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M Stegmüller

Publications and source records attributed to M Stegmüller.

14 recordsLinked to original sources
PubMed1999

In vivo microscopy of murine islets of Langerhans: increased adhesion of transferred lymphocytes to islets depends on macrophage-derived cytokines in a model of organ-specific insulitis.

Environmental factors contribute to the pathogenesis of type 1 diabetes (insulin-dependent diabetes mellitus). Multiple low doses of streptozotocin (MLDS) induce hyperglycaemia and insulitis in mice. Previously we demonstrated that adhesion of lymphocytes to endothelium of islets is only increased when donor animals were diabetic and recipient mice had received 5 mg/kg streptozotocin (STZ). Therefore we used streptozotocin to evaluate the immunological relevance of such an irritation of islets. Lymphocytes, separated from diabetic mice (MLDS), were fluorescently labelled and injected to recipient mice that had received 5 mg/kg STZ. With in vivo microscopy we measured lymphocyte flow and adherence in islets. Expression of vascular cell adhesion molecule-1 (VCAM-1) and intracellular adhesion molecule-1 (ICAM-1) in the pancreas was assessed using immunohistochemistry. Very late antigen-4 (VLA-4) and leucocyte function-associated antigen-1 (LFA-1) expression on transferred lymphocytes was measured with flow cytometry. Pretreatment of recipients with antibodies to cytokines or silica reduced lymphocyte adherence to islet endothelium from 2.04% (goat immunoglobulin G; IgG) or 1.82% (rat IgG) to 0.47, 0.58, 0.39 or 0. 19% for monoclonal antibody (mAb) interferon-gamma (IFN-gamma), polyclonal antibody (pAb) tumour necrosis factor-alpha (TNF-alpha), pAb interleukin (IL)-1alpha or silica, respectively. Reduced adhesion was associated with a decreased expression of VCAM-1 and ICAM-1 in islets of treated recipients compared with mice treated with 5 mg/kg STZ alone. In conclusion, pretreatment of recipients with 5 mg/kg STZ leads to an increased expression of adhesion molecules in the islets and lymphocyte adhesion to islet endothelium in vivo, demonstrating an immune response of the islets. Prevention of increased expression of ICAM-1 or VCAM-1 and reduction of lymphocyte adhesion in islets by silica or antibody indicate an involvement of macrophages and macrophage derived cytokines in the generation of this immune response.

Animals↗
PubMed1999

Macrophage and lymphocyte homing in experimental diabetes.

Diabetes mellitus was induced in C57BL/6 mice by multiple low doses of streptozotozin (STZ). By transferring lymphocytes from these diabetic animals to healthy recipient mice insulitis can be induced in healthy recipient mice. On day 21 after the start of STZ-treatment splenic lymphocytes were separated in vitro and stained with the fluorochrom acridine red for adoptive transfer. The recipient mouse had been pretreated with a subdiabetogenic dose of STZ (5 mg/kg) i.p. 24 h prior to the lymphocyte transfer. With in vivo microscopy we measured the lymphocyte adherence to the endothelium of islets of the recipient mouse. After the administration of mAbs directed against LFA-1, ICAM-1, murine VCAM-1, VLA-4, MadCAM or alpha4,beta7-integrin prior to the cell transfer we could demonstrate a significant decrease of donor lymphocyte adherence in islets (P<0.01). The pretreatment of the recipient mice with STZ 24 h before the transfer of lymphocytes might attract macrophages to the islets. Therefore we pretreated the recipients with antibodies to cytokines or silica. mAb IFN-gamma, pAb TNF-alpha, pAb IL-1alpha or silica reduced lymphocyte adherence to islet endothelium significantly (P<0.01). The presented results support the following interpretation: The pretreatment of the recipient mice with the islet specific toxin STZ in subdiabetogenic doses attracts macrophages to the islets. The macrophages release cytokines leading to an increased expression of adhesion molecules on the endothelium of the islets. The consequence is lymphocyte homing selectively to the islets. The cascade of lymphocyte homing is complex and various pairs of adhesion molecules are involved. The discussion on the importance of the single pairs of adhesion molecules is irrelevant, since the cascade of lymphocyte homing can be disturbed by the application of a mAb to any one adhesion molecule involved in the cascade of lymphocyte homing.

Animals↗
PubMed1998

Changes in lymphocyte subsets during normal pregnancy.

Peripheral blood lymphocytes from healthy women were studied during pregnancy and postnatally, and were compared with lymphocytes from an age-matched non-pregnant control group. Compared with non-pregnant women, the total white cell count was significantly increased at all pregnancies and also post-partum. In pregnancy the absolute number and percentage of T lymphocytes was slightly elevated while almost no changes in B cells were found. No significant changes were found in the percentage of suppressor/cytotoxic (CD8+), of helper/inducer (CD4+) T lymphocytes, nor of CD4+/CD8+ ratio at any stage of pregnancy and puerperium. The most remarkable changes of the immune system occurred in the group of HLA-DR+ and CD56+ activated T cells. The cell numbers showed a significant increase in the first trimester (< 14 weeks) and decreased slightly from stage to stage. Lower values in NK (natural killer) cells and higher levels of IL-2 receptor positive T lymphocytes did not reach significant levels of change.

Adult↗
PubMed1997

Lymphocyte subsets in patients with ovarian and breast cancer.

Peripheral blood lymphocytes (PBL) from patients with ovarian or breast cancer or benign lesions of the breast, respectively, have been analysed for expression of phenotypic and activation markers by flow cytometry. The results were compared with those of a control group of healthy women. The relative proportion as well as the absolute counts of B lymphocytes were similar in both groups and in the control group. The absolute number of T cells was decreased in breast cancer patients (p < 0.05). The CD4+/CD8+ ratio was significantly depressed in ovarian cancer patients (p < 0.05), but not in breast cancer patients. In the ovarian cancer group, the percentage of CD3+ T cells expressing HLA-DR (p < 0.05) as well as CD3+ T cells expressing CD16 and CD56 (p < 0.05) was significantly higher. The relative proportion as well as the absolute counts of CD3+ T cells expressing the IL-2 receptor (CD25) were significantly higher (p < 0.001), respectively, in breast cancer patients (p < 0.05). These results suggest that gynaecological cancer is associated with specific alterations in the T cell population.

Adult↗
PubMed1994

Growth inhibition of xenotransplanted human carcinomas by a monoclonal antibody directed against the epidermal growth factor receptor.

In the athymic nude mice model with xenotransplanted human carcinomas, the effect of a monoclonal antibody (MAb 425), directed against the human epidermal growth factor (EGFR), on tumour growth was studied. Five different solid human breast carcinomas and one vulvar epidermoid cancer cell line (A431) were transplanted in nude mice, and treated with MAb 425 2.2 mg intraperitoneally (i.p.) on day 7 post-transplantation. Tumours with EGFR concentrations of > or = 16 fmol/mg soluble cytosolic protein showed growth inhibition, whereas the growth pattern of EGFR-negative tumours was unaffected. Variation of MAb 425 dosage (1.1 versus 2.2 mg) revealed no difference in the growth inhibiting effect. Different application schedules (application on day 0, 12 or 26) showed different onsets and durations of tumour growth inhibition. Repeated application (1.1 mg, day 0 and 12) was followed by a prolonged inhibitory effect. Our results suggest that growth inhibition of EGFR-positive tumours by MAb 425 may lead to an additional treatment option for patients with EGFR-positive cancer.

Animals↗
PubMed1993

Immuno-biochemical assay for determination of nuclear steroid receptors during tamoxifen therapy.

The exact knowledge of hormone receptor status is critical for therapeutic strategies in hormone-dependent tumors. The influence of tamoxifen on estrogen receptor concentration has to be taken into account when evaluating results in tamoxifen-treated patients. We studied the receptor modulation of tumors xenotransplanted into nude mice (one breast and one endometrial carcinoma) after injection of 50 micrograms tamoxifen/mouse. To differentiate between unoccupied and occupied receptors, determinations were done by an enzyme immunoassay for the estrogen receptor under low- and high-salt extraction. With low-salt extraction we found a temporary decrease of the estrogen receptor concentration within the first hours after tamoxifen treatment. This decrease lasted for several days before recovery to pretreatment levels occurred. The hormone-receptor complexes, tightly bound to acceptor sites of the DNA, increased more than 15 times within 24 h. These values remained at increased levels for 2-7 days, after which a decrease to initial level was observed.

Animals↗
PubMed1993

Functional analysis of tumor-associated lymphocytes from gynecological tumors.

Tumor-Associated Lymphocytes (TAL) were isolated from peritoneal fluids of six ovarian cancer patients and pleural effusion from eight breast cancer patients, respectively. In one case we obtained ascitic fluid as well as pleural effusion because of intraabdominal metastatic breast carcinoma. The collected cells were cultured in a complete medium and supplemented with human interleukin-2 (nIL-2) in a concentration of 1000 Units/ml. Phenotyping was not always possible due to rapid decay of the cells. Cytotoxicity was determined with a fluorescence-based assay, in some cases at different stages of cell growth. In two cases TAL from ascitic fluids showed increased cytotoxic activity after a longer cultivation period. TAL from pleural effusions showed cytotoxic activity against the target cell lines in two cases only. Some of these TAL did not proliferate any more but died within 24 h. With the functional analysis we wanted to investigate the cytotoxic potential against natural killer (NK)-sensitive and NK-resistant (Raji) cell lines. The results demonstrate the ability of some of the TAL populations to destroy tumor cells.

Adult↗
PubMed1992

Influence of chemotherapy on hormone receptor concentration in a xenotransplanted endometrial cancer.

There is growing evidence that chemotherapy may influence the hormone receptor capacity in human carcinomas. The consideration of this assumption may be of importance for the therapeutic management of tumors with metastatic spread which underwent previous adjuvant chemotherapy. Therefore we investigated the influence of six different kinds of chemotherapy on the hormone receptor concentration and the percentage of receptor positive cells in xenotransplanted endometrial cancer. Our results can be summarized as follows: (1) We find neither a significant decrease in hormone receptor capacity after chemotherapeutic treatment (biochemical determination), nor do we see a decrease in the percentage of ER/PR pos. cells (immunohistochemistry). (2) On the other hand, there is no increase in hormone receptor concentration inducible by chemotherapy and no increase in ER/PR pos. cells immunohistochemically.

Adenocarcinoma↗
PubMed1983

The effect of sex steroids and hormonal contraceptives upon thymus and spleen on intact female rats.

In view of a possible influence on oral contraceptives upon the immune system, the effect of chronic treatment of intact adult female rats with sex steroids and contraceptive preparations upon the thymus and the spleen was investigated. Daily injections with 10 micrograms estradiol, estradiol benzoate, or diethyl stilbestrol for 2 weeks resulted in a marked but reversible involution of the thymus, while the spleen was not affected. Androgens exerted a significant effect at a dose of 0.3 mg, and progestogens only when 2 mg were given. When various contraceptive preparations were injected for 4 weeks, there was a total involution of the thymus which persisted even 2 weeks after cessation of treatment. The effect appeared to be mainly due to the estrogenic component. Progestogens intensified the reduction of thymic weight only at higher doses. Histological examinations revealed that estrogen treatment alone resulted in a reduction of the cortex and a depletion of lymphocytes. When contraceptive preparations were administered, the medulla was also reduced, and both cortex and medulla were replaced by reticular and adipose tissue. The estrogen receptors of thymus cytosol showed dissociation constants between 0.34 and 0.49 nM in diestrous rats, progesterone-treated rats and ovariectomized rats, and binding capacities between 6.5 and 2.6 fmoles/mg protein. It remains, however, to be shown whether the estrogen-induced involution of the rat thymus may lead to an impairment of immune responses.

Androgens↗