PubMed Health⌕ Search

Biomedical subjects

J W De Groot

Publications and source records attributed to J W De Groot.

12 recordsLinked to original sources
PubMed1999

Local low-dose IL-2 therapy.

Interleukin-2 (IL-2) is a powerful drug for treating cancer. However, it is only powerful if it is properly applied. That is, IL-2 should be applied at the tumor site, because at the transition of normal and malignant tissue are the tumor infiltrating cells. These should be activated by IL-2. Local application implies that IL-2 can be used in relatively low doses. It is becoming clear that even a single injection of IL-2 can cure cancer. IL-2 can also enhance the therapeutic effects of irradiation and Cisplatin. Locally applied IL-2 therapy is virtually non-toxic.

Animals↗
PubMed1996

Optimal regimes for local IL-2 tumour therapy.

In this report we present studies on optimal regimes for regional IL-2 therapy, focused on dose, schedule and site of injection. Original data obtained in 2 murine tumour models show that all 3 factors are of importance. Anti-tumour responses were most effective when IL-2 was administered regionally 5 to 10 times, at doses ranging from 7,000 to 33,000 IU/day every day or every other day. This resulted in cure rates of more than 40% in mice bearing ascitic tumour that had also disseminated to liver and lungs. The importance of these data is discussed in the light of previous results of our group. These results illustrate that the doses and schedules used in this study are not effective exclusively in these 2 tumour models but may have a more general applicability.

Animals↗
PubMed1994

Effect of immunomodulators on specific tumor immunity induced by liposome-encapsulated tumor-associated antigens.

Reconstituted membranes consist of liposomal structures formed by removal of detergent from solubilized membrane constituents. The membrane-like configuration of reconstituted membranes makes them attractive as vehicles for presentation of tumor-associated antigens and induction of immune responses. In this study the potential of immunomodulators was assessed to enhance the specific immune response induced by immunization with reconstituted membranes prepared from SL2 lymphosarcoma cells. Reconstituted membranes containing muramyl tripeptide phosphatidylethanolamine (MTP-PE) provided better protection against a challenge with SL2 cells than did reconstituted membranes containing alternative immunomodulators. Local administration of IL-2 at the immunization sites further augmented the protection induced by reconstituted membranes with MTP-PE, but was ineffective when administered with plain reconstituted membranes. Immunity elicited by the triple modality of reconstituted SL2 membranes with MTP-PE and IL-2 was specific for SL2 cells. Systemic immunity was obtained against a challenge with a 100-fold higher number of SL2 cells than was reached after immunization with reconstituted membranes alone (10(5) vs. 10(3) SL2 cells). Macrophages isolated from the peritoneal cavity of immunized mice 5 to 7 days after tumor challenge expressed high in vitro cytotoxicity. However, in contrast to the observed specificity of the systemic immunity, macrophages killed both SL2 cells and non-related P815 cells. Neither major cytotoxic lymphocyte activity nor substantial cytotoxic antibody titers were detectable. These results clearly indicate that the approach using reconstituted membranes combined with particular immunomodulators warrants further exploration for the development of safe, well-characterized cancer vaccines.

Adjuvants, Immunologic↗
PubMed1993

Critical factors for liposome-incorporated tumour-associated antigens to induce protective tumour immunity to SL2 lymphoma cells in mice.

Physical and immunogenic properties of reconstituted membranes designed for the presentation of tumour-associated antigens (TAA) to the immune system are described. Proteins and lipids of crude membranes of SL2 murine lymphosarcoma cells were partially solubilized with octylglucoside. Reconstituted membranes, consisting mainly of unilamellar vesicles with a diameter of 0.03-0.15 microns, were formed by detergent removal and were purified by floatation in a discontinuous sucrose gradient to remove non-lipid-bound protein. Subcutaneous immunization of syngeneic mice with reconstituted membranes or with purified reconstituted membranes induced protection against an intraperitoneal challenge with 10(3) viable SL2 cells. Reconstituted membranes were more immunogenic than crude membranes in immunoprotection experiments when compared on the basis of protein dose. Detergent removal was required to obtain an immunogenic presentation form of SL2 membrane antigens and to avoid toxicity associated with the detergent. Reconstitution of SL2 membranes in the presence of exogenous phospholipid slightly increased the fraction of protein that associated with the reconstituted membranes. However, the immunogenicity of the solubilized membrane TAA was not significantly affected by the presence of exogenous phospholipid. The reconstitution procedure described may be useful in identifying membrane factors required for the induction of immune responses against TAA. The versatility of the system may be employed to develop safe alternatives for whole-cell vaccines.

Animals↗
PubMed1992

Reconstituted membranes of tumour cells (proteoliposomes) induce specific protection to murine lymphoma cells.

Antigens presented on cell membranes or on liposomes are usually more immunogenic than antigens in soluble form, this being one of the reasons for the weak immunogenicity of extracted tumour-associated transplantation antigens (TATA). The main objective of this study is to solubilize TATA from tumour cells and to present them on a membrane-like structure to the immune system. Crude tumour cell membranes of SL2 lymphosarcoma cells (a spontaneously arising, weakly immunogenic tumour) were solubilized with octylglucoside or sodium deoxycholate, and reconstituted membranes (proteoliposomes) were prepared by detergent removal. Mice immunized s.c. with reconstituted membranes were protected against an i.p. challenge with tumour cells. Although octylglucoside solubilized only 41% of the membrane proteins, the reconstituted membranes were as immunoprotective as crude membranes. (Glyco)proteins were probably the major membrane components in the reconstituted membranes that induce immunoprotection, as mice immunized with preparations constituted of (glyco)lipids from SL2 cells could not reject SL2 cells. If Freund's complete adjuvant was used with the first immunization injection, no potentiation of the elicited immune responses was observed. Besides the membrane TATA, SL2 cells contained an apparently non-membrane-bound TATA, which was found in the cytoplasm. It is concluded that detergent solubilization of membranes and subsequent preparation of reconstituted membranes can be used to obtain membrane tumour-associated antigens that retain activity for induction of protective tumour immunity. The major advantage of this method is that membrane proteins are solubilized and are subsequently presented on a membrane-like structure that resembles the tumour cell membrane. On theoretical and practical grounds it provides a promising alternative for whole-cell vaccines.

Animals↗
PubMed1989

Differences in the induction of macrophage cytotoxicity by the specific T lymphocyte factor, specific macrophage arming factor (SMAF), and the lymphokine, macrophage activating factor (MAF).

Specific T cell factors, such as specific macrophage arming factor (SMAF), are involved in the initiation of the immune response. Induction of SMAF-producing T lymphocytes in vivo and of SMAF production by T lymphocytes in vitro is dependent on the presence of intact tumor cells, and is independent of antigen presentation by macrophages. SMAF renders peritoneal macrophages cytotoxic for tumor cells. The armed peritoneal macrophages expressed a specific cytotoxicity. However, antigen-presenting cells can trigger lymphokine-producing T lymphocytes. These T lymphocytes produce lymphokines (e.g. macrophage activating factor (MAF] that activate macrophages. The MAF-activated macrophages express a non-specific tumoricidal activity. In the present study, we investigated the difference in the induction of macrophage cytotoxicity by SMAF and MAF. The following differences were found: 1) SMAF renders peritoneal resident macrophages cytotoxic, whereas MAF could only render peritoneal exudate macrophages cytotoxic. 2) SMAF requires only a 4-h incubation with macrophages, whereas MAF activates macrophages optimally after 12 h. 3) SMAF-armed macrophages recognize only the specific target cell(s), and thus, the cytotoxicity is specific in its expression. MAF activated macrophages were non-specifically cytotoxic. 4) Lipopolysaccharide (LPS) in the culture medium did not enhance the cytotoxicity of SMAF-armed macrophages. In contrast, MAF induced tumoricidal activity was enhanced by adding LPS to the culture medium. 5) After adsorption chromatography with anti-murine interferon-gamma (IFN-gamma), the arming capacity of SMAF supernatant was not reduced, whereas the activating capacity of the MAF supernatant was significantly reduced or abrogated. After immunization of mice with allogeneic tumor cells, SMAF-producing lymphocytes were detected in the draining lymph nodes already 4 days after immunization and up to 12 days. Lymphocytes with the capacity to produce MAF were present in the draining lymph nodes 14-24 days after immunization. Our data indicate that the T cell factors SMAF and MAF can both render macrophages cytotoxic, but act in a different way and during different stages of the cellular immune response against allogeneic tumor cells.

Animals↗
PubMed1986

Tumor growth stimulatory macrophages induced by a subclinical bacterial infection in vivo.

Nonelicited peritoneal macrophages obtained from normal mice from our animal house unexpectedly expressed a strong tumor growth stimulatory effect in vitro. Macrophages expressing this stimulatory effect had an aberrant morphology compared to the morphology of normal macrophages as observed by electron microscopy. The results of immunization of these affected mice with tumour cells led to the usual lymphocyte sensitization. No external symptoms were observed, and the mice looked healthy. Treatment of the affected macrophage donors with antibiotics resulted in the abolishment of the tumor growth stimulatory effect by the macrophages. Thus, this tumor cell growth stimulation by macrophages was probably due to a subclinical infection of the mice.

Animals↗
PubMed1983

Eradication of tumor cells after injection into immunized hosts compared with the eradication of tumor cells after transfer of immune peritoneal exudates into tumor-bearing recipients.

DBA/2 mice were immunized against the syngeneic SL2 lymphoma by two or five injections with irradiated lymphoma cells given IP or SC, respectively. The antitumor efficacy induced in immunized mice was tested by (a) IP injection of the immunized mice with nonirradiated tumor cells and (b) transfer of the total 'immune' peritoneal exudate, the cellular fraction only, or the cell-free fraction only, IP into tumor-bearing recipients, or (c) tumor neutralization tests (Winn assay). It was shown that immunized mice were able to reject 5 X 10(7) SL2 tumor cells (8 of 14 mice survived greater than 100 days), while in most transfer experiments 2 X 10(5) SL2 cells could be eradicated. In the tumor neutralization experiments a number of 10(6) SL2 cells were eradicated. When the immune exudates were given before the inoculations of SL2 tumor cells the number of survivors increased significantly. Further, it was shown that the cellular fraction is the major contributor to the antitumor effect in the transfer experiments, since there was no significant difference in tumor eradication after injection of a complete immune exudate and after injection of the isolated cellular fraction. Injection of the noncellular fraction had no measurable antitumor effect. An increase in the number of injections with total peritoneal exudates from immunized mice did not result in an increase in tumor eradication in the tumor-bearing recipients. Extra stimulation (IP) of immunized mice with 10(4) nonirradiated cells 6 days after the last immunization resulted in an increase of the antitumor efficacy of these peritoneal exudates of these mice when collected 4-24 h after this stimulation. Extra stimulation with 10(6) irradiated cells had no measurable effect.

Animals↗
PubMed1982

Peritoneal cell populations during tumour injection.

The response of peritoneal cells to the SL2 lymphoma was studied in immunized and non-immunized mice to elucidate further the cellular events that lead to tumour rejection in an allogeneic and a syngeneic tumour system. Anti-tumor immunity was induced by intraperitoneal injection of normal, irradiated or mitomycin-C treated tumour cells. Four different immunization schedules were tested. The response of the peritoneal cells was investigated by studying the peritoneal cell population kinetics (appearance and/or disappearance of various cell types e.g. mononuclear phagocytes, lymphocytes, PMNS and mast cells). Total cell counts were done using phase contrast microscopy, differential cell counts were done on cytocentrifuge slides, stained with May Grünwald-Giemsa. The activity of the lysosomal enzyme beta-glucuronidase present in mononuclear phagocytes was also studied. The results indicated that the composition and morphology of the cellular fraction of the peritoneal exudate changes quite dramatically during tumour rejection. Especially the beta-glucuronidase activity of the mononuclear phagocytes line varies significantly. The observed changes in the cellular population depended upon the dose of tumour cells injected i.p. No significant differences were observed between the peritoneal cell populations of mice grafted i.p. with irradiated or with mitomycin-C treated tumour cells. On the other hand when mice previously immunized with three injections with 10 irradiated or mitomycin-C treated tumour cells were challenged i.p. with various doses of tumour cells, the immune potency against the tumour is greater after previous immunization with irradiated SL2 cells than after immunization with mitomycin-C treated tumour cells.

Animals↗