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Biomedical subjects

D P Braun

Publications and source records attributed to D P Braun.

At least 19 recordsLinked to original sources
PubMed1994

Monocyte-mediated enhancement of endometrial cell proliferation in women with endometriosis.

OBJECTIVE: To investigate the capacity of monocytes from women with endometriosis to influence endometrial cell proliferation. DESIGN: Uterine endometrial cells were cultured in the presence and absence of autologous blood monocytes for 72 hours before assessment of endometrial cell proliferation by thymidine incorporation. SETTING: Patients were tested at initial presentation for evaluation of infertility and/or endometriosis. PATIENTS, PARTICIPANTS: Fertile controls, n = 17; infertile controls, n = 9; untreated endometriosis, n = 29. INTERVENTIONS: None. RESULTS: Endometrial cell proliferation was enhanced significantly by blood monocytes in patients with endometriosis but was suppressed significantly by blood monocytes in fertile controls. Endometrial cell proliferation was not affected significantly by blood monocytes in infertile controls analyzed as a group, but a subset of infertile patients also showed enhancement of endometrial cell proliferation by blood monocytes. CONCLUSIONS: Blood monocytes from patients with endometriosis and a subset of patients with unexplained infertility enhance autologous endometrial cell proliferation, whereas blood monocytes from fertile patients suppress endometrial cell proliferation. The capacity of monocytes to enhance endometrial cell proliferation appears to require both monocyte-derived factors that stimulate endometrial cell proliferation and endometrial cells capable of responding to those stimulatory factors. If either of these factors is absent, monocytes either suppress or have no effect on endometrial cell proliferation.

Adult↗
PubMed1994

Effect of danazol in vitro and in vivo on monocyte-mediated enhancement of endometrial cell proliferation in women with endometriosis.

OBJECTIVE: To investigate danazol's effect in vitro and in vivo on the ability of peripheral blood monocytes (PBM) from women with endometriosis to stimulate endometrial cell proliferation. DESIGN: Uterine endometrial cells from untreated or danazol-treated patients with endometriosis were cultured with or without autologous or heterologous PBM in the presence of different concentrations of danazol for 72 hours before assessment of endometrial cell proliferation by thymidine incorporation. SETTING: Not for profit clinical research institute and academic cell culture laboratory. PATIENTS: Women of reproductive age undergoing laparoscopy for endometriosis, 19 untreated patients and 17 danazol-treated patients. INTERVENTIONS: Peripheral blood monocytes and endometrial biopsies obtained at laparoscopy. Danazol (800 mg/d) administered for 2 to 6 months (treated group) or added to cell cultures in concentrations of 10(-6), 10(-7), or 10(-9) M. RESULTS: Endometrial cell proliferation was enhanced by autologous or heterologous PBM from untreated patients with endometriosis but was unaffected or suppressed by PBM from danazol-treated patients. Danazol in vitro reduced PBM-enhanced endometrial cell proliferation. Endometrial cell proliferation from danazol-treated patients was not enhanced by PBM from untreated patients with endometriosis. CONCLUSIONS: Danazol treatment in vitro or in vivo suppresses PBM-mediated enhancement of endometrial cell proliferation. The effects are against both PBM and endometrial cells, suggesting that danazol affects monocyte-derived growth-stimulating factors and endometrial cell response to growth-stimulating factors.

Adult↗
PubMed1994

The role of cell-mediated immunity in pathogenesis of endometriosis.

It is well recognized that cell-mediated immune responses contribute to the elimination of foreign antigens and cells from the invading organism. It is also likely that the immune system can recognize and eliminate altered or misplaced autologous cells such as ectopic endometrial cells. This mechanism may be operative in most women, preventing the development of endometriosis. Recent studies in women with endometriosis demonstrate functional changes in cells of the immune system including monocytes/macrophages, natural killer cells, cytotoxic T-lymphocytes and B cells. These changes suggest decreased surveillance, recognition and destruction of the misplaced endometrial cells and possible facilitation of their implantation and development of endometriosis. Peripheral blood monocytes (PBM) and peritoneal macrophages (PM) may play a key role in this respect, and may control the function of other immune cells. We have demonstrated that in normal fertile women without endometriosis, PBM and PM suppress endometrial cell proliferation in vitro. In endometriosis, PBM stimulate and PM inhibit endometrial cell proliferation and the cytotoxic effect of PM is inversely correlated with the stage of the disease. The decrease in PM cytotoxic function is controlled by prostaglandin synthesis. In infertile women without endometriosis, the effects of PM and PBM are variable. In about one third of patients, the effects of PM and PBM suggest subclinical endometriosis; in the remaining two thirds of patients the effects of PM and PBM are similar to those of fertile controls. Interestingly, endometrial cells in women with endometriosis are more sensitive to the stimulatory effect of PBM, and more resistant to the cytotoxicity of the immune cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Autoantibodies↗
PubMed1993

Sensitivity of tumoricidal function in macrophages from different anatomical sites of cancer patients to modulation of arachidonic acid metabolism.

The sensitivity of cancer patient macrophages from different anatomical sites to arachidonic acid metabolism was investigated in tumor cell cytotoxicity assays. Alveolar macrophages and peripheral blood monocytes from 13 non-small cell lung cancer patients, peritoneal macrophages and peripheral blood monocytes from 13 ovarian cancer patients, and comparable macrophages from control patients with nonmalignant lung or gynecological diseases were tested. Inhibitors of either the cyclooxygenase pathway or the lipoxygenase pathway together with specific metabolites of each pathway were used to evaluate how these different macrophage populations are regulated by eicosanoids. In addition, metabolic studies were performed to compare directly the arachidonic acid metabolism of macrophages obtained from these different anatomical locations. The results demonstrate that the peripheral blood monocytes from lung cancer and ovarian cancer patients and the peritoneal macrophages from ovarian cancer patients are sensitive to cyclooxygenase inhibition; this was not seen with comparable macrophages from the relevant control patients. Sensitivity to modulation by cyclooxygenase inhibition correlated with increased cyclooxygenase metabolism and with the capacity of prostaglandin to mediate suppression of tumoricidal function in these populations of cancer patient macrophages. In contrast, alveolar macrophages from cancer patients were not sensitive to either cyclooxygenase inhibition or to prostaglandin-mediated suppression. No such differential influences were revealed for the lipoxygenase pathway of arachidonic acid metabolism in any macrophage population tested. Thus, eicosanoids, particularly those of the cyclooxygenase pathway, can be a critical immunoregulatory feature of certain tumor microenvironments.

6-Ketoprostaglandin F1 alpha↗
PubMed1993

Mitogen induced production of polyclonal IgG is decreased in women with severe endometriosis.

PROBLEM: The etiology and/or pathogenesis of endometriosis may involve aspects of both humoral and cellular immunity. METHOD: In this investigation, we analyzed the ability of B lymphocytes from distinct patient groups for production of IgG1, IgG2, and IgG3 following in vitro stimulation with polyclonal B-cell mitogens (pokeweed mitogen and Staphylococcus aureus Cowan strain I) after in vitro stimulation with polyclonal B-cell activators. RESULTS: We observed that the in vitro production of IgG1, IgG2, and IgG3 was identical among fertile controls (no endometriosis; N = 22), infertile women without endometriosis (N = 22), infertile women without endometriosis (N = 20) and patients with stage 1 or 2 endometriosis (N = 31). In contrast, in vitro IgG2 production was significantly reduced among women with stage 3 or 4 endometriosis (N = 11) compared to controls (P < 0.001). CONCLUSION: Since the number of circulating B cells was similar in each patient group studied, the reduced production of IgG2 in patients with stage 3 or 4 disease was not merely due to fewer antibody producing cells in those subjects, and we speculate that the observed decrease in polyclonal IgG2 production among these patients is due to a primary defect. In additional studies, we observed that polyclonal IgG2 production was normal among stage 3 or 4 patients treated with danazol (N = 11), but significantly reduced in patients treated with gonadotropin releasing hormone agonists (N = 8). Although not conclusive, these data suggest that danazol may have the capacity to correct the defective production of polyclonal IgG2 in patients with severe endometriosis.

Antibody Formation↗
PubMed1992

The development of cytotoxicity in peritoneal macrophages from women with endometriosis.

OBJECTIVE: To assess the activation status of peritoneal macrophages from women with endometriosis. DESIGN: Peritoneal macrophages from patients undergoing laparoscopy were tested for cytotoxic activity against a cultured hepatoma cell line. SETTING: Patients were tested at initial laparoscopy or at the completion of therapy. PATIENTS AND PARTICIPANTS: Fertile controls (n = 27), infertile controls (n = 20), untreated endometriosis (n = 43), danazol-treated endometriosis (n = 22), and gonadotropin-releasing hormone agonist (GnRH-a)-treated endometriosis (n = 13) were tested. INTERVENTIONS: Danazol (800 mg/d) or GnRH-a therapy for 6 months. RESULTS: Cytotoxicity was elevated in stage I and II endometriosis (P less than 0.02) and in infertile controls (P less than 0.05) compared with fertile controls. Cytotoxicity in stage III and IV endometriosis was lower (P less than 0.02) than in stage I and II endometriosis. Indomethacin in vitro increased cytotoxicity (P less than 0.05) in stage III and IV endometriosis but not in the other groups tested. Cytotoxicity in danazol or GnRH-a-treated patients was increased (P less than 0.05 or greater) compared with untreated patients with comparable stage of disease. CONCLUSIONS: Peritoneal macrophage cytotoxicity in women with endometriosis is affected by (1) the extent of endometriosis, (2) prostaglandin metabolism, and (3) treatment with danazol or GnRH-a.

Cytotoxicity, Immunologic↗
PubMed1991

Impaired tumoricidal function of alveolar macrophages from patients with non-small cell lung cancer.

The capacity of alveolar macrophages and peripheral blood monocytes from patients with non-small cell lung cancer to develop tumoricidal function after in vitro stimulation with different macrophage activators was investigated. Alveolar macrophages were found to be impaired in their ability to develop cytotoxic activity compared with either the peripheral blood monocytes from the same patients or alveolar macrophages from patients with nonmalignant lung disorders. This result was observed consistently under diverse culture conditions and with different macrophage activators including gamma-interferon (gamma-IFN), granulocyte-macrophage colony-stimulating factor (GM-CSF), phorbol myristate acetate, or endotoxin. The impairment in tumoricidal function observed in alveolar macrophages was not associated with reduced target cell binding compared to peripheral blood monocytes. Alveolar macrophages from patients with lung cancer were found to secrete significantly greater amounts of tumor necrosis factor (TNF) and interleukin-1 (IL-1) than either peripheral blood monocytes from the same patients or alveolar macrophages from the patients with nonmalignant disorders. These results are consistent with either different regulatory pathways for cytotoxicity and cytokine secretion in the alveolar macrophages of patients with lung cancer or diversity in the subpopulations of cells responsible for these functions.

Carcinoma, Non-Small-Cell Lung↗
PubMed1990

The in vitro development of cytotoxicity in response to granulocyte/macrophage-colony-stimulating factor or interferon gamma in the peripheral blood monocytes of patients with solid tumors: modulation by arachidonic acid metabolic inhibitors.

The capacity of granulocyte/macrophage-colony-stimulating factor (GM-CSF) and interferon gamma (IFN gamma) to elicit monocyte cytotoxicity in vitro in the peripheral blood monocytes of patients with solid tumors was investigated. The cytotoxicity elicited by IFN gamma was significantly reduced in cancer patient monocytes compared to normal monocytes. The cytotoxicity elicited by GM-CSF, however, was comparable between cancer patient monocytes and normal monocytes, but was lower than that induced by IFN gamma. Indomethacin, a cyclooxygenase inhibitor, significantly augmented IFN gamma-elicited cytotoxicity in cancer patient monocytes, but not in normal monocytes. In contrast, indomethacin augmented GM-CSF-elicited cytotoxicity in both cancer patient monocytes and normal monocytes. Nordihydroguaiaretic acid (NDGA), a lipoxygenase inhibitor, was found to suppress cytotoxicity in response to IFN gamma and GM-CSF in both cancer patient monocytes and normal monocytes. The addition of leukotrienes to NDGA-treated cultures restored the development of cytotoxicity. Thus there are differences in the in vitro response of cancer patient monocytes and normal monocytes to distinct biological activators. Furthermore, these responses can be manipulated by agents that modulate arachidonic acid metabolism.

Adult↗
PubMed1989

Lymphokine-activated killer cell induction in tumor-infiltrating leukocytes from colon cancer patients.

Lymphokine-activated killer (LAK) cell induction was evaluated in the peripheral blood mononuclear cells (PBMC) from 28 colon cancer patients and in the tumor-infiltrating leukocytes (TIL) from 20 of the patients' colon cancer specimens. Modulation of LAK cell induction in TIL and PBMC by inhibitors of arachidonic acid metabolism also was examined. LAK cells were induced in vitro in isolated TIL and PBMC by culturing with 500 U/ml of recombinant interleukin-2 (IL-2) for 3 to 5 days, and this was followed by the assessment of cytolytic activity against natural killer (NK)-resistant Chang hepatoma cells. LAK cell induction in the TIL was depressed significantly, compared with LAK cell induction in the PBMC of colon cancer patients (P less than 0.01). In the majority of cases, indomethacin augmented LAK cell induction in the TIL (P = 0.073 for the entire group, compared with cultures not treated with indomethacin) and nordihydroguaiaretic acid (NDGA) depressed LAK cell induction (P less than 0.05 for the entire group, compared with cultures not treated with NDGA). Further characterization of the mechanisms responsible for modulating LAK cell induction in the TIL of cancer patients may identify ways to optimize their use in adoptive cellular immunotherapy.

Adult↗
PubMed1989

A phase I clinical trial of recombinant interleukin-2 by periodic 24-hour intravenous infusions.

Recombinant interleukin-2 (rIL-2) (NSC# 600664; Hoffmann-La Roche, Inc., Nutley, NJ) was studied in a phase I clinical trial in 33 patients with advanced, measureable cancer of the colon or malignant melanoma, Eastern Cooperative Oncology Group (ECOG) performance status O-1, and no prior chemotherapy or radiotherapy. The goal of the study was to identify a dose and schedule of IL-2 to generate maximal immune modulation with tolerable toxicity. Such a regimen might allow the addition of other treatment modalities and/or prolonged treatment duration in later trials. Each patient received IL-2 as a continuous 24-hour infusion once weekly for 4 weeks and then twice weekly for 4 weeks. Five treatment groups received from 10(3) U/m2 to 3 x 10(7) U/m2 per 24-hour infusion. The maximal tolerated dose was 3 x 10(7) U/m2/d twice weekly. Patients treated twice weekly at 1 x 10(7) and 3 x 10(7) U/m2/d had immune modulation in terms of lymphocytosis, eosinophilia, increased natural killer (NK) activity, and elevated numbers of peripheral blood mononuclear cells expressing CD16, OKT10/Leu-17, and Leu-19 surface markers. Endogenous generation of peripheral blood lymphokine-activated killer (LAK) activity was demonstrated by lysis of NK-resistant Daudi targets, in patients treated at 3 x 10(7) U/m2/d. Biochemical and hematological abnormalities were moderate and reversible. Clinical toxicity included hypotension, myalgia, arthralgia, stomatitis, fever, fatigue, nausea, headache, chills, diarrhea, and oliguria at high doses. Cardiovascular toxicity was tolerable for most patients and reversed after IL-2 was stopped. Two of six melanoma patients at 3 x 10(7) U/m2/d achieved partial responses by the end of the eighth week. This IL-2 schedule appears to produce potentially clinically useful immune enhancement with tolerable toxicity.

Adolescent↗
PubMed1988

Appearance and phenotypic characterization of circulating Leu 19+ cells in cancer patients receiving recombinant interleukin 2.

The effects of recombinant interleukin 2 (rIL-2) therapy on peripheral blood mononuclear cells expressing the Leu 19 surface marker were evaluated in 20 cancer patients. Leu 19 is a protein with a molecular weight of 220,000 expressed on 15% of normal peripheral blood mononuclear cells and is found on a majority of cells that mediate non-major histocompatibility complex-restricted cytotoxicity. Increased relative and absolute numbers of circulating Leu 19+ cells were observed in all patients receiving rIL-2. Increases in Leu 19+ cells were due in part to the development of a subpopulation of "bright" Leu 19+ cells (Leu 19b+) that possessed a higher density of membrane Leu 19 antigen than Leu 19+ cells assayed prior to therapy. Further characterization of rIL-2 induced Leu 19+ cells by dual immunofluorescence revealed considerable phenotypic heterogeneity within this population based on the coexpression of "dim" CD8 (CD8d+), CD16, and CD2 markers. The percentage of Leu 19+ CD8d+ cells was increased during rIL-2 therapy and comprised up to 60% of all circulating Leu 19+ cells. CD16+ and CD16- subsets of Leu 19+ cells were also increased by rIL-2. The density of CD16 antigen coexpression varied inversely with the density of Leu 19. Conversely, whereas the percentage of Leu 19 cells coexpressing CD2 was also increased by rIL-2 administration, the density of CD2 antigen expression was higher on the Leu 19b+ subset of cells. The development of circulating lymphokine-activated killer activity in three patients was temporally associated with the development of increased levels of circulating Leu 19+ cells. These studies demonstrate that rIL-2 administration induces preferential increases in cells expressing the natural killer and lymphokine-activated killer cell-associated marker Leu 19 and that these increases are associated with the development of circulating lymphokine-activated killer activity. Furthermore, Leu 19+ cells are comprised of phenotypically heterogeneous subsets which undergo characteristic changes during rIL-2 administration.

Antigens, Differentiation↗
PubMed1988

In vivo effects of recombinant IL-2. I. Isolation of circulating Leu-19+ lymphokine-activated killer effector cells from cancer patients receiving recombinant IL-2.

This study was designed to isolate and phenotypically characterize lymphokine-activated killer (LAK) cells generated in vivo during administration of high dose rIL-2 to cancer patients. The development of circulating LAK effector cells in these patients was demonstrated by the ability of fresh PBL to exhibit lytic activity against the NK-resistant Daudi cell line and fresh tumor cells without prior in vitro culture with rIL-2. Kinetic studies demonstrated that circulating LAK effector cells are detectable 4 to 6 wk after the initiation of rIL-2 therapy. Cells isolated by FACS revealed that circulating LAK cells are Leu-19+, Leu-17+ but CD5-. We have previously reported that circulating Leu-19+ cells are heterogeneous with regard to the expression of CD16 and CD8. Since sorting of cells expressing Leu-19 and either low quantities of CD8 or CD16 resulted in cytolytic activity in both the positive and negative fractions, these latter two markers do not identify subpopulations of Leu-19+ cells with or without LAK cytolytic activity. Although all LAK cells generated in vivo were Leu-19+, we generated LAK cells from the Leu-19- subpopulation after in vitro culture with rIL-2, suggesting that at least some of in vitro generated LAK cells are derived from Leu-19- precursor cells. These LAK cells did not, however, express the Leu-19 surface marker. Based on the functional data reported in this paper, we conclude that circulating LAK effector cells are a phenotypically heterogeneous population that express surface Ag in association with NK cells and not T lymphocytes.

Antigens, Neoplasm↗
PubMed1988

Monocyte functional studies in asymptomatic, human immunodeficiency disease virus (HIV)-infected individuals.

Various aspects of monocyte-associated function were evaluated in the peripheral blood mononuclear cells of male homosexuals who were infected with the human immunodeficiency disease virus (HIV). The functional assessments included indomethacin-sensitive regulation of blastogenesis and lymphokine-activated killer (LAK)-cell induction, chemiluminescent responses of mononuclear leukocytes to opsonized zymosan, and the expression of HLA-DR antigen on CD-14-positive monocytes. The results obtained demonstrate that each of these functions is abnormal in asymptomatic individuals who have HIV core antigen (p24) in their circulation. These results suggest that monocyte abnormalities which could contribute to immune dysfunction in HIV-infected patients can be detected early during the course of HIV infection and are associated with the expression of serum HIV antigen.

HIV Core Protein p24↗
PubMed1987

Modification of the effects of cytotoxic chemotherapy on the immune responses of cancer patients with a nonsteroidal, antiinflammatory drug, piroxicam. A pilot study of the Eastern Cooperative Oncology Group.

We have attempted to modify the manner in which chemotherapy influences immune function in lung cancer patients by adding the nonsteroidal, antiinflammatory drug (NSAID) piroxicam to a cytotoxic drug treatment regimen. Eighteen previously untreated patients with lung cancer received cytotoxic chemotherapy with mitomycin-C (10 mg/m2), vinblastine (6 mg/m2), and cis-platinum (40 mg/m2) (MVP) on day 1 of a 21-day treatment cycle; 12/18 patients also received piroxicam (20 mg/day) beginning 10 days prior to MVP and persisting throughout the 21-day treatment cycle. In vitro tests included (a) phytohemagglutinin (PHA) responsiveness in the presence of indomethacin or interleukin-2 (IL-2), (b) natural killer cell (NK) function, and (c) PHA-induced IL-2 synthesis. In the 6 patients treated with MVP alone, depressed PHA reactivity was found pretherapy, which was augmented by indomethacin, but not by IL-2; this was associated with impaired production of IL-2. By days 7-14, PHA reactivity, IL-2 responsiveness, and IL-2 production rebounded to normal. By days 14-21, PHA reactivity had declined once again in association with increased indomethacin-regulation and impaired IL-2 responsiveness and production. In the 12 patients who received MVP plus piroxicam, PHA and IL-2 assays improved by days 7-14 and indomethacin-regulation was normal; moreover, this improvement persisted throughout the 21-day treatment cycle. Immunological rebound persisted through as many as 3 consecutive 21-day MVP plus piroxicam treatment cycles in patients who were continuously monitored. In contrast to these results, piroxicam did not alter the way chemotherapy affected NK function. These results demonstrate that the immunomodulatory effects of cytotoxic chemotherapy can be modified or ameliorated by adding an NSAID to the cytotoxic drug treatment regimen; for certain functions, such as mitogen-stimulated blastogenesis or IL-2 production, sustained immunological rebound without immunosuppression can be achieved by this maneuver.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1987

Modulation of immune function in cancer patients.

This paper will focus on three aspects of work which we have conducted in our laboratory over the past several years. Firstly, it will present results of studies in which we have found a selective inhibition of suppressor cell function in solid tumor cancer patients treated with cytotoxic drugs. Secondly, it will show that this selective inhibition results in an augmentation of other forms of immune reactivity and, in particular, an enhanced interleukin-2 production and response to this. Finally, it will demonstrate how we have made use of that information to intervene pharmacologically to modulate the immunosuppression which usually follows the use of cytotoxic drugs in solid tumor cancer patients.

Antineoplastic Agents↗