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S Ben-Efraim

Publications and source records attributed to S Ben-Efraim.

At least 55 records · Page 3Linked to original sources
PubMed1988

Indomethacin stimulation of macrophage cytostasis against MOPC-315 tumor cells is inhibited by both prostaglandin E2 and nordihydroguaiaretic acid, a lipoxygenase inhibitor.

Indomethacin enhanced macrophage cytostasis against MOPC-315 tumor cells in vitro. The effect of indomethacin was inhibited by prostaglandin E2 and by the lipoxygenase inhibitor nordihydroguaiaretic acid. Prostaglandin E2 and nordihydroguaiaretic acid also inhibited indomethacin stimulation of macrophage thymidine incorporation. Indomethacin inhibited macrophage prostaglandin E2 formation and stimulated leukotriene B4 synthesis. Nordihydroguaiaretic acid inhibited leukotriene B4 production. Our data indicate that eicosanoids play a role in regulating macrophage cytostasis.

Animals↗
PubMed1988

Induction by an immunogenic immunomodulating agent of nonspecific T cell suppression of lymphocyte responsiveness in MLR but not of antibody production.

Spleen cells derived from BALB/c mice that had been repeatedly immunized with the methanol extraction residue (MER) fraction of tubercle bacilli exhibited a depressed capacity to act as responder cells in allogeneic and syngeneic mixed lymphocyte reactions (MLR). Previously reported studies revealed that such spleen cells are also defective in the in vitro generation of antibodies. In order to determine the nature of the cells responsible for the depressed MLR reactivity, purified populations of splenic macrophages, B lymphocytes, T lymphocytes originating from normal and from MER-immunized mice, and cell culture supernatants were added to MLR mixtures consisting of normal mouse splenocytes. Macrophages originating from MER-immunized mice and their culture supernatants exerted a significantly higher suppressive effect on MLR than that of corresponding preparations from normal mice. Splenic T cells originating from MER-immunized mice and their supernatants also significantly suppressed the MLR response. However, the same T cell populations that were inhibitory in MLR failed to suppress the in vitro generation of antibodies against sheep red blood cells in the presence of either MER or 2-mercaptoethanol. These and previously reported findings indicate that a nonspecific immunomodulating agent, MER, can, under certain conditions of treatment, elicit the induction of nonspecific suppressor T cells for MLR but not for antibody production, and, accordingly, can inhibit cellular and humoral immunological responsiveness by different mechanisms.

Adjuvants, Immunologic↗
PubMed1988

Tumoricidal and immunomodulatory activities of drugs and implications for therapy of mice bearing a late stage MOPC-315 plasmacytoma.

The effectiveness of a relatively low dose of cyclophosphamide (15 mg/kg CY), melphalan (2.5 mg/kg L-PAM) or the monofunctional form of CY (150 mg/kg MoCY) for the cure of mice bearing a large primary s.c. MOPC-315 tumor and extensive metastases has been shown to be dependent on the cooperation of the drugs' tumoricidal activity with T-cell-dependent antitumor immunity, the latter facilitated by the drug's immunomodulatory activity. Here, we have compared the curative effectiveness of three additional drugs: methyl nitrosourea (MNU), hydroxyurea (OH-urea) and bis-chloroethyl nitrosourea (BCNU). Among these drugs, only a relatively low dose of BCNU (15-20 mg/kg) was effective in curing most mice (85%) bearing a large, late stage tumor. A higher dose of BCNU (40 mg/kg, LD10) was much less effective. After an optimal dose of BCNU, the proliferative capacity of the tumor cells 24 h after therapy was reduced by greater than 97%. However, viable tumorigenic cells were still present in the primary tumor and enhanced T-cell-dependent antitumor immunity was necessary for their eradication. The cured mice were resistant to tumor rechallenge. When a low curative dose of L-PAM was followed by OH-urea, the therapeutic effectiveness was not affected, but when this dose of L-PAM was followed by a high nontoxic dose of MNU (100-150 mg/kg), the therapeutic effectiveness was diminished even though MNU was highly tumoricidal (i.e. greater than 99% inhibition of proliferative activity). Thus, BCNU appears to be similar to CY, L-PAM and MoCY in its mechanism of MOPC-315 tumor eradication. The alkylating activity of CY, L-PAM, MoCY and BCNU appears to be critical for their combined tumoricidal and immunomodulatory effects. Since BCNU is the simplest of these four drugs with respect to metabolic pathway, a further study with BCNU and related constructs may shed some light on the biochemical mechanisms of their mode of action. At least one reason for the ineffectiveness of OH-urea or MNU at either low or nontoxic high doses was poor tumoricidal or immunomodulatory activity, respectively. Thus, it seems important to consider both the tumoricidal and immunomodulatory activities of drugs when developing regimens for effective chemotherapy.

Adjuvants, Immunologic↗
PubMed1988

Successful contact sensitization to chromate in mice.

Mice of the randomly bred strain ICR and of the inbred strain BALB/c could be successfully sensitized to chromate by repeated topical applications of a solution of potassium bichromate in dimethyl sulfoxide. The specificity of chromium sensitization was ascertained by ear tests, specific desensitization by intravenous injection of potassium bichromate and by histological ear sections showing marked infiltrates of leukocytes following ear application of chromium-dimethyl sulfoxide in already sensitized animals. It is concluded that mice may provide a useful experimental model for study of contact sensitivity to chromium.

Animals↗
PubMed1987

Differences in sensitivity to melphalan between con A-activated and nonactivated human T-cell subsets.

In vitro treatment with melphalan (L-PAM, L-phenylalanine mustard), 2 micrograms/2 X 10(6) cells, significantly decreased the total number of E-rosette-positive (E+) T lymphocytes from peripheral blood (PBL) of healthy human donors as well as those of the OKT4 (precursor suppressor/helper/inducer T cells) and OKT17 populations (suppressor cells within the OKT4 subset). The OKT8 population (cytotoxic/mature suppressor cells) was not affected by a similar L-PAM treatment. The sensitivity of concanavalin A (Con A)-activated E+ T-cell populations to subsequent L-PAM treatment in vitro was different from that of Con A-untreated T cells: Thus, L-PAM treatment did not affect the expression of OKT3 and OKT4 antigens, increased the percentage of OKT17 cells, and inhibited the expression of OKT8 antigen. Depletion of OKT8 from Con A-activated E+ T cells (OKT4+-OKT8(-)-OKT17+) did not affect their suppressive activity on PHA stimulation in L-PAM-treated as well as untreated cells. Further depletion of OKT17+ cells from the OKT4+-OKT8(-)-OKT17+ subset (OKT4+-OKT8(-)-OKT17-) abolished the suppressive effect on PHA stimulation. Suppressive activity of the OKT4+-OKT8(-)-OKT17- subset was again evident after treatment of this population with L-PAM. The results obtained indicate that the sensitivity to L-PAM treatment of various T-cell phenotypes is changed by Con A activation and that after depletion of specific T suppressor cells L-PAM seems affect the immunoregulatory circuit within the Con A-activated OKT4 subset.

Antigens, Surface↗
PubMed1987

Synergy between low-dose chemotherapy and immunotherapy in mouse L1210 leukemia.

A high dose of 4 mg/kg of daunorubicin (DAU) given in combination with immunostimulation by the P40 immunomodulatory fraction of Corynebacterium granulosum and glutaraldehyde (GA)-treated tumor cells coupled with tetanus toxoid (P40 + GA-L1210-Tet) was more effective than DAU alone for treatment of L1210 mouse leukemia. A combination of low doses of DAU (0.0625-0.25 mg/kg) and P40 + GA-L1210-Tet was more effective than either P40 + GA-L1210-Tet or DAU alone. The cured mice were resistant to challenge with a high tumorigenic dose of L1210 tumor cells. A combination of various doses of mitomycin (1-4 mg/kg) with P40 + GA-L1210-Tet was more effective than mitomycin alone and was at least as effective as P40 + GA-L1210-Tet alone. Administration of DAU (0.5-4 mg/kg) to noninoculated C57BL/6 X DBA/2 mice resulted in increase of stimulation in vitro of collected spleen cells by mitogens.

Animals↗
PubMed1987

Leukotriene D4 and indomethacin enhance additively the macrophage cytostatic activity in vitro towards MOPC-315 tumour cells.

Leukotriene C4, the precursor of leukotriene D4 (LTD4), was earlier shown to activate macrophages, as indicated by lysosomal enzyme discharge. This event is limited by LT-induced secretion of PGE2, which inhibits the functions of these cells. The circumstance that activated macrophages may exert cytostatic activity towards tumour cells prompted us to study the effect of LTD4 and indomethacin on the cytostatic activity of macrophages as expressed by inhibition of [3H]thymidine incorporation in MOPC-315 plasmacytoma tumour cells. Decrease in incorporation, caused by separate administration of the two substances, was additively enhanced upon exposure of the co-culture of macrophages and tumour cells to the two substances simultaneously. Tumour cells alone are not affected by the substances, but the low rate of thymidine incorporation by macrophages alone was increased by LTD4 in the presence of indomethacin. Decrease of thymidine incorporation into tumour cells co-cultured with macrophages is attributed to a macrophage-mediated, rather than to a direct, influence of LTD4 and indomethacin on tumour cells. An increase in macrophage-mediated cytostasis by LTD4 requires the inhibition of endogenous PGE2 production in macrophages.

Animals↗
PubMed1986

The difference between 5-fluorouracil and melphalan in their ability to promote antitumor immune response against MOPC-315 plasmacytoma.

The anticancer chemotherapeutic drugs melphalan (L-phenylalanine mustard; L-PAM), 5-fluorouracil (5-FU), methotrexate (MTX), and daunorubicin (DAU) were tested for their toxic activity against MOPC-315 tumor cells in vitro. L-PAM, 5-FU, and DAU had a marked toxic effect whereas MTX did not affect the rate of thymidine incorporation in the tumor cells. L-PAM (7.5 mg/kg) induced permanent regression of large s.c. MOPC-315 plasmacytoma tumors, 5-FU (200-250 mg/kg) induced transient regression of MOPC-315 tumors with reappearance starting on the 6th day after the 5-FU injection and DAU (5 mg/kg) was not effective. L-PAM treatment restored the cytotoxic potential of spleen cells of tumor-bearing mice against target MOPC-315 tumor cells whereas spleen cells from tumor-bearing mice treated with 5-FU were unable to mount a cytotoxic response. L-PAM and 5-FU were also assayed for their effect in vitro on induction of suppressor T cells by ConA. L-PAM treatment in vitro markedly reduced the induction of suppressor T cells by ConA whereas 5-FU had no effect. It is suggested that anticancer chemotherapeutic drugs can be classified in "immunopromoting" (L-PAM as prototype) and "nonimmunopromoting" (5-FU as prototype) on the basis of their effect in vivo on established tumors and their effect on induction of suppressor T cells by ConA.

Adjuvants, Immunologic↗
PubMed1986

Split immunosuppression of contact cell-mediated and of IgE hypersensitivity responses to dinitrofluorobenzene in mice.

Contact sensitivity (CS), anti-DNP (dinitrophenyl) IgG and IgE type antibodies were induced by skin applications of the contact sensitizer dinitrofluorobenzene. CS response was suppressed by treatment with the monovalent hapten dinitrobenzene sulfonate (DNBS) but was not affected by treatment with the DNP-conjugates (DNP22-Ficoll, DNP17-polyethylene glycol and DNP2-polyvinylpyrrolidone). On the other hand, IgE type response was depressed by treatment with the various DNP conjugates but was not affected by DNBS. The IgG type response was not appreciably affected by any of the treatments.

Animals↗
PubMed1985

Effect of methanol extraction residue tubercle bacillus fraction treatment in vivo and in vitro on the release and activity of suppressor factor inhibiting the efferent phase of contact sensitivity in mice.

BALB/c mice subjected to injection of dinitrobenzenesulfonate (DNBSO3) and skin painting with dinitrofluorobenzene (DNFB) produce splenic T-suppressor (Ts) cells that, when transferred to DNFB-sensitized recipients, suppress the efferent (eff) phase of contact sensitivity (CS). Splenocyte populations containing such Ts-eff cells release a specific soluble suppressor factor (SSF) in vitro that similarly suppresses CS in sensitized recipient mice. Treatment with the methanol extraction residue (MER) tubercle bacillus fraction, a known immunomodulating agent, of animals exposed to DNBSO3 and DNFB ("DNBSO3-DNFB" donors) prevented release of SSF by their spleen cells at in vitro incubation. Incubation of DNBSO3-DNFB donor splenocytes with MER in vitro also abolished SSF release, and treatment with MER of test animals prior to DNFB sensitization prevented the suppressive action of subsequently administered SSF. The observations are discussed with regard to the potentiating capacities of MER on cellular immunity and states of resistance.

Adjuvants, Immunologic↗
PubMed1985

In vitro selective effect of melphalan on human T-cell populations.

In vitro treatment with 2 micrograms/2 X 10(6) cells melphalan (L-PAM: L-phenylalanine mustard) significantly decreased the total number of T lymphocytes from peripheral blood (PBL) of healthy human donors and of the OKT4 population (precursor suppressor/helper/inducer) T cells as defined by monoclonal antibodies OKT3 and OKT4, respectively. No changes in the OKT+8 lymphocyte population (cytotoxic/mature suppressor cells) were observed following the same treatment. Preincubation of PBL with L-PAM at concentrations that do not affect the rate of DNA synthesis in PHA-stimulated lymphocytes inhibited the generation of T suppressor lymphocytes by ConA, as shown by their effect on PHA stimulation. Treatment of allogeneic PBL with L-PAM had no effect on mature suppressor T cells already induced by ConA, as shown by incubation of PBL with L-PAM after incubation with ConA.

Antibodies, Monoclonal↗
PubMed1985

Melphalan-induced enhancement of tumor cell immunostimulatory capacity as a mechanism for the appearance of potent antitumor immunity in the spleen of mice bearing a large metastatic MOPC-315 tumor.

Exposure of MOPC-315 cells from the primary tumor nodule to a low concentration (0.5 nmol/ml) of melphalan (L-phenylalanine mustard; L-PAM) rendered the tumor cells capable of bringing about the generation of a potent primary antitumor cytotoxic response. Accordingly, the level of antitumor cytotoxicity generated by normal spleen cells immunized in vitro with L-PAm-treated tumor cells was at least five-fold greater than the level generated in response to untreated tumor cells. The marked superiority of L-PAM-treated tumor cells over untreated tumor cells in bringing about the generation of antitumor cytotoxicity was evident over a wide range of responder to stimulator cell ratios. The higher level of antitumor cytotoxicity exhibited by normal spleen cells immunized with L-PAM-treated tumor cells as compared with untreated tumor cells was not merely the result of direct drug-mediated tumoricidal activity, thereby reducing the number of tumor cells present which can act as cold target cell inhibitors during the 51Cr release assay. This is apparent from the observation that the level of antitumor cytotoxicity generated in response to a given percentage of stimulator tumor cells pretreated with 0.5 nmol L-PAM/ml, a drug concentration associated with retention of 60% tumor cell proliferative capacity, is substantially greater than that generated in response to less than half that percentage of untreated stimulator tumor cells. Moreover, stimulator tumor cells exposed to a fully antiproliferative concentration of L-PAM brought about the generation of a higher level of antitumor cytotoxicity than stimulator tumor cells exposed to mitomycin C at a concentration which inhibited the proliferation of the tumor cells to the same extent as the L-PAM. A low concentration of L-PAM which was effective in rendering isolated tumor cells from the primary tumor nodule capable of bringing about the generation of antitumor cytotoxicity was also effective in inducing the appearance of potent antitumor immune potential in tumor bearer splenic cells containing metastatic tumor cells.

Animals↗
PubMed1985

Effect of melphalan in vitro on induction of murine suppressor T cells by ConA.

The effect of treatment with melphalan in vitro on the activity of spleen cells from BALB/c mice was investigated. Incubation of spleen cells with 1.5-5 micrograms melphalan/1 X 10(7) inhibited subsequent mitogenic stimulation by ConA or PHA and the allogeneic response of BALB/c spleen cells against C57B1 target spleen cells. Incubation of spleen cells with ConA led to induction of suppressor T cells which when added to fresh cultures inhibited the allogeneic response. Preincubation of spleen cells with melphalan even at low concentrations (0.15-0.5 micrograms 1 X 10(7) cells) which do not directly affect mitogenic stimulation or allogeneic response partially inhibited the generation of suppressor T cells by ConA. Treatment with melphalan had no effect on already induced suppressor T cells as shown by incubation of spleen cells with melphalan (0.15-5 micrograms/1 X 10(7) cells) after incubation with ConA. Addition of cells treated with melphalan alone (without ConA) to fresh cultures led to an increase in the allogeneic response.

Animals↗
PubMed1985

Effects of the methanol extraction residue (MER) tubercle bacillus fraction on the production of antibodies in vitro. III. Consequence of prior sensitization to MER.

Mice repeatedly immunized with the methanol extraction residue fraction of tubercle bacilli (MER) in incomplete Freund's adjuvant produced high titers of circulating antibodies against MER, as assessed by the enzyme-linked immunosorbent assay (ELISA) method. Spleen cells derived from these animals failed to respond to the usual nonspecific immunopotentiating influence of MER on the primary production of antibodies (generation of specific plaque-forming cells) in vitro to sheep red blood cells. The defect was expressed by B lymphocytes and splenic macrophages, but not by splenic T lymphocytes or peritoneal exudate macrophagic cells. Impaired responsiveness by spleen cells from MER-immunized animals to nonspecific immunostimulation was also expressed with regard to another, unrelated biological response modifier, lipopolysaccharide. There was no impairment of responsiveness to polyclonal mitogenic stimulation. Possible mechanisms of the effects described are discussed.

Adjuvants, Immunologic↗
PubMed1985

Effect of melphalan administration on the activity of natural killer and natural cytotoxic spleen cells of normal and tumor-bearing mice.

The effect of melphalan (L-PAM; L-phenylalanine mustard) administration on natural killer (NK) and natural cytotoxic (NC) activities of spleen cells from normal noninoculated BALB/c mice and mice bearing large MOPC-315 plasmacytoma tumors was investigated. Injection of L-PAM (7.5 or 15.0 mg/kg) had no effect on NK and NC activities of spleen cells from normal mice whereas stimulation by PHA was markedly suppressed. NK activity was markedly suppressed in spleens of tumor-bearing mice whereas NC activity was not affected. Therapy with L-PAM of tumor-bearing mice led to transient recovery of NK activity which was possibly related to the effect of L-PAM on macrophage suppressive activity on NK cells. It is concluded that NK and NC cell activities and the response to PHA stimulation are selectively affected by L-PAM administration.

Animals↗