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Biomedical subjects

D A Clark

Publications and source records attributed to D A Clark.

At least 307 records · Page 17Linked to original sources
PubMed1986

Active suppression of host-vs-graft reaction in pregnant mice. VII. Spontaneous abortion of allogeneic CBA/J x DBA/2 fetuses in the uterus of CBA/J mice correlates with deficient non-T suppressor cell activity.

The mammalian fetus has been viewed as an unusually successful type of "allograft" and "unexplained" spontaneous abortion as a possible example of maternal rejection. Previous studies have shown the presence of small lymphocytic suppressor cells in the murine decidua which block the generation and reactivation of anti-paternal cytotoxic T lymphocytes (CTL) and lymphokine-activated killer cells (LAK) by elaborating a factor that inhibits the response to interleukin 2 (IL 2). A deficiency of these suppressor cells was associated with implants of xenogeneic Mus caroli embryos in the Mus musculus uterus which are infiltrated by maternal lymphoid cells and aborted. We have also shown a deficiency of such suppressor cells in the lymph nodes draining the uterus of CBA/J females in the process of aborting their semi-allogeneic CBA X DBA/2 F1 progeny. CBA/J females possess significantly lower levels of decidua-associated non-T suppressor cells on day 8.5 to 10.5 of allopregnancy than do mothers that will produce large litters of live babies. The F1 embryos are infiltrated by maternal lymphocytes prior to abortion, and the infiltration and abortion rate appears to be augmented by pre-immunization with paternal DBA/2 spleen cells. Susceptibility to spontaneous abortion is dependent upon maternal age and strain of male mate, and the high abortion rate of CBA/J mated to DBA/2 males can be reduced by immunization with BALB/c spleen cells. The CBA/J x DBA/2J mating combination provides a model of spontaneous abortion in which immunologic factors play an important role and demonstrates that the association between deficiency of decidua-associated suppressor cells and xenopregnancy failure also holds true for the failure of allopregnancies resulting from natural within-species mating.

Abortion, Spontaneous↗
PubMed1986

Intraepithelial leukocytes contain a unique subpopulation of NK-like cytotoxic cells active in the defense of gut epithelium to enteric murine coronavirus.

Initially the intraepithelial leukocytes (IEL) of specific pathogen free (SPF) mice were compared with those of mice held without isolation and were found to differ markedly in total number and distribution of cell surface antigens. The IEL from SPF mice expressed significantly less Thy-1, Lyt-1, and Lyt-2 antigens than their conventional counterparts. The local cell-mediated immune response of mucosal lymphocytes to an enteric murine coronavirus (MHV-Y) was studied in inbred strains of naive SPF mice. A potent in vitro cytotoxic activity was demonstrated by mucosal leukocytes, especially IEL, and spleen cells for MHV-Y-infected syngeneic and allogeneic target cells. The cytotoxicity was not restricted by the major histocompatibility complex. Targets infected with Pichinde virus, an enveloped nonenterotropic virus, were not lysed by these cells. The phenotype of the IEL effector cell was asialo GM1+, Thy-1-, Lyt-1-, Lyt-2-. This cell represents a small subpopulation of the total IEL. After the in vivo administration of anti-asialo GM1 sera, the virus-specific cytotoxic function of the IEL was markedly diminished in in vitro assays, and there was enhanced persistence of virus in gut tissues in vivo. The IEL effector population is defined as a natural killer-like cell that appears to be active in the defense of the gut epithelium to a murine enteric coronavirus.

Animals↗
PubMed1986

Balloon angioplasty of coronary bifurcation lesions: the kissing balloon technique.

Initial experience with the technique of "kissing balloon" angioplasty is described in 52 patients undergoing coronary angioplasty. Guiding catheters employing both the femoral and brachial approach were used in all but two of the coronary angioplasties and, in addition, the bilateral femoral approach was used in the renal and peripheral angioplasties. Initial success was achieved in 51 (98%) patients. Abrupt closure requiring urgent coronary revascularization occurred in one patient six hours following the completion of the procedure. Another patient developed a new Q-wave on the electrocardiogram and moderate elevation of CPK-MB fraction following the procedure due to loss of a diagonal branch. No deaths occurred in this series. Angiographic restenosis developed in ten patients. In the recurrence group, five had repeat kissing balloon angioplasty, two had repeat single vessel angioplasty, and three patients chose elective surgical revascularization. Based on our experience, the technique of kissing balloon coronary angioplasty can be performed safely utilizing the brachio-femoral technique. The risk of major side branch occlusion can be minimized with this technique and the overall complication rate does not significantly differ from that of our experience in single vessel coronary angioplasty. Patient selection criteria are based upon the angiographic relationship of the major branch to the side branch and is important in determining the initial and long-term success of this technique.

Adult↗
PubMed1986

Phosphorus-31 nuclear magnetic resonance measurements of 2,3-DPG degradation in human adult and cord blood erythrocytes.

We have measured the percent change in 2,3-diphosphoglycerate (DPG) concentration in cord blood erythrocytes and adult erythrocytes during incubation at 37 degrees C using 31P nuclear magnetic resonance spectroscopy. DPG concentrations remained unchanged during the first 4.0 +/- 0.9 h (mean + SD) for cord blood erythrocytes and 6.0 +/- 1.0 h for adult blood erythrocytes. After this plateau phase, cord blood and adult erythrocyte DPG concentrations decreased at a rate of 11.6 +/- 0.4 and 11.4 +/- 0.5% of the baseline DPG concentration per hour, respectively. There was no statistically significant difference in the percent rate of DPG degradation when comparing cord blood erythrocytes to adult erythrocytes during either the plateau phase or the decay phase. Starting at the onset of the decay phase, the neonate 3-P DPG resonance shifted downfield at a rate of 0.03 +/- 0.006 ppm per hour; the adult 3-P DPG resonance shifted downfield at a rate of 0.02 +/- 0.003 ppm per hour.

2,3-Diphosphoglycerate↗
PubMed1986

Predictors of severity of attacks of acute pancreatitis.

In an attempt to reduce the current morbidity and mortality from acute pancreatitis, a prospective randomized multicentre trial was begun in August 1982. Part of this study involved an attempt to develop a set of prognostic indices which would identify patients with severe pancreatitis on the day of admission to hospital. An analysis of a predetermined set of 10 indices (age, blood pressure, white cell count, blood urea, serum calcium, aspartate aminotransferase, lactate dehydrogenase, blood glucose, arterial blood pH and PO2) on admission to hospital, in 100 patients, is presented. The positive predictive value of these indices (excluding age) is 90%. These indices are readily available in most hospitals, and allow the early identification of the high risk patient with an accuracy equal to or better than that previously reported.

Acute Disease↗
PubMed1986

Production of immunosuppressor factor(s) by preimplantation human embryos.

Embryonic loss prior to implantation appears to be a significantly frequent phenomenon and this is further reinforced by the very low pregnancy rates reported by in vitro fertilization and embryo transfer programs. Implantation failure may possibly be the result of rejection of the antigenic embryo by the hostile maternal immune system. The mechanism by which embryos in successful pregnancies escape these rejection responses may depend upon their ability to produce factor(s) that suppress in vitro mitogen-induced lymphocyte proliferation. Only 43% of cleaved embryos demonstrated this ability. We postulate that successful pregnancies are dependent upon the production by embryos of immunosuppressor factor(s) that has a direct suppressive effect on the maternal immune response.

Blastocyst↗
PubMed1986

Free fatty acids of human meconium.

Meconium samples of 20 healthy full-term babies were analyzed for free fatty acid content. The total fatty acid content per net weight varied by as much as 9-fold between samples. Considerable variability was also observed in the individual fatty acids found in each sample. Palmitic, stearic and oleic acids were the most abundant fatty acids. Significant amounts of arachidonic and linoleic acids were found. Long-chain iso fatty acids, which are rare in mammalian tissue, were found. The source of these fatty acids is unknown, but intestinal lipases and transplacental origins may be important.

Fatty Acids, Nonesterified↗
PubMed1986

Immune presensitization and local intrauterine defences as determinants of success or failure of murine interspecies pregnancies.

Putatively immuno-incompetent Mus musculus females exhibited failure to support pregnancy of Mus caroli embryos. These results for M. musculus females (i.e. treated by cyclosporine A, of the nu/nu genotype, and as an interspecies chimaera) can be explained in immunological terms. Mus musculus females possessed pre-sensitized cytotoxic T cells against Mus caroli antigen. Nu/nu mice possessed activated NK cells and macrophages, and selectively discriminated against Mus caroli embryos early in pregnancy unlike normal +/+ females; the requirement for T cells to activate non-specific cytotoxic effector mechanisms was bypassed in nu/nu mice. Mus caroli are not inbred, and interspecies chimaeras which are tolerant of the antigens on the Mus musculus donor strain were not tolerant of cells from unrelated Mus caroli. Interspecies chimaeras also behaved as if they were pre-sensitized to Mus caroli. Our results show that Mus caroli embryos recruit fewer active suppressor cells even when gestating in Mus caroli decidua as compared to Mus musculus embryos in Mus musculus decidua and that the ability of Mus caroli placental cells to directly inhibit cytotoxic effector cell killing was inherently less than the inhibitory activity of placental cells from Mus musculus. Mus caroli embryos therefore appear to be less well defended against maternal immune attack even when gestating in a uterus possessing compatible Mus caroli decidual tissue.

Animals↗
PubMed1986

T lymphocytes in the intestinal epithelium and lamina propria of mice.

Mesenteric lymphoblasts have a predilection to localize selectively in the murine small intestine within 24 hr after adoptive transfer. In this report, we quantify the localization and intraintestinal distribution of radiolabelled mesenteric lymph node (MLN) T and B blasts in relation to the in situ distribution of intestinal T and B cells which were detected immunohistochemically. Our results show that, within 24 hr after transfer, MLN T blasts localized predominantly in the intestinal epithelium and villus lamina propria, whereas B blasts were found mostly in the basal lamina propria of the gut. In the epithelium and villus lamina propria, 100% and 68%, respectively, of labelled were of thymic origin; this cell type comprised 54% of labelled cells in the basal lamina propria. This pattern of localization was the reverse of the distribution of T lymphocytes and B-cell derived plasmacytes residing in the intestinal wall. These results suggest that MLN T lymphocytes may be a component of common mucosal immunological system and may be integrated with peripheral immunity according to the immunological needs of the host.

Animals↗
PubMed1986

Immunoregulatory molecules of trophoblast and decidual suppressor cell origin at the maternofetal interface.

The mammalian fetus expresses a variety of paternal histocompatible, oncofetal, and trophoblast antigens against which the mother can mount an immune response. Survival of the "fetal graft" appears to depend upon local immunosuppressive mechanisms in lymph nodes draining the uterus and at the intrauterine implanation site itself. Nonspecific not-T-Fc-receptor-bearing small lymphocytes containing cytoplasmic granules present in successfully allopregnant mice can suppress both the generation of maternal-antipaternal killer T cells and the infiltration of cytotoxic T lymphocytes into sponge-matrix allografts during the effector phase of the immune response. These suppressor cells are deficient at the implantation sites of xenogeneic and allogeneic mouse embryos that are susceptible to maternal immunity and are destined to resorb. A soluble suppressor factor of approximately 100,000 daltons in size can be obtained from the suppressor cells and acts to block the response of T cells to interleukin-2 by interfering with IL-2 receptors. The development of the suppressor cells in the decidua requires certain hormonal signals as well as signals provided by trophoblast cells. Freshly explanted or cultured murine trophoblast cell lines elaborate soluble factor(s) that are active in recruitment or activation of suppressor cells. Since suppressor cells may be isolated from decidua of successfully allopregnant humans, the suppressor cell mechanism and its regulation may represent a key factor in the protection of the "fetal allograft" from rejection by maternal immunity.

Abortion, Spontaneous↗
PubMed1986

Effects of ethanol on cultured human megakaryocytic progenitors.

Ethanol intoxication may result in the suppression of platelet production in human beings through direct toxicity to the bone marrow. To determine whether this suppression is due in part to a toxic effect on megakaryocytic progenitors, human bone marrow was cultured for 15 days in plasma clots, and megakaryocytic colonies were enumerated. Addition of ethanol to cultures at the beginning of incubation resulted in a reduction in megakaryocytic colonies only when the initial ethanol concentration exceeded 1 g/dl, well above physiologically tolerated levels. However, when cultures were treated with lower concentrations of ethanol (0.5 g/dl) after seven days of incubation, a reduction of megakaryocytic colony formation also occurred. These results suggest that development of a human cell more differentiated than the megakaryocytic progenitor is sensitive to ethanol toxicity at or near concentrations observed in vivo and is in accord with clinical features of the reversible alcohol-induced thrombocytopenic syndrome.

Cell Differentiation↗
PubMed1986

Effects of recombinant erythropoietin on murine megakaryocytic colony formation in vitro.

The availability of pure recombinant erythropoietin permits the study of its effects on hematopoietic progenitors free from those of other factors that may copurify with it. Mouse bone marrow cells were cultured in plasma clots in the presence of recombinant human erythropoietin. This factor supported megakaryocytic colony formation in a dose-dependent fashion, with plateau growth at 1 U erythropoietin per milliliter of culture medium. Erythropoietin did not increase the number of granulocyte-macrophage colonies. Plasma clots per se were not essential for megakaryocytic colony formation, because recombinant erythropoietin also supported colony growth in soft agar containing 25% serum. However, little colony formation was observed in serum-free soft agar cultures containing erythropoietin. Colony formation supported by suboptimal concentrations of erythropoietin was additive to that supported by suboptimal amounts of medium conditioned by pokeweed mitogen-stimulated spleen cells or by WEHI-3 cells. Delayed addition of conditioned medium to cultures resulted in a 50% to 100% decline in the number of megakaryocytic colonies by 12 to 48 hours, which was abolished by the inclusion of erythropoietin in the original culture medium. Delayed addition of erythropoietin by 24 hours to cultures resulted in loss of its effect on colony formation. These results indicate that erythropoietin has an effect on murine megakaryocytic colony formation in vitro and show that at least a portion of this effect is exerted during the early stages of colony development.

Animals↗
PubMed1985

Suppressor cells in human decidua.

Decidual suppressor cells have been found in the murine system. These cells are absent at the implantation sites of interspecies mouse embryos which become infiltrated by maternal cytotoxic cells. Suppression is also deficient at the sites of the spontaneous resorption of fetuses in allomated intraspecies pregnancies. This study was carried out to determine whether similar suppressor cells were present in the decidua during successful human allopregnancies. Decidua was obtained from gestations of 13 to 15 weeks and from term gestations, and the lymphocytes were tested for their ability to suppress the response of their peripheral blood lymphocytes to concanavalin A. Eight of eight 13- to 15-week decidual lymphocytes proved to be suppressive. At term seven of twelve lymphocyte preparations at a lower concentration of cells and six of seven at a higher concentration showed suppression. Suppressor cells appear to be present in human decidua and may play a role in preventing maternal immunologic attack on the allogenic embryo, thereby preventing spontaneous abortion.

Cells, Cultured↗
PubMed1985

Peritoneal neutrophilic cell response in necrotizing enterocolitis.

Neutropenia commonly occurs in neonates with necrotizing enterocolitis (NEC). In an attempt to determine the etiology of this neutropenia, we observed the peripheral and peritoneal neutrophil cell responses of seven infants at the time of surgery. Six of seven patients had diminished peripheral neutrophil counts within 24 hours prior to surgery, with substantial mobilization of mature neutrophils into the peritoneum. We also looked at the rat peritoneum as a model for neutrophilic cell consumption using casein and Vibrio cholerae enterotoxin to cause neutrophil mobilization. With both agents, significant mobilization of neutrophils into the peritoneum occurred. Bone marrow stores in the animals were substantially decreased, but neutropenia was not observed. We speculate that the neutropenia of NEC is largely a consequence of neutrophil mobilization into the peritoneum, perhaps initiated by dietary protein and/or bacterial toxin.

Agranulocytosis↗
PubMed1985

Murine intestinal intraepithelial lymphocytes I. Relationship of a novel Thy-1-,Lyt-1-,Lyt-2+, granulated subpopulation to natural killer cells and mast cells.

Highly purified populations of intraepithelial lymphocytes (IEL) were obtained from the murine small intestine. We found that 84% of IEL expressed Lyt-2 and that 45-55% possessed the unique phenotype, Thy-1-,Lyt-1-,Lyt-2+. Sixty percent of IEL had granules in their cytoplasm and thus resembled the large granulated lymphocytes associated with natural killer (NK) activity. However, less than 15% of IEL had NK activity in a 6-h assay. This activity resided in a subpopulation of Lyt-2- lymphocytes, leaving a large population of Thy-1-,Lyt-1-,Lyt-2+ granulated cells (45-55% of IEL) with unknown function. Sensitive radioenzymic assays for histamine showed that IEL from healthy CBA mice do not contain this amine. IgE-binding assays revealed that IEL, unlike mast cells, do not carry high-affinity receptors for IgE. Thus, only a small percentage of granulated IEL (less than 15%) possess NK activity, whereas 45-55% of IEL have granules, lack typical characteristics of mast cells, express the unique antigenic phenotype, Thy-1-,Lyt-1-,Lyt-2+ and have unknown function.

Animals↗
PubMed1985

Murine intestinal intraepithelial lymphocytes II. Comparison of freshly isolated and cultured intraepithelial lymphocytes.

Highly enriched preparations of intraepithelial lymphocytes (IEL) containing a large subpopulation of granulated cells were isolated from the murine small intestinal mucosa. We cultured IEL in media containing interleukin 2 (growth media conditioned with 20% concanavalin A supernatant; Con A CM) or mast cell growth factor(s) (growth media conditioned with 40% WEHI-3 supernatant; WEHI CM) and compared the physical and functional properties of the cultured cells to freshly isolated IEL. IEL cultured in Con A CM developed enhanced cytotoxicity against YAC-1, compared to freshly isolated IEL, and spontaneous cytotoxicity for P815 targets. Most of these cultured cells were Thy-1+ Lyt-1- Lyt-2+, and contained cytoplasmic granules similar to those seen in electron photomicrographs of other cytotoxic cell populations. IEL cultured in WEHI CM gave rise to cells that morphologically resembled mast cells. Unlike freshly isolated IEL, the cells stained metachromatically, contained 200-450 ng of histamine/10(6) cells and expressed high-affinity receptors for IgE. Our data clearly show that, although IEL do not themselves have physical characteristics of mast cells, they do contain mast cell precursors. In addition, IEL grown in the presence of T cell growth factors give rise to an activated cytotoxic cell population which is mostly granulated and Thy-1+ Lyt-1- Lyt-2+.

Animals↗