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Biomedical subjects

D A Clark

Publications and source records attributed to D A Clark.

At least 343 records · Page 19Linked to original sources
PubMed1984

Sensitivity to suppression of cytotoxic T cell generation by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is dependent on the Ah genotype of the murine host.

Susceptibility of mice to a variety of toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is genetically determined by the Ah locus. To determine if immunotoxicity following TCDD exposure was also regulated by the Ah locus, we tested the ability of low dose TCDD (4 ng/kg) to suppress the generation of allospecific cytotoxic T cells (CTL) by lymphocytes from "susceptible" C57B1/6, and "resistant" DBA/2, and from C57B1/6XDBA/2J F1 hybrid mice in vitro. To determine if TCDD acted directly on the "susceptible" lymphoid cells, the immune response of C57B1/6 leads to DBA/2 and DBA leads to C57B1/6 bone marrow chimeras was also measured. C57B1/6 and F1 mice proved susceptible to suppression consistent with the dominant effect of Ah. Susceptibility to suppression in chimeric mice, however, was determined by the Ah genotype of the host and not by the genotype of the grafted lymphomyeloid cells. Mixing experiments demonstrated that suppression of CTL generation by TCDD was due to suppressor T cells. The frequency of CTL precursors was not affected by TCDD. These results are consistent with the idea that TCDD acts by an Ah locus-dependent mechanism to indirectly promote development of suppressor T cells that block the generation of CTL from their precursors.

Animals↗
PubMed1984

Anemia of prematurity: determinants of the erythropoietin response.

This study was undertaken to determine the factors that are important in determining the erythropoietin response in low-birth-weight infants during the period of so-called anemia of prematurity. In the first weeks of life oxygen consumption in a group of 21 infants gradually increased as hemoglobin level fell. The magnitude of the erythropoietin response inversely varied with the central venous oxygen tension (P-vO2) (r = -0.55, P less than 0.001). When the P-vO2 declined to less than 30 torr, erythropoietin values were uniformly increased above the "normal" range (defined as the values associated with P-vO2 greater than 38 torr). Erythropoietin values varied inversely with hemoglobin but in general did not exceed the values observed for normal adult men. The erythropoietin values in the infants were remarkably lower at any given hemoglobin level when compared with those of older children with anemia resulting from bone marrow failure. In general, elevations of erythropoietin were seen when the hemoglobin concentration declined to less than 10.0 gm/dl. Change in heart rate did not appear to be a reliable indicator of the presence of anemia; rather, it correlated best with oxygen consumption.

Adult↗
PubMed1984

Recruitment of cytotoxic cells by ectopic grafts of xenogeneic, but not allogeneic, trophoblast.

In previous studies we showed that survival of Mus caroli embryos in the Mus musculus uterus was dependent on trophoblast genotype; M musculus trophoblast was protective while M caroli trophoblast was not. In this report we compare the immune response of M musculus to ectopic grafts of pure trophoblast of M caroli and M musculus genotypes to elucidate further differences between the properties of trophoblast from the two species that might account for the failure of M caroli trophoblast to protect the fetus. Grafts of M caroli or DBA/2J ectoplacental cone (EPC) or embryonic tissue (E) were placed beneath the renal capsule of Ha(ICR) mice that were untreated or had been immunized with M caroli lymphocytes or with P815 mastocytoma cells. No consistent morphological difference could be demonstrated between the xenografts and allografts by gross or histological examination. Cellular infiltration of allogeneic and xenogeneic EPC graft sites occurred in immunized mice within 5 days of grafting. Cells specifically cytotoxic to M caroli lymphoblasts were isolated from the xenogeneic graft sites, but no allogeneically sensitized cytotoxic cells could be demonstrated. These results show that xenoantigens expressed on trophoblast induce a cytotoxic immune response more readily than alloantigens.

Animals↗
PubMed1984

Local active suppression by suppressor cells in the decidua: a review.

The immunological survival of the antigen-bearing mammalian feto-placental unit is determined by the functional properties of the tissues at the feto-maternal interface. Antigen-specific systemic suppressor mechanisms such as suppressor T cells and nonantigen-specific suppressive serum factors appear not to play a major role in protection of the fetus. A novel type of non-MHC specific suppressor cell accumulates locally in the decidua of successfully allopregnant mice. This decidua-associated suppressor is a small lymphocytic cell possessing cytoplasmic granules, lacks T cell markers, and is deficient in number and activity at the implantation sites of viable xenogeneic Mus caroli embryos gestating in the uterus of Mus musculus animals at the time that maternal lymphoid cells begin to infiltrate the xenoembryos. These Mus caroli embryos subsequently resorb. Further experimental studies suggest that the trophoblast cells associated with successful pregnancy recruit bone-marrow derived maternal non-T suppressor cells to the decidua and thus, by an indirect mechanism, may act to protect the fetus from effector cells of the mother's immune system.

Animals↗
PubMed1984

Differences in thromboxane production between neonatal and adult platelets in response to arachidonic acid and epinephrine.

In this study, we have investigated the possible role of the pro-aggregatory arachidonic acid (AA) metabolite thromboxane, in the impaired function of neonatal platelets. In platelet-rich plasma thromboxane production (measured by radioimmunoassay of thromboxane B2) was not different between neonates and adults when stimulated by thrombin (at 0.1 or 1.0 U/ml) or collagen (70 micrograms/ml) although neonatal platelets produced decreased thromboxane (TBX2) postepinephrine stimulation. In response to 1 U/ml thrombin, adult and neonatal platelet-rich plasmas produced mean values of 3.41 +/- 0.35 (SEM) and 3.11 +/- 0.49 pmol of TXB2/10(6) platelets, respectively. Production of TXB2 in response to 0.1 U/ml thrombin was not dissimilar between neonates (1.01 +/- 0.46 pmol) and adults (1.04 +/- 0.38 pmol). When collagen was used as the aggregating agent, TXB2 production was also not significantly different with values of 2.44 +/- 0.48 and 1.90 +/- 0.46 pmol/10(6) platelets produced by adult and neonatal platelet-rich plasma, respectively. In response to 200 microM epinephrine, adult platelets produced 1.03 +/- 0.39 pmol TXB2/10(6) platelets while neonatal platelet TXB2 production was significantly decreased (0.15 +/- 0.04; P less than 0.05). Thromboxane production in response to AA, however, was markedly elevated in neonatal platelet-rich plasma. When 200 and 400 microM concentrations of AA were used as the aggregating stimuli, neonatal platelet rich plasma produced 3.17 +/- 0.77 and 8.0 +/- 1.47 pmol TXB2/10(6) platelets, respectively. These values were significantly elevated P less than 0.02 and less than 0.005) when compared to mean values of 0.41 +/- 0.10 and 3.32 +/- 0.15 pmol in adult platelet-rich plasma.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1984

Studies of the accuracy of measurements of serum high density lipoprotein cholesterol levels.

Titration of serum lipoproteins with three different precipitants--heparin-MnCl2 92 mmol.L-1, dextran sulfate-MgSO4, and phosphotungstate-MgCl2--revealed gross errors in the high density lipoprotein cholesterol (HDL-C) levels measured in some hyperlipidemic sera. Dilution studies of eight normal sera with the phosphotungstate method revealed that the most reliable estimate of the HDL-C level was the level measured in the least diluted aliquot that yielded a good precipitate. With a heparin-MnCl2 kit, serial dilution of a lipemic serum demonstrated a requirement for a blank correction. Establishing an accurate estimate of the HDL-C level sometimes requires knowledge of the titration curve of the lipoprotein precipitant being used, a blank correction, and data obtained from dilution studies (or studies with increased precipitant levels) on the serum in question.

Cholesterol, HDL↗
PubMed1984

Acquired immune hemolytic anemia associated with IgA erythrocyte coating: investigation of hemolytic mechanisms.

We have investigated the hemolytic mechanisms in a patient with acquired immune hemolytic anemia whose red cells appeared to be coated with IgA alone. The clinical course was similar to that of patients with hemolytic anemia mediated by warm-reacting IgG antibody. Splenic sequestration of red cells was demonstrated, and marked reduction of hemolysis occurred after corticosteroid therapy. Antibody was eluted from the patient's red cells and used to sensitize normal red cells in vitro. These sensitized red cells were not lysed by fresh autologous serum, nor did they fix detectable amounts of C3. However, red cells sensitized by eluted antibody were lysed by normal human peripheral blood monocytes in a system designed to demonstrate antibody-dependent cell-mediated cytotoxicity. Monocyte-mediated hemolysis of sensitized red cells was inhibited by the addition of low concentrations of normal serum IgA to the system, but not by IgG. The ability of the eluate to induce monocyte-mediated hemolysis was abolished by its adsorption on Sepharose-bound anti-IgA, but not by preincubation with Sepharose-bound anti-IgG. In addition, normal human monocytes were demonstrated to ingest eluate-sensitized red cells. These data demonstrate an in vitro interaction of IgA-sensitized red cells with leukocytes and suggest a possible mechanism for the patient's hemolysis.

Aged↗
PubMed1984

Studies on pure red cell aplasia. XI. Results of immunosuppressive treatment of 37 patients.

Thirty-seven patients with pure red cell aplasia (PRCA) were seen between 1966 and 1982. Ten patients had accompanying diseases described in association with PRCA, while the remainder had primary PRCA. All but two patients were treated with some form of immune manipulation, including corticosteroids, cytotoxic drugs, antithymocyte globulin, splenectomy, thymectomy, and plasmapheresis. Twenty-three patients (66%) had a remission induced by immunosuppression. In addition, there were 5 spontaneous remissions (14%). Cytotoxic drugs administered in combination with corticosteroids were the most effective form of treatment, producing 18/32 remissions (56%). Twelve of these remissions were in patients resistant to corticosteroids or in patients who had relapsed while taking them. Thirteen of the 23 patients in whom remissions were induced and one-fifth of the patients with spontaneous remissions have relapsed to date. However, with additional treatment, a second remission was induced in 10/13. Fifty-four percent of the patients with induced remissions remained transfusion-free during most of the follow-up period. Median survival in patients with primary PRCA was greater than 10 yr, whereas in patients with secondary PRCA, it was 4 yr. Infection was a major cause of morbidity and mortality. This study demonstrates the value of a variety of immunosuppressive treatments of patients with PRCA.

Adolescent↗
PubMed1984

Sensitivity of human carcinoma cell lines to lysis by blood natural killer cells correlating with surface expression of carcinoembryonic antigen.

The HCT-8R clone of the HCT-8 human colon tumor line, which expresses increased quantities of carcinoembryonic antigen (CEA) on its surface, was discovered to have an enhanced susceptibility to lysis by natural killer (NK) cells in human peripheral blood. This increase in susceptibility to lysis by peripheral blood mononuclear cells was not explained by stimulation of interferon release by HCT-8R cells but rather was found to be attributable to an increased susceptibility of HCT-8R cells to lysis by those NK cells that bind to sheep erythrocytes (E-RFC). Cold target competition experiments and single-cell assay for cytotoxic cells suggested that the presence of surface CEA did not increase lysis of HCT-8R by facilitating "recognition" by E-RFC-type cytotoxic cells but by rendering HCT-8R cells more susceptible to the lytic mechanism of NK cells. The magnitude of expression of surface CEA by a variety of human carcinoma cell lines with a few exceptions and subclones of HCT-8 also correlated with increased susceptibility to lysis by blood mononuclear cells. The possible clinical significance of these findings was discussed.

Antibody-Dependent Cell Cytotoxicity↗
PubMed1984

Differences in lymphocyte responsiveness to lymphokines in two inbred strains of Syrian hamster.

Two inbred strains of Syrian hamster have been shown to display differences in splenic NK cell activity both endogenously and after infection with Pichinde virus. On further investigation of these differences, it was found that the spleens and thymuses of the high NK strain, MHA, displayed greater cellularity than those of the low NK strain, LSH. Additionally, thymocytes from MHA hamsters were found to proliferate to a greater extent than those of LSH hamsters in response to Con A-induced conditioned medium plus lectin. Splenocytes from MHA hamsters showed high levels of lymphokine-activated killer cell (LAK) activity after culture in conditioned medium, in contrast to LSH splenocytes cultured under the same conditions. By limiting dilution analysis, spleens from MHA hamsters were found to contain a greater frequency of LAK precursors than those from LSH hamsters. The data suggest that the relative concentrations of lymphopoietic cells is genetically determined.

Animals↗
PubMed1983

Increased sensitivity to complement of erythroid and myeloid progenitors in paroxysmal nocturnal hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria is an acquired hemolytic anemia characterized by a membrane defect leading to increased sensitivity of erythrocytes, granulocytes, platelets, and bone-marrow erythroid and myeloid cells to complement-mediated lysis. To determine whether the phenotype of paroxysmal nocturnal hemoglobinuria is also expressed on erythroid and myeloid progenitors, marrow cells from five patients with the disease were exposed to a sucrose hemolytic system and then assayed for colony-forming units-erythroid (CFU-E), burst-forming units-erythroid (BFU-E), and colony-forming units-granulocyte/macrophage (CFU-GM). A 50 percent or greater decrease in the numbers of erythroid and myeloid colonies was noted when marrow cells from the patients with paroxysmal nocturnal hemoglobinuria were exposed to a sucrose solution of low ionic strength in the presence of complement but not in its absence. Such a decrease was not noted in similarly treated normal marrow cells or in marrow cells from a patient with the disease in remission. These results suggest that in paroxysmal nocturnal hemoglobinuria, CFU-E, BFU-E, and CFU-GM express a membrane abnormality similar to that on erythrocytes, and that the disease is the result of a change occurring at the level of the pluripotent hematopoietic stem cell.

Adult↗
PubMed1983

Interspecific hybrids and chimeras in mice.

Interspecific hybrids and chimeras in mammals provide unique tools for investigating problems in genetics and embryology, because of the degree of disparity between the two component genotypes. We have attempted to produce hybrids and chimeras between Mus musculus, the laboratory mouse, and Mus caroli, a wild species of mouse from Southeast Asia. M. musculus and M. caroli do not normally interbreed, although sterile hybrids can be produced at a low rate by artificial insemination. Extrinsic problems of genotypic incompatibility between the fetus and the maternal environment seem to be involved in poor hybrid survival, since M. caroli blastocysts also die when transferred to the M. musculus uterus. Death is associated with the generation of maternal T-cells which are cytotoxic to M. caroli target cells in vitro. It is not yet clear whether this immune response is the primary cause of death or is secondary to breakdown of some other components of the fetal-maternal interaction. It is clear, however, that it is the trophoblast layer that mediates survival or death of the foreign embryonic cells in the M. musculus juterus, since M. caroli inner cell mass cells can survive to term after injection into M. musculus blastocysts: Viable interspecific chimeras result. Even more convincing evidence is provided by the production of viable M. caroli offspring by trophoblast vesicle reconstitution using trophoblast of M. musculus genotype and inner-cell mass of M. caroli type. Studies of properties of isolated trophoblast tissues have indicated that M. caroli trophoblast may differ from M. musculus in both its antigenic and immunosuppressive properties. Elucidation of trophoblast-uterine interactions in these various interspecific pregnancies is being aided by the development of an in situ marker system, which can distinguish cells of the two species in sectioned material by in situ hybridization with a M. musculus satellite DNA probe. This same marker is also proving a very powerful tool for analyzing cell lineage development in chimeras.

Animals↗
PubMed1983

Cellular and genetic basis for suppression of cytotoxic T cell generation by haloaromatic hydrocarbons.

Generation of allospecific cytotoxic T cells in C57Bl/6 mice is significantly impaired following exposure to TCDD at doses as low as 4 ng/kg. T helper activity, as assessed by the ability to produce Interleukin 2, and frequency of CTL precursors appear unaffected in treated animals and thus the TCDD-induced suppressor cells we have described are primarily responsible for the reduction in the CTL response. Suppression of CTL generation in DBA/2 mice requires a 10--100-fold greater dose than in C57Bl/6, consistent with the observation that the Ah locus gene(s) of DBA/2 mice code for TCDD receptors with low binding affinity for TCDD. Other haloaromatic hydrocarbons (3,3'4,4'-tetrachlorobiphenyl and Aroclor 1254), capable of binding to the TCDD receptor, also suppress CTL generation, whereas the 2,2',4,4',6,6'-hexachlorobiphenyl molecule that lacks affinity for the TCDD receptor does not suppress CTL. The immunotoxic effects of TCDD in C57B/6 and DBA/2 mice occur at dose levels below those required to induce mixed-function oxidase enzymes in the liver. Suppression of CTL by TCDD is associated with increased susceptibility to lethal herpes virus type II infection. These data suggest that low levels of TCDD may interact with cytoplasmic receptors for TCDD in the thymus and induce biologically significant immunosuppression through activation of suppressor cells.

Animals↗
PubMed1983

Pharmacokinetics of metronidazole in patients undergoing peritoneal dialysis.

After a single 500-mg intravenous dose of metronidazole, plasma and dialysate levels were measured over a 7.5-h period in five patients undergoing peritoneal dialysis for terminal renal failure. Approximately 10% of this dose was removed by dialysis during that period, and therapeutic levels were maintained in plasma. No routine adjustment in the dosage of metronidazole appears necessary in patients undergoing peritoneal dialysis.

Adult↗
PubMed1983

Interaction between bovine casein and V. cholerae enterotoxin in the rabbit ileal loop.

Secretory IgA from human breast milk neutralizes cholera enterotoxin in the rabbit ileal loop system. No similar protection by purified bovine milk proteins could be demonstrated; however, one bovine milk protein, casein, had a deleterious effect on intestine exposed to very small quantities of enterotoxin. Highly purified cholera toxin (10 or 100 ng) was incubated with bovine protein solutions for 60 min at 37 degrees C. One-milliliter aliquots were then injected into prepared rabbit intestine loops. The animals were sacrificed at 18 h and the intestinal loop contents were aspirated, and a volume to length of loop ratio (V/L) was determined. The activity of 100 ng of toxin was not enhanced by the majority of bovine milk proteins, but bovine casein caused a 14-40% increase in the fluid production (V/L of casein + toxin versus toxin, 1.05 versus 0.92 and 1.82 versus 1.30). All of the bovine proteins but casein inhibited the action of low dose enterotoxin. Bovine casein caused a 78-90% increase in fluid production by loops exposed to a suboptimal toxin dose (10 ng) (V/L of casein + toxin versus toxin, 1.12 versus 0.63 and 0.95 versus 0.50). Virtually all of this enhancement of enterotoxin fluid response resided in the purified alpha-casein fraction.

Animals↗
PubMed1983

In vitro activity and in vivo correlates of alloantigen-specific murine suppressor T cells induced by allogeneic pregnancy.

The fetus that results from allogeneic mating in an outbred population bears a variety of antigens against which the maternal immune system reacts, but the type of immunity that is elicited by pregnancy does not mediate graft rejection. Previous studies have demonstrated the presence of nonspecific non-thymus derived suppressor cells in the lymph nodes draining the uterus (DLN) and in the uterine decidua during first allogeneic pregnancy. These suppressor cells appear to be small lymphoid cells that inhibit the generation of cytotoxic T cells (CTL) against paternal alloantigens. We now report that after a single allogeneic pregnancy, C3H and A strain mice develop paternal alloantigen-specific suppressor T cells (Thy-1.2+, Lyt-1-2+) that are distributed systemically in peripheral lymph nodes and spleen. These suppressor cells appear to act directly on CTL generation because the frequency of CTL precursors and the ability to produce T helper cells in response to paternal alloantigens remains unchanged after allogeneic pregnancy. Suppressor T cell activity could be detected both in vitro and in vivo, and the presence of suppression in vivo was associated with increased uterine weight 5 days after inoculation of allogeneic paternal tumor cells into the uterus of pseudopregnant mice. Nevertheless, both subcutaneous and intrauterine tumor inocula regressed in these mice with suppressor T cells. The possible role of suppressor T cells in contrast to non-T suppressor cells in successful reproduction and allopregnancy-induced tolerance is discussed.

Animals↗