Biomedical subjects

W Den Otter

Publications and source records attributed to W Den Otter.

At least 91 records · Page 5Linked to original sources

PubMed1991

Parathymic lymph nodes during growth and rejection of intraperitoneally inoculated tumor cells.

The omental lymphoid organ (OLO) is a part of the greater omentum composed of vascularized milky spots situated between fat cells and containing lymphocytes, plasma cells and macrophages. We analysed the disappearance of intraperitoneally injected tumor cells from the peritoneal cavity and their infiltration into and disappearance from the OLO and the parathymic lymph nodes (PTLN) that drain the peritoneal cavity. After intraperitoneal inoculation of irradiated syngeneic tumor cells, they were visible in the OLO within 24 h. After 3 days, no tumor cells were seen anymore, but there were many macrophages that had phagocytosed tumor cells. After intraperitoneal inoculation of nonirradiated syngeneic tumor cells, a solid growing tumor mass developed in the OLO. The PTLN were also invaded by these nonirradiated tumor cells within 24 h as transfer of cell suspensions of these lymph nodes into naive mice leads to the death of the recipient mice due to tumor growth. However, from day 6 onwards, after tumor inoculation, these lymph nodes contained no tumor cells, despite progressive tumor growth intraperitoneally and in the liver and lungs. In allogeneic mice, tumor cells were rejected in the OLO after 7-10 days. Simultaneously, the number of lymphocytes and macrophages increased and a plasma cell reaction developed. The PTLN did not have tumor-inducing potency at any stage after intraperitoneal tumor injection. This study suggests, that the PTLN are more effective in the (local) eradication of tumor cells than the OLO. Still, considering its immunological potential, the OLO might be important as 'inducer' of immunological reactions in the peritoneal cavity.

Animals↗

PubMed1990

Parental age in sporadic hereditary retinoblastoma.

Of 104 children with sporadic hereditary retinoblastoma born between 1945 and 1970, we studied the age of their parents at the birth and compared this age with the mean age of parents at the birth of their children during the same period in The Netherlands. The mean age of fathers at the birth of their children with sporadic hereditary retinoblastoma (33.7 years) was significantly higher than the mean age of fathers at the birth of their children in the general population (32.5 years) (P less than .05, one sided). Similarly, the mean age of mothers at the birth of their children with sporadic hereditary retinoblastoma (31.2 years) was significantly higher than the mean age of mothers at the birth of their children in the general population (29.5 years) (P less than .05, one sided). We further analyzed this parental age factor by measuring the relative risk of age groups and comparing the incidence of sporadic hereditary retinoblastoma in the various parental age groups with the incidence of sporadic hereditary retinoblastoma in the total population. Mothers 35 years of age or older had a relative risk of 1.7 to have a child with sporadic hereditary retinoblastoma compared with mothers in the population in general (P = .006, one sided). Similarly, fathers 50 years of age or older had a relative risk of 5.0 to have a child with sporadic hereditary retinoblastoma compared with fathers in the population in general (P = .04, one sided). No parental age effect was found in children with nonhereditary retinoblastoma. We conclude that a high paternal and a high maternal age are significant risk factors for sporadic hereditary retinoblastoma.

Adult↗

PubMed1990

Insulin-like growth factor gene expression in human smooth muscle tumors.

A role for insulin-like growth factors (IGF) in autocrine or paracrine growth stimulation of tumor cells has been proposed for tumors of different origins. We have studied IGF gene expression in human uterus smooth muscle (myometrium) and in a panel of benign (leiomyoma) and malignant (leiomyosarcoma) smooth muscle tumors. Using RNA transfer blot analysis we could demonstrate that in smooth muscle tissue and tumors IGF genes are differentially expressed. The mRNA species detected had the same size as reported for IGF mRNAs from other tissues. However, the abundance of the IGF gene transcripts varied from tissue to tissue. The amounts of IGF mRNAs detected in smooth muscle tumors were compared to the levels found in normal smooth muscle. The IGF-I gene was expressed at high levels in normal myometrium and in leiomyomas but appears to be repressed in leiomyosarcomas. Also the IGF-I peptide was detected in myometrium and in leiomyomas, but in leiomyosarcomas the level was substantially lower. The IGF-II gene was expressed at low levels in normal myometrium and leiomyomas but is activated in leiomyosarcomas. With increasing malignancy from the two major IGF-II mRNA species, 6.0 and 4.8 kilobases, in particular the 6.0-kilobase mRNA is produced at higher levels. In conclusion, these data suggest that for IGF-I a role in tumor cell growth is not likely, but probably IGF-II is involved in malignant smooth muscle tumor growth progression.

Female↗

PubMed1990

Major-histocompatibility-complex-class-II-positive cells and interleukin-2-dependent proliferation of immune T cells are required to reject carcinoma cells in the guinea pig.

Tumor immunity induced by bacillus Calmette-Guérin was studied in the line 10 hepatocellular carcinoma (line 10) in the strain-2 guinea pig. Line 10 immunity was investigated in vitro with a lymphocyte proliferation assay using line 10 tumor protein extracted with 3 M KCl and in vivo by adoptive transfer of line-10-immune spleen cells. Monoclonal antibodies against guinea pig leucocyte markers were used to block functional properties of the immune cells in order to determine which cell types or cell markers are involved in the immune response to the line 10 tumor. In vitro cells from the spleen, peripheral blood and regional lymph node of immune animals reacted with a proliferative response to line 10 protein. This antigen-specific response was caused by T cells and was regulated by major histocompatibility complex (MHC) class II molecules. In blocking experiments it was found that CT5 (anti-PanT), or MSgp4 [anti-(MHC class I antigen)] monoclonal antibodies did not block but sometimes stimulated the proliferative response. The effect of H159 (anti-PanT) was irregular, while H155 [anti-(T helper)], and 5C3 [anti-(IL-2 receptor)] monoclonal antibodies blocked the response almost completely. We studied the relevance of the results in vitro obtained and found that mAb 5C3 [anti-(IL-2 receptor)] inhibited the adoptive transfer of line 10 immunity, suggesting that the rejection of line 10 cells is caused by a mechanism that is interleukin-2 (IL-2)-dependent. Moreover, complement lysis of MHC-class-II-antigen-positive immune spleen cells inhibited completely the rejection of the line 10 tumor cell challenge in the adoptive-transfer experiments. In conclusion, our data show that MHC class II molecules or cells possessing these molecules are involved in immunity against line 10 tumor cells, as (a) monoclonal antibodies against MHC class II antigens inhibited the in vitro proliferative response of T cells to tumor antigens and (b) removal of MHC-class-II-positive immune spleen cells abrogated the antitumor effect in the adoptive-transfer experiments. Interleukin-2-dependent proliferation of immune T cells is required for the rejection of line 10 tumor cells.

Animals↗

PubMed1990

Major histocompatibility complex class II antigen expression during potentiation of line-10 tumor immunity after intralesional administration of bacillus Calmette-Guérin.

Intralesional injection of BCG into an established line-10 hepatocellular carcinoma in the strain-2 guinea pig causes regression of the tumor and induction of line-10 immunity. We found that the animals were already protected for a second challenge with line-10 tumor cells 7 days after BCG treatment. We studied whether this early induction of immunity was correlated with the expression of MHC class II antigens on line-10 tumor cells and was correlated with an increased expression of MHC class II antigens on leukocytes in the primary tumor and in the regional lymph node (Ln. axillaris accessorius). The MHC class II antigens and the leukocyte subpopulations were measured with monoclonal antibodies and flow cytofluorometry. In the draining lymph node the number of nucleated cells increased about 10-fold during the first 5 days after intralesional injection of BCG. At this time the MHC class II antigen expression of these cells was increased from 21%-32% in the naive controls to 39%-53% in animals with BCG-treated tumors. This implies that the number of MHC-class-II-positive cells increased about 20-fold in the draining lymph node. Surprisingly, the increase in percentage of MHC-class-II-antigen-positive cells was mainly due to an increase of IgM-positive B cells from 8%-11% to 22%-41% and an increase of IgG-positive B cells from 7%-27% to 25%-44%. In the tumor, BCG treatment induced a small increase of MHC-class-II-antigen-positive cells from 11%-12% to 15%-20%. Probably this increase came not from tumor cells but mainly from a BCG-induced infiltration of mononuclear cells, as an increase of T cells from 14% to 20%, an increase of macrophages from 8% to 18%, and an increase of B cells from 0 to 6% was observed. We conclude that the potentiation of anti-(line-10 tumor cell) immunity correlated with a 20-fold increase of MHC-class-II-antigen-positive cells in the lymph nodes and a small increase in the number of MHC-class-II-antigen-positive tumor-infiltrating cells.

Animals↗

PubMed1990

Mechanisms of tumour rejection in the murine DBA/2-SL2 concomitant immunity system.

The mechanisms of rejection of secondary tumours were studied in concomitant immunity using transplants of standard-size solid SL2 tumours in syngeneic DBA/2 mice. In such a system primary tumor implants are not rejected, in contrast to secondary tumour implants. The second tumour was mainly rejected 2-4 days after implantation. Both primary tumour and secondary tumour implants (which are rejected) contained hardly any lymphocyte infiltrate, whereas, 2-4 days after implantation they contained 40%-50% macrophages, which were cytotoxic in vitro. Transfer (s.c.) of these tumours to naive mice showed that cellular infiltrates in the secondary implants did not always cause tumour rejection. Serum collected on day 4 after implantation of the secondary tumour was cytotoxic to SL2 tumour cells in vitro, whereas serum from mice with only primary implants was not cytotoxic on day 4 after implantation. Preliminary characterization of this cytotoxic factor showed that it was heat-labile, as cytotoxicity disappeared after 30 min at 56 degrees C, the molecular mass of the factor was higher than 100 kDa, and it was not IgG. We hypothesize that secondary tumours in the DBA/2-SL2 concomitant immunity system are rejected mainly between 2 and 4 days after implantation as a result of the combined action of cytotoxic serum and the presence of 40%-50% cytotoxic macrophages. The primary tumour is not rejected at 2-4 days after implantation as there is no cytotoxic factor.

Animals↗

PubMed1990

Tumor infiltrating leukocytes (tils) during progressive tumor growth and BCG-mediated tumor regression.

Tumor regression was induced by intralesional injection with BCG, 7 days after inoculation of line 10 hepatocellular carcinoma cells into strain 2 guinea pigs. Tumor-infiltrating leukocytes (TILS) were characterized immunohistochemically with 11 monoclonal antibodies (MoAbs) during the induction phase of line 10-immunity, and during immune-mediated regression of the tumor, at days 12 and 28 after tumor cell inoculation, respectively. At day 5 after BCG-injection (day 12 after tumor cell inoculation), there were no major differences between the TIL subpopulations of the BCG-treated and untreated tumors. The TILS were mainly T-cells, as identified by MoAbs against Pan T-cells (CT5), T-cytotoxic/suppressor cells (CT6) and T-helper/inducer cells (H155). A limited number of macrophages was also present. However, at day 21 after BCG-treatment (28 days after tumor cell inoculation), the fibrous stroma was increased dramatically in most of the BCG-treated tumors, and as a result, the tumor cell islets were smaller than in control tumors. In the BCG treated tumors, the numbers of T-cells and macrophages were increased. In growing and regressing tumors, MHC class I and II antigens were strongly expressed in TILS and in the tumor stroma. Line 10 tumor cells prior to inoculation expressed no MHC class I or II antigens. In the centers of the tumor islets at days 12 and 28, expression of these antigens was not found. However, MHC class I and II antigens were expressed on tumor cells at sites where they lay close to the fibrous stroma or TILS. This observation was made in progressively growing tumors and was most apparent in BCG-treated tumors.

Animals↗

PubMed1990

Expression of insulin-like growth factor 1 in sarcomas.

The expression of insulin-like growth factor-1 (IGF-1) was studied in normal tissues, in eight benign lesions and in 50 sarcomas. In palmar fibromatosis the spindle cells in cell-dense areas exhibited a strong immunoreactivity. IGF-1 was variably found in leiomyosarcomas (7/8), malignant schwannomas (7/9), synovial sarcomas (2/3), liposarcomas (3/6), fibrosarcomas (1/3), malignant fibrous histiocytomas (10/18) and in one angiosarcoma. Two rhabdomyosarcomas failed to express IGF-1 and only the spindle cell component of synovial sarcomas was positive. Immunoreactivity for IGF-1 in 10 malignant filrous histiocytomas (MFH) appeared to be related to co-expression of smooth muscle actin. These findings imply that MFHs can be subdivided into a group of tumours which are devoid of morphological and immunophenotypic evidence of differentiation and a group which manifest immunophenotypic differentiation.

Actins↗

PubMed1990

Mycobacterial antigens stimulate rheumatoid mononuclear cells to cartilage proteoglycan depletion.

In a coculture with porcine articular cartilage explants unstimulated blood mononuclear cells (BMC) from patients with rheumatoid arthritis (RA), but not from healthy controls, induced proteoglycan depletion of dead cartilage. Specific stimulation of the RA BMC with Mycobacterium tuberculosis (MT), in comparison with concanavalin A (Con-A), strongly enhanced the proteoglycan depletion of living cartilage; this was not found with the BMC of healthy controls. However, the MT induced proliferative responses of the same BMC were similar in healthy controls and patients with RA. Neither the proliferative response nor the proteoglycan depletion was influenced by the presence of HLA-DR4 in the donor, whether patients with RA or healthy control. The proliferative responses of the RA BMC seemed to correlate inversely with the proteoglycan depletion. We conclude that stimulation of RA BMC with mycobacterial antigens may elicit effector pathways that induce proteoglycan depletion, independent of T cell proliferation.

Adult↗

PubMed1990

The effect of human interleukin 1 on proteoglycan metabolism in human and porcine cartilage explants.

Human interleukin 1 (IL-1), up to 100 pg/ml, causes a decrease of the proteoglycan content of human (old and young) as well as porcine cartilage explants, without stimulating the proteoglycan release from the cartilage. The proteoglycan depletion is stronger in young than in old human cartilage and stronger in human than in porcine cartilage. The proteoglycan synthesis is considerably more inhibited by IL-1 in young than in old human cartilage. Our data suggest that an IL-1 induced inhibition of the proteoglycan synthesis, rather than a stimulation of proteoglycan breakdown causes the proteoglycan depletion of the cartilage. The data furthermore suggest a clear difference between young and old human cartilage, with respect to their sensitivity for IL-1. IL-1 in a concentration of 500 pg/ml causes in all 3 kinds of cartilage explants chondrocyte damage that might be relevant in the cartilage destruction during rheumatoid arthritis.

Aged↗

PubMed1989

Immunotherapy of mice with a large burden of disseminated lymphoma with low-dose interleukin 2.

Successful immunotherapy with recombinant interleukin 2 (rIL-2) of mice bearing a large burden of lymphokine-activated killer-resistant disseminated SL2 lymphoma is described. When mice were challenged i.p. with 2 x 10(4) SL2 cells on day 0 and treated with daily i.p. injections of 5,000 units rIL-2 on days 3-7, no therapeutic effect was observed. However after treatment with daily IL-2 injections on day 10-14, 25% of the mice survived. Ten days after this tumor challenge more than 10(8) SL2 cells were present growing as ascitic tumor. On day 10, SL2 cells were also present as solid tumor in the greater omentum and as metastases in lungs and liver. Surviving mice were able to reject a second challenge with SL2 cells given on day 60. A second challenge with P815, another DBA/2 tumor, resulted in death of the mice due to tumor development. This finding is of particular importance as the SL2 cells are resistant to lymphokine-activated killer activity. Thus local (i.p.) injection of low dose rIL-2 can cause the systemic rejection of advanced and metastasized cancer. Our data indicate that IL-2 can strongly enhance a specific immune reaction against tumor cells.

Animals↗

PubMed1989

Early diagnosis of bilateral retinoblastoma reduces death and blindness.

The influence of early diagnosis on sight and survival was studied in 130 patients with bilateral retinoblastoma. Nineteen patients died of this condition. Statistical analysis predicted that 12 of these 19 early deaths could have been prevented if doctors' delay had been less than 1 week. Consequently, a reduction of 65% in mortality is possible. Similarly, statistical analysis also predicted that the number of patients with resulting blindness could be reduced by 40%. Central registration and monitoring of retinoblastoma families would greatly improve early diagnosis.

Adolescent↗

PubMed1989

Two specific T cell factors that initiate immune responses in murine allograft systems. A comparison of biologic functions.

It has been suggested that Ag-specific T cell factors play a role in the early phase of cellular immune responses. Two of these factors are studied in this paper. The first factor is specific macrophage arming factor (SMAF), that binds to (arms) macrophages and renders them specifically cytotoxic against tumor cells. The second factor is involved in the induction of an early (2 h) mast cell-dependent hypersensitivity reaction, that precedes the delayed-type hypersensitivity response (mast cell arming T cell factor; MTCF). In this study we compare both factors in an allogeneic murine tumor system (C57BL (H-2b) mice sensitized against SL2 (H-2d) lymphoma cells), both factors were: 1) dependent on T lymphocytes for their production, 2) detectable in serum 2 to 3 days after immunization, and 3) MHC (H-2)-Ag specific. Immunochemical studies showed that both factors have a molecular mass between 45 and 90 kDa and bind to the mAb 14-30 (directed against specific T cell factors), but not to anti-kappa/lambda L chain antibodies. Furthermore, it was shown that SMAF produced in vitro could induce a mast cell-dependent early 2-h hypersensitivity reaction against SL2 tumor cells, and resembled in this way MTCF. We concluded that the biologic activities and immunochemical characteristics of SMAF and MTCF are similar. Both factors are produced during the early stages of the immune response and seem to play a role in the initiation of the cell-mediated immune response.

Animals↗

PubMed1989

Initial immunochemical characterization of specific macrophage-arming factor.

This paper describes the initial immunochemical characterization of specific macrophage-arming factor (SMAF). SMAF is an antigen-specific factor that is released by (sensitized) T lymphocytes after contact with the specific antigen. It renders macrophages specifically cytotoxic. The specificity is dependent on the tumor-mouse combination. In allogeneic systems the specificity is H-2-directed, whereas in the syngeneic systems the specificity is tumor-specific. SMAF has a molecular mass of 65-85 kDa (established by gel filtration). By affinity chromatography SMAF could not be adsorbed with anti-(kappa + lambda light chain) immunoglobulins or anti-IgG from SMAF-containing supernatants. SMAF could be adsorbed with the monoclonal antibody 14-30 (directed against specific T-cell factors), and could be eluted from columns containing the latter. Furthermore, SMAF could also be adsorbed with and eluted from affinity chromatography columns to which specific tumor cell membranes or KCl extracts of these tumor cell membranes were coupled. Other tumor cell membranes could not adsorb SMAF. Together these data show that SMAF is not an antibody but a T-cell factor with an antigen-specific recognition site.

Animals↗

PubMed1989

Production of specific macrophage-arming factor precedes cytotoxic T lymphocyte activity in vivo during tumor rejection.

Recently we published a hypothesis on the immunological events occurring during tumor rejection. One of the implications of this hypothesis is that specific macrophage-arming factor (SMAF) is produced early during the initiation of the immune response, whereas the "classical" cell-mediated immune response components, such as cytotoxic T lymphocytes (CTL), are produced later, that is, during the amplifier-effector phase. In this paper we establish the kinetics of the induction of (a) lymphocytes producing SMAF and (b) CTL. Groups of DBA/2 mice were injected i.p. once, twice or three times with irradiated and/or non-irradiated syngeneic SL2 tumor cells, the injections being given at intervals of 10 days. After each of these injections the production of SMAF and the expression of CTL activity were established. The results showed that in the peritoneal cavity SMAF-producing lymphocytes appeared earlier than cytotoxic lymphocytes (CTL). In addition, it was shown (a) that SMAF does not interfere with the in vitro cytotoxicity expressed by CTL and (b) that in addition to CTL memory cells, SMAF-producing memory cells were also induced after injection of syngeneic tumor cells. These data support the hypothesis that SMAF is involved in the early phase of the cellular immune response against tumors, whereas CTL are induced later.

Animals↗

PubMed1989

Non-cytotoxic asialo-GM1-positive cells exert antimetastatic activity.

Metastasis can be inhibited by asialo-GM1-positive spleen cells, and in this paper we show that there are two such spleen cell populations. One population is adherent and non-cytotoxic to YAC cells, whereas the other population is non-adherent and cytotoxic to YAC cells. Both cell populations exert an antimetastatic activity in cyclophosphamide-treated mice that are inoculated with LL2 Lewis lung carcinoma cells. We conclude that the antimetastatic activity is not only exerted by cytotoxic asialo-GM1-positive cells (apparently natural killer cells), but also by adherent, non-cytotoxic asialo-GM1+, Thy1.2-, IgG- cells. This means that the latter exert their antimetastatic activity by a non-cytotoxic mechanism.

Animals↗

PubMed1989

Local interleukin-2 therapy in bovine ocular squamous cell carcinoma. A pilot study.

Five cows bearing bovine ocular squamous cell carcinoma (BOSCC) were treated with low doses of recombinant human interleukin-2 (rhIL-2). A dose of 2500 U rhIL-2 was injected intralesionally and another 2500 U were injected into the subparotid regional lymph node once a day during a period of 5 consecutive days. This cycle of 5 days was repeated after an interval of 2 days. Total regression of the tumor was observed in three out of five animals. One cow showed tumor regression (greater than 80%) accompanied by metastases to the regional lymph node that were observed from the fifth week after the beginning of the treatment. Growth of the tumor of the fifth animal was retarded after treatment. In vitro proliferation of peripheral blood lymphocytes was investigated in two animals and tumor-infiltrating lymphocytes in one animal during incubation in various rhIL-2 concentrations. Cytotoxic activity of both cell populations against P815, Yac-1 and BOSCC-derived cell lines increased during incubation with rhIL-2. Cultured BOSCC-infiltrating lymphocytes showed predominant killing of the BOSCC-derived autologous cell line after 4 weeks of culture. Preliminary phenotype analysis did not give conclusive results with respect to the types of cells responsible for killing.

Animals↗

PubMed1989

Heritability of breast cancer and its role in pre-menopausal cases.

The causes for the pre-menopausal incidence peak in breast cancer are still controversial. Other cancers also show an early incidence peak. Since the mammary tissue only starts to develop in puberty, the pre-menopausal incidence peak for breast cancer is comparable to the 'juvenile' peak in other cancers (retina, kidney). The four-mutation model for oncogenesis can explain pre-menopausal breast cancer. The model suggests that malignant transformation of a cell is due to four specific oncogenic mutations. These specific mutations accumulate during the proliferation of somatic cells. According to the model, one inherited oncogenic mutation can cause hereditary cancer. In this case only three additional specific mutations have to be accumulated during somatic cell proliferation. Epidemiological data and mathematical calculations indicate that in this case tumors occur early in life. Thus, the four-mutation model for oncogenesis predicts that the impact of heritability in pre-menopausal breast cancer is more significant than is generally believed. At this point, molecular biological studies are needed, to identify the involved specific mutations. Other implications of the model are an increased incidence of second primary tumors and an increased sensitivity for mutagenic factors in these patients.

Adult↗