Search PubMed⌕ Search

Biomedical subjects

S W Russell

Publications and source records attributed to S W Russell.

At least 91 records · Page 5Linked to original sources
PubMed1979

Macrophage-mediated tumor cell killing: lack of dependence on the cyclooxygenase pathway of prostaglandin synthesis.

M phi obtained directly from disaggregated murine Moloney sarcomas produced PGE2 and a hydroxy fatty acid derivative as the major products of arachidonic acid metabolism. M phi-immunoreactive PGE synthetic rates decreased substantially and cytotoxic activity was lost when freshly explanted tumor M phi were held in culture 24 hr. Such cultured M phi remained in a partially activated "primed" state, however, wherein the addition of minute (ng) amounts of bacterial lipopolysaccharide (LPS) returned cytolytic activity and PGE synthesis to original levels. Indomethacin-induced blockade of the M phi cyclooxygenase pathway inhibited PG synthesis by LPS-stimulated, primed M phi without affecting the return of cytolytic activity. We conclude, therefore, that the production of PG had no direct role in the mediation of tumor cell killing by activated M phi isolated from these neoplasms.

Animals↗
PubMed1978

B-tropic oncornavirus production by BALB/c methylcholanthrene-induced sarcoma cells.

Six oncogenic cell lines were established from primary sarcomas that had been induced in thymectomized, aged, BALB/cSt mice by the injection of 3-methylcholanthrene. Of these lines, three produced B-tropic murine leukemia virus (MuLV), i.e. MuLV that would patently infect fibroblasts of BALB/c origin but not those from NIH Swiss mice. One of these lines, M-138, produced large quantities of virus, permitting the isolation of milligram quantities of B-tropic MuLV. Neonatal BALB/c mice injected with the M-138 MuLV developed high plasma levels of the species-specific virion antigen p30, but during 9 months of observation failed to manifest clinical signs of leukemia. Plasma p30 levels of NIH Swiss mice (non-permissive host) that were inoculated also as neonates with the same virus preparation, remained undetectable by radioimmunoassay. Xenotropic MuLV, i.e. that which infects cells of species other than the species of origin, was released by one of the three remaining cell lines. Two of the six original lines have remained free of detectable oncornavirus production. Our results suggest that cell lines that are stable sources of large quantities of B-tropic MuLV may be easily obtainable by the described manipulations. Equally important, however, is the fact that these data re-emphasize the danger that is inherent in assuming that a cell line is virus-free simply because it was isolated from a chemical carcinogen-induced neoplasm

Animals↗
PubMed1978

Development and persistence of cytolytic T lymphocytes in regressing or progressing Moloney sarcomas.

Intratumoral T lymphocytes were recovered sequentially after induction of regressing or progressing Moloney sarcomas in BALB/c mice and were assayed quantitatively for their ability to kill specifically the tumor (MSC) cells used for induction. The cytolytic activities of the two lymphocyte populations described two distinct biphasic kinetic profiles that were similar in amplitude and duration but separated from each other by 4-6 days. In progressing neoplasm, there was a rapidly occuring accumulation of T lymphocytes highly cytolytic for MSC cells. This response, however, was not sustained and disappeared in association with the onset of unchecked tumor growth. In contrast, T lymphocyte cytolytic activity developed more slowly in regressing sarcomas and attained peak levels coincident with the beginning of tumor regression. Similar changes in cytolytic activity characterized T lymphocytes in lymph nodes draining tumors. When cultured in vitro for 4 days, non-cytotoxic T lymphocytes from regional lymph nodes draining progressing sarcomas regained very high levels of cytolytic activity. Such restitution was diminished, however, if MSC cell lysates, macrophages or macrophages fed MSC cell lysates were present during the culture period. These experiments provided presumptive evidence that T lymphocyte-mediated cytolytic activity was lost in progressively growing Moloney sarcomas as a consequence of suppression in vivo of the genesis and/or functional expression of cytolytic T lymphocytes, perhaps by macrophages and/or soluble tumor antigen.

Animals↗
PubMed1978

Resurgence of killing and in vivo protection mediated by lymphocytes cultured from lymph nodes draining Moloney sarcomas.

We have previously documented the development and subsequent disappearance of cytolytic activity mediated by lymphocytes from lymph nodes draining Moloney sarcomas destined either to regress or grow progressively. We now report that these tumour-draining lymphnode cells (LNC) that were no longer cytotoxic, spontaneously regenerated peak levels of killing after culture in vitro for 4 days in the absence of exogenous tumour antigen. Cytolytic activity, which was antigenically specific, was mediated by T lymphocytes. Resurgence of cytolytic activity in vitro was accompanied by proliferative changes (DNA synthesis, blast transformation, cell division) which peaked on the 3rd day of culture. Although normal, nonimmune LNC underwent quantitatively similar proliferative changes in culture, the killing that developed was weak and antigenically nonspecific. Transfer of cultured, tumour-draining LNC to immunologically compromised, syngeneic mice conferred complete protection from Moloney sarcoma progression. Adoptive transfer could be delayed for 6 days after tumour induction without loss of protection. These results suggest that there exists in Moloney sarcoma-bearing mice a mechanism that limits the differentiation of pre-killer cells into cytolytically active T lymphocytes, and that such inhibition is eliminated when LNC are explanted into culture.

Animals↗
PubMed1977

Functional characterization of a stable, noncytolytic stage of macrophage activation in tumors.

The state in which macrophages (Mphi) from regressing Moloney sarcomas could kill tumor target cells was a highly labile one which decayed rapidly in vitro. Thereafter, regressor Mphi were noncytolytic. Mphi from several different progressing sarcomas failed to kill, even when challenged with target cells immediately after explantation. Similarly, thioglycollate-induced peritoneal Mphi (TG-Mphi) did not kill. Noncytolygic Mphi derived either from progressing sarcomas or from long-term (up to 96 h) cultures of regressor Mphi were exquisitely sensitive to stimulation by bacterial lipopolysaccharide (LPS); picogram/milliliter amounts induced killing. Similar concentrations of LPS had no demonstrable effect on TG-Mphi. Thus, tumor Mphi generally appeared to have been primed in vivo, with those in regressing sarcomas having additionally acquired cytolytic activity. Inability of progressor Mphi to kill apparently stemmed from lack of, or failure to respond to, the signal needed in vivo to trigger cytolytic activity, rather than the total absence of activation.

Cytotoxicity, Immunologic↗
PubMed1977

Isolation of T-lymphocytes from disaggregated tumors, with high purity and good percentage recovery.

A combination of two cell separation methods was utilized for the isolation of thymus-derived lymphocytes (TL) from enzymatically disaggregated tumors. Passage through Sephadex G-10-glass bead columns to remove adherent cell types followed by exposure to IgG-coated sheep red blood cell monolayers for removal of Fc receptor-bearing inflammatory cells provided functional TL suspensions of high purity with good percentage recovery.

Animals↗
PubMed1977

Inflammatory cells in solid murine neoplasms. IV. Cytolytic T lymphocytes isolated from regressing or progressing Moloney sarcomas.

Highly purified suspensions of intratumoral T lymphocytes, recovered 11 and 13 days after induction of regressing or progressing Moloney sarcomas, were compared in their ability to lyse specifically the MSC cells used for tumor induction. Cytolytic activity, expressed in terms of lytic units/10(6) T cells, was similar for intratumoral T cell suspensions obtained 11 days after induction of either regressing (3.1 +/- 1.3 LU/10(6) T cells) or progressing (4.3 +/- 1.8) neoplasms. By 13 days post-induction, regressing tumors contained T lymphocytes with an increased cytolytic activity (11.1 +/- 4.5) whereas those from progressing tumors were strikingly less able to kill MSC cells (less than or equal to 0.2). This dramatic loss in cytotoxicity could not be attributed to errors associated with the enzymatic disaggregation method, inhibition by copurified endogenous tumor cells, or immunosuppression induced by viral infection. The changes in functional activity of intratumoral T lymphocytes from the two types of sarcoma appeared to be correlated with the stage of neoplasia. In this model system, cytolytic activity of T lymphocytes increased during spontaneous tumor regression whereas losses in cytotoxicity occurred coincident with the onset of inexorable progression.

Animals↗
PubMed1977

Inflammatory cells in solid murine neoplasms. III. Cytotoxicity mediated in vitro by macrophages recovered from disaggregated regressing Moloney sarcomas.

Macrophages (Mphi) were recovered from disaggregated, spontaneously regressing Moloney sarcomas for in vitro testing of their cytotoxic capabilities. At a 3:1 ratio, Mphi in monolayers efficiently killed (51Cr release) a variety of tumor target cells without regard to antigenic specificity. Within 24 hr most of their cytolytic potential was lost. Killing could be restored, however, if Mphi were replated at higher cell densities. A soluble, heat-stable, dialyzable inhibitor of thymidine incorporation, which did not interfere with cellular proliferation, also was produced by Mphi recovered from Moloney sarcomas. The finding of such a competitive inhibitor, probably cold thymidine, in supernatants further opened to question the validity of radioisotope incorporation into DNA as a measure of Mphi-mediated cytostasis. The data presented suggest that Mphi may participate in the regression process by directly killing tumor cells, thus complementing the antigen-specific cytolytic capabilities of the T lymphocytes that are also found in large numbers within regressing Moloney sarcomas.

Animals↗
PubMed1976

Inflammatory cells in solid murine neoplasms. I. Tumor disaggregation and identification of constituent inflammatory cells.

Mechanical and enzymatic methods of disaggregating tumors were studied with the goals of (1) minimizing cell losses while (2) maintaining functional and surface membrane markers needed to objectively identify inflammatory cells (IC)1 in resultant suspensions. Application of the principles and methods described makes accurate estimation of the percentage of each IC type present in neoplasms possible for the first time. Compared to purely mechanical means of disaggregating tumors, all enzyme mixtures tested markedly increased yields of viable cells/g neoplasm. Best results were obtained with a combination of collagenase and a protease of broader substrate range (alpha chymotrypsin, papain, pronase or trypsin). The combination of enzymes that gave the highest yields with the least effect on inflammatory cell markers was trypsin, collagenase and DNAse (TCD). Because mechanical injury appeared to be the greatest single cause of cell loss (the enzymes themselves had little direct effect), potential sources were identified and either eliminated or minimized. With TCD, depending on the tumor system, cell recovery (measured as DNA recovered in cell suspensions) was as high as 50% and yields were as much as 6.9 X 10(8) viable cells/g tumor. Complete disaggregation was not required to obtain representative IC populations from tumor fragments. Neutrophils, eosinophils and mast cells from disaggregated neoplasms were counted in Giemsa stained cytocentrifuge preparations based on their unique morphologic appearances. Macrophages were identified by their capacity to phagocytose zymosan, a function which proved highly resistant to the effect of enzymes. Flourescent microscopic identification of brain associated thymus antigen (BATA) allowed quantification of T lymphocytes, since this marker was virtually unchanged by enzyme exposure. Surface immunoglobulin (Ig) was stripped from B lymphocytes most rapidly by pronase and chymotrypsin, slowly by trypsin and papain, and not at all by collagenase. Ig positive cells therefore could be quantified in suspensions generated by collagenase or very short (20 min) exposure of fragments to trypsin.

Animals↗
PubMed1976

Inflammatory cells in solid murine neoplasms. II. Cell types found throughout the course of Moloney sarcoma regression or progression.

Regressing and progressing Moloney sarcomas, induced in BALB/c mice by the injection of cultured sarcoma cells (MSC)1, were sampled for histologic analysis and then disaggregated using mixtures of trypsin, collagenase and DNAse or collagenase and DNAse alone. The types of inflammatory cells (IC) found in resultant cell suspensions were determined 6, 11, 14 and 18 days post inoculation. Inflammatory infiltrates were composed almost exclusively of three cell types; neutrophils, T lymphocytes and macrophages. The extent to which each was found in tumors was related to the time post inoculation. Neutrophils were part of an early acute inflammatory response seen in both developing regressing and progressing sarcomas. The onset of regression was associated histologically with the appearance within tumors of a mononuclear inflammatory infiltrate. T lymphocytes and macrophages were the principal constituents. A higher percentage of T lymphocytes was recovered at all sampling times from regressing, compared to progressing, sarcomas. During development of the mononuclear inflammatory infiltrate there were relatively more large T cells in regressing, than in progressing tumors, and the percentage of macrophages was higher. Thereafter, the proportion of macrophages in the recovered cell population was approximately the same for both types of tumor. Such equality was more apparent than real, however, since IC were restricted to the peripheries of progressing sarcomas after the acute inflammatory phase, but continued to be found throughout regressing neoplasms. The effective ratio of macrophages and T lymphocytes to tumor cells therefore was much lower in progressing sarcomas than was suggested by percentage figures. The data presented support the concept that T lymphocytes are instrumental in causing the regression of Moloney sarcomas, possibly through interactions with macrophages.

Animals↗
PubMed1972

Naturally occurring canine glomerulonephritis.

The 8 dogs with glomerulonephritis in this study had progressive renal disease characterized by proteinuria, azotemia and hypoalbuminemia, without peripheral edema and ascites. Observed by light, fluorescence and electron microscopy, the glomeruli were diffusely but irregularly involved. By light microscopy, there was focal mesangial proliferation, and the peripheral portions of many glomerular capillary loops were thickened by eosinophilic material along the endothelial sides of basement membranes. Immunofluorescence studies demonstrated granular deposits of IgG and beta1C-globulin outlining glomerular basement membranes and within the mesangium. Ultrastructurally, there were electron-dense deposits in the mesangium and within the endothelial side of glomerular basement membranes. Subepithelial deposits were never seen. The majority of clinical and morphologic features suggested a glomerulonephritis of immune-complex type. However, the unique aspects of the ultrastructural lesion precluded this assumption based solely on morphologic criteria.

Animals↗
PubMed1972

Cytolysis induced by human lymphotoxin.

By phase-contrast cinemicroscopy, highly purified human lymphotoxin induced two forms of cytolysis-one characterized by slow (1 to 2 hours) swelling (ballooning-type) and the other by sudden (3 to 5 minutes) shrinkage of the cell body and violent agitation of residual debris (popcorn-type). Specifically sensitized lymphocytes likewise caused both forms of lysis, morphologically indistinguishable from lymphotoxin-induced cytolysis. Lymphotoxin also inhibited cell division; mitoses diminished and virtually ceased before the onset of cytolysis. Many of the ultrastructural features preceding early lysis were similar to those associated with failure of osmoregulatory mechanisms-ie, condensation of mitochondria, dilation of rough-surfaced endoplasmic reticulum, separation of polysomes into individual units and expansion of the cell sap. After exposure to lymphotoxin for 12 hours or more, most remaining cells exhibited these same ultrastructural changes but lacked striking mitochondrial lesions.

Animals↗