.

In order to identify and characterize the mediator(s) of rapid expulsion, infant rats were passively immunized against oral challenge with 200 infectious Trichinella spiralis muscle larvae by oral or intraperitoneal (i.p.) administration of secretions or sera from infected rats. Milk whey from infected dams provided a modest level of protection when fed to pups. Immunoglobulins from T. spiralis-infected rat serum protected suckling pups when injected intravenously (i.v.) into lactating dams 2 days prior to pup challenge. Intraperitoneal injection of pups with serum immunoglobulins also enabled them to express rapid expulsion. The protective component of serum was precipitated with 40% (NH4)2SO4 and was not affected by heating to 56 degrees, although antibodies mediating passive cutaneous anaphylaxis were inactivated by both treatments. Oral transfer of biliary immunoglobulins collected from infected rats at various times during a primary infection provided no protection to pups. However, serum immunoglobulins from rats infected for 42 days or longer transferred rapid expulsion to pups. Absorption of protective serum immunoglobulins with subclass-specific reagents revealed that IgG1 played a significant role in protection.

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PubMed1986

Isolation and characterization of protective T cells induced by Listeria monocytogenes.

Rats convalescing from a recent infection with Listeria monocytogenes generate T cells which can protect recipient rats against a challenge infection with that organism. Using monoclonal antibodies that react with some but not all rat peripheral T cells, the T-cell mediators of acquired resistance to infection (TCRI) were isolated by panning and characterized by using a fluorescence-activated cell sorter. Many L. monocytogenes-immune TCRI were relatively large cells as judged by their light-scattering properties. That finding accords with previously reported cytokinetic data and velocity sedimentation analyses which revealed that the majority of L. monocytogenes-immune TCRI are lymphoblasts. In the current investigation, the surface antigenic profile of these mediator T cells was revealed as W3/25+ OX8+ OX4+ RT6.1-. That phenotype is identical to that of L. monocytogenes-induced prekiller cells which are formed as part of the animal's cell-mediated response to infection. Like prekiller cells and their differentiated counterparts, L. monocytogenes-immune TCRI adhere preferentially to monolayers of syngeneic fibroblasts. The results indicate that L. monocytogenes-immune TCRI belong to a minor subset of peripheral T cells which also contains T cells that have the cytotoxic potential by which L. monocytogenes-induced prekiller cells have been defined.

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PubMed1986

Monoclonal antibody analysis of Listeria monocytogenes-induced cytotoxic lymphocytes.

An immunizing infection with Listeria monocytogenes provides a potent stimulus for the formation of prekiller lymphocytes. Their cytolytic potential is revealed when the cells are restimulated in vitro by Listeria antigens. Listeria monocytogenes-induced cytotoxic lymphocytes and the prekiller cells from which they are derived were characterized in respect to their surface antigenic markers. Using monoclonal antibodies, B-cell depleted lymphocytes from the thoracic duct of Listeria immune rats were fractionated into subsets by a combination of panning and sorting techniques. Listeria monocytogenes-induced cytotoxic lymphocytes and their prekiller cell precursors were demonstrated to have the phenotype W3/25-, OX8+, OX4+, W3/13+ (high density), OX19+ (low density), RT6.1-. The OX8+, RT6.1- subset, which contained prekiller cells, constituted approximately 6% of lymph-borne T cells. The data indicate that these microbial antigen-induced cytotoxic lymphocytes belong to a minor subset of peripheral T cells whose surface antigenic properties distinguish them from natural killer cells.

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PubMed1985

T-cell co-operation in the mediation of acquired resistance to Listeria monocytogenes.

Monoclonal antibodies were used to select T-cell subsets that mediate delayed-type hypersensitivity (DTH) and acquired cellular resistance (CRI) in rats infected with Listeria monocytogenes. The mediators of DTH were identified as W3/25+ OX8- T cells. The latter comprised a subset distinct from that which could protect recipient rats against a Listeria challenge. The protective T cells had a W3/25- OX8+ phenotype. The T-cell mediators of cellular resistance to infection (TCRI) failed to augment the expression of DTH; however, the mediators of DTH (TDTH) significantly enhanced the protective capacity of TCRI. This property of TDTH correlated with the ability of the cells to promote the focal deployment of TCRI and macrophages at sites of soluble Listeria antigen injection in skin, and in peritoneal exudates induced by killed L. monocytogenes. These findings illustrate the co-operative interaction of activated T cells in acquired resistance to L. monocytogenes, and imply that DTH has a purposeful role in the host defence against infection.

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PubMed1985

Life-phase specific induction and expression of rapid expulsion in rats suckling Trichinella spiralis-infected dams.

Rat dams infected with 1000 Trichinella spiralis muscle larvae, 4 weeks prior to breeding, provided their suckling offspring with immunity to challenge with 200 muscle larvae at 2 weeks of age. The immunity was expressed in the elimination of 75-99% of the challenge dose within 24 hr. The intestinal worm burden did not decline significantly after the initial expulsion. Infected dams continued to protect their offspring during three breeding cycles, for as long as 26 weeks after infection. Immunity was conferred upon pups by dams that had been selectively immunized with the parenteral phase of the parasite's life cycle. Immunization with a drug-terminated enteral infection was ineffective as was enteral immunization followed by the parenteral phase. Further analysis revealed that rapid expulsion by pups was dependent on the number of mature muscle larvae recovered from dams immunized with NBL. By comparison, the expulsive capacity of the same dams was not improved by increasing the numbers of NBL within the range tested.

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PubMed1984

Rapid expulsion of Trichinella spiralis in suckling rats.

Orally administered Trichinella spiralis muscle larvae were rapidly expelled by rat pups suckling an immune dam. The immunity was delivered in the milk; substantial resistance was conferred on normal rat pups suckled for only 24 hours by a Trichinella-immune foster mother. The pups were protected by oral or systemic administration of specific serum antibodies. When infused into a normal lactating dam, these antibodies accumulated in the serum of her suckling pups.

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PubMed1984

The mediators of acquired resistance to Listeria monocytogenes are contained within a population of cytotoxic T cells.

T cells from peritoneal exudates induced in rats convalescing from a recent infection of Listeria monocytogenes were fractionated into two subsets based on their ability to bind monoclonal antibodies to cell-surface determinants that are expressed on some but not all peripheral T cells. Two phenotypically distinct subsets, one recognized by the antibody MRC OX8 and the other by W3/25, were assayed for their protective capacity in Listeria-challenged recipients, and for their ability to kill unmodified syngeneic fibroblasts in vitro. The two activities were mediated by the OX8+ subset which comprised approximately half the T cells in the exudates.

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PubMed1984

The cellular response to Listeria monocytogenes is mediated by a heterogeneous population of immunospecific T cells.

Immunospecific T cells cooperate with macrophages in the expression of delayed type hypersensitivity and cellular resistance to Listeria monocytogenes. The mediator cells involved are generated in response to an immunizing Listeria infection. Immunospecific T cells are formed in lymphoid tissue and appear briefly in the blood. Many localize at sites of microbial implantation, but others leave the blood spontaneously and infiltrate tissues throughout the body. Both circulating T cells and those in tissues participate in the expression of delayed type hypersensitivity and cellular resistance. Several lines of evidence suggest that these two phenomena are mediated by heterogeneous but possibly cooperating T cell populations.

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PubMed1984

Activation of Listeria monocytogenes-induced prekiller T cells by interleukin-2.

Thymus-dependent lymphocytes, or T cells, of rats infected with Listeria monocytogenes acquire a potent cytolytic capability when the cells are restimulated in vitro by Listeria antigens. Activation of such Listeria monocytogenes-dependent cytotoxic T lymphocytes requires both antigen and histocompatible accessory cells, but only when the responder T cells have been specifically depleted of lymphocytes that are responsive to accessory cell alloantigens. When unselected T cells are used, significant activation occurs in specific-antigen-free cultures containing allogeneic accessory cells. This seeming paradox is explained by the fact that a lymphokine generated in mixed leukocyte cultures can promote the terminal differentiation of cytotoxic T lymphocytes precursors. This lymphokine has tentatively been identified as interleukin-2. The results suggest that a three stage process is involved in the activation of Listeria monocytogenes-dependent cytotoxic T lymphocytes. The first stage occurs in response to an immunizing Listeria monocytogenes infection and itself involves two significant events, the polyclonal priming of prekiller cells and the generation of Listeria antigens-specific helper T cells. During the second stage, helper T cells are stimulated by Listeria antigens to release interleukin-2. This process is efficiently executed only in the presence of histocompatible accessory cells. The third stage in the activation process requires neither accessory cells nor antigen and involves the interleukin-2-driven differentiation of prekiller cells.

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PubMed1983

Trichinella spiralis: selective intestinal immune deviation in the rat.

In rats, infections with 100-2000 Trichinella spiralis muscle larvae lead to a prompt immunity that is expressed in parasite expulsion within 14 days. Rats infected with more than 2000 larvae display impaired immunity with rejection delayed by 50% (7 days) or more. Suppression is selective for expulsive immunity as the antifecundity response of rats is directly proportional to dose and is expressed sooner in heavily infected subjects. Suppression of intestinal expulsive immunity was suggested by the fact that, with low doses (2000 larvae or less), worm rejection was inhibited by cortisone, whereas cortisone inhibited antifecundity but had no discernable effect on worm rejection in high-dose infections. Evidence for local immune deviation as opposed to systemic immunosuppression was obtained in experiments using parabiotic rats. When one partner was infected with 6000 worms and the other with 200, the rat infected with 200 parasites showed earlier rejection than was seen in single controls infected with 200 worms. The prolonged survival of high-dose adults was not accompanied by a change in the site of worm residence in the gut. Immunological parameters such as serum antibody levels, the number of activated cells or specific anti-T. spiralis lymphocytes in thoracic duct lymph were all increased in a dose-dependent manner. These experiments therefore demonstrate a novel autoprotective mechanism by which adult T. spiralis selectively reduce the expression of expulsive immunity in the gut.

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