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Biomedical subjects

E S Kleinerman

Publications and source records attributed to E S Kleinerman.

89 records · Page 5Linked to original sources
PubMed1984

Lymphokine-activated human blood monocytes destroy tumor cells but not normal cells under cocultivation conditions.

The possibility that tumoricidal human blood monocytes would recognize and destroy tumorigenic targets but leave bystander nontumorigenic cells unharmed was investigated. Highly purified preparations of peripheral blood monocytes isolated from normal human donors were activated in vitro by incubation with human lymphokines encapsulated in multilamellar liposomes. The cytotoxic properties of these monocytes against several tumorigenic and nontumorigenic allogeneic target cell populations were assessed by an in vitro radioisotope-release assay. Various combinations of three tumorigenic and three nontumorigenic target-cell populations, labeled with either [3H]thymidine or [14C]thymidine, were mixed and plated onto monolayers of blood monocytes. In all combinations used, activated monocytes specifically lysed only allogeneic neoplastic cells. At least in vitro, activated human blood monocytes can recognize and selectively destroy neoplastic cells.

Cell Line↗
PubMed1984

Constitutive production and release of a lymphokine with macrophage-activating factor activity distinct from gamma-interferon by a human T-cell leukemia virus-positive cell line.

Culture supernatant fluids from the human T-cell leukemia virus-positive cell line C10/MJ-2 were found to contain a soluble factor with macrophage-activating factor (MAF) activity. The MAF activity of this culture supernatant fluid was stable at 100 degrees for 2 min and was unaffected by treatment with human anti-gamma-interferon (IFN-gamma) monoclonal antibody. Both treatments neutralized greater than 97% IFN-gamma activity from the supernatant fluid as measured by virus neutralization. Furthermore, this MAF activity was not due to contamination with endotoxins since the Limulus amebocyte lysate assay was negative (less than 0.125 ng/ml) and preincubation of the C10/MJ-2 supernatant fluid with polymyxin B did not diminish its activating potential. By contrast, human IFN-gamma rendered human monocytes tumoricidal only when combined with Salmonella typhosa lipopolysaccharide (LPS) at a minimum dose of 0.2 ng/ml. The concentrations of both LPS and IFN-gamma were crucial to achieve activation since IFN-gamma at doses less than 10 units/ml did not activate human monocytes even when combined with maximal doses of LPS (0.5 ng/ml). Finally, when human IFN-gamma admixed with LPS was preincubated with polymyxin B, its activating potential was completely abrogated. Collectively, these data suggest that the human T-cell line C10/MJ-2 constitutively produces a diffusable product distinct from IFN-gamma which activates human monocytes to lyse tumor cells. Thus, this cell line could provide a good source of a unique human MAF for future purification procedures.

Cell Line↗
PubMed1983

Tumoricidal activity of human monocytes activated in vitro by free and liposome-encapsulated human lymphokines.

Human peripheral blood mononuclear cells from normal donors obtained by separation on a Percoll gradient were incubated with free or liposome-entrapped lymphokines produced from concanavalin A-stimulated lymphocytes and then were tested for cytotoxic activity against tumor cells. The treated monocytes lysed tumorigenic melanoma and glioblastoma target cells, but had no effect on three types of nontumorigenic target cells. The activation of monocytes to become tumoricidal was caused by macrophage-activating factor (MAF) and not by contamination with endotoxins, concanavalin A, or interferon. The endocytosis of liposomes containing MAF, but not of those containing control supernatants, led to the activation of cytotoxic properties in the monocytes. Activation by liposome-encapsulated MAF was very efficient and required less than 1/800th of the amount of free MAF necessary to achieve the same levels of cytotoxicity. Thus, the encapsulation of mitogen-induced MAF in liposomes could provide an effective approach for the activation of blood monocytes in situ.

Cell Line↗
PubMed1983

Activation of tumoricidal properties in human blood monocytes by liposomes containing lipophilic muramyl tripeptide.

Peripheral blood monocytes were isolated from normal human donors by separation on a continuous Percoll gradient and adherence to yield preparations of blood monocytes with a high degree of purity (greater than 99%). The monocytes were incubated in vitro with medium alone or with multilamellar liposomes that contained either a lipophilic derivative of muramyl dipeptide, muramyl tripeptide (MTP-PE), or medium. The cytotoxic properties of the monocytes were assessed by an in vitro radioisotope release assay against various allogeneic targets. Monocytes that have phagocytosed liposomes containing MTP-PE were rendered tumoricidal. These monocytes lysed cells of three different tumorigenic lines but not cells of two nontumorigenic lines. The ability of MTP-PE-activated human blood monocytes to recognize and selectively lyse neoplastic cells was also demonstrated under cocultivation conditions. We conclude that human blood monocytes can be rendered tumoricidal after interaction with liposomes containing MTP-PE.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1982

Effect of L-phenylalanine mustard, adriamycin, actinomycin D, and 4'-(9-acridinylamino)methanesulfon-m-anisidide on naturally occurring human spontaneous monocyte-mediated cytotoxicity.

We have shown previously that cis-diamminedichloroplatinum(II) (cis-DDP), an active antineoplastic agent, and X-irradiation enhanced human spontaneous monocyte-mediated cytotoxicity in vitro. To ascertain whether this is a unique property of cis-DDP or common to other effective antineoplastic agents, we studied the effect of L-phenylalanine mustard (L-PAM), Adriamycin (ADR), actinomycin D, and 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA) on spontaneous monocyte-mediated cytotoxicity, cis-DDP, ADR, L-PAM, and m-AMSA under appropriate in vitro conditions all increased spontaneous monocyte-mediated cytotoxicity. Activation involved (a) direct monocyte activation (cis-DDP and ADR); (b) inactivation of suppressor lymphocytes (X-irradiation); (c) a combination of the two (L-PAM); or (d) mechanisms not yet elucidated (m-AMSA). In contrast, incubating mononuclear leukocytes with 0.4 microgram actinomycin D per ml depressed monocyte-mediated killing. Thus, while stimulation of "nonspecific" killing is not a unique property of cis-DDP, it is not a universal effect of all chemotherapy agents. The stimulation and enhancement of already existing host defense mechanisms may be an important additional way in which many chemotherapeutic agents exert their antitumor effect.

Aminoacridines↗
PubMed1981

Pharmacology of human spontaneous monocyte-mediated cytotoxicity. I. Enhancement by salicylates and steroids.

The effect of various antiinflammatory agents on the spontaneous cytotoxicity of human mononuclear cells in vitro was assessed. Acetylsalicylic acid (ASA) and hydrocortisone enhanced spontaneous monocyte-mediated cytotoxicity compared to control values. This enhancement could not be mediated through inhibition of prostaglandin biosynthesis since indomethacin had no effect on cytotoxic function and since the direct addition of PGE2 to the cell cultures did not inhibit the expression of cytotoxicity. Likewise, salicylic acid (SA), which had no effect on prostaglandin biosynthesis, also enhanced monocyte cytotoxicity. Stimulation of monocyte-mediated cytotoxicity resulting in more efficient antigen removal and thus decreasing antigen persistence may be an additional mechanism by which ASA, SA, and hydrocortisone modulate the destructive inflammatory response in rheumatoid arthritis.

Anti-Inflammatory Agents↗
PubMed1980

Defective monocyte killing in patients with malignancies and restoration of function during chemotherapy.

Spontaneous monocyte-mediated cytotoxicity (SMMC) in 34 patients treated with a chemotherapeutic regimen including cisplatin for various malignancies was depressed (median 7% 51Cr release) compared with SMMC in 31 normal controls (median 43%; p < 0.0001). Cytotoxicity in 7 patients with stage III or IV ovarian carcinoma was then followed during six cycles of chemotherapy with a cisplatin-containing regimen. All patients had initial cytotoxic values of < 8%, and in all SMMC increased at least three-fold between the third and fifth cycle of chemotherapy. This study lends support to the concept that cancer patients have depressed monocyte function. Cisplatin-containing chemotherapy seems to enhance monocyte function in vitro and in vivo.

Cisplatin↗
PubMed1980

Enhancement of naturally occurring human spontaneous monocyte-mediated cytotoxicity by cis-diamminedichloroplatinum(II).

The effect of the antineoplastic agent cis-diamminedichloroplatinum(II) (cis-DDP) on spontaneous cytotoxicity of human mononuclear cells in vitro was assessed. cis-DDP enhanced spontaneous monocyte-mediated cytotoxicity 300% compared to control values. Further, this spontaneous monocyte killing developed earlier (3 to 4 days) than did that of untreated cells (5 to 7 days). Since monocyte cytotoxicity is under the control of lymphocyte suppressor cells, the effect of cis-DDP on separated populations of lymphocytes and monocytes was examined. Unlike X-irradiation which enhanced monocyte cytotoxicity through the indirect pathway of inactivation of lymphocyte suppressors, cis-DDP directly stimulated the monocyte population. Direct stimulation of killer monocytes may be an important mechanism of the antitumor effect of cis-DDP.

Cell Separation↗
PubMed1978

Abortive and productive infections of human mononuclear phagocytes by type I herpes simplex virus.

The ability of Type I herpes simplex (HSV) to replicate in normal human monouclear phagocytes was investigated. Mononuclear leukocytes were obtained from the peripheral blood of patients by Ficoll-Hypaque gradient centrifugation, and the monocytes were isolated by allowing the cells to adhere to tissue culture dishes. The monocytes (10(5.0) cells) were infected (10(7.0) PFU HSV) either immediately after isolation or were cultured in vitro for varying numbers of days and were then infected. Inoculation of freshly isolated monocytes resulted primarily in an abortive infection. HSV antigens were produced by the cells, as determined by a indirect fluorescent antibody technique, and empty herpes capsid structures were detected by electron microscopy of the inoculated monocytes; however, no increase in virus titer was noted in the cultures. Inoculation of viable cells that had been maintained for 7 days in culture resulted in a productive infection. An increase in titer was noted 24 hours after inoculation, and normal virus maturation was documented by ultrastructural study of the infected cells. The experiments show that the interaction of HSV with human mononuclear phagocytes is complex, and the data suggest that whether or not the cell replicates infectious virus may depend on the functional activity of the cell.

Antigens, Viral↗
PubMed1976

Effect of virus infection on the inflammatory response. Depression of macrophage accumulation in influenza-infected mice.

To better define the mechanisms by which viruses depress immune function, the effect of influenza infection on the ability of macrophages to accumulate at sites of inflammation was determined. Mice were inoculated with virus, and their inflammatory response measured in vivo by counting the number of leukocytes which accumulated in the peritoneal cavity 2 days after an intraperitoneal injection of phytohemagglutinin. Mice infected with influenza had a 57% and 65% depression of total leukocyte and macrophage accumulation, respectively, as compared to the response of uninfected mice. In contrast, bacterial pneumonia did not produce a decrease in the macrophage response. This indicated that the depression was produced by the virus infection rather than being a nonspecific phenomenon accompanying any inflammatory focus in the lung. The in vitro chemotactic responsiveness of normal peritoneal macrophages incubated with infectious influenza virus was 53% of normal. These experiments suggest that influenza infection may depress a host's ability to mobilize macrophages to inflammatory sites in vivo by inhibiting their chemotactic responsiveness.

Animals↗
PubMed1975

Depressed monocyte chemotaxis during acute influenza infection.

The chemotactic responsiveness of monocytes from patients with serologically proven influenza infection has been quantified in vitro. Individuals with acute influenza had a significant (P less than 0-001) depression of monocyte chemotaxis. The depression ranged from 40% to 72% during acute infection but rose to normal by three weeks after recovery. When isolated mononuclear leucocytes from the recovered patients were incubated with the infecting strain of virus (Port Chalmers), a 49-54% inhibition of chemotaxis was obtained. These findings support the hypothesis that the altered immune responsiveness and increased predisposition to superinfections found frequently in patients with influenza can be due to the ability of the virus to depress monocyte function.

Acute Disease↗
PubMedDate not supplied

Administration of liposomal MTP-PE by the local physician: the role of the research nurse.

Accrual and retention of patients are critical for the successful completion of a research study. In clinical trials involving liposomal muramyl tripeptide phosphatidylethanolamine, time commitment, loss of income, and potential treatment costs were identified as factors that might cause patients to refuse this form of therapy. As a result, the principal investigator, from M.D. Anderson Cancer Center, and representatives from CIBA-GEIGY Corporation entered into an unusual agreement that allowed patients to receive most of the 6-month outpatient treatment course from their local physician. The involvement of local healthcare providers in the care and treatment of study patients presented a unique challenge to the oncology research nurse managing the clinical trials. This article describes how muramyl tripeptide phosphatidylethanolamine therapy was successfully implemented in several communities nationwide and highlights the various roles in which the research nurse served to prepare and support patients and local clinicians throughout the treatment course.

Acetylmuramyl-Alanyl-Isoglutamine↗