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Biomedical subjects

J C Weissler

Publications and source records attributed to J C Weissler.

33 records · Page 2Linked to original sources
PubMed1989

Idiopathic pulmonary fibrosis: cellular and molecular pathogenesis.

Diffuse involvement of the pulmonary interstitium with abnormal fibrous tissue is a process that occurs in many settings. There are many possible etiologies for pulmonary fibrosis, but in the majority of individuals, a clear cause cannot be determined and a diagnosis of idiopathic pulmonary fibrosis (IPF) results. Despite limited knowledge concerning the etiology, recent advances in biomedical technology offer great promise for increasing our understanding of IPF. This review will focus on current concepts of the pathogenesis and therapy of IPF.

Bronchoalveolar Lavage Fluid↗
PubMed1989

Human pulmonary natural killer (NK) cells exhibit limited lymphokine-activated killer (LAK) activity.

The spontaneous activity of natural killer (NK) cells against most solid tumor targets is low but can be increased by incubation with interleukin 2 (IL-2). This phenomenon, termed lymphokine-activated killer (LAK) activity, has been used in recent clinical trials against some pulmonary malignancies. We compared the LAK activity of blood and lung lymphocytes after activation with IL-2. Lung lymphocytes did not develop LAK activity despite demonstrating a significant increase in NK activity against K562 targets after incubation with IL-2. This functional difference correlated with a reduced expression of Leu-19, a marker present on virtually all LAK cells derived from peripheral blood, on lung NK cells. Because pulmonary macrophages (PM) are important regulators of NK function, we next investigated whether PM could be responsible for the functional and phenotypic differences noted. Measuring NK and LAK activity in parallel, we found that the addition of PM to IL-2-activated lymphocytes resulted in a preferential suppression of LAK activity and a loss of Leu-19 expression from IL-2-activated blood lymphocytes as well as a Leu-19+ T cell clone. We conclude that pulmonary NK cells are phenotypically and functionally different from peripheral blood NK cells and that this likely reflects local regulation, perhaps by PM.

Antigens, Differentiation↗
PubMed1989

Enhanced accessory cell function by alveolar macrophages from patients infected with the human immunodeficiency virus: potential role for depletion of CD4+ cells in the lung.

Mononuclear phagocytes, including alveolar macrophages (AM), can be infected by the human immunodeficiency virus (HIV). Acting as accessory cells (AC), AM could infect CD4 lymphocytes through cell-to-cell contact and by inducing T cell proliferation, which increases lymphocyte susceptibility to infection. Using normal allogeneic T cells as responders, AM from infected individuals demonstrated an enhanced ability to stimulate a Con A and pokeweed mitogen lymphocyte proliferation assay compared with normal AM. Exogenous IL 1 enhanced the stimulation of a mitogen response by normal AM, but not from HIV-positive individuals, suggesting increased levels of this cytokine may explain the observed enhancement. However, increased IL 1 secretion by AM from HIV-infected patients could not be demonstrated, either in a bioassay or antigenically using an ELISA for IL-1 beta. Syncytia formation was observed when AM from asymptomatic HIV-positive individuals were cultured with normal T cells, suggesting viral transmission was occurring. Finally, in individual patients the stimulation of a mitogen response was inversely correlated with the CD4/CD8 ratio and total CD4 count, suggesting that enhanced AC function and CD4 cell depletion may be related in vivo. These findings indicate that enhanced AM accessory cell function is seen in HIV-infected individuals and could be a potential mechanism for CD4 cell depletion in the lung.

Acquired Immunodeficiency Syndrome↗
PubMed1988

Human natural killer cells enhance a mixed leukocyte reaction.

Natural killer cells (NK) have been reported to down-regulate the initiation of T cell responses in animal models. In the current study, highly purified CD16+ human NK cells were obtained by cell sorting and their effect on the stimulation of allogeneic T cells (MLR) determined. NK cells did not directly stimulate T cell proliferation. However, when added to a population of loosely adherent mononuclear cells (LAM), NK enhanced the ability of these accessory cells to stimulate T proliferation. This effect was not reproduced by the addition of sorted CD5 + T cells, sorted CD16- cells, or control lymphocytes to the MLR. The effect of NK on the MLR was not restricted by class II antigens and was similar to the effect of adding IL-1 to MLR cultures. These results demonstrate that human NK cells are capable of enhancing a T cell response.

Antigen-Presenting Cells↗
PubMed1988

Treatment of pneumonia in patients at risk of infection with gram-negative bacilli.

Patients with a history of chronic debilitating disease due to a variety of causes are known to be at risk for infection with coliform gram-negative bacilli when they present with community-acquired pneumonia. Empiric treatment with broad-spectrum parenteral antibiotics is often begun in such patients pending the result of blood and other cultures. The optimal duration of broad-spectrum empiric therapy in such patients when cultures fail to reveal a specific pathogen is unknown. Review was made of the charts of 131 patients with community-acquired pneumonia admitted to the hospital and treated with broad-spectrum parenteral antibiotics in whom a specific pathogen was never isolated. Overall, 89 percent of these patients were cured without complication or relapse. Patients receiving broad-spectrum therapy for four days or less due to rapid clinical improvement had a successful outcome in 95 percent of cases. It is concluded that broad-spectrum parenteral antibiotic therapy can safely be abbreviated provided response to therapy is prompt.

Aminoglycosides↗
PubMed1987

Pulmonary emphysema: current concepts of pathogenesis.

Pulmonary emphysema is a major public health problem and is primarily a disease of smokers. The pathogenesis of emphysema in smokers is likely to be multifactorial and may involve protease-antiprotease imbalance, abnormal host response to injury, the inactivation of antiproteases by oxidants, and direct damage of lung tissue by pulmonary phagocytes. The data regarding current concepts of pathogenesis of emphysema in smokers are reviewed in this article.

Blood Proteins↗
PubMed1987

Mononuclear cells in human lung parenchyma. Characterization of a potent accessory cell not obtained by bronchoalveolar lavage.

Human alveolar macrophages from bronchoalveolar lavage are usually poor accessory cells for antigen-induced T-lymphocyte proliferation and poor stimulators of allogeneic mixed leukocyte reactions (MLR) when compared to peripheral blood monocytes. In contrast, cells harvested from minced lungs are good stimulators of a MLR. We have characterized the accessory cells obtained after enzymatic digestion of human lung tissue. Pulmonary mononuclear cells were separated from the dissociated lung cell mixture on Ficoll-Hypaque. Loosely adherent cells (LAM) were obtained after an overnight incubation on plastic culture dishes of initially adherent mononuclear cells. LAM were significantly more effective than were pulmonary mononuclear cells (p less than 0.05), firmly adherent cells (p less than 0.05), alveolar macrophages obtained by bronchoalveolar lavage (p less than 0.05), or monocytes (p less than 0.05) in stimulating allogeneic resting T-cells. Addition of indomethacin and catalase markedly improved T-cell proliferation induced by LAM. Enrichment for Fc receptor negative or for nonphagocytic cells further enhanced the MLR-stimulating capacity of LAM. Phase-contrast studies demonstrated an enrichment in cells compatible with dendritic cells in LAM as compared to firmly adherent cells. We conclude that there are potent accessory cells in human lung that are loosely adherent, Fc receptor negative, and poorly phagocytic, and thus are dissimilar from classic macrophages. We hypothesize that cells similar to dendritic cells might play a role in the initiation of immune responses in lung parenchyma.

Antibodies, Monoclonal↗
PubMed1987

Natural killer cell function in human lung is compartmentalized.

Natural killer (NK) cells are a subpopulation of lymphocytes capable of killing a variety of neoplastic targets. NK can limit pulmonary metastases in animal models and could be important mediators of tumor defense in human lung. Previous studies in humans have suggested, however, that pulmonary NK cells obtained by bronchoalveolar lavage (BAL) are functionally inert. We purified lymphocytes from human lung tissue and compared the NK activity of these cells with lymphocytes purified from peripheral blood. The activity of NK cells obtained from minced whole lung specimens was comparable to that found in peripheral blood. Monoclonal antibodies to 2 markers found on peripheral blood large granular lymphocytes (LGL) were utilized to determine the phenotype of pulmonary NK cells. Lymphocytes expressing Leu 11b were responsible for pulmonary NK activity as all NK function was abrogated by pretreatment with anti-Leu 11b and complement. In contrast, lymphocytes expressing Leu 7 had little NK activity. Although the frequency of lymphocytes expressing Leu 7 or Leu 11 in blood was comparable, there were significantly more (p less than 0.001) Leu 7+ lymphocytes in the lung than Leu 11+ cells. Immunofluorescent staining of lung tissue demonstrated that LGL expressing Leu 11 were confined largely to the lung interstitium, whereas LGL expressing Leu 7 were frequently located in alveoli and larger airways. These findings suggest that NK function is present in the human lung and that it is compartmentalized with the NK-active Leu 11+ lymphocytes located primarily in the lung interstitium.

Adult↗
PubMed1987

Pulmonary natural killer cell activity is reduced in patients with bronchogenic carcinoma.

Natural killer (NK) cells are a subpopulation of lymphocytes capable of killing a variety of tumor targets. They can limit pulmonary metastases in vivo and thus might be important effectors of tumor defense in human lung. Lymphocytes were purified from whole lung specimens obtained from patients with lung cancer undergoing curative resection, and their NK activity was compared with that of lymphocytes purified from normal lung specimens obtained from cadavers undergoing medicolegal autopsy. The NK activity of pulmonary lymphocytes obtained from the patients with lung cancer was significantly lower (p less than 0.05) than the NK activity of normal lungs. This reduction occurred despite high levels of blood NK activity in the patients with cancer, suggesting that NK cells might be locally suppressed in the lungs of patients with bronchogenic carcinoma. Because human pulmonary macrophages (PM) are known to be potent inhibitors of NK function, we investigated the role that PM might play in the reduction of NK activity in these patients. The PM obtained from the patients with lung cancer released soluble inhibitors of NK activity when stimulated with lipopolysaccharide. Release of these inhibitors was blocked by indomethacin, strongly suggesting a role for arachidonic acid metabolites as an inhibitor of pulmonary NK function. Inhibition of NK function by PM may occur in vivo, as a significant inverse correlation (r = -0.71, p less than 0.001) existed between the NK activity of lymphocytes obtained from a lung and the number of PM present in the lung.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
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↗
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↗