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Biomedical subjects

F M Griffin

Publications and source records attributed to F M Griffin.

At least 37 records · Page 2Linked to original sources
PubMed1985

In vivo activation of macrophage C3 receptors for phagocytosis.

We assessed the effects of exposure to immune complexes in vivo on macrophages' Fc receptor function and C3 receptor function. Peritoneal macrophages from mice injected intraperitoneally with immune complexes were markedly impaired in their ability to phagocytize via their Fc receptors but had acquired the ability to phagocytize via their C3 receptors. In vivo activation of macrophages' C3 receptors for phagocytosis required T lymphocytes, because macrophages from athymic mice could not be activated by injection of immune complexes. The requirement for both T lymphocytes and immune complexes for activation of macrophages' C3 receptors in vivo is identical to the requirements for activation of macrophages' C3 receptors in vitro, suggesting that the mechanisms we have identified for activation of these receptors in vitro are the same mechanisms by which the receptors are activated for phagocytosis in vivo. The susceptibility of macrophages' Fc receptors to blockade by immune complexes and the activation of their C3 receptors for phagocytosis in a milieu containing immune complexes suggest that it may be macrophages' C3 receptors, not their Fc receptors, that are primarily responsible for promoting phagocytosis of opsonized microorganisms in immune hosts.

Animals↗
PubMed1985

Use of phytohemagglutinin response to determine the extent that somatic cell mutation accounts for 6-thioguanine resistance of human blood mononuclear cells.

We investigated the likelihood that human peripheral blood mononuclear cells which incorporate tritiated thymidine in the presence of 6-thioguanine (6-TG) are mutants by comparing findings for cells from the same blood specimen cultured in the presence or absence of phytohemagglutinin (PHA). After 42 h in culture, autoradiography revealed that about 0.1% of cells from healthy control donors and 1% of cells from patients receiving chemotherapy for breast cancer labeled in the absence of PHA. About 5% of this number labeled when 6-TG was added to the medium. This high frequency of cells labeling in the presence of 6-TG suggested that many cells were resistant to 6-TG for reasons other than mutation at the HGPRT locus. Despite a labeling index of about 30% in the presence of PHA alone, the addition of PHA to cells cultured with 6-TG did not increase the labeling index over that observed with 6-TG alone. Also, in the presence of 6-TG there was a significant correlation between labeling indices for cells from the same blood specimen cultured with or without PHA. These findings suggest that the two conditions measured the same population of non-mutant cells. These studies reinforce observations made by the developers of this technique and other laboratories which indicate that refinements will be required before the assay can be used to study somatic cell mutation in human populations. Such refinements are underway in several laboratories; although not definitive, the approach and procedures used in this report which investigated the original assay procedure provide methods and criteria to judge whether modifications of assay techniques improve the quantification of in vivo human somatic cell mutation.

Cells, Cultured↗
PubMed1985

Augmentation of macrophage complement receptor function in vitro. V. Studies on the mechanisms of ligation of macrophage Fc receptors required to trigger macrophages to signal T lymphocytes to elaborate the lymphokine that activates macrophage C3 receptors for phagocytosis.

We previously described a unique lymphokine that activates macrophage C3 receptors for phagocytosis. The lymphokine is generated when T lymphocytes receive a signal from macrophages that have ingested IgG-coated material. In the present work, we examined the mechanisms by which macrophage Fc receptors must be engaged for macrophages to signal lymphocytes to elaborate the lymphokine. We found that ingestion mediated by any of the three classes of murine macrophage Fc receptors was sufficient to trigger macrophages, and that engagement of macrophage Fc receptors by immobilized immune complexes was effective as well. We also found that ligation of Fc receptors by an anti-Fc receptor IgG antibody or by its F(ab')2 or Fab fragments also triggered macrophages. The ability of monovalent ligation of the receptor to elicit biologic activity suggests that this system may be of value in elucidating general mechanisms by which ligand binding of receptors is transduced into biologic effects.

Animals↗
PubMed1985

Effects of differentiation in vivo and of lymphokine treatment in vitro on the mobility of C3 receptors of human and mouse mononuclear phagocytes.

The C3 receptors of human peripheral blood monocytes are able to move laterally within the plasma membranes of the cells and remain mobile even when the cells develop into "macrophages" in vitro. In contrast, the C3 receptors of mouse peritoneal macrophages are immobile. To determine whether these differences are species differences or differences between cells of different stages of differentiation, we assessed the mobility of C3 receptors of mouse peripheral blood monocytes and of human pulmonary alveolar and peritoneal macrophages. The C3 receptors of mouse monocytes were mobile, whereas the C3 receptors of human tissue macrophages were immobile. The C3 receptors of macrophages mediate avid particle binding but do not normally promote ingestion. We have described a unique lymphokine that activates mouse peritoneal macrophage C3 receptors for phagocytosis by freeing them from their plasma membrane anchors. In the present experiments, we found that the lymphokine also freed the C3 receptors of human macrophages and activated them for phagocytosis. We conclude that the immobilization of C3 receptors appears to be a marker for the differentiation of human and mouse mononuclear phagocytes, that the differentiation of mononuclear phagocytes is influenced by the milieu in which the cells develop, that in vitro-differentiated macrophages may not accurately represent tissue macrophages, and that a lymphokine activates the C3 receptors of both human and mouse macrophages for phagocytosis by allowing the receptors lateral mobility within the cell plasma membrane.

Animals↗
PubMed1984

Augmentation of macrophage complement receptor function in vitro. IV. The lymphokine that activates macrophage C3 receptors for phagocytosis binds to a fucose-bearing glycoprotein on the macrophage plasma membrane.

Macrophage receptors for the third component of complement (C3) are normally immobilized and unable to diffuse within the cell's plasma membrane and, even though they promote avid particle binding, are unable to promote phagocytosis of C3-coated particles. We have previously identified a lymphokine that activates macrophage C3 receptors for phagocytosis and have found that it acts by freeing the receptors so that they can diffuse within the macrophage plasma membrane. It seemed likely to us that the initial lymphokine-macrophage interaction would occur at the macrophage surface, perhaps via a specific lymphokine receptor. Since the binding of many ligands to cells is mediated by cell surface glycoproteins, we examined the protein and sugar requirements for murine peritoneal macrophages to respond to the lymphokine. Macrophages treated with the neutral protease Dispase lost the ability to respond to the lymphokine, and inclusion of L-fucose in the incubation medium containing lymphokine and macrophages inhibited markedly the macrophages' response to the lymphokine, suggesting that the lymphokine exerts its effects by first binding to fucose residues on a glycoprotein receptor on the macrophage surface. Further evidence for the essential role of macrophage surface fucose was obtained by demonstrating that pretreatment of macrophages with either fucosidase or gorse lectin, a fucose-binding lectin, strikingly disabled the cells from responding to the lymphokine. All treatments that prevented lymphokine activation of macrophage C3 receptors for phagocytosis also prevented lymphokine-induced C3 receptor mobility. These results strongly suggest that the lymphokine binds to a fucose-bearing macrophage surface glycoprotein, perhaps a specific lymphokine receptor. They also strengthen our hypothesis that, for a receptor to be able to promote phagocytosis, it must be able to diffuse within the macrophage plasma membrane.

Animals↗
PubMed1984

Functional characteristics of the macrophage receptors for IgG-Fc and C3: failure to detect C3 receptor-mediated extracellular cytolysis by mouse peritoneal macrophages.

The ability of several immunologic ligands to mediate extracellular cytolysis of sheep erythrocytes (E) by mouse macrophages was studied. E coated with rabbit IgG (EIgG), but not nonsensitized E or E coated with rabbit IgM (EIgM), were lysed and phagocytized by resident peritoneal macrophages as well as by macrophages activated in vivo with either BCG or Corynebacterium parvum or in vitro with lymphokine. EIgM incubated with mouse serum to deposit the third component of complement (C3) onto E (EIgMC) were ingested by thioglycolate-elicited and lymphokine-treated macrophages, but not by the other macrophage populations examined. However, none of the macrophages performed lysis of EIgMC, suggesting that engagement of macrophage C3 receptors by target cell-bound C3 was not a sufficient trigger for cytolysis. Lysis of E coated with both IgG and C3 (EIgGC) was moderately elevated over that of EIgG; this enhancement was not abolished after proteolytic destruction of the macrophage C3-rosetting capacity, indicating that C3 receptors were not responsible. EIgGC and EIgMC were more susceptible to hypotonic lysis than were either E, EIgG, or EIgM, suggesting that enhanced lysis of serum-treated E may be partially explained by increased E fragility.

Animals↗
PubMed1984

A human lymphokine activates macrophage C3 receptors for phagocytosis: studies using monoclonal anti-lymphokine antibodies.

We have identified a human T lymphocyte cell line, the Mo line, that constitutively elaborates a lymphokine that activates macrophage receptors for the third complement component (C3) for phagocytosis. The molecule is physically, functionally, and immunologically very similar, if not identical, to a previously characterized murine lymphokine. Both molecules were inactivated by the same physical and chemical treatments, activated macrophage C3 receptors for phagocytosis, and freed macrophage C3 receptors to move within the cell's plasma membrane. In addition, both the human and the murine products were recognized by the same monoclonal antibodies. Treatment with monoclonal antibodies abolished both the ability of lymphokine-containing supernatants to mobilize macrophage C3 receptors and the supernatants' ability to activate C3 receptor-mediated phagocytosis. The dose-response curves for both effects of the antibodies were identical, strongly suggesting that a single molecule was responsible for both effects and that the lymphokine activated marophage C3 receptors for phagocytosis by freeing the anchored receptors and allowing them to diffuse within the cell's plasma membrane. These findings strengthen the hypothesis that, for a receptor to promote phagocytosis, it must be able to diffuse within the macrophage plasma membrane.

Animals↗
PubMed1984

Activation of macrophage complement receptors for phagocytosis.

Macrophage complement receptors, while innately incapable of promoting phagocytosis, can be activated to do so by a number of inflammatory stimuli and by several immunologic mechanisms. Studies with a complement receptor-activating lymphokine reveal that activation occurs as a result of mobilization of innately immobile receptors and suggest that receptor mobility is a prerequisite for phagocytosis. Since Fc receptors are susceptible to blockade by immune complexes at inflammatory sites, phagocytosis mediated by macrophage complement receptors may be of prime importance in vivo.

Animals↗
PubMed1984

Disseminated histoplasmosis in patients with the acquired immune deficiency syndrome.

The ongoing epidemic of acquired immune deficiency syndrome (AIDS) has affected homosexual men, intravenous (IV) drug abusers, Haitians, hemophiliacs, and others. Defects in cell-mediated immunity place these patients at risk for opportunistic infections. We recently saw three men from Alabama with disseminated infection due to Histoplasma capsulatum. Two of these men were homosexual and the other was an IV drug abuser. These three patients had evidence of depressed cellular immunity consistent with a diagnosis of AIDS. Infection caused by organisms indigenous to certain geographic areas of the United States may become more common in patients with AIDS as the epidemic continues.

Acquired Immunodeficiency Syndrome↗
PubMed1982

Thioglycollate-elicited mouse peritoneal macrophages are less efficient than resident macrophages in antibody-dependent cell-mediated cytolysis.

Peritoneal macrophages (M phi) obtained after i.p. injection of Brewer thioglycollate medium (TG) were substantially less efficient than resident (R) M phi in an assay of antibody-dependent cell-mediated cytolysis (ADCC) in which 51Cr-labeled sheep erythrocytes were used as target cells. The TG-M phi did not display any generalized functional defects, and indeed were "activated" relative to R-M phi by several morphologic, biochemical, and functional criteria. The ADCC deficiency was observed with TG-M phi from four strains of mice, and was not altered by the use of different types of target cells or different sensitizing IgG antibodies. Treatments that significantly enhanced R-M phi ADCC activity, either inhibition of phagocytosis by tosyl lysine chloromethyl ketone or stimulation of M phi enzyme secretion and O2- production, resulted in only a modest enhancement of TG-M phi ADCC. The effect of i.p. TG injection on M phi ADCC activity was not mimicked by in vitro exposure of R-M phi to TG. In vivo experiments demonstrated that agar, a component of TG, was sufficient to elicit M phi that resembled TG-M phi morphologically and functionally. We discuss the possibility that the ADCC deficiency of TG-M phi may be a characteristic of cells involved in the subsidence of an acute inflammatory response.

Animals↗
PubMed1981

Augmentation of macrophage complement receptor function in vitro. III. C3b receptors that promote phagocytosis migrate within the plane of the macrophage plasma membrane.

We have previously reported that treatment with a unique lymphokine enables resident mouse peritoneal macrophages to phagocytize via their complement receptors and we have presented evidence that the lymphokine act by enabling complement receptor engagement by C3b ligands to generate a phagocytic signal, thereby linking the cell surface binding event with the intracellular phagocytic machinery. In the present experiments, we used immobilized immune complexes to study the topography of C3b receptors of resident mouse peritoneal macrophages treated with the lymphokine. Our results indicate that lymphokine treatment enables the macrophages' C3b receptors to migrate within the plane of the cells' plasma membrane and that manipulations of macrophages that abrogate one response to the lymphokine, complement receptor mobility, also abrogate the other response, complement receptor-mediated phagocytosis. These findings strongly suggest that lateral mobility of a ligand-bound receptor within the macrophage plasma membrane is an essential component of the phagocytic signal. Moreover, our results indicate that the difference in complement receptor function among various populations of macrophages is not due to the expression of different types of complement receptors by the different macrophage populations but rather to a difference in the relationship of the C3b receptor with other plasma membrane or intracellular components.

Antigen-Antibody Complex↗
PubMed1981

Phagocytosis requires repeated triggering of macrophage phagocytic receptors during particle ingestion.

The phagocytic functions of polymorphonuclear leukocytes and mononuclear phagocytes are crucial elements in host defence against a variety of invading microorganisms. Phagocytosis is a highly selective process, requiring specific interactions between the surface of the particle to be ingested and the plasma membrane of the phagocytic cell. The phagocyte can therefore discriminate between 'ingestible' and 'non-ingestible' particles even when the different particles are located in close proximity on the plasma membrane of the phagocytic cell. Previous work has demonstrated that these specific interactions between particle and phagocyte are required not only for the initiation of phagocytosis--that is, attachment of the particle to the phagocytic cells and generation of a signal to trigger phagocyte pseudopod extension--but also for the subsequent progression of pseudopods over the entire surface of the particle. We present evidence here that the continued interactions between phagocyte plasma membrane receptors and particle-bound ligands do not function merely to direct otherwise random phagocyte pseudopod movement, but instead are required for the repeated generation of intracellular phagocytic signals during the entire ingestion process.

Animals↗
PubMed1981

Roles of macrophage Fc and C3b receptors in phagocytosis of immunologically coated Cryptococcus neoformans.

I have studied the roles of macrophage Fc and C3b receptors in the cell's interaction with encapsulated Cryptococcus neoformans and have defined the effects of a lymphokine that enhances macrophage complement receptor function, the effects of ingestion of soluble immune complexes, and the effects of corticosteroid treatment upon the ability of macrophages to phagocytize cryptococci via these receptors. Neither uncoated nor C3-coated cryptococci were phagocytized, whereas IgG-coated cryptococci were avidly phagocytized by mouse peritoneal macrophages. Treatment of macrophages with the lymphokine enabled them to ingest C3-coated cryptococci. Prior ingestion of soluble immune complexes severely compromised macrophages' ability to phagocytize cryptococci via their Fc receptors but did not affect their ability to ingest cryptococci via their complement receptors. Corticosteroid treatment severely impaired the ability of macrophages to respond to the lymphokine. Based upon these experimental observations, I have constructed a model for normal host defense mechanisms against disease due to C. neoformans.

Animals↗
PubMed1981

Kinetics of phototoxicity of Fischer's medium for L5178Y leukemic cells.

The uncontrolled exposure of Fischer's medium to cool white fluorescent (CWF) light or other sources emitting near-ultraviolet or visible light absorbance by riboflavin is a crucial random variable in experiments which utilize L5178Y cells and this medium. The radiation effects of CWF light result in the rapid development of toxic photoproducts in the medium which are cytostatic at lower doses of radiation and cytotoxic at higher doses. After a 24-hr suspension in medium irradiated for 3 or 48 hr, the cloning efficiencies of cells subsequently plated in light-protected medium were 87 and 3%, respectively. The corresponding near-ultraviolet doses for these periods of exposure to CWF light were 0.22 x 10(4) for a 3-hr exposure and 3.47 x 10(4) J/sq m for a 48-hr exposure. Cells incubated in lightly irradiated medium resumed growth at nearly normal rates following a 24- to 48-hr period in which no increase in cell numbers occurred. Exposure of medium containing riboflavin, but not tryptophan or tyrosine, to CWF light also produces toxic medium. Tryptophan enhances riboflavin-induced phototoxicity, whereas tyrosine diminishes this effect. As photosusceptibility of this system is very high, Fischer's medium must be fully protected from all sources of light absorbable by riboflavin.

Animals↗
PubMed1980

Effects of soluble immune complexes on Fc receptor- and C3b receptor-mediated phagocytosis by macrophages.

The effects of ingestion of soluble immune complexes upon macrophage phagocytic function was studied. Ingestion of immune complexes severely impaired the macrophage's ability to ingest IgG-coated particles but did not alter its ability to interact with particles by means other than its Fc receptors. Treatment of macrophages that had ingested immune complexes with supernates containing the previously described lymphokine that augments macrophage complement receptor function failed to enhance the cells' interaction with either IgG-coated erythrocytes or zymosan particles but markedly enhanced their ability to phagocytize via their complement receptors. The possible significance of these findings in immunologically mediated inflammation is discussed.

Animals↗
PubMed1980

Sodium azide inhibition of complement-mediated functions.

Moderate concentrations of sodium azide (0.1-0.2%) significantly inhibited guinea-pig and human complement-mediated lysis of both IgM- and IgG-sensitized sheep erythrocytes. The reduction in cytolysis was not attributable to non-specific ionic effects, to inactivation of native complement components by azide, or to irreversible interactions of azide with sensitized erythrocytes. Mouse complement-dependent opsonization of sensitized erythrocytes, as judged by macrophage complement receptor-mediated attachment and phagocytosis of the erythrocytes, was comparably inhibited by sodium azide, suggesting that azide acted within the sequence of the first four components of the classical complement pathway.

Animals↗