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Biomedical subjects

M F Lipscomb

Publications and source records attributed to M F Lipscomb.

At least 55 records · Page 3Linked to original sources
PubMed1986

Inability of human alveolar macrophages to stimulate resting T cells correlates with decreased antigen-specific T cell-macrophage binding.

Alveolar macrophages (AM) from the majority of human volunteers are defective antigen presenting cells (APC) in T cell proliferation assays despite the display by the cells of HLA-D region antigens. We have confirmed that AM secrete relatively little interleukin 1 (IL 1), but addition of exogenous IL 1 did not improve the capacity of AM to initiate antigen-induced T cell proliferation. Thus, the presence of HLA-D region antigens and IL 1 is not sufficient to enable an accessory cell to act as an APC. We developed a T cell-accessory cell binding assay to investigate early events in T cell activation. AM demonstrated a diminished capacity as compared with monocytes to bind antigen-specific T cell clones. Nevertheless, AM often induced proliferation of T cell clones as effectively as monocytes, indicating that antigen display was intact. The inefficiency of AM in bind T cell clones correlated with their reduced capacity to induce resting T cells to express IL 2 receptors, secrete IL 2, and proliferate in response to antigen. Indirect immunofluorescence established that similar percentages of AM and monocytes expressed LFA molecules, but the density of the molecules was greater on monocytes than AM. A role for LFA antigens in the physical binding of T cells to monocytes was demonstrated by blocking antigen-specific binding with a monoclonal antibody to LFA-1 antigen. LFA-1 antibody also blocked the low levels of specific binding between AM and T cell clones, indicating that LFA-1-ligand interactions were operative between these two cell types. These studies indicate that there are critical cell membrane characteristics that promote binding of T cells to APC in addition to T cell receptor-antigen interactions. This combination of nonspecific and specific interactions leads to avid T cell-APC binding that may be essential for activation of resting T cells. Furthermore, we postulate that the failure to AM to act as effective APC results from an inability to bind T cells efficiently.

Adult↗
PubMed1986

Human pulmonary macrophages. Functional comparison of cells obtained from whole lung and by bronchoalveolar lavage.

Previous studies have demonstrated that pulmonary macrophages (PM) recovered from bronchoalveolar lavage (BAL) are relatively poor accessory cells for antigen-induced T-lymphocyte proliferation. These studies have suggested that the immune function of macrophages obtained by BAL is representative of the majority of PM. We compared macrophages obtained by BAL with PM from whole lung minces (MIN) for their ability to stimulate T-lymphocyte proliferation. Both populations of PM had similar expression of HLA-DR antigen and were of comparable maturity as determined by staining for MO2 antigen. Production of interleukin 1 by both groups of PM was similar and was significantly less than that produced by monocytes (p less than 0.05). Both populations of PM functioned poorly as antigen-presenting cells when compared with monocytes (p less than 0.05). However, PM from MIN stimulated a mixed leukocyte reaction significantly more (p less than 0.05) than did PM from BAL. Our data suggest that whereas BAL obtains a population of PM with an immunologic function that is largely similar to PM obtained from whole lung, some differences in function may exist.

Antigen-Presenting Cells↗
PubMed1986

Tumor killing by human alveolar macrophages and blood monocytes. Decreased cytotoxicity of human alveolar macrophages.

Tumor killing by human alveolar macrophages (AM) might be an important mechanism of pulmonary defense against neoplastic disease. We compared AM and blood monocytes (Mo) for the ability to kill 2 neoplastic targets, A549 human lung adenocarcinoma cells and P815 mastocytoma cells. Blood monocytes were able to kill both targets, whereas AM killed neither. Tumor killing by Mo was spontaneous and was not increased by incubation with lipopolysaccharide. Because the P815 target is highly sensitive to lysis by hydrogen peroxide (H2O2), it afforded the opportunity to compare AM and Mo for the ability to kill tumors by the production of toxic oxygen compounds. Comparable amounts of superoxide anion were produced by AM and Mo after stimulation with phorbol myristate acetate. However, luminol-enhanced chemiluminescence of AM was far less than that of Mo, suggesting that AM could not utilize the myeloperoxidase-H2O2-halide ion system for tumor killing. The addition of exogenous peroxidase to cultures of AM and P815 cells enabled AM to kill this tumor cell. Our results suggest that as Mo mature into AM, their ability to kill tumor cells declines and that AM may be unable to kill H2O2-sensitive tumors because of a loss of myeloperoxidase during maturation.

Animals↗
PubMed1986

Human alveolar macrophages: HLA-DR-positive macrophages that are poor stimulators of a primary mixed leukocyte reaction.

Previous studies demonstrated that alveolar macrophages (AM) from most normal human volunteers failed to stimulate the antigen-induced proliferation of peripheral blood T lymphocytes although greater than 90% of AM expressed HLA-DR antigens. The current studies establish that AM also fail to induce allogeneic peripheral blood mononuclear cells to proliferate in a mixed leukocyte reaction (MLR). Suppressive activity by AM was not an explanation for their failure to induce an MLR. Indirect immunofluorescence established the presence of both HLA-DR and DQ antigens on the majority of AM and the persistence of these antigens on cells in culture for up to 6 days, the period of time required to observe a maximal MLR. Metabolic labeling experiments also demonstrated that HLA-DR antigens were synthesized by AM. It was recently reported that AM secrete relatively small amounts of IL 1, an important ancillary signal provided by accessory cells to enhance the stimulation of lymphocyte proliferation. However, addition of optimal concentrations of IL 1 to cultures containing AM failed to enhance the MLR. Thus, there is at least one additional, but as yet undefined, requirement for an accessory cell to induce an optimal MLR besides the display of HLA-D region antigens and the secretion of IL 1. In contrast, AM were effective in specifically stimulating proliferation of alloreactive T cell lines, suggesting that at least some cell lines do not require this nonspecific undefined second signal. We speculate that although AM may not initiate primary immune responses in the lung, they may be important in maintaining immune-mediated inflammatory responses by specifically restimulating already activated T cells.

Adult↗
PubMed1985

The binding of antihistone antibodies to Crithidia luciliae kinetoplasts is growth cycle-dependent.

The Crithidia luciliae immunofluorescence (CLIF) assay is widely used to test for native DNA (nDNA) antibodies in the diagnosis and management of systemic lupus erythematosus. However, sera from patients with drug-induced lupus erythematosus or rheumatoid arthritis, which should not contain nDNA antibodies, occasionally react with the CL kinetoplast. We examined 36 sera from patients with systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome, and drug-induced lupus erythematosus, who had positive CLIF tests. All 36 sera were also antinuclear antibody-positive with homogeneous and/or peripheral staining patterns on mouse kidney substrates. After hydrochloric acid extraction of the CL smears to remove histone and other nuclear protein antigens, 14 of the 36 sera no longer produced a positive result on the CLIF test. Ten of these 14 sera again gave a positive CLIF result after the hydrochloric acid-extracted Crithidia substrate had been reconstituted with purified histone. These studies demonstrated that kinetoplast binding was due to antihistone antibodies in at least 10 of 36 initially CLIF-positive sera. Antihistone antibodies were then purified with a histone-affinity column, and these purified antibodies were reactive with CL kinetoplasts. Thus, the CLIF test is not specific for nDNA antibodies. Additional studies using CL from different days of culture indicated that histone antigen expression in the CL kinetoplast was a function of the life cycle of this organism and is most readily detected 2 days after initiation of culture.

Animals↗
PubMed1985

Bronchoalveolar cells from sarcoid patients demonstrate enhanced antigen presentation.

The recognition of foreign antigens by T lymphocytes in association with lung antigen-presenting cells may be critical in the initiation of the mononuclear alveolitis and granuloma formation of pulmonary sarcoidosis. However, it has been shown that bronchoalveolar cells (BAC) from normal volunteers function poorly as antigen-presenting cells. Therefore, the ability of sarcoid BAC to serve as accessory cells for antigen-dependent autologous T cell proliferation, as measured by tritiated thymidine uptake, was compared with that of normal BAC. Although irradiated sarcoid BAC supported antigen-induced T cell proliferation, normal BAC did so poorly (p less than 0.005). Because it has been shown that sarcoid BAC produce more interleukin 1 (IL 1) than normal BAC, it was considered that the enhancement of antigen-induced proliferative responses could result from an increased amount of IL 1, and that contaminating monocytes in the peripheral blood T cell preparations displayed the antigen for T cell recognition. Therefore, it was necessary to establish that antigen-induced T cell responses required HLA-D region compatibility between the sarcoid BAC and T lymphocytes. BAC from sarcoid patients stimulated antigen-specific proliferation in T cells lines matched for at least one HLA-D-region antigen, but failed to stimulate T cell lines that were unmatched for both antigens. This finding indicates that cells in bronchoalveolar lavage fluids from sarcoid patients were fully capable of acting as antigen-presenting cells. The identification of antigen-presenting cells in the lungs of patients with sarcoidosis together with the previous findings of activated T cells, enhanced IL 1 production, and spontaneous interleukin 2 release in sarcoid patients is compatible with the hypothesis that local cell-mediated immunity is involved in the pathogenesis of pulmonary sarcoidosis.

Adult↗
PubMed1984

Reappraisal of the specificity of the Crithidia luciliae assay for nDNA antibodies: evidence for histone antibody kinetoplast binding.

Five different high-titer histone antibody-containing sera were assayed by the Crithidia luciliae indirect immunofluorescence (CLIF) technic. Three of these sera produced kinetoplast binding at titers of 1/40 to 1/80. The kinetoplast binding activity was abolished by HCl acid pretreatment of the Crithidia substrate, suggesting that the kinetoplast binding activity was not due to antibodies against native DNA (nDNA). Histone antibodies were purified from two of the three positive sera by affinity chromatography utilizing purified preparations of histone. Both purified antibody preparations also had kinetoplast-binding activity, confirming that the Crithidia kinetoplast contains histone-like proteins. Therefore, Crithidia luciliae (CL) kinetoplast binding activity does not necessarily indicate the presence of anti-nDNA antibodies. Routinely pretreating the CL substrate with 0.1 N HCl would eliminate the possibility of histone antibody kinetoplast binding in the CLIF assay. Whether such pretreatment would alter the binding of anti-NDNA to the kinetoplast remains to be determined.

Antibodies↗
PubMed1984

The accessory cell function of human alveolar macrophages in specific T cell proliferation.

The capacity of alveolar macrophages to support mitogen- and antigen-induced proliferation of autologous, monocyte-depleted T cells in normal, nonsmoking volunteers was studied. Purified T cells failed to proliferate in response to mitogen or antigen, whereas co-culture with peripheral blood monocytes restored responsiveness. Alveolar macrophages (AM) reconstituted the response of T cells to mitogen, indicating that AM can deliver a second proliferative signal. AM, however, were markedly inferior to monocytes in supporting antigen-induced proliferation. Thus, in 19 normal volunteers, the mean response of immune T cells to diphtheria toxoid in cultures reconstituted with normal AM was only 25% of the proliferative response to diphtheria in cultures with monocytes. Although four volunteers demonstrated antigen-presenting function equivalent to monocytes, in the remaining 15 antigen-presenting ability of AM was less than 15% that of monocytes. The difference in antigen-presenting function between AM and monocytes was not due to a difference in their display of HLA-D/DR determinants because 80% of AM were HLA-DR positive. The role of suppression in the diminished antigen-presenting function of AM was assessed in 12 volunteers utilizing mixing experiments. Eight volunteers demonstrated suppressor AM but four did not, suggesting that AM from at least some normal individuals have a faulty antigen-processing mechanism. Taken together, these studies demonstrate that AM may play three different roles in modulating T lymphocyte responses, i.e., they may present antigen, they may suppress normal responses, or they may remain immunologically inert. The factors that determine which function is expressed in vivo may determine the pulmonary response to inhaled antigen.

Adult↗
PubMed1984

Comparison of substrates for the detection of antinuclear antibodies in normals and in patients with connective tissue and other diseases.

There has been some controversy regarding the relative merits of cell lines versus frozen tissue substrates for the detection of antinuclear antibodies (ANA) by indirect immunofluorescence. We have compared two cell lines (KB and HEP2) with frozen mouse kidney for the detection of ANA in several groups of individuals. Cell lines were more likely to detect ANA than frozen mouse kidney in normal individuals and in hospital and clinic patients with diseases other than connective tissue diseases when sera were examined at manufacturer's recommended screening dilutions. There was also a trend for the cell lines to demonstrate ANA more frequently than mouse kidney in patients with systemic lupus erythematosus and other connective tissue diseases, but the differences were not statistically significant. Centromere antibodies could be reliably suspected only on cell lines and could be confirmed only if mitotic figures were present.

Adolescent↗
PubMed1984

The migration of bronchoalveolar macrophages into hilar lymph nodes.

The migration of bronchoalveolar macrophages ( BAMs ) into hilar lymph nodes ( HLNs ) was investigated in order to assess their potential importance in pulmonary immune responses. 51Chromium- or 111Indium-labeled broncholaveolar cells ( BACs ) or purified BAMs were inoculated into the tracheas of syngeneic guinea pigs, and the number of cells that reached HLN at 24-72 hours was estimated by 1) measuring the cell-associated radioactivity in HLN and 2) counting the radiolabeled cells in autoradiographic preparations. It was determined that 400-2900 BAM/10(7) inoculated BACs or BAMs reached the HLNs within a 3-day period. From this data, it was calculated that in a normal animal as many as 8700 BAMs might reach HLNs daily. These migratory phagocytes are potentially important in facilitating the systemic spread of macrophage-resistant intracellular organisms from the lung. Furthermore, following phagocytosis and killing of microorganisms in the alveolus, BAMs might migrate to HLNs and present antigen to stimulate a primary immune response.

Animals↗
PubMed1983

Conversion of androstenedione to testosterone and other androgens in guinea-pig alveolar macrophages.

Alveolar macrophages obtained by bronchoalveolar lavage of lungs of male and female guinea pigs were incubated with tritium-labelled androstenedione to evaluate the steroid metabolizing enzymes in these cells. The radiolabeled metabolites were isolated and thereafter characterized as testosterone, 5 alpha-androstanedione, 5 alpha-dihydrotestosterone, androsterone, isoandrosterone, 5 alpha-androstane-3 alpha, 17 beta-diol and 5 alpha-androstane-3 beta, 17 beta-diol. Thus, the following androstenedione metabolizing enzymes are present in guinea-pig alveolar macrophages: 17 beta-hydroxysteroid dehydrogenase, 5 alpha-reductase, 3 beta-hydroxysteroid dehydrogenase and 3 alpha-hydroxysteroid dehydrogenase. The predominant androstenedione metabolizing enzyme activity present in alveolar macrophages was 17 beta-hydroxysteroid dehydrogenase. The rate of testosterone formation increased with incubation time up to 4 h, and with macrophage number up to 1.6 X 10(7) cells per ml. Androstenedione metabolism was similar in alveolar macrophages obtained both from male and female guinea pigs. These results suggest that alveolar macrophages may be a site of peripheral transformation of blood-borne androstenedione to biologically potent androgens in vivo and, therefore, these cells may contribute to the plasma levels of testosterone in the guinea pig.

Androgens↗
PubMed1983

Persistence of influenza as an immunogen in pulmonary antigen-presenting cells.

Influenza antigens inoculated into the lung induce local immune responses. It has been proposed that this induction might be partly regulated by local antigen-presenting cells. The purpose of the current study was to inoculate heat-inactivated influenza virus into the tracheae of guinea pigs and determine the quantity of antigens that became cell-associated. Second, we determined how long antigen-presenting bronchoalveolar cells that had taken up virus in vivo retained their ability to specifically stimulate virus-immune T lymphocytes. Radioiodinated heat-inactivated influenza virus was inoculated into the tracheae of guinea pigs. The animals were killed from 30 min to 14 days after intratracheal inoculation, and radioactivity was determined in cells isolated from lung tissue. At least one-third of the radioactivity in the lungs was cell-associated from 1 to 14 days post-inoculation. In separate studies, heat-inactivated virus was inoculated into the airways of guinea pigs, and animals were killed at various times thereafter. Bronchoalveolar cells from these animals were compared with those from uninoculated controls in their ability to specifically stimulate virus-immune T cells to proliferate in vitro. Bronchoalveolar cells from virus-inoculated animals specifically stimulated T lymphocytes for up to 7 days after virus inoculation. These studies suggest that immunogenic virus persists in the lung within antigen-presenting cells for at least 1 week and possibly for up to 2 weeks. The persisting immunogenic stimulus after the termination of viral infections might be critical in ensuring the development of a local protective immune response.

Animals↗
PubMed1983

Alveolar macrophages in pulmonary immune responses. I. Role in the initiation of primary immune responses and in the selective recruitment of T lymphocytes to the lung.

Antigen inoculated intratracheally (IT) into animals can induce primary immune responses and selectively recruit specific T cells to the lung. In the current study, the role of alveolar macrophages (AM) in these two responses was investigated. Antigen-pulsed bronchoalveolar cells (BAC) inoculated IT into guinea pigs generated a population of immune T cells that proliferated in vitro on reexposure to antigen-pulsed macrophages (Mø). The possibility that antigen-pulsed donor BAC shed antigen that was subsequently processed and presented by host Mø was ruled out by genetic experiments. Thus, peritoneal exudate lymphocytes (PEL) from (2 X 13)F1 guinea pigs primed with antigen-pulsed BAC from strain 2 animals responded preferentially to antigen-pulsed strain 2 Mø rather than to antigen-pulsed strain 13 Mø. In a second set of studies, antigen-pulsed BAC inoculated IT into guinea pigs selectively recruited antigen-specific T cells to the lung. Genetic experiments verified that inoculated BAC were the source of the antigen-presenting cells responsible for selective recruitment. Thus, antigen-pulsed strain 2 BAC inoculated IT recruited a greater proportion of (2 X 13)F1 T cells that recognized antigen in the context of strain 2 Mø than F1 T cells that recognized antigen on strain 13 Mø. Taken together, these studies suggest that AM contribute to the regulation of pulmonary immunity by both inducing T lymphocyte immunity and selectively recruiting specific T cells to the lung.

Animals↗
PubMed1983

A morphological study of the role of phagocytes in the clearance of Staphylococcus aureus from the lung.

A nonlethal dose of Staphylococcus aureus was inoculated into the mainstem bronchus of mice in order to study the influx of polymorphonuclear leukocytes (PMN). The goal was to determine the routes of entry of PMN into the lung following bacterial challenge, the relative importance of PMN as compared to alveolar macrophages (AM) in the uptake of S aureus, and the role of lymphatics in clearance of intact microorganisms. Resident AM took up S aureus within minutes of inoculation, but PMN were subsequently recruited to the lung and were the predominant cell containing S aureus by 4 hours following inoculation. PMN were recruited from arteries, capillaries, and venules. Emigration of PMN into alveolar spaces occurred between type I epithelial cells as well as between type I and type II epithelial cells. Lymphatics played only a minor role in the clearance of S aureus.

Animals↗
PubMed1982

The antigen-induced selective recruitment of specific T lymphocytes to the lung.

The purpose of the present studies was to investigate the mechanisms by which specific T lymphocytes accumulate in the lung. After the intratracheal (IT) inoculation of influenza virus into guinea pigs, the detection of specific T lymphocytes in the lung coincided with the development of immunity in both hilar nodes and systemic lymphoid tissue. Animals immunized in the footpads with virus failed to develop immune responses in the lung unless rechallenged IT with immunogen. In adoptive transfer experiments, IT inoculation of influenza into nonimmune guinea pigs, followed immediately by the i.v. injection of a mixture of 3H-thymidine-labeled syngeneic T lymphocytes specific for influenza virus and 14C-thymidine-labeled syngeneic T lymphocytes specific for an irrelevant antigen resulted in the selective accumulation of the virus-specific T lymphocytes in the lung. Taken together, these studies indicate that the selective recruitment by antigen of circulating immune cells is one of the mechanisms by which specific T cells accumulate in the lung.

Animals↗