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Biomedical subjects

D G Colley

Publications and source records attributed to D G Colley.

At least 109 records · Page 6Linked to original sources
PubMed1986

Effects of anti-schistosomal chemotherapy on immune responses, protection and immunity. II. Concomitant immunity and immunization with irradiated cercariae.

Resistance of mice to challenge infections of Schistosoma mansoni was evaluated before and after elimination of their primary, established S. mansoni infections with the chemotherapeutic drug praziquantel. Mice treated after either 10 or 20 weeks of primary infection were challenged 6 or 10 weeks after treatment. Mice infected for for 10 weeks prior to treatment expressed progressively less resistance 6 and 10 weeks after treatment. By 10 weeks after treatment significant levels of protection were no longer observed. Resistance waned more slowly if mice were treated 20 weeks after infection, and there was still significant expression of resistance to challenge 10 weeks after treatment. A separate set of experiments evaluated the use of highly irradiated cercariae as a vaccine in mice that had been previously infected with S. mansoni and cured with praziquantel. It was observed that effective immunizations were possible in previously infected mice. These studies demonstrate that established resistance waned after treatment and the rate of loss of protection was dependent upon the duration of infection prior to treatment. Furthermore, the irradiated cercarial vaccine studies indicate that in the murine model induction of immunological resistance was feasible following chemotherapeutic treatment of infected populations.

Animals↗
PubMed1986

Effects of anti-schistosomal chemotherapy on immune responses, protection and immunity. III. An effective regimen of praziquantel does not alter immune capabilities of normal mice.

Praziquantel is a broad spectrum anti-helminthic drug active against a variety of parasitic trematodes and cestodes. This report studies the effects of a schistosomacidal regimen of praziquantel on the generation of the cell-mediated and humoral response capabilities of normal, uninfected mice. Three doses of 100 mg praziquantel/kg body weight at 4-hr intervals cured several strains of mice with Schistosoma mansoni infections of several intensities. When this curative regimen was applied to normal, uninfected mice it did not alter peripheral blood leukocyte counts, circulating eosinophil numbers or splenic weights. Neither did this regimen alter the development of responsiveness to sheep erythrocytes (SRBC) as measured by dermal delayed-type hypersensitivity (DTH) or the number of splenic plaque forming cells. Furthermore, DTH and serum antibody responses to a soluble antigen (bovine serum albumin) were also comparable in treated and untreated mice. It appears that an anti-schistosomacidal regimen of praziquantel does not alter normal murine cellular or humoral immune responses.

Animals↗
PubMed1986

Effects of immunomanipulations on resistance induced by irradiated Schistosoma mansoni cercarial sensitization of C57BL/6 and CBA/J mice.

Mice sensitized with radiation-attenuated Schistosoma mansoni cercariae were treated by a variety of procedures known to interrupt immunoregulatory circuitries in attempts to alter the resistance induced by irradiated cercarial sensitization. Both highly resistant C57BL/6 and the often poorly resistant CBA/J strains were examined. Immunomanipulations included adult thymectomy, or administration of different drugs in relation to the time of challenge infection (day 0). Adult thymectomy was performed 3 weeks prior to sensitization or 3 weeks prior to challenge. Drug treatment included cyclophosphamide given at a dose of 20 mg/kg on alternate days, day -11 through day +11, cimetidine at 50 mg/kg/day, day -7 through day +21, or indomethacin at 2.5 mg/kg/day, day 0 through day +10. In most experiments, irradiated cercarial sensitized C57BL/6 mice developed significant resistance which was not altered by the immunomanipulative regimens used. If however, as fortuitously occurred in two adult thymectomy experiments, irradiated cercarial sensitization did not induce significant resistance, immunomanipulation by adult thymectomy allowed the development of a significant protected state. Similarly, adult thymectomy or cimetidine treatment in concert with immunization of CBA/J mice conferred moderate, statistically significant levels of stable resistance in this normally "less resistant" strain.

Animals↗
PubMed1986

Immune responses during human schistosomiasis. XII. Differential responsiveness in patients with hepatosplenic disease.

Thirty-four hospitalized patients and 12 ambulatory patients, all with hepatosplenic schistosomiasis mansoni were evaluated in regard to their peripheral blood mononuclear (PBMN) cell responses to schistosomal antigenic preparations and compared with groups of 40 patients with the hepatointestinal form and 39 patients with the more common, chronic intestinal form of schistosomiasis mansoni. PBMN cell blastogenic responses were measured upon exposure to schistosomal egg antigens (SEA), adult worm antigens (SWAP) and a cercarial antigenic preparation (CERC). All groups had some individuals who did not respond to some or all of these preparations. In the hospitalized hepatosplenic group greater than 50% did not respond to SEA. Analysis of the responses in each group revealed that all responders could be subdivided into moderate and high responders. High responders to SEA had experimental minus control values of greater than 8,000 counts per minute (CPM). For SWAP and CERC, this arbitrary cut-off value was greater than 25,000 CPM and greater than 11,000 CPM, respectively. The percent of high SEA responders in the groups differed considerably. This was 23% in the chronic intestinal group, 40% in the chronic hepatointestinal group, 67% for ambulatory hepatosplenic patients and 20% for hospitalized hepatosplenic patients. Previous studies had demonstrated that 94% of patients with early (2-3 month) acute schistosomiasis mansoni were high responders to SEA and none were nonresponders. Furthermore, at the other end of the spectrum, 100% of former schistosomiasis mansoni patients (treated and cured 7-35 years previously) were high responders to SEA. None were nonresponders to any of the antigen preparations. It is proposed that during acute infection all patients express vigorous responses to SEA. Upon continued infection most patients (75%) modulate this florid response. However, continued high responders comprise 40% of the chronic hepatointestinal cases and almost 70% of the ambulatory hepatosplenic patients. These latter 2 groups may likely represent early forms of the severe clinical disease found in the hospitalized hepatosplenic patient population. Fifty percent of the hospitalized group appear anergic and no longer respond to SEA, while only 20% are high responders. Long after chemotherapy it appears that the anti-SEA regulatory mechanisms of former chronic patients have subsided, leaving strong anti-SEA responsiveness.

Acute Disease↗
PubMed1985

111In-labeled eosinophils: localization of inflammatory lesions and parasitic infections in mice.

Based upon recent development of practical isolation techniques for eosinophils, labeling and in vivo imaging of eosinophils has been achieved. Isolation of cells was performed utilizing a Percoll density gradient. The eosinophils were subsequently labeled by a modified 111In-oxine method. Migration of eosinophils in response to intradermal ear-pinna injections of SEA (soluble schistosoma egg antigen), S. mansoni eggs, E. coli, and turpentine was followed with gamma-ray camera imaging from 4 to 48 h. Maximal localization, determined by Gamma 11 data processing, occurred by 4-h post-injection of radiolabel. SEA and S. mansoni eggs provided a greater stimulus for localization than E. coli or turpentine. Neutrophils did not preferentially accumulate. Tissue distribution of labeled eosinophils was greatest in the spleen, followed by liver and bone. 111In-labeled-eosinophil scans are sensitive to parasitic infections, although somewhat nonspecific.

Animals↗
PubMed1985

Demonstration of leukocyte inhibitory factor in human Schistosomiasis mansoni and its evaluation from patients in an endemic setting.

Leukocyte migration inhibitory Factor (LIF) is produced by the peripheral blood mononuclear cells (PBMN) of most patients with Schistosoma mansoni infection upon their exposure to soluble egg antigens (SEA). PBMN of some patients also respond to adult worm (SWAP) antigens by LIF production. LIF is stable at 37 degrees C for 60 min but is sensitive to heating at 56 degrees C for even 30 min. The serine protease inhibitor PMSF destroyed LIF activity at concentrations of 10(-2) to 10(-3) M. Concanavalin A stimulated production of detectable levels of LIF by 8 hr, while SEA and SWAP did so by 15 and 39 hr, respectively. PBMN of healthy normal controls did not produce LIF upon exposure to SEA or SWAP. PBMN of a few field controls (stool negative subjects from an endemic area) produced detectable LIF activity when exposed to SEA or SWAP. PBMN from most infected (stool positive) patients from an endemic area produced LIF when exposed to SEA and only occasionally did so to SWAP. Previous studies have shown that most often only the PBMN of former, cured patients, and not chronically infected patients, produce the lymphokine activity termed mitogenic factor (MF). The current data indicate that because LIF is primarily produced by actively infected patients, its production may be controlled by different immunoregulatory mechanisms. Furthermore, although most SEA-related responses are highly immunoregulated in active, chronically infected patients, SEA appears to be a better stimulus for patient PBMN production of LIF than SWAP.

Chronic Disease↗
PubMed1985

Demonstration of splenic auto-anti-idiotypic plaque-forming cells in mice infected with Schistosoma mansoni.

Mice exposed to 35 cercariae of the human helminth Schistosoma mansoni develop chronic (greater than 16wk) infections characterized by immunoregulation of their cell-mediated granulomatous responses to schistosome eggs. Evidence was sought regarding the possible development of anti-idiotypic responses against the responses to soluble egg antigens (SEA). Sera were collected from CBA/J mice with chronic S. mansoni infections. Multiclonal idiotypic, anti-SEA antibody (id) was prepared from these pooled sera by affinity chromatography on an SEA immunoadsorbent column. Analysis of the id preparations by polyacrylamide gel electrophoresis demonstrated that this material contained only immunoglobulin heavy and light chains. A modified reverse plaque-forming cell (PFC) assay was developed to quantify anti-idiotypic (anti-id) PFC in spleen cell preparations from infected and age-matched control CBA/J mice. Expression of anti-id PFC began 2 to 3 wk after onset of egg production and continued throughout the course of infection. Positive selection of anti-id-reactive spleen cells by panning cell preparations from chronic mice on id-coated plates resulted in an enrichment of anti-id PFC in the id-adherent population. Conversely, the number of PFC reactive with SEA (id-producing PFC) was lowered by panning on id-coated plates. These data demonstrate the occurrence of anti-id responses during schistosomiasis mansoni. It is possible that such an immunoregulatory mechanism could play an important role in how an animal modulates the granulomatous response that leads to the formation of pathologic lesions and in the maintenance of this chronic infection.

Animals↗
PubMed1985

Immune responses during human Schistosomiasis mansoni. XI. Immunologic status of patients with acute infections and after treatment.

Sixteen patients, 8 to 30 yr of age, with acute (toxemic) phase schistosomiasis mansoni were studied immunologically within 2 to 3 mo of their exposure to Schistosoma mansoni cercariae, and were monitored after chemotherapy. Total leukocyte levels and peripheral blood eosinophilias were higher in these patients than in similar individuals with chronic schistosomiasis mansoni. In contrast to chronic patients, the eosinophilias of the acute cases were decreased rather than elevated upon treatment. Total lymphocyte population (T and B cell) percentages were not altered during acute infection. Lymphoid subset (T3+, T4+, and T8+) analysis revealed elevated levels of both T4+ and T8+ cells. In vitro blastogenic responses of peripheral blood mononuclear cells (PBMN) to heterogeneous schistosome-derived antigens (eggs, SEA; adult worms, AW; and cercariae, CERC) were evaluated. SEA responsiveness was considerably higher than that of patients with chronic S. mansoni infections. The ratios of SEA to AW responses in acute cases gave a mean of 2.0, as opposed to 0.5 for a comparable group of chronically infected patients. The sera of most acute patients already contained suppressive factors that specifically decreased schistosomal antigen-induced PBMN blastogenesis. Chemotherapy of acute cases lead to a diminution of PBMN responsiveness to SEA and CERC. Treatment of patients with chronic infections lead to the elevation of such responses. PBMN from patients with acute infections produced lymphokine leukocyte inhibition factor upon exposure of the cells to SEA but not AW. A similar pattern was true for production of the lymphokine activity mitogenic factor. Levels of antibody in sera of acutely infected patients against SEA, CERC, and AW were considerably higher than levels in sera of chronically infected patients matched for age and intensity of their infections. These high antibody titers persisted for at least 6 mo after treatment, and were unrelated to the intensity of infection. The immunologic status of these patients with acute schistosomiasis mansoni differed considerably from patients with chronic infections. These findings re-emphasize the immunoregulatory events that apparently develop upon continued exposure to schistosomes and their products during chronic infection.

Acute Disease↗
PubMed1985

Production of the lymphokine soluble immune response suppressor (SIRS) during chronic experimental schistosomiasis mansoni.

Chronic schistosomiasis mansoni is a helminthic infection characterized by cell-mediated anti-egg granulomatous reactions and a variety of associated immunoregulatory phenomena. Soluble immune response suppressor (SIRS) is a lymphokine produced by activated suppressor T lymphocytes in various experimental settings. This report demonstrates the presence of SIRS in the sera of mice with chronic schistosomiasis mansoni (at least 20 wk of infection), but not in the sera of mice with earlier infections. Also, cultures of isolated, intact, hepatic, egg-focused granulomas from chronically infected mice released detectable levels of SIRS. These are the immunomodulated lesions characteristic of this infection. Large, intense, unmodulated granulomas obtained from acutely infected mice did not release SIRS. There is, therefore, a strong association between the presence of SIRS in the serum, the production of SIRS by intact lesions, and the chronic, immunomodulated stage of schistosomiasis mansoni.

Animals↗
PubMed1984

Immunoregulation in experimental schistosomiasis. II. Soluble egg antigen-induced chronic spleen cell augmentation of baseline lymphocyte reactivity.

Spleen cells from mice harboring infections of Schistosoma mansoni for 20 weeks exposed to Con A or to soluble schistosome egg antigenic preparation (SEA), treated with Mitomycin C (Mc), and cocultured with spleen cells from either normal or infected mice caused an augmented baseline [3H]TdR incorporation by the otherwise unstimulated responder cells. This regulation required an in vitro induction phase. SEA-exposed, Mc-treated normal spleen cells had no effect on responder cell cultures. SEA-stimulated, Mc-treated chronic spleen cell augmentation was effective on responder cell populations from either normal mice or mice infected with S. mansoni for 8 weeks. Augmentation was most pronounced when assayed on cells from infected mice assayed over a 5-day incubation. In addition, it is demonstrated that these Con A- and SEA-elicited activities are mediated by soluble mediators which lack H-2 restriction.

Animals↗
PubMed1984

Immunoregulation in experimental Schistosomiasis. III. Role of macrophages in soluble egg antigen-induced chronic spleen cell augmentation of baseline lymphocyte reactivity.

Spleen cells from mice infected for 20 weeks with Schistosoma mansoni, exposed in vitro to soluble schistosomal egg antigens (SEA), treated with mitomycin C (Mc), and cocultured with syngeneic responder spleen cells increased the baseline proliferation of the otherwise unstimulated responder cells in cocultures. The role of macrophages in this "spontaneous" thymidine incorporation was studied directly by removal of macrophages on Sephadex G-10 columns. Removal of esterase-positive, Sephadex G-10-adherent cells (macrophages) greatly reduced the amount of SEA-induced, chronically infected spleen cell-mediated stimulation observed in cocultures. It also reduced an elevated background of spontaneous DNA synthesis seen with control cultures of spleen cells from infected animals. Depletion of T lymphocytes from chronic spleen cell populations by treatment with anti-Thy 1.2 serum and complement prior to exposure to SEA partially abrogated the augmentation effect. Comparison of these results with mitogen (concanavalin A)-induced spleen cell-mediated stimulation (which is elevated, rather than reduced, by macrophage removal) and with known alterations in splenic T- and B-lymphocyte ratios in chronic murine schistosomiasis suggests that antigen-stimulated, chronically infected splenic macrophage-dependent baseline augmentation may depend on specific T-lymphocyte-derived lymphokine induction. These results may reflect a general mechanism whereby animals harboring a persistent, chronic infection can respond quickly to a second or challenge infection or a flareup of the primary infection.

Animals↗
PubMed1984

The formation of surface membrane vesicles from schistosomula of Schistosoma mansoni.

Intact surface membrane vesicles were obtained and purified from the schistosomula of Schistosoma mansoni. The method of preparation of the vesicles involved treating the schistosomula in a buffered high salt medium for 1 h at 4 degrees C (Step 1), and then for 1 h at 25-37 degrees C (Step 2). Vesicles were formed from mechanically- and skin-transformed schistosomula, and their size and number depended on the temperature of Step 2. The majority of the vesicles expressed surface membrane concanavalin A receptors and parasite antigens on their outermost surfaces. When incubated with sensitized peripheral blood mononuclear cell preparations from humans exposed to schistosomal preparations, the vesicles stimulated lymphocyte transformation as effectively as soluble egg and adult worm antigens. Although both preparations contained identical proteins, small vesicles were less effective than large vesicles in stimulating lymphocyte transformation. Hence, vesicles prepared under a variety of conditions might be used to study those factors which influence the presentation of membrane-bound surface antigens to the immune system of the host.

Animals↗
PubMed1984

Evaluation of natural killer activity in human schistosomiasis.

Natural killer (NK) activity was assayed in peripheral blood mononuclear cells of patients with schistosomiasis, of patients following treatment, and of uninfected control subjects. The patient populations were from villages in the Qalyub Province, Egypt and around Belo Horizonte , Brazil. NK activity was assayed by the cytotoxicity of 51Cr-labelled K562 target tumor cells. In neither infected population were significant alterations from normal levels found in the percent cytotoxicity per 10(6) cells, or in the lytic units that expressed 25% cytotoxicity. Likewise, prior treatment (2 and 6 months previously) did not alter the group NK activity detected. Similarly, in the Egyptian study there was no difference in the percentage of large granular lymphocytes between the infected and uninfected groups. In parallel studies in Egyptian and Brazilian schistosomiasis patients we did not find any evidence that this chronic infection consistently altered circulating NK activity.

Adolescent↗
PubMed1984

Modulation of Schistosoma mansoni egg-induced granuloma formation. III. Evidence for an anti-idiotypic, I-J-positive, I-J-restricted, soluble T suppressor factor.

Modulation of pathogenic egg-induced hepatic granuloma formation in chronically Schistosoma mansoni-infected mice is an immunoregulatory process. Adoptive transfer and in vitro studies have demonstrated that this suppression involves various T lymphocyte circuitries, and the participation of soluble suppressor factors has recently been noted in these systems. The present study has partially characterized a soluble suppressive activity extracted from the thymus glands of chronically infected mice (SmTsF) that modulates granuloma formation in acutely infected mice. The suppressive effect of SmTsF could be administered by multiple i.v. injections or by slow release from osmotic minipumps implanted i.p. Homologous and reciprocal transfers of SmTsF prepared from B10.A(3R) and B10.A(5R) donors indicated that SmTsF-induced suppression required homology between the donor and recipient at the I-J subregion of the major histocompatibility complex. Furthermore, the use of immunoabsorbents prepared with anti-I-Jk and anti-I-Jb sera demonstrated that CBA/J (H-2k) SmTsF was retained by, and could be recovered from, anti-I-Jk insoluble columns, but was unaffected by parallel treatment with anti-I-Jb sera. Subsequent immunoabsorbent studies showed that SmTsF did not bind to soluble egg antigenic (SEA) columns, and thus demonstrated a lack of idiotype, anti-antigen activity. However, columns prepared by using anti-SEA IgG from chronically infected syngeneic mice retained SmTsF suppressive activity, and it could be recovered by alkaline elution. These data are compatible with an interpretation that the suppressive activity expressed anti-idiotypic reactivity. Thus a thymus extract obtained from chronic, modulated, S. mansoni-infected mice can induce granuloma suppression in acutely infected mice. This activity is associated with an I-J determinant-bearing, possibly anti-idiotypic moiety or moieties. These observations further implicate some of the Ts cascades reported in other systems in the regulation of cell-mediated pathogenesis in chronic experimental schistosomiasis.

Animals↗
PubMed1984

Immune responses and immunoregulation in relation to human schistosomiasis in Egypt. II. Cimetidine reversal of histamine-mediated suppression of antigen-induced blastogenesis.

The effect of histamine on cell-mediated immune responses of chronic schistosomiasis patients was tested by peripheral blood mononuclear cell (PBMN) reactions to phytohemagglutinin-P (PHA) and soluble schistosomal antigenic preparations derived from eggs (SEA) or adult worms (SWAP). PBMN responses to PHA were suppressed by exogenous histamine (10(-5)M), and the addition of cimetidine (CIM) (10(-4)M), an H2-receptor antagonist, reversed this suppressive effect. Histamine primarily suppressed PBMN responses to suboptimal and optimal PHA concentrations. Exogenous histamine (10(-5)M) also suppressed PBMN responses of 27 schistosomiasis patients to SEA and SWAP, respectively. The addition of CIM (10(-4)M) to suppressed cultures reversed the effect of exogenous histamine. Most importantly, the addition of CIM to schistosomal antigen-induced cultures, without exogenous histamine, significantly increased patients' PBMN responses to SEA and SWAP. The mean optimal increase in SEA responses of 19 patients was 390%. With SWAP-induced responses of 21 patients this increase was 165%. The use of 10(-4)M diphenhydramine (DPH), an H1-receptor antagonist, resulted in general suppression of both PHA-induced and schistosomal antigen-induced PBMN responses. Lower concentrations of DPH lead to variable responses but did not result in consistent abrogation of the histamine-induced suppression. These data imply that an histamine-induced, H2-receptor-mediated suppressor circuit often helps modulate antigen-specific responsiveness of PBMN from patients with chronic schistosomiasis.

Adult↗
PubMed1983

Identification of lipoxygenase products from arachidonic acid metabolism in stimulated murine eosinophils.

The presence of arachidonic acid lipoxygenase pathways in murine eosinophils was demonstrated by the isolation and identification of several lipoxygenase products from incubations of these cells. The most abundant arachidonate metabolite from murine eosinophils stimulated with ionophore A23187 and exogenous arachidonic acid was 12-S-hydroxyeicosatetraenoic acid (12-S-HETE), and the next most abundant was 15-HETE. Two families of leukotrienes were also recovered from these incubations. One family comprised the hydrolysis products of leukotriene A4, and the other included products derived from the 14,15-oxido analog of leukotriene A4 (14,15-leukotriene A4). Two double oxygenation products of arachidonate were also identified. These compounds were a 5,15-dihydroxyeicosatetraenoic acid (5,15-diHETE) and a 5,12-dihydroxyeicosatetraenoic acid (5,12-diHETE). Eosinophil stimulation promoter is a murine lymphokine which enhances the migration of eosinophils. When murine eosinophils were incubated with eosinophil stimulation promoter in concentrations sufficient to produce a migration response, a 2-3-fold increase in the production of 12-HETE was observed compared to unstimulated cells. Coupled with the recent demonstration that arachidonic acid lipoxygenase inhibitors suppress the migration response to eosinophil stimulation promoter and that 12-HETE induces a migration response, this observation provides further evidence in support of the hypothesis that eosinophil stimulation promoter stimulation of eosinophils results in the generation of lipoxygenase products which modulate the migratory activity of the cells.

Animals↗
PubMed1983

The effects of indomethacin on in vitro peripheral blood mononuclear cell reactivity in human schistosomiasis.

The peripheral blood mononuclear cell (PBMN) proliferative responses of cells from patients with schistosomiasis were studied in the presence and absence of indomethacin in the culture medium. PBMN cultures were exposed to antigenic extracts of either adult S. mansoni worms (SWAP) or cercariae (CAP), and assayed for the incorporation of tritiated thymidine. More than 70% of the 48 patients studied with SWAP and the 40 patients studied with CAP, were not substantially effected by the addition of indomethacin to the cultures. The remainder (less than 30%) was augmented more than 50% by indomethacin and comprise a group which gave initially low responses to these antigenic preparations. Further analysis indicated that in some schistosomal patients the effect of an adherent suppressor cell population may, in part, be based on a prostaglandin-mediated, indomethacin-sensitive suppressive mechanism. However, the majority of patients, most of whom display adherent suppressor cells, are unaffected by indomethacin. Apparently, other adherent cell suppressor mechanisms are responsible for the regulation observed.

Adolescent↗