Biomedical subjects

D P Braun

Publications and source records attributed to D P Braun.

At least 19 recordsLinked to original sources

PubMed2001

Apoptosis in endometrial glandular and stromal cells in women with and without endometriosis.

BACKGROUND: The aetiology of endometriosis is unknown. Ectopic dissemination of the endometrial cells gives origin to endometriotic lesions, but occurs in women with and without endometriosis. It has been suggested that increased ectopic cell survival facilitates their implantation. The objectives of this study were to evaluate endometrial apoptosis in women with endometriosis according to: (i) cyclic changes, (ii) glandular and stromal contribution, and (iii) stage of the disease. METHODS: The subjects were women undergoing diagnostic laparoscopy and endometrial biopsies for suspected endometriosis. Spontaneous apoptosis was evaluated using TdT-mediated dUTP-biotin nick end-labelling (TUNEL) assay. Apoptotic cells per 10 mm(2) (apoptotic index) in an area of 10-50 mm(2) in 5 microm endometrial tissue sections were counted and location of these cells was recorded. RESULTS: The apoptotic index in glandular epithelium was lower in endometriosis than controls (26.0 +/- 5.5 versus 51.2 +/- 9.7, P = 0.03) but not in the stroma (36.3 +/- 6.4 versus 48.4 +/- 11.3, NS). In controls, apoptosis was highest during the late secretory/menstrual and early proliferative phases and cyclic variability was apparent. In endometriosis, this cyclic variability was lost. There was a trend toward decreased apoptosis with increasing stage of the disease, but the differences lacked statistical significance. CONCLUSIONS: Spontaneous apoptosis is decreased in the endometrial glands in women with endometriosis, especially during late secretory/menstrual and early proliferative phases of the cycle. This may indicate increased viability of endometrial cells shed during menses, facilitating their ectopic survival and implantation.

Adult↗

PubMed2000

Cytokine biosynthesis by tumor-infiltrating T lymphocytes from human non-small-cell lung carcinoma.

PURPOSE: The purpose of this work was to assess the capacity of tumor-infiltrating leukocytes (TIL) from human non-small-cell lung carcinoma (NSCLC) specimens to synthesize type-1 and type-2 cytokines. METHODS: TIL were isolated from tumors following digestion with collagenase/DNase and further enriched by ficoll-hypaque gradient centrifugation. Membrane phenotypes and intracellular cytokine protein expression of TIL were assessed by flow cytometry. RESULTS: The majority of TIL expressed the CD3 antigen with a CD4:CD8 ratio of approximately 2:1. Other leukocytes such as macrophages (CD14), B lymphocytes (CD20), and natural killer (NK) cells (CD56) were also found to infiltrate the tumors, but in significantly lower numbers. Owing to the limited recovery of non-CD3(+) leukocytes, our analysis of cytokine biosynthesis has focused on T lymphocytes. In the absence of activation, a small percentage of CD3(+) TIL synthesized cytokines ( <4%). Following activation with anti-CD3+interleukin-2 (IL-2), CD3(+) TIL synthesized predominantly a type-1 cytokine profile; however, the type-2 cytokines, IL-6 and IL-10, were also detected in a small percentage of infiltrating cells. Following activation with phorbol 12-myristate 13-acetate + ionomycin, CD3(+) TIL also expressed more type-1 than type-2 cytokines and in significantly greater numbers of cells. The CD3(+)CD8(+) component of the TIL synthesized only type-1 cytokines, whereas the CD3(+)CD4(+) component synthesized both type-1 and type-2 cytokines. CONCLUSION: These results show that the majority of the TIL isolated from NSCLC specimens are T lymphocytes with the capacity to synthesize type-1 cytokines.

Adenocarcinoma↗

PubMed1998

Functional analysis of tumor-infiltrating leukocytes in breast cancer patients.

BACKGROUND: The immune system is capable of responding to cancer as evidenced by systemic, regional, and intratumoral leukocyte activation. For individual patients there is no predictable relationship between leukocyte composition, or function, and the prognosis of the disease. MATERIALS AND METHODS: Leukocytes from tumor tissues (TIL, n = 17), axillary lymph nodes (LNL, n = 26), and peripheral blood (PBL, n = 25) of human breast cancer patients were evaluated for the ability to synthesize type 1 cytokines (TNF alpha, IFN gamma, and IL-2) and type 2 cytokines (IL-4, IL-6, and IL-10) by flow cytometry. The capacity of these cells to mediate in vitro cytotoxicity against the ZR 75-1 breast cancer cell line was simultaneously evaluated. RESULTS: To cells (CD3+) were the major leukocyte population detected in each tissue with CD4+ cells being predominant in TIL, LNL, and PBL. Type 1 cytokines were the predominant type produced by stimulated T cells for each population with a statistically greater proportion of IFN gamma + T cells in TIL as compared with LNL and PBL (P = 0.013 and 0.04, respectively). However, LNL and PBL had a significantly greater proportion of IL2+ T cells as compared with TIL from the same patient (P = 0.02 and 0.01, respectively). The tumoricidal function could be stimulated with recombinant human IL-2 in each leukocyte population with substantially higher levels of activity being produced in TIL from node-positive as compared with node-negative patients. CONCLUSIONS: This study demonstrates that there are differences in the capacity of leukocytes from different anatomical sites of breast cancer patients to synthesize immunostimulatory cytokines and mediate tumor cell cytotoxicity. Such differences may reflect prognostically distinct subgroups of patients and might also provide a rationale for the development of biological approaches to therapy in selected patients.

B-Lymphocytes↗

PubMed1998

Cytolysis of eutopic and ectopic endometrial cells by peripheral blood monocytes and peritoneal macrophages in women with endometriosis.

OBJECTIVE: To compare the ability of peripheral blood monocytes (PBM) and peritoneal macrophages (PM) to mediate the in vitro cytolysis of endometrial cells from eutopic and ectopic endometrium in women with endometriosis. DESIGN: Prospective study of immune function. SETTING: Institute for the Study and Treatment of Endometriosis and university-based research laboratories. PATIENT(S): Twenty-four women with endometriosis (15 in stage I/II, 9 in stage III/IV) and 4 patients treated with GnRH agonists. INTERVENTION(S): Peritoneal fluid and peripheral blood were sampled and eutopic and ectopic endometrium were biopsied during diagnostic laparoscopy. MAIN OUTCOME MEASURE(S): Lysis of autologous endometrial cells. RESULT(S): Peripheral blood monocytes were significantly more cytolytic than peritoneal macrophages against autologous uterine endometrial cells. However, PBM and PM displayed a similar degree of cytolysis against a hepatoma cell line. Ectopic endometrial cells were significantly more resistant to cytolysis by autologous PBMC than were matched eutopic endometrial cells, and were completely resistant to cytolysis by autologous PM. CONCLUSION(S): The reduced capacity of PM from women with endometriosis to mediate the destruction of endometrial cells coupled with the increased resistance of ectopic endometrial cells to macrophage-mediated cytolysis may facilitate the survival of these cells within the peritoneal cavity of women with endometriosis.

Adult↗

PubMed1998

Spontaneous apoptosis of endometrial tissue is impaired in women with endometriosis.

OBJECTIVE: To evaluate spontaneous apoptosis in single-cell suspensions of eutopic and ectopic endometrium from women with endometriosis and in eutopic endometrium from fertile controls without endometriosis. DESIGN: Paired specimens of eutopic and ectopic endometrial tissue from patients with endometriosis and eutopic endometrium from controls were assessed for spontaneous apoptosis. SETTING: Institute for the Study and Treatment of Endometriosis and university-based research laboratories. PATIENT(S): Fertile controls (n = 10) and women with untreated endometriosis (n = 16). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Spontaneous apoptosis assessed with an ELISA-based cell death detection kit. RESULT(S): Spontaneous apoptosis (monitored by absorbance) of eutopic endometrium from patients with endometriosis and fertile controls was 0.63 +/- 0.1 and 1.43 +/- 0.11, respectively. Among patients with endometriosis, spontaneous apoptosis of ectopic endometrium was 0.26 +/- 0.06. Decreased apoptosis of ectopic versus eutopic endometrium was observed independent of cycle phase. CONCLUSION(S): The susceptibility of endometrial tissue to spontaneous apoptosis is significantly lower in women with endometriosis than in fertile controls. We suggest that decreased susceptibility of endometrial tissue to apoptosis contributes to the etiology or pathogenesis of endometriosis.

Apoptosis↗

PubMed1998

Endometriosis: abnormal endometrium and dysfunctional immune response.

This review highlights recent studies that illuminate the role of the immune system in endometriosis. The findings are discussed in the framework of a model which proposes that endometriosis reflects an immunological selection process. Endometrial cells, which are inherently resistant to apoptosis and immune-mediated elimination, acquire the capacity to utilize the products of an activated immune system to establish ectopic foci of disease. Cyclical inflammatory/immune cell stimulation that fails to eliminate ectopic endometrial implants results in progressive immunological derangement and associated pathophysiological changes which are characteristic of the disease.

Endometriosis↗

PubMed1997

Augmentation of impaired tumoricidal function in alveolar macrophages from lung cancer patients by cocultivation with allogeneic, but not autologous lymphocytes.

It has been reported that the in vitro development of tumoricidal function in alveolar macrophages from lung cancer patients is reduced significantly when compared to that in peripheral blood monocytes from the same patients or alveolar macrophages from control patients. In the present investigation, a method for potentiating the development of tumoricidal function in alveolar macrophages from lung cancer patients is described. This method, which relies on priming the macrophages with purified, allogeneic peripheral blood lymphocytes from normal donors, could not be demonstrated when autologous lymphocytes from lung cancer patients were used in the priming coculture. The augmentation of tumoricidal function appears to be mediated by one or more soluble factors, since supernatants from cocultures of alveolar macrophages and allogeneic peripheral blood lymphocytes could enhance the cytotoxic function of freshly obtained alveolar macrophages. Furthermore, it appears that NK cells are necessary for this effect, since depletion of CD56+/CD57+ cells from allogeneic lymphocytes eliminated their capacity to enhance alveolar macrophage cytotoxic function. The augmentation of cytotoxic function elicited in alveolar macrophages by this method was not associated with changes in the secretion of tumor necrosis factor alpha, or interleukin 1 beta.

CD3 Complex↗

PubMed1997

Modulation of tumoricidal function in alveolar macrophages from lung cancer patients by interleukin-6.

Previous studies have demonstrated that alveolar macrophages from lung cancer patients are impaired in their ability to develop tumoricidal function when stimulated by activators such as interferon gamma + lipopolysaccharide. However, these same macrophages have been shown to develop significant tumoricidal function when precultured with macrophage-depleted allogeneic peripheral blood lymphocytes from normal donors, an effect that was lost by the elimination of natural killer cells from the allogeneic lymphocyte population. In the present study, the effect of each activation condition on the expression of mRNA for interleukin-1 alpha (IL-1 alpha), IL-1 beta, tumor necrosis factor alpha (TNF alpha) and IL-6 was determined using reverse transcription/polymerase chain reaction. The results show that the non-permissive activation condition is associated with the expression of mRNA for IL-6 while the permissive activation condition is not. Antibodies against IL-6 were subsequently shown to permit the development of tumoricidal function in alveolar macrophages stimulated with interferon gamma + lipopolysaccharide while IL-6 protein was shown to inhibit the stimulatory action of allogeneic lymphocytes on the development of tumoricidal function in the same alveolar macrophages. Neither the permissive (i.e. allogeneic lymphocyte stimulation) nor the non-permissive (i.e. interferon gamma + lipopolysaccharide) activation condition had any effect on the capacity of alveolar macrophages from lung cancer patients to express mRNA for IL-1 alpha, IL-1 beta or TNF alpha. These results show that IL-6 can regulate the ability of alveolar macrophages from lung cancer patients to be stimulated by interferon gamma + lipopolysaccharide to develop significant tumoricidal function. They also show that allogeneic lymphocytes have the capacity to down-regulate IL-6 mRNA synthesis by alveolar macrophages thereby permitting the development and/or expression of macrophage tumoricidal function.

Antibodies↗

PubMed1997

Cytolytic activity of peripheral blood blast cells from patients with acute myeloid leukemia.

The results of the present study demonstrate that cells with the morphologic and phenotypic characteristics of blast cells that are obtained from the peripheral blood of patients with newly-diagnosed or recurrent acute myeloid leukemia (AML) can be stimulated by gamma interferon + lipopolysaccharide (IFN/LPS) to mediate in vitro cytolysis of an NK-insensitive hepatoma cell line. The conditions of IFN/LPS induction and subsequent assessment of cytotoxicity that were employed were identical to those used conventionally to test macrophage-mediated tumor cell cytotoxicity. What was totally unexpected was that these same blast cells, in the absence of stimulation with IFN/LPS, were also found to mediate high levels of spontaneous cytotoxicity against autologous bone marrow cells and against the U937 human promonocytic leukemia cell line in vitro. This high level of spontaneous cytotoxicity against autologous bone marrow or U937 promonocytic leukemia cells was not enhanced by IFN/LPS or MCSF under conditions that stimulated cytotoxic function in normal blood monocytes and was markedly reduced by pretreatment of the blast cells with IL2 under conditions that induced potent NK/LAK-mediated cytotoxicity. Neutralizing antibodies against TNFalpha and/or IL1alpha/beta eliminated the cytolytic function of blast cells against autologous bone marrow or U937 promonocytic leukemia targets. These findings demonstrate the existence of a population of cells with the morphologic characteristics of blast cells in the peripheral blood of AML patients which has the capacity to mediate spontaneous cytolysis of autologous bone marrow cells or a promonocytic leukemia cell line. These cells may be an immature variant of normal precursors produced as a consequence of the disordered hematopoietic environment in the marrow of AML patients. Alternatively, this function may be mediated by a subset of the leukemic blasts themselves.

Adult↗

PubMed1996

Basal and stimulated secretion of cytokines by peritoneal macrophages in women with endometriosis.

OBJECTIVE: To evaluate basal (constitutive) and stimulated synthesis of tumor necrosis factor alpha (TNF alpha), interleukin (IL)-8, IL-10 by peritoneal macrophages (PM) in women with endometriosis. DESIGN: Peritoneal macrophages were cultured in the presence or absence of lipopolysaccharide (LPS) for 24 hours. Peritoneal fluids (PF) and PM supernatants were assayed for cytokines using ELISA. SETTING: Institute for the Study and Treatment of Endometriosis and university-based research laboratories. SUBJECTS: Fertile controls undergoing tubal ligation (n = 8) and women with endometriosis (n = 17). INTERVENTION: Peritoneal fluid samples were obtained at the time of diagnostic laparoscopy (endometriosis group) or laparoscopy for tubal ligation; both were performed in the midluteal phase of the cycle. RESULTS: Both basal and LPS stimulated production of TNF alpha, IL-8, and IL-10 by the PM were elevated significantly in women with endometriosis as compared with the fertile controls. CONCLUSIONS: This study demonstrated that cytokines TNF alpha, IL-8, and IL-10 are synthesized at greater than normal levels by basal and stimulated PM from women with endometriosis. The levels of TNF alpha and IL-8 correlated with the levels in the PF, suggesting that PM are the principal source of these cytokines in the PF.

Ascitic Fluid↗

PubMed1996

Spontaneous and induced synthesis of cytokines by peripheral blood monocytes in patients with endometriosis.

OBJECTIVE: To investigate the capacity of peripheral blood monocytes (PBM) from women with endometriosis to secrete tumor necrosis factor-alpha (TNF-alpha), interleukin (IL) IL-6, IL-8, and IL-10. DESIGN: Peripheral blood monocytes were cultured in the presence and absence of lipopolysaccharide for 24 hours before assessment of cytokines in supernatants by enzyme immunoassay. SETTING: Institute for the Study and Treatment of Endometriosis and university-based research laboratories. PATIENTS AND PARTICIPANTS: Fertile controls, n - 10; women with endometriosis, n = 20. INTERVENTIONS: None. RESULTS: Basal synthesis of TNF-alpha, IL-6, and IL-8 and the lipopolysaccharide-stimulated synthesis of TNF-alpha by PBM from women with endometriosis was significantly greater in comparison to that of fertile controls. Endometriosis had no effect on the basal or stimulated synthesis of IL-10. CONCLUSIONS: These data show that endometriosis is associated with increased basal and stimulated synthesis and secretion of several different cytokines by PBM. Each of the cytokines found to be affected has the capacity to play a role in the symptomatology or pathogenesis of the disease.

Cytokines↗

PubMed1995

Differential expression of VLA beta 1 (CD29) on monocytes from patients with endometriosis.

PROBLEM: Previous studies have established that in vitro proliferation of endometrial cells is enhanced by peripheral blood monocytes (PBM) and suppressed by peritoneal macrophages (PM) from patients with endometriosis but only suppressed by PBM and PM obtained from normal subjects. The functional activity of PBM and PM is influenced by the engagement of numerous cell surface receptors with their respective physiological ligands. METHOD: In this study, PBM and PM from fertile women (Group 1), women with unexplained infertility (Group 2), and women with limited (Group 3) or severe (Group 4) endometriosis were isolated in order to analyze these cells for the expression of CD54, CD58 and HLA-DR (immunoglobulin supergene antigens) CD18 and CD29 (integrins) and CD44 (an addresin). These cell surface antigens are involved in monocyte/macrophage trafficking, activation, signal transduction and/or adhesion. RESULTS: No differences were detected in the percentage of PBM expressing CD18, CD44, CD54, CD58, or HLA-DR among the four groups of subjects. Furthermore, the density of these antigens expressed on PBM was identical in patients and control subjects. In contrast, the percentage of PBM expressing CD29 (also known as VLA beta 1) and the density of CD29 expressed per cell were significantly reduced (P < 0.01) in patients with limited endometriosis compared to controls and patients with severe disease. Interestingly, although the percentage of CD29+ PBM from women with severe endometriosis was not statistically different from the percentage of CD29+ PBM from controls, the density of CD29 expressed per cell was significantly elevated among patients with severe disease. Analysis of PM from the four subject groups revealed no differences in CD29 expression or density. However, the percentage of PM expressing CD18 was significantly decreased in patients with limited (but not severe) endometriosis. CONCLUSION: Since both CD18 and CD29 play a role in cell trafficking and/or adhesion, alterations in their expression among patients with endometriosis suggest that these integrin beta chains may play a role in the pathogenesis of the disease.

Endometriosis↗

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

Suppression of the development of tumoricidal function in gamma interferon-treated human peripheral blood monocytes by lipopolysaccharide: the role of cyclooxygenase metabolites.

Bacterial lipopolysaccharide (LPS) is generally regarded as one of the most potent macrophage activators. Thus, LPS has been used as an obligatory second signal to stimulate macrophage cytotoxic function against a wide array of bacterial and neoplastic targets. In this study, however, we define conditions under which LPS can suppress the development of cytotoxic function in normal human peripheral blood monocytes. When monocytes were treated with a priming dose of gamma interferon (gamma-INF), followed 18-24 hr later by a triggering dose of LPS, significant cytotoxic function developed. However, when monocytes were treated with even minimal amounts of LPS during priming with interferon, the development of cytotoxic function following stimulation with a second, triggering dose of LPS was virtually abolished. This effect could be produced from 0 to 14 hr following the addition of gamma-INF. The inhibition of monocyte cytotoxicity which was produced by LPS treatment during priming was dose dependent and could not be overcome by modifying either the priming dose of gamma-IFN or the triggering dose of LPS. The suppression was largely overcome, however, by treatment with the cyclooxygenase inhibitor, indomethacin. The possibility that LPS-induced suppression of monocyte cytotoxicity was mediated by products of the cyclooxygenase pathway was supported further in this study by demonstrating that LPS stimulated the production of significant amounts of prostaglandin E2 (PGE2) from monocytes and that this was facilitated by gamma-IFN. In kinetics studies, it appeared that LPS suppression of monocyte activation was correlated temporally with a heightened sensitivity to suppression by exogenously added PGE2, a condition which was reduced greatly by the end of the priming phase.(ABSTRACT TRUNCATED AT 250 WORDS)

Cell Death↗

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↗