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Biomedical subjects

L Weiss

Publications and source records attributed to L Weiss.

At least 37 records · Page 2Linked to original sources
PubMed1992

Immunotherapy of minimal residual disease in conjunction with autologous and allogeneic bone marrow transplantation (BMT).

Recent investigations in animal models of human lymphoid and myeloid leukemia suggest that induction of immune-mediated antitumor effects is feasible at the stage of minimal residual disease (MRD) using allogeneic immunocompetent lymphocytes following initial reconstitution with T cell depletion and/or activation of reconstituting syngeneic or allogeneic immune cells by recombinant interleukin-2 (rIL2). Pilot clinical trials in patients with leukemias and lymphomas at high risk to relapse following autologous bone marrow transplantation (BMT) suggest that beneficial antitumor effects may be achieved at the stage of MRD by home immunotherapy as soon as hematopoietic reconstitution occurs using rIL2 (Cetus) and alpha interferon (Roferon A) (Hoffmann LaRoche). Although results obtained from our open trial seem encouraging, prospective randomized trials and longer observation periods are needed in order to confirm immune-mediated antitumor effects in conjunction with autologous BMT in patients with malignant hematological disorders at high risk to relapse. Likewise, it seems that amplification of anti-leukemia effects following allogeneic BMT is feasible by post-transplant infusion of donor's peripheral blood lymphocytes for prevention and/or treatment of relapse.

Adolescent↗
PubMed1992

Radiosensitivity and responsiveness to recombinant interleukin-2 of effector cells of graft vs. host disease and mixed lymphocyte reaction in mice.

Synergistic effects of recombinant interleukin-2 (IL-2) or irradiated spleen cells were investigated in vivo and in vitro. Irradiated (750 cGy) C57BL/6 spleen cells infused to sublethally irradiated (500 cGy) BALB/c mice treated with IL-2 (1,000 U 3 times/day) caused graft vs. host-like disease (GVHD) in 3 of 11 mice. Similarly irradiated allogenic spleen cells caused no GVHD in irradiated recipients not administered IL-2. No sign of autologous GVHD was found in mice that received irradiated syngeneic spleen cells with IL-2. Addition of recombinant IL-2 in vitro to mixed lymphocyte reactions (MLR) using irradiated (500 cGy) allogeneic responder spleen cells augmented the 3H-TdR uptake fourfold compared to cultures without IL-2, but was 44-fold below the allogeneic response of nonirradiated C57BL/6 spleen cells. Il-2-induced cell proliferation was also noted in syngeneic MLR, but did not lead to GVHD in in vivo experiments. The data suggest that IL-2 may potentiate GVHD and alloreactivity induced by an adequate number of irradiated, nondividing but viable allogeneic spleen cells and/or that secretion of IL-2 by alloactivated T lymphocytes, supplied exogenously in the present study, may play a role in the GVHD syndrome. Since neither viable but nonreplicating T cells nor IL-2 alone caused GVHD, it is suggested that endogenously produced IL-2 by alloactivated T lymphocytes may be important in the development of the GVHD syndrome, independent of its main function of enhancing T lymphocyte proliferation. On the other hand, the lack of GVHD following administration of high numbers of irradiated or nonirradiated syngeneic spleen cells with IL-2 implies that allogeneic T lymphocytes and not IL-2 activated MHC-nonrestricted cytotoxic cells play a role in inducing the GVHD syndrome in vivo.

Animals↗
PubMed1992

The role of recombinant cytokines and other immunomodulators on engraftment following allogeneic bone marrow transplantation in mice.

BALB/c mice were conditioned by total body irradiation (TBI) with a suboptimal (475 cGy) or optimal (600 cGy) radiation dose for induction of chimerism subsequent to administration of 10(7) (BALB/c x C57BL/6) F1 (F1) bone marrow cells in order to test whether a variety of recombinant cytokines and other immunomodulators caused positive or negative effects on engraftment at different time intervals post-bone marrow transplantation (BMT). Engraftment in recipient mice conditioned by the minimal dose of TBI permitting 100% induction of chimerism (600 cGy) was not impaired following treatment with recombinant human interleukin 2 (IL2) (10(4) Cetus Units x 3/day i.p.), alpha interferon (alpha IFN) (10(4) units/day i.p.), gamma interferon (gamma IFN) (10(4) U/day i.p.) and combinations of IL2 + alpha IFN as well as IL2 + gamma IFN given either 5 days prior to or 5 days following BMT. Likewise, neither PGE2 (50 micrograms x 2/day i.p.) nor indomethacin (25 micrograms x 2/day i.p.) given either immediately prior to or immediately following BMT for 3 consecutive days had any detectable effect on chimerism. To investigate the putative beneficial effects of IL2 in enhancing marrow engraftment, BALB/c mice were irradiated with a suboptimal dose of TBI (475 cGy) followed by reconstitution with 10(7) F1 marrow cells supplemented with 2 x 10(6) F1 spleen cells. IL2 (10(4) U x 3/day i.p. x 5 days) was administered either prior to TBI, between TBI and BMT, immediately following BMT, or starting 2 weeks post-BMT.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Barrier cells: stromal regulation of hematopoiesis and blood cell release in normal and stressed murine bone marrow.

Murine hematopoietic bone marrow is heterogenous in respect to bone-lining cells, hematopoiesis, and release of blood cells. In diaphyseal femoral marrow, bone-lining cells are largely osteoblasts, indifferent endosteum, blood cells, and reticular cells. Hematopoiesis is sustained by rather differentiated progenitors, as myelocytes and polychromatophilic erythroblasts. But in sharply restricted loci within trabeculated bone in the distal medial femoral metaphysis, bone-lining cells are dominated by newly discovered fibroblastic, contractile, stromal barrier cells; activated, multilaminar and branched, enveloping putative stem cells; and extending into the marrow, where they enclose hematopoietic clusters of rather early progenitors, as promyelocytes; and basophilic erythroblasts. Barrier cells may endocytize granules released individually by vicinal differentiating granulocytes, preventing tissue damage. Barrier cells envelope blood vessels and insinuate processes into their wall, augmenting blood-marrow barriers, preventing release of immature cells. Further, extensions of venous sinuses made of extraordinarily thin barrier cell processes receive released blood cells. With heightened hematopoiesis due to mutant hemolytic anemias or after administration of interleukin-1, barrier cells and their associated structures are greatly increased, spreading beyond normally restricted loci. But in microenvironment-deficient mutants, barrier cells are fewer, less activated, and less granulated. Barrier cells thus appear important in hematopoiesis and in the release of blood cells from bone marrow.

Animals↗
PubMed1991

Comparative study of in vitro inhibition of activation of the classical and alternative pathways of human complement by the magnesium and sodium salts of the anti-inflammatory peptide N-acetyl-aspartyl-glutamic acid (NAAGA).

The inhibitory activity of the sodium salt of the anti-inflammatory peptide N-acetyl-aspartyl-glutamic acid (NAAGA) on activation of the classical and alternative pathways of human complement was compared with that of the clinically used magnesium salt of NAAGA (NAAGA-Mg). Sodium salt of NAAGA (NAAGA-Na) inhibited both pathways of activation in a dose-dependent manner at concentration ranging from 1 to 10 mM by acting on formation and/or function of the C3 convertases as shown by the inhibitory capacity of the peptide on the release of the C3 cleavage fragment C3b and C3a. NAAGA-Na was as effective as NAAGA-Mg in inhibiting classical pathway activation at concentration above 10 mM. NAAGA-Na was more effective than NAAGA-Mg in inhibiting the alternative pathway since the sodium salt did not interfere with Mg-dependent formation of the alternative pathway C3 convertase.

Animals↗
PubMed1991

Deformation-driven, lethal damage to cancer cells. Its contribution to metastatic inefficiency.

Direct and indirect, in vivo and in vitro observations are in accord with the hypothesis that as a consequence of their deformation within capillaries, cancer cells undergo sphere-to-cylinder shape-transformations that create a demand for increased surface area. When this demand cannot be met by apparent increases in surface area accomplished by nonlethal, surface "unfolding," the cell surface membrane is stretched; if expansion results in more than a 4% increase in true surface area, the membrane ruptures, resulting in cancer cell death. It is suggested that this deformation-driven process is an important factor in accounting for the rapid death of circulating cancer cells that have been trapped in the microvasculature. Therefore, this mechanism is thought to make a significant contribution to metastatic inefficiency by acting as a potent rate-regulator for hematogenous metastasis.

Animals↗
PubMed1991

Effects of doxorubicin on the sensitivity of L1210 leukemia cells to deformation-associated trauma.

Most of the cancer cells arrested in the microcirculation during hematogenous metastasis are rapidly killed; one major mechanism is surface-membrane rupture, associated with the mechanical deformation of cancer cells in capillaries. The feasibility of increasing the susceptibility of cancer cells to lethal, deformation-associated trauma by doxorubicin, was tested in an in vitro mechanical model system, by filtering suspensions of L1210 leukemia cells through 8-microns pore-size Nuclepore membranes, with or without prior incubation with 10(-7)M doxorubicin. The results showed that mechanically-induced loss of cancer cells immediately after filtration was increased from 18 to 55% in cells previously exposed to doxorubicin for 48 h. The results indicate the feasibility of chemotherapeutic enhancement of the mechanical killing-action of the microvasculature as a potential rate-regulator of hematogenous metastasis.

Animals↗
PubMed1991

Myocardial beta-adrenergic adenylate cyclase complex in a canine model of chagasic cardiomyopathy.

Infection of beagles with an opossum-derived strain of Trypanosoma cruzi (Tc-O) results in features of early and chronic chagasic cardiomyopathy, that is, increases in PR interval, atrioventricular block, and frequent ventricular premature contractions, ventricular tachycardia, and decreased left ventricular ejection fraction. These signs are not observed in animals infected with a canine strain of T. cruzi (Tc-D). To understand the biochemical basis for these early cardiac effects, we examined the beta-adrenergic adenylate cyclase complex in myocardial membranes prepared from animals infected with either of the two strains. In animals infected with Tc-O (symptomatic), the maximum velocity (Vmax) decreased and concentration of agonist resulting in 50% of Vmax (Kact) increased for isoproterenol-dependent adenylate cyclase activity; in animals infected with Tc-D (asymptomatic), Vmax and Kact for isoproterenol were unchanged from control, uninfected animals. beta-Receptor density decreased by 20% in symptomatic animals with no change in affinity, whereas no differences were observed between uninfected and infected asymptomatic animals. A complex pattern of changes was apparent in the guanine nucleotide binding protein, Gs, in the setting of infection. Alterations in cholera toxin-dependent ADP-ribosylation patterns as well as immunochemical detection with anti-G alpha s antisera suggested a change in the biochemical nature of the Gs species and not necessarily a physical loss of this protein. Reconstitution of adenylate cyclase activity in cyc- membranes demonstrated a decrease in hormone-sensitive Gs activity in membranes prepared from symptomatic animals without a change in activity demonstrable in the presence of Gpp(NH)p. Collectively, the results suggest that the depression in beta-adrenergic adenylate cyclase activity associated with symptomatic infection of beagles with T. cruzi occurs primarily as a result of changes in the Gs protein complex, most likely resulting in an uncoupling of the beta-adrenergic receptor from the Gs protein.

Adenosine Diphosphate Ribose↗
PubMed1991

The effect of total or partial T lymphocyte depletion on susceptibility to influenza virus infection and development of antiviral immunity in lethally irradiated mice reconstituted with immune syngeneic bone marrow grafts.

In a previous study, we showed that lethally irradiated mice reconstituted with bone marrow (BM) enriched with spleen cells obtained from A/PR8/34 influenza virus-immune donors had an improved survival rate compared to the survival seen in recipients of naive BM, immune BM or T cell-depleted BM obtained from immune mice. Our purpose was to determine which cell population was responsible for this effect. We therefore compared the resistance to influenza virus of lethally irradiated BALB/c mice reconstituted with BM from immune donors enriched with 20% spleen cells following either incubation with anti-Thy-1, anti-Lyt-2 or anti-L3T4 monoclonal antibodies prior to transplantation, thereby leading to in vivo depletion of antibody-treated lymphocyte subsets. Mice were infected with influenza virus 1 day after BM transplantation. Equal survival rates were observed in recipients of unmanipulated BM and spleen cells obtained from immune donors and recipients of similar inocula treated with monoclonal anti-helper (L3T4) or anti-cytotoxic/suppressor (Lyt-2) antibodies prior to inoculation. The survival rate of all these groups was increased in comparison with mice receiving anti-Thy-1 treated BM and spleen cells, suggesting that both L3T4 and Lyt-2 T cell subsets play a role in protection against virus infections.

Animals↗
PubMed1991

Effects of cytoskeletal perturbation on the sensitivity of Ehrlich ascites tumor cell surface membranes to mechanical trauma.

Evidence presented previously indicated that shape changes in circulating cancer cells within the microvasculature may lead to rapid, lethal rupture of the cell surface membranes, thereby contributing to the inefficiency of this phase of hematogenous metastasis. As the cytoskeleton is known to regulate cell shape and, in at least some cases, to be attached to the surface membrane, we have determined whether or not it plays a role in inhibiting lethal, deformation-associated, mechanically induced surface membrane trauma. Thus, Ehrlich ascites tumor (EAT) cells were treated with different cytoskeleton-perturbing agents, and their susceptibility to filtration trauma on passage through Nuclepore membranes was determined. In contrast to the involvement of the cytoskeleton in nonlethal cell deformation, agents which disrupt intracellular networks of microtubules, microfilaments and intermediate filaments had little or no direct effect on EAT cell susceptibility to rapid, mechanically induced, lethal trauma.

Acrylamide↗
PubMed1991

[Structure and function of receptors for C3 cleavage fragments].

Most of the biological effects derived from complement activation depends on interactions between cleavage fragments of complement components and cells bearing specific receptors. This review overviews structure and function of receptors for C3 cleavage fragments. Genes encoding for CR1, CR2 and CR3 have been cloned and they code for integral transmembrane glycoproteins which function as cellular receptors for human C3b, C3dg/C3d and C3bi fragments respectively. These receptors have a wide cellular distribution and participate in transport of immune complexes, phagocytosis and regulation of immune response. Alterations of expression of these molecules are observed in pathology.

Complement C3↗
PubMed1990

Quantitation of endogenous lectin expression in 3LL tumors, growing subcutaneously and in the kidneys of mice.

By means of microdensitometry and image analysis, quantitative measurements were compared of endogenous lectin expression in tissue sections from 3LL carcinomas growing in the subcutis and kidneys of mice following the direct injection of cancer cells. The lectins were visualized by means of a modification of the ABC-peroxidase technique. In comparison with the subjective, visual inspection of similar materials reported previously, these quantitative techniques not only confirmed, but also provided additional information on site-associated changes in 3LL cell populations. Previously, 2 classes of cancer cells were recognized within the tumors on the basis of staining intensity, compared with 3 classes in the present study and, in addition, the relative areas occupied by these 3 densitometric classes were determined by image-analysis. Both "low" and "high" integrated intensities were significantly greater in the kidney tumors in 11 of 24 cases, and in 6 of 24 cases of s.c. tumors. The areas occupied by "high" and "low" intensity cells were significantly higher in 14 of 24 kidney tumors, and in 2 of 24 s.c. tumors. The results indicate often marked differences in endogenous lectin expression, between 3LL cancer cells from a common source, after direct delivery and growth in 2 different anatomic sites. These results indicate the necessity of taking into account analogous changes, when comparing these and other properties of cancer cell populations in metastases with those in primary tumors, with respect to both the generation of site-associated differences and their possible site-associated abrogation.

Animals↗
PubMed1990

Induction of cell-associated interleukin 1 through stimulation of the adhesion-promoting proteins LFA-1 (CD11a/CD18) and CR3 (CD11b/CD18) of human monocytes.

Serum-free culture of human monocytes in the presence of monoclonal antibodies to the LFA-1 alpha chain (CD11a), CR3 alpha chain (CD11b) or beta chain (CD18) bound to Sepharose induced the dose-dependent production of cell-associated interleukin (IL) 1 activity and of IL 1 alpha and IL 1 beta antigens, but no release of extracellular IL 1 activity or antigen in the culture medium. Triggering of IL 1 production was also observed with insolubilized anti-CD11/CD18 F(ab')2 antibodies. Two cross-linked antibodies recognizing distinct epitopes on the CD11b molecule induced cell-associated IL 1. Soluble antibodies did not induce IL 1 production. The kinetics of induction of IL 1 by stimulation of adhesion-promoting proteins differed from those of IL 1 induction by adhesion to plastic. The lack of induction of IL 1 release by stimulation of the CD11/CD18 molecules resembled the intracellular accumulation of IL 1 induced by lipid A. Induction of IL 1 by adhesive processes may be a mechanism by which T cells trigger IL 1 production by monocytes during antigen presentation.

Antigens, Differentiation↗
PubMed1990

Extracellular matrix derived from Trypanosoma cruzi infected endothelial cells directs phenotypic expression.

Infection of confluent human umbilical vein endothelial cells by the parasite Trypanosoma cruzi results in the appearance of an altered heparan sulfate proteoglycan (HSPG) isolated from the extracellular matrix of infected endothelial cells (ECMi). HSPG from ECMi differed from HSPG obtained from the extracellular matrix of uninfected endothelial cells (ECMu) by virtue of an 8-10-fold increase in sulfation and a different elution pattern using DEAE Sepharose chromatography. Analysis of the HSPG that binds to acidic fibroblast growth factor (aFGF) revealed that infection increased the proportion of HSPG that binds to aFGF by 35%. Heparitinase and alkaline borohydride treatment of aFGF-binding HSPG and chromatographic resolution on Sepharose CL4B column revealed an infection-associated 10-fold increase in sulfation of the GAG side chain with no significant change in the migration of the core protein. In addition, the aFGF binding HSPG isolated from ECMi demonstrated a markedly attenuated synergistic mitogenic activity with aFGF in a cell proliferation assay. All of the infection associated changes in HSPG could be demonstrated in HSPG obtained from uninfected endothelial cell cultures grown on ECMi. Hence, the ECMi is associated with signals capable of modulating the ECM associated metabolism of uninfected endothelial cells. This facility of ECMi was also shown to extend to patterns of Gs protein synthesis as revealed by Western blot analysis. The observation that the ECM produced by infected endothelial cells can direct the synthetic patterns of uninfected endothelial cells in a manner uniquely observed in infected endothelial cells suggests a plausible pathway by which infection of only a few cells can ultimately result in the coordinate responses of neighboring uninfected cells.

Chagas Disease↗
PubMed1990

Mechanisms for the biomechanical destruction of L1210 leukemia cells: a rate regulator for metastasis.

Mechanical trauma appears to be one significant cause of the rapid intravascular death of cancer cells and, as such, could act as an important rate regulator for the metastatic process. Intravascular mechanical trauma to cancer cells is thought to be a consequence of shape transitions, occurring when they are deformed from spherical shape by entry into, and passage along, capillaries having smaller diameters than themselves. These transitions from spherical shape require increases in surface area; first, an apparent increase in surface area is accomplished by a reversible, nonlethal surface membrane unfolding. If this is insufficient to meet geometric demands, it is followed by a true increase in surface area, resulting in increased tension in the cancer cell surface membrane, leading to its lethal rupture.

Animals↗
PubMed1979

Contribution of macrophages to interactions between tumor cells and other tissues assessed in an in vitro system.

The modification of the tissues surrounding solid tumors is usually attributed exclusively to interactions between the normal tissues and the cancer cells in the tumor, in spite of the fact that tumors contain many different types of non-cancer cells including macrophages. As an experimental model for some facets of the cellular interactions between tumor and normal tissues, we have assessed the individual contributions of macrophages and cancer cells to the differential inhibition of neural retina (NR) cell aggregation by co-culturing NR cells with small numbers of macrophages or cancer cells alone, as well as with both natural (ascites tumors) and artificial mixtures. Cells from human colonic adenocarcinoma inhibited NR aggregation to a greater extent than normal colon mucosa. Aggregation of NR cells was inhibited by macrophages from mice and rats, and to a greater extent by cancer cell suspensions of mouse Ehrlich and rat Walker 256 lines from spinner culture or in the ascites form. Combinations of macrophages and cancer cells indicated that their inhibitory effects were neither additive nor synergistic. Cell-free media from macrophages and cancer cell cultures were equally effective inhibitors of aggregation. The results suggest that the interaction between a malignant tumor and the surrounding normal tissue can be modified by cancer cells, tumor macrophages and their products.

Adenocarcinoma↗