Biomedical subjects

E Schlick

Publications and source records attributed to E Schlick.

At least 37 records · Page 2Linked to original sources

PubMed1987

Protein deficiency reduces natural antitumor immunity.

Clinical data have shown that neoplastic diseases and/or related therapies frequently result in protein depletion of tumor-bearing patients. Depressions of acquired and specific immunity caused by protein depletion are well known. In an experimental model protein depletion was induced by lack of nutritional protein in otherwise isocaloric conditions in BALB/c and C57BL/6 mice over various time periods (max. 35 days). The results show that natural immune effector cells, natural killer cells, and monocyte/macrophages also during treatment with biological response modifiers (BRM) are depressed in their cytotoxic potentials in vitro and in vivo. Substantial and critical reductions of bone marrow cellularity (bone marrow nucleated cells) were also observed. In contrast, preliminary results show that if, following protein depletion, mice were treated parenterally with amino acids (Neo-aminomel, Boehringer-Ma. Co., FRG) complete restoration of immune parameters takes place. Adequate protein status is shown to be a crucial factor for natural immunity and therapy with BRM.

Animals↗

PubMed1987

Immune response by biological response modifiers.

Several biological response modifiers (BRMs) were demonstrated to increase myelopoiesis and effector cell responses (M phi and natural killer cell activity) in vivo. The increased myelopoiesis was reflected by an increase in bone marrow cellularity and granulocyte-M phi colony-forming cells (GM-CFU-C). The increase in myelopoiesis appeared to be related to a concomitant increase in colony-stimulated factor (CSF) production and secretion by M phi and bone marrow cells. CSF induction by BRMs increased myelopoiesis and counteracted the myelosuppressive and immunosuppressive effects of cyclophosphamide. CSF induced in vivo by BRMs attained high titers and were maintained over a longer period than exogenously injected CSF, which was rapidly cleared from serum.

Adjuvants, Immunologic↗

PubMed1986

1,25-Dihydroxycholecalciferol-induced differentiation of myelomonocytic leukemic cells unresponsive to colony stimulating factors and phorbol esters.

The murine myelomonocytic leukemia cell line WEHI-3B D+, which differentiates in response to granulocyte colony stimulating factor (G-CSF), can also be induced to differentiate into monocyte-macrophages by phorbol myristate acetate (PMA) treatment, whereas the WEHI-3B D- subline, which is unresponsive to G-CSF and PMA, can be induced to differentiate to granulocytes as well as monocytes by 1,25-dihydroxycholecalciferol [1,25-(OH)2 D3], the biologically active metabolite of vitamin D3. A newly developed variant of the WEHI-3B D+ line, named WEHI-3B D+ G, which was responsive to G-CSF but not to PMA, was also differentiated to granulocytes by 1,25-(OH)2 D3. Although vitamin D3 has been reported to induce macrophage differentiation in responsive tumor cells, this is the first demonstration that 1,25-(OH)2 D3 can induce granulocyte differentiation. In both differentiation pathways, cessation of cellular proliferation accompanies changes in morphologic and cytochemical properties of the cells. This suggests that leukemic cell lines unresponsive to differentiation agents acting at the cell surface retain their ability to differentiate in response to agents that do not act via the plasma membrane such as 1,25-(OH)2 D3, which has cytosolic/nuclear receptors. Vitamin D3 could act through different cellular pathways inducing differentiation or by bypassing only the first step of a common differentiation cascade used by agents with cell surface receptors such as CSF. These results suggest that low doses of 1,25-(OH)2 D3 may be useful in combination with hemopoietic growth factors (CSFs) as therapeutic agent to induce leukemic cell differentiation in vivo.

Animals↗

PubMed1986

Selective killing of human T-lymphotropic virus-I infected leukemic T-cells by monoclonal anti-interleukin 2 receptor antibody-ricin A chain conjugates: potentiation by ammonium chloride and monensin.

Adult T-cell leukemia is a progressive disease produced by infection of mature T-cells with the human T-lymphotropic virus-I (HTLV-I). These retrovirus infected T-cells express large numbers of receptors for interleukin 2 (or T-cell growth factor). Due to the presence of these receptors, these leukemic T-cells can be selectively killed in vitro by monoclonal anti-interleukin 2 receptor antibody covalently linked to the A chain of the plant toxin, ricin (anti-TAC-A), suggesting that such immunotoxins may be useful in the therapy of this disease. In this report we demonstrate that the lysosomotropic agent ammonium chloride and the carboxylic ionophore monensin substantially potentiate the cytotoxicity of anti-TAC-A on HUT 102 cells, a long-term cultured HTLV-I infected T-cell line. Anti-TAC-A alone produces half-maximal inhibition of protein synthesis in HUT 102 cells at a concentration of 2.2 X 10(-10) M (the 50% inhibitor, concentration). Addition of ammonium chloride or monensin augments the potency of anti-TAC-A killing 100-fold (50% inhibitory concentration = 2.5 X 10(-12) M) and 400-fold (50% inhibitory concentration = 8 X 10(-13) M), respectively; furthermore, these agents accelerate rate of anti-TAC-A intoxication and increase the specific killing of interleukin 2 receptor-bearing leukemic cells. At concentrations which cause only minor harm to colony forming hematopoietic progenitor cells (granulocyte-erythroid, monocytic, megakaryocytic colony forming unit, granulocyte-macrophage colony forming unit, macrophage colony forming unit, and granulocyte colony forming unit), anti-TAC-A alone is able to eliminate greater than 99.99% of an HTLV-I infected T-cell population. In the presence of ammonium chloride or monensin, respectively, a 3.5- and 20-fold greater cytoreduction of HTLV-I infected T-cells is achieved. Combined treatment with anti-TAC-A and monensin may offer an efficient and highly selective means of purging bone marrow of patients with adult T-cell leukemia, which may then be used for autologous marrow transplantation.

Ammonium Chloride↗

PubMed1986

In vivo induction of terminal differentiation of malignant myelopoietic progenitor cells by CSF-inducing biological response modifiers.

We have investigated the mechanisms by which colony-stimulating factor (CSF)-inducing biological response modifiers (BRM) may have beneficial effects on tumor-bearing hosts undergoing anti-tumor therapy. First, we have documented that treatment of mice with the chemically defined BRM maleic anhydride divinyl ether copolymer (MVE-2), which induces CSF secretion by macrophages (M phi) and bone marrow cells (BMC), significantly increased growth and differentiation of normal myelopoietic cells and counteracted the myelosuppressive effects of cyclophosphamide (CY). Second, we established that MVE-2 may exert CSF-mediated antitumor effects on certain leukemic tumor cells. Serum from mice pretreated in vivo with MVE-2, which contained CSF, induced terminal differentiation of cloned tumor cells from the CSF responsive WEHI-3B D+ subline in vitro, but not from the WEHI-3B D- subline, which is unresponsive to CSF. In vivo experiments showed that treatment of mice bearing the WEHI-3B D+ tumor first with CY and three days later with the CSF inducer MVE-2, significantly increased their survival time and rendered 20% to 50% of the tumor-bearing mice disease free. No such effects were obtained in mice bearing the WEHI-3B D- tumor. Thus, the induction of CSF or other differentiation factors by some BRMs may result in therapeutic effects against certain leukemias based on at least two distinct mechanisms: In addition to their restorative effects on normal bone marrow functions, CSF-inducing BRMs may also prevent further leukemogenesis by induction of terminal differentiation of leukemic cells.

Animals↗

PubMed1986

Biological response modifiers: regulators of the cellular immune system and adjuvants in antitumor therapy.

Pharmacokinetic studies of five biological response modifiers (BRMs) show diverse regulator functions on effector cell responses and a capacity to cause the secretion of specific soluble factors. Of the five BRMs tested, MVE-2, Poly ICLC, OK-432, and alpha beta IFN were capable of stimulating both natural killer (NK) cell and macrophage (M phi) tumoricidal activity, whereas BM 41-332 augmented only NK cells. Following one treatment with the aforementioned BRMs, M phi activity remained elevated for a longer period (10-14 days) than did NK cell activity (6-9 days). Of particular interest, multiple treatment with BRMs led to a downregulation of NK cell activity (hyporesponsiveness). Three soluble secretory products were induced by these BRMs (colony stimulating factor, CSF; prostaglandin E, PGE; and interferon, IFN). Treatment with MVE-2 and Poly ICLC led to a significant increase in bone marrow cellularity and GM-CFV-C. Results of studies with the cyclo-oxygense-inhibited indomethacin indicate that CSF and PGE are produced and/or secreted by different cellular mechanisms. The depression of effector cells (NK, bone marrow, and GM-CFU-C), as the result of cyto-reductive treatment with cyclophosphamide, could be reversed by treatment with MVE-2. A significantly earlier time to recovery of these effector cells was achieved following MVE-treatment. When MVE-2 was used as an adjuvant to initial tumor cyto-reductive chemotherapy, more successful antitumor response was achieved, indicating that MVE-2 functioned to elevate a substantial effector cell response as well as reconstituting bone marrow cellularity.

Adjuvants, Immunologic↗

PubMed1986

Comparative evaluation of multiple lymphoid and recombinant human interleukin-2 preparations.

Six lymphoid human interleukin-2s (nIL-2s) [four from peripheral blood mononuclear cells (PBMC) and two from JURKAT cells] and six recombinant IL-2s (rIL-2s) were obtained for comparative evaluation. The main issues addressed were possible differences among the preparations in potency in T cell growth assays and other functional assays, and the possible presence of other cytokine activities or contaminants. Each preparation was assigned a standardized IL-2 activity in reference units (RU) by comparing its T cell growth promoting activity against the Biological Response Modifiers Program IL-2 (JURKAT) reference reagent. Relative to the IL-2 unitage indicated by the suppliers, the RU varied from 110-fold less to 38.5-fold more for the various preparations. Two nIL-2s and two rIL-2s contained significant levels of endotoxin. One nIL-2 contained low levels of both alpha and gamma interferon (IFN), and one nIL-2 had a high level of gamma IFN. All other IL-2s were negative for IFN activity. All IL-2 preparations significantly augmented human natural killer (NK) activity, although the amount of RU required varied from 0.1 to 50 RU. Four nIL-2s and three rIL-2s induced human PBMC to produce gamma IFN, whereas two nIL-2s and one rIL2 did not. All nIL-2s had substantial amounts of B cell growth factor activity, whereas none of the rIL-2s consistently displayed this activity. All IL-2s stimulated the tritiated thymidine [3H]TdR incorporation of human PBMC in the absence of other stimuli, in addition to augmenting the response to mitogen or alloantigens. Some nILs and IL-2s had effects on human monocytes such as inhibiting migration, inducing cytotoxic or growth inhibitory activity against tumor cells, and causing changes in cell surface markers. The IL-2s were also tested for activity in vitro and in vivo in mice. Although there was a 12-fold variation in activity among the preparations, all but one of the IL-2s showed augmentation of the mixed lymphocyte reaction activity and all IL-2s tested stimulated macrophage cytotoxicity in vitro. All IL-2s tested enhanced the mixed lymphocyte-allogeneic tumor cell reaction resulting in greater production of cytotoxic T cells. However, significant quantitative differences in potency were evident among the various IL-2 preparations, especially the nIL-2s. Only very high doses of IL-2 (intraperitoneal injection of 100,000 RU/animal) induced in vivo augmentation of splenic or peritoneal NK cells, although all IL-2s tested increased NK activity against tumor target cells in vitro with substantially lower doses (10-100 RU/ml).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1986

[Protein deficiency, host defense and natural anti-tumor immunity].

Natural immuneffector cells, namely natural killer cells and monocyte/macrophages, have become in recent years an important part of theory and practice of immunotherapy. This is especially the case for therapy of malignant tumors with biological response modifiers (BRMs). Many BRMs increase cytotoxicity against tumor cells and cell numbers of natural immuneffector cells. Protein depletion on the other hand, which often is part of malignant diseases, results in well known negative effects on acquired and specific immunity. The data which are presented here show that depressions of natural immuneffector cells in terms of cytotoxicity and cell numbers also occur after protein depletion. The same is true for their pool, the bone marrow. The potentials of BRM therapy are considerably decreased. Host defense mechanisms in normal and protein depleted nutritional status, immunological tumor defense and BRM therapy are presented in the survey.

Adjuvants, Immunologic↗

PubMed1986

Adjuvant chemoimmunotherapy of cancer: influence of tumor burden and role of functional immune effector cells in mice.

Starting from the observation that success of combined treatment of MBL-2 tumor-bearing mice with the alkylating agent cyclophosphamide (CY; 150 mg/kg) and the immunomodulator maleic anhydride divinyl either copolymer (MVE-2; 25 mg/kg) was dependent upon a 1-3-day interval between treatment with CY and MVE-2, we have further analyzed in vitro and in vivo the relationship between tumor burden and the activity of immune effector cells in an adjuvant chemoimmunotherapy setting with CY and MVE-2. Treatment of MBL-2 tumor-bearing mice with CY (50-200 mg/kg) caused a dose- and time-dependent decrease in the i.p. tumor burden, which correlated with a significant increase in their median survival time. CY increased also the sensitivity of the residual MBL-2 tumor cells to Mø-mediated immunotherapy. The therapeutic efficacy of Mø-mediated immunotherapy with MVE-2, however, was restricted due to adverse effects of CY on the host's immune and hematopoietic functions. The time sequence with which these CY related positive effects on tumor burden and s(Tu)I, as well as the adverse effects on macrophages and hematopoietic functions occurred, gives sufficient explanation for the narrow window in time for successful immunotherapy with MVE-2 after preceding chemotherapy with CY. We therefore propose to modify the conventional chemoimmunotherapy of MBL-2 tumor-bearing mice by combining it with an intermittent in vivo transfer of in vitro cultivated Mø (therapy sequence: CY----Mø transfer----MVE-2), which would result in an increased Mø:MBL-2 tumor cell ratio at the site of the tumor while reducing the adverse effects of CY on macrophage functions.

Animals↗

PubMed1985

Differential ability of human blood monocyte subsets to release various cytokines.

We have shown that two human monocyte subsets can be isolated from the peripheral blood of healthy donors; these subsets possess different morphological, cytochemical, functional, and in vivo trafficking properties [1]. In this report, these two subsets were further characterized. One subset (intermediate monocytes, IM) has been shown to have significantly lower acid phosphatase activity and total cellular protein content as well as lower peroxidase activity when compared with another subset (regular monocytes, RM). The overall activation status of the two subsets (as determined by their alkaline phosphodiesterase activity) was identical. We also examined the capacity of these subsets to release various cytokines with or without polyriboinosinic and polyribocytidylic acid (Poly I:C) stimulation. There was no appreciable difference in their ability to release interferon (IFN), interleukin 1 (IL-1), and prostaglandin E (PGE) without stimulation, while IM produced slightly, but significantly, higher amounts of colony-stimulating factor (CSF) than RM. The amount of IFN released by IM in response to poly I:C was approximately three times higher than the amount of IFN released by RM. IL-1 was also released in higher amounts by IM than by RM in response to poly I:C. IM were also found to release more CSF than RM in response to poly I:C. In contrast, it was noted that IM secrete significantly less PGE response to poly I:C than do RM. These findings indicate that two purified human monocyte subsets, distinguishable by maturation markers, differ significantly in their ability to release various cytokines after stimulation; this difference may be relevant to potential in vivo roles of these immunoregulatory cells.

Acid Phosphatase↗

PubMed1985

Secretion of colony-stimulating factors by human monocytes and bone marrow cells after in vitro treatment with biological response modifiers.

The results of this study indicate that human interferons (hIFNs) may have bimodal effects in vitro on human myelopoiesis. Low concentrations of hIFN alpha (1-10 U/ml), hIFN beta (1-100 U/ml), and hIFN gamma (1 U/ml) stimulated in vitro increased secretion of colony-stimulating factors (CSF) by human blood monocytes, which induced growth and differentiation of granulocyte-macrophage progenitor cells. High concentrations of hIFNs alpha, beta, gamma (greater than 100 U/ml), however, had direct antiproliferative effects on granulocyte-macrophage progenitors. Both effects could be blocked by monoclonal antibodies against hIFN alpha and hIFN gamma, as well as by heteroantiserum against hIFN beta. Human IFNs did not appear to be involved in mediating the response to the chemically defined biological response modifiers (BRMs) poly ICLC (polyriboinosinic-polycytidylic acid poly-L-lysine) and BM 41.332 (2-cyano-1-[(2-methoxy-6-methyl-pyridin-3yl)-methyl]-aziridine), since neutralizing antibodies against the human IFNs (anti-IFN alpha, beta, gamma) did not block the poly ICLC and BM 41.332-induced secretion of CSF by human blood monocytes. In contrast to hIFNs, poly ICLC and BM 41.332 also stimulated adherent human mononuclear bone marrow cells to secrete CSF, which induced growth and differentiation of nonadherent granulocyte-macrophage progenitors. The studies presented here thus support the concept that selected BRMs might be useful to stimulate in vivo secretion of myelopoietic growth factors and thereby promote granulocyte and monocyte/macrophage functions.

Antigen-Antibody Complex↗

PubMed1985

Effects of protein depletion on NK cell cytotoxicity and bone marrow cellularity.

Tumor bearing patients have repeatedly been shown to develop states of protein (PD). PD has frequently been associated with depression of acquired immunity. In contrast, little is known about the effects of PD on natural killer (NK) cell cytotoxicity and on bone marrow cellularity and how modulation of these parameters by maleic anhydride divinyl ether copolymer (MVE-2) would be affected. BALB/c mice 6-10 weeks old were fed normal diets (18% protein) (ND mice) or protein deficient isocaloric diets (PD mice) for 35 days. On days 5, 9, 15, 23, and 35 assays were performed. Three days prior to each assay day, some groups received MVE-2 i.p. In PD mice spontaneous NK activity was reduced by some 80%. After MVE-2 the levels only rose to half the amount of activity of ND mice, although in both groups an increase of NK activity took place. BMC levels of PD mice were also strongly decreased. After MVE-2, increases of BMC in PD mice were quite weak and did not reach the level of normal unstimulated BMC. In PD mice we found body weight loss of 46%, reduction in albumin and total protein of 22% and complete disappearance of prealbumin after 5 days of diets. Preliminary results indicate that repletion with amino acids (NeoAminomel L12.5 o.K.H. Salvia, Boehringer Mannheim Co.) is able restore NK activities and BMC levels.

Animals↗

PubMed1985

Modulation of myelopoiesis by CSF or CSF-inducing biological response modifiers.

We have compared the effects on number and function of bone marrow progenitors and peripheral effector cells of the myelomonocytic lineage of treatment with the 2-cyanaziridine compounds Azimexone and BM 41.332 to those of maleic anhydride divinyl ether copolymer (MVE-2) or granulocyte-macrophage colony stimulation factor (GM-CSF). Within a few hours after i.p. injection of either Azimexone or BM 41.332, there was a dose-dependent increase in serum CSF levels, CSF secretion by mononuclear bone marrow cells (BMC) and macrophages (M phi), which was followed by an increase in granulocyte-M phi committed stem cells (GM-CFU-C), nucleated BMC, and peripheral blood leukocytes. Optimal effects occurred 3 days after 50 mg/kg Azimexone or 25 mg/kg BM 41.332. Three i.p. injections of 50 mg/kg Azimexone into mice pretreated with cyclophosphamide (CY) (150 mg/kg) were able to significantly restore suppressed bone marrow cellularity (GM-CFU-C and nucleated BMC). Azimexone also increased the number of peripheral M phi in normal or CY-treated mice, without inducing detectable tumoricidal activity. These M phi, however, retained their capacity to become fully activated (cytotoxic) by appropriate activation signals such as IFN or LPS. Analogous to the 2-cyanaziridines. MVE-2 (at 25 mg/kg) had similar stimulatory effects on myeloid functions in normal mice. MVE-2 induced, in addition, a significant augmentation of cytoxicity by both M phi and NK cells. In contrast, single or multiple injections of semipurified GM-CSF into normal mice (1000 U or 5000 U per mouse) failed to detectably stimulate myelopoietic growth and differentiation. 2-cyanaziridine compounds thus offer the potential of selectively augmenting growth and differentiation of myelomonocytic cells in normal and bone marrow-depressed mice without appreciably affecting their immunological status.

Adjuvants, Immunologic↗

PubMed1985

Immunomodulatory effects in mice of polyinosinic-polycytidylic acid complexed with poly-L-lysine and carboxymethylcellulose.

In this report, we describe the immunomodulatory characteristics of poly(I,C)-LC, a synthetic, double-stranded nucleic acid polymer, polyinosinic-polycytidylic acid, that is complexed with poly-L-lysine and solubilized by the addition of carboxymethylcellulose. We consistently observed, both in vitro and in vivo, stimulation of macrophage cytotoxicity and augmentation of natural killer-cell activity by poly(I,C)-LC. This immunomodulator also increased the allogeneic mixed-lymphocyte response, without any blastogenic effect on responder cells cultured in the absence of allogeneic stimulator cells. Further, the addition of poly(I,C)-LC to an allogeneic mixed-lymphocyte tumor reaction did not stimulate the development of cytotoxic effector T-cells. Poly(I,C)-LC did, however, have adjuvant activity when admixed with irradiated tumor cells in the immunization of syngeneic mice. Unlike classic adjuvants, poly(I,C)-LC also enhanced the development of specific cytotoxic T-lymphocytes when it was injected either i.v. or i.p. in conjunction with a vaccine delivered at an intradermal site. The results indicate that poly(I,C)-LC has considerable potential as an immunotherapeutic agent, with the ability not only to induce macrophage and NK cell activation but also to stimulate specific cytotoxic T-lymphocytes.

Adjuvants, Immunologic↗

PubMed1985

In vivo modulation of myelopoiesis and immune functions by maleic anhydride divinyl ether copolymer (MVE-2) in tumor-free and MBL-2 tumor-bearing mice treated with cyclophosphamide.

Treatment of normal or MBL-2 tumor-bearing mice with cyclophosphamide (CY) caused severe suppression of myelopoiesis and macrophage (M phi) functions, both of which may limit further use of chemotherapy. Additional treatment with the chemically defined biological response modifier maleic anhydride divinyl ether copolymer (MVE-2) was able to ameliorate the myelosuppressive effects of CY and to restore normal bone marrow cellularity. The stimulatory effects on myelopoiesis, however, could only be obtained by administering MVE-2 at greater than or equal to 3 days after CY, which correlated with an MVE-2-induced simultaneous increase in granulocyte and/or macrophage colony-stimulating factor secretion by bone marrow cells or M phi. Injection of MBL-2 tumor-bearing mice with MVE-2, at 3 days after Cy treatment, caused a decrease in tumor burden and a significant increase in median survival time as compared to treatment with CY alone. At the same time, MVE-2 induced an increase in the number of cytotoxic M phi and a complete restoration within the myelopoietic lineage, which might prevent delayed side effects of CY, such as secondary infections, and might permit more intensive chemotherapeutic treatment. Treatment of MBL-2 tumor-bearing mice with MVE-2, at 6 days after CY, induced a significant increase in M phi cytotoxicity but did not prolong median survival time, probably due to a rapid regrowth of tumor after treatment with CY. Our studies thus show that successful combined therapy with the primary cytotoxic agent CY and the biological response modifier MVE-2 depends on precise timing of the drug regimen and is influenced by the extent and reversibility of CY-induced immunosuppression, as well as by the kinetics of recruitment of new effector cells from bone marrow and by the tumor burden present at the time of treatment.

Animals↗

PubMed1985

Effects of poly(I,C)-LC on growth and differentiation of normal and malignant myelopoietic progenitor cells.

Polyriboinosinic-polycytidylic acid with poly-L-lysine stabilized with carboxymethylcellulose [poly(I,C)-LC] augmented, in a dose- and time-dependent manner, secretion of colony-stimulating factor (CSF) by peritoneal macrophages (M phi) and bone marrow cells (BMC). Optimal effects were found after 2 days of in vitro culture of the cells with 50 micrograms/ml of poly(I,C)-LC or 14 h to 3 days after a single intraperitoneal injection of 1-2 mg/kg of poly(I,C)-LC into normal mice. The increase in CSF secretion by M phi and BMC was paralleled in vivo by an increase in serum CSF levels, followed by a rise in committed granulocyte and M phi progenitor cells (GM-CFU-C), nucleated BMC, and blood leukocytes of myelomonocytic origin. Poly(I,C)-LC at doses greater than 4 mg/kg, however, were strongly myelosuppressive. In vitro treatment of undifferentiated myelomonocytic leukemia cells from the WEHI-3B cell line with 10-1,000 micrograms/ml of poly(I,C)-LC resulted in a significant increase in CSF secretion by the leukemic cells and a concomitant inhibition of their proliferation. Incubation of cells from the WEHI-3B D+ subline, which differentiate in response to GM-CSF or G-CSF, with 50-100 micrograms/ml poly(I,C)-LC in agar cultures induced in approximately 45% of the leukemic colonies a differentiation into granulocytes and/or M phi. Poly(I,C)-LC, however, had no effect on differentiation of cells from the CSF unresponsive WEHI-3B D- subline. The CSF-inducing biological response modifier poly(I,C)-LC thus has the potential to stimulate growth and differentiation of normal, as well as differentiation of malignant myelopoietic progenitor cells.

Animals↗

PubMed1985

Pharmacokinetic and therapeutic activity of polyinosinic-polycytidylic acid stabilized with poly-L-lysine in carboxymethylcellulose [poly(I,C)-LC].

Polyinosinic-polycytidylic acid stabilized with poly-L-lysine in carboxymethylcellulose [poly(I,C)-LC] significantly augmented natural killer (NK) cell activity in several tissues. Macrophage (M phi) tumoricidal activity was also markedly increased. Both effector cells were active for 9 days. Poly(I,C)-LC also increased effector cell response in vitro. Injections of poly(I,C)-LC resulted in elevated effector cell responses in four of five routes tested. Treatment with poly(I,C)-LC led to an earlier reconstitution of bone marrow cells, NK cell activity, and M phi effector cell activity in mice pretreated with cyclophosphamide (Cytoxan). Combined treatment of MBL-2 tumor cells with cytoreductive chemotherapy and poly(I,C)-LC resulted in an enhanced therapeutic response.

Animals↗

PubMed1984

Characterization of biological response modifier release by human monocytes cultured in suspension in serum-free medium.

Human monocytes have been shown to be critical immunoregulatory cells for a variety of frequently measured in vitro human immune functions and are secretors of potent biologic response modifiers ( BRMs ). These BRMs , such as interferon (IFN), colony stimulating factor (CSF) and prostaglandin E (PGE), may play important roles in the host immune response to cancer. A new approach for culturing circulating peripheral blood monocytes has been developed to retain the native characteristics of these cells, avoiding possible alteration or activation by adherence. The ability of elutriator-purified human monocytes to secrete IFN and PGE was examined under conditions of suspension culture as well as after adherence, and no difference in secretion of these BRMs was noted. In contrast, Teflon-cultured monocytes demonstrated a significantly enhanced CSF release over culturing in polystyrene plates. A new serum-free medium has also been developed, and monocytes cultured in vitro in this medium showed a 5-fold increase in IFN release, and up to a 72% increase in CSF release when compared to optimal standard culture medium (containing 10% AB serum) and an increased stimulation index for PGE release. By these procedures, hundreds of millions of highly purified human monocytes can be sterilely isolated in suspension and cultured in suspension in serum-free medium with retention of BRM-releasing capabilities. This system should permit more detailed molecular studies of monocytes (in which serum can be an impediment) and may also facilitate clinical therapy studies involving the in vivo transfer of monocytes activated in suspension in vitro.

Blood Physiological Phenomena↗