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Biomedical subjects

H T Holden

Publications and source records attributed to H T Holden.

At least 19 recordsLinked to original sources
PubMed1988

Differential in vitro modulation of suppressor and antitumor functions of mouse macrophages by lymphokines and/or endotoxin.

Peritoneal macrophages of normal mice exhibited natural suppressor activity, as indicated by their ability to inhibit the proliferation of spleen cells in response to stimulation with phytohemagglutinin (PHA) or concanavalin A (Con A). Their suppressor function could be modulated in vitro with a variety of treatment regimens. High-dose lipopolysaccharide (LPS) (LPSH; 10 micrograms/ml) or lymphokines (supernatant from Con A-stimulated spleen cells) plus low-dose LPS (LPSL; 10 ng/ml) caused a reduction in the suppressor activity of adherent peritoneal macrophages. In contrast, these same treatments induced the macrophages to become tumoricidal and cytostatic for tumor cells, indicating a major dissociation between the regulation of suppressor and cytotoxic activities of macrophages. The lack of correlation between these activities was further demonstrated by macrophages that had been activated in vitro by Corynebacterium parvum: these cells expressed high tumoricidal and cytostatic activities, and also strong suppressor activity. The suppressor function could be selectively downregulated by in vitro pretreatment with LPSH.

Adjuvants, Immunologic↗
PubMed1979

Activation of mouse macrophages by pyran copolymer and role in augmentation of natural killer activity.

Inoculation of mice with pyran copolymer resulted in activation of natural killer (NK) cells as well as macrophages. Conditions optimal for the boosting of NK activity seemed to differ from those optimal for macrophage activation as assessed by cytostasis of tumor target cells. Peak levels of macrophage cytostatic reactivity were found at about 7 days after drug injection and were only achieved by the highest doses of pyran tested. Macrophage activation was consistently higher in the peritoneal cavity than in the spleen, regardless of route of administration, in contrast to the failure of i.v. pyran to induce high NK reactivity in peritoneal exudate cells. At 2-3 days after pyran treatment of older mice, NK augmentation reached peak levels, but only minimal macrophage activation was found. Despite these differences, macrophages played a role in regulating NK activity in pyran-treated mice. Functional macrophages appeared to be required for augmentation of NK activity by pyran, since boosting was impaired by prior in vivo inoculation of silica. Macrophages also appeared able to inhibit NK activity. In younger mice that exhibited high spontaneous levels of NK activity, pyran treatment produced a substantial reduction in NK activity to levels below those of untreated mice. This depression coincided with the time of peak levels of macrophage cytostasis. Furthermore, removal of adherent cells from the spleen cells of these pyran-treated mice resulted in levels of NK activity almost as high as those of untreated mice. The possibility that the depression of NK activity in young mice by pyran copolymer is due to suppressor cells is discussed.

Animals↗
PubMed1979

In vitro induction of T-lymphocyte-mediated cytotoxicity by infectious murine type C oncornaviruses.

We have developed a system to induce oncornavirus-specific secondary cytotoxic response in vitro. When Moloney strain of murine sarcoma virus-immune spleen cells were cultivated with purified infectious Moloney murine leukemia virus (M-MuLV) or with supernates of tissue culture cells containing infectious virus, a virus-specific secondary cytotoxic response directed against type-specific determinant(s) of M-MuLV was generated in vitro, as determined by a 4-h 51Cr-release assay. The effector cells were susceptible to the treatment with anti-Thyl.2 plus complement, but were unrelated to natural killer cells (NK), because they could not lyse some target cells specific for M-MuLV in both the induction phase and the interaction between effector cells and target cells. Furthermore, a product of the env gene of M-MuLV, perhaps gp70, appeared to be responsible for this response, because viruses with recombinations in the env gene between ecotropic M-MuLV and a xenotropic virus failed to induce a response. When infectious M-MuLV was exposed to UV-light at different doses, the ability of UV-treated M-MuLV to induce a secondary cytotoxic response decreased in parallel with infectivity, indicating that infectivity was necessary for the induction of this response.

Animals↗
PubMed1979

Suppression of lymphokine production by macrophages infiltrating murine virus-induced tumors.

Immune spleen cells from mice injected with murine sarcoma virus (MSV) can produce migration inhibition factor (MIF) in vitro after stimulation with intact tumor cells. We have now found that this effector function can be regulated by suppressor macrophages present in the tumor. The cells from the tumor (CfT) exert a strong suppressive effect even after treatment with anti-Thy 1.2 plus complement but lose this capacity if adherent or phagocytic cells are removed, suggesting that the macrophage is the suppressor cell. The effects of the suppressor cells were exerted on a proliferation-independent function of the lymphocytes, since MIF production, as well as its suppression, occurred even after proliferation of the lymphocytes was blocked by mitomycin-C. The implications of these findings are that macrophages can suppress some early events involved in the activation of lymphocytes by antigen and that they do so through a mechanism that does not relate to the proliferation of the cells.

Animals↗
PubMed1979

Cytolytic activity of macrophages isolated from primary murine sarcoma virus (MSV)-induced tumors.

Macrophages isolated from regressing or progressing tumors induced by murine sarcoma virus (MSV) were tested for cytolytic activity in a 18-h 51Cr release assay. Macrophages from the tumors of mice injected 14 days earlier with stocks of MSV-producing regressor or progressor tumors had comparable levels of cytotoxicity. However, macrophages from the progressively growing tumors, 50--65 days after the inoculation with the progressor virus, had lower levels of cytotoxicity than those from the regressing tumors (day 14). On the other hand, macrophages from progressively growing MSV tumors (day 14) in nude mice had little or no detectable cytolytic activity. In a fractionation study, using the 1-g velocity sedimentation technique, cells from regressing tumors (day 14) showed at least two peaks of cytolytic activity, one at about 4 mm/h and another at 6--7 mm/h. In contrast, none of the cell fractions of tumors from nude mice (day 14) showed cytolytic activity. Since bacterial lipopolysaccharide (LPS) has been shown to augment the cytolytic activity of primed macrophages, its effect on cells from MSV tumors was evaluated. Cytolytic activity of the cells from regressing or progr-ssing tumors that had pre-existing cytolytic activity was augmented by the addition of LPS during the assay period, but LPS treatment did not activate inactive fractions or change the distribution patterns of the cytolytic activity in fractions from 1-g velocity sedimentation.

Animals↗
PubMed1979

Functional heterogeneity and T cell-dependent activation of macrophages from murine sarcoma virus (MSV)-induced tumors.

In studies on the functional activity of macrophages isolated from murine sarcoma virus (MSV)-induced tumors, we have found that these cells may suppress immune responses as well as act as effector cells against the tumor. Previously, we reported that macrophages from the tumor could inhibit the antitumor response by suppressing proliferation-dependent immune functions. Here, we demonstrate that macrophages can also suppress the production of migration inhibition factor (MIF) and macrophage activation factor (MAF), two lymphocyte activities that are independent of cell proliferation. Conversely, we and others have found that macrophages from the tumor can exert an antitumor, cytolytic effect. In this study, using 1 g velocity sedimentation separation techniques, we have been able to identify 2-3 subpopulations of cytolytic macrophages in regressing tumors but in progressing tumors, only the smallest subpopulation of macrophages was active. T cells appeared to be required for activation of macrophages within the tumor, since MSV tumors induced in athymic, nude mice did not contain cytolytic macrophages.

Animals↗
PubMed1979

The effect of immunopharmacological agents on mouse natural cell-mediated cytotoxicity and on its augmentation by poly I:C.

Treatment of young mice with lethal X-irradiation (900 R), cyclophosphamide, or hydrocortisone significantly depressed their spontaneous NK activity. The same treatments, however, did not inhibit the augmentation of NK function by poly I:C, suggesting the existence of a treatment resistant pre-NK cell. Both the spontaneous activity and its augmentation were readily inhibited by macrophage-toxic agents such as silica and carrageenan in vivo. Since the NK cells themselves were not macrophages, as shown by the inability of silica or carrageenan to block in vitro cytolysis of target cells, we postulated that macrophages were required to maintain NK activity in vivo and that they were essential accessory cells in the augmentation. The induction of interferon by poly I:C was also inhibited by silica and carrageenan. The augmentation of NK activity induced by poly I:C was consistently accompanied by the rise in serum IF levels of the treated mice, and its inhibition by the macrophage-toxic agents was followed by decreased production of interferon. These observations support our hypothesis that macrophages, in response to poly I:C, produced interferon which in turn activated NK cells to become cytolytic.

Animals↗
PubMed1979

Augmentation of mouse natural killer cell activity by interferon and interferon inducers.

Interferon (IF), in addition to its anti-viral capacity, is increasingly being found to be a regulator of cell division, cell surface antigens, and cell function. To determine whether IF also plays a role in the regulation of natural killer (NK) cell activity in mice, the in vivo and in vitro effects of IF and IF inducers on NK activity were studied. We observed that pyran, lipopolysaccharide, and polyinosinicopolycytidylic acid (poly I:C) as well as crude and purified IF preparations significantly elevated splenic NK levels in normal mice within 3 to 24 hr of i.p. administration. Normal spleen cells treated with poly I:C or IF in vitro also had augmented NK activity. Poly I:C and IF were themselves not cytotoxic and their presence was not required during the lytic process, indicating that IF acts on lymphocytes to activate NK function. The addition of anti-IF in the incubation medium completely blocked the boosting of NK activity by poly I:C or IF. The characteristics of the effector cells activated by IF were consistent with those of NK cells rather than macrophages, since the boosted effector cells were not retained by a rayon column or removed by carbonyl iron. Moreover, they were resistant to treatment with anti-Thy 1.2 serum plus complement, which eliminated mature T cells.

Animals↗
PubMed1979

Correlation between natural and antibody-dependent cell-mediated cytotoxicity against tumor targets in the mouse. II. Characterization of the effector cells.

Direct comparison of the effector cells mediating natural killer (NK) activity against mouse tumor cells and antibody-dependent cell-mediated cytotoxicity (ADCC) against mouse tumor target cells coated with alloantisera indicated that NK cells and K-cells (effector cells mediating ADCC) may belong to the same subpopulation of lymphocytes, but they have a different mechanism of killing. Effector cells mediating NK activity and ADCC were nonadherent, nonphagocytic Fc receptor-bearing cells that sediment at 3.5-4.5 mm/hour. Treatment with anti-Thy 1.2 serum in the absence of complement resulted in an increase of NK activity, whereas this treatment caused a substantial loss in ADCC. Both NK activity and ADCC were equally sensitive to the in vivo or in vitro effects of X-irridiation. In vivo inoculations of high doses of hydrocortisone resulted in a reduction of NK activity, but ADCC was not affected. NK cells were trypsin-sensitive, with a profound decrease in the cytolytic activity being observed in a 4-hour 51Cr release assay. The activity, however, could be recovered after overnight incubation at 37 degrees C. Trypsin treatment did not inhibit ADCC as measured by the 18-hour assay.

Animals↗
PubMed1979

Identification and separation of Thy-1 positive mouse spleen cells active in natural cytotoxicity and antibody-dependent cell-mediated cytotoxicity.

The expression of the Thy-1 antigen on mouse spleen cells responsible for NK activity and ADCC was investigated by using a monoclonal IgM anti-Thy-1.2 antibody. Both C-mediated cytotoxicity and the fluorescence-activated cell sorter were used to fractionate cells. The effector cells were found to be heterogeneous in their expression of Thy-1. Effector cells from nude BALB/c mice were predominantly Thy-1 positive; some of the NK cells in CBA spleens appeared to be Thy-1 positive, but at least one-third of the lytic activity was due to Thy-1 negative cells. The effects of treatments on NK cytotoxicity and ADCC were very similar, supporting the hypothesis that the same cells mediate both activities.

Animals↗