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Biomedical subjects

M I Luster

Publications and source records attributed to M I Luster.

At least 163 records · Page 9Linked to original sources
PubMed1983

Selective immunosuppression resulting from exposure to the carcinogenic congener of benzopyrene in B6C3F1 mice.

B6C3F1 mice were exposed to two congeners of benzopyrene, either the carcinogen benzo(a)pyrene (B(a)P) or the non-carcinogen benzo(e)pyrene (B(e)P. Exposure of mice to B(a)P resulted in a reduced number of IgM and IgG antibody plaque forming cells (PFC) to the T-dependent (TD) antigen SRBC and IgM PFC's to the T-independent (TI) antigen LPS. The IgM response to hapten conjugated TI antigens was examined using TNP-LPS for reactivity of less mature B cells (B1) and TNP-Ficoll for more mature B cells (B2). Exposure to B(a)P severely depressed the TNP-Ficoll PFC response by up to 77% without altering the TNP-LPS response. These data indicated that exposure to B(a)P alters differentiation and antibody production in mature B cells to both TD and B2 TI antigens. No change in PFC was observed following exposure to B(e)P. Mishell-Dutton co-cultures confirmed that B cells were affected and that T helper cells or suppressor Mphi were not involved. Parameters of cell-mediated immunocompetence including delayed cutaneous hypersensitivity to KLH, allograft or tumour cell rejection and susceptibility to Listeria monocytogens were unaltered in B(a)P treated mice.

Animals↗
PubMed1983

Immunochemical evidence for two 3-methylcholanthrene-inducible forms of cytochrome P-448 in rat liver microsomes using a double-antibody radioimmunoassay procedure.

Double-antibody radioimmunoassay (RIA) procedures were developed for the determination of two forms of cytochrome P-448 in crude liver microsomes at the picogram level. The antisera used in the RIAs were produced against two forms of cytochrome P-448 isolated from livers of rats treated with 3,4,5,3',4',5'-hexachlorobiphenyl (3,4,5-HCB) and 3-methylcholanthrene (3-MC), referred to as cytochromes P-448HCB and P-448MC, respectively. The results obtained with RIA procedures were consistent with results of radial immunodiffusion analysis, sodium dodecyl sulfate/polyacrylamide gel electrophoresis, and estimation of aryl hydrocarbon hydroxylase (AHH) activity. Utilizing the RIAs, both forms of cytochrome P-448 were found in significant quantities in liver microsomes of rats treated with 3-MC, 3,4,5-HCB, isosafrole, and Aroclor 1254 but only in minute concentrations in untreated and phenobarbital-treated rats.

Animals↗
PubMed1982

Assessment of myelotoxicity caused by environmental chemicals.

Potential antineoplastic agents must be screened for the delayed toxicity that occurs in many cases of drug-induced bone marrow aplasia. In vitro clonal assays for hematopoietic progenitor cells have been developed to assess the degree of myelotoxicity. This adverse side effect is often the limiting factor in the development of new cancer chemotherapeutics. In addition, many environmental chemicals are cytotoxic to rapidly proliferating cells, but a systematic assessment of their myelotoxicity has not been performed. We have used clonal marrow assays to investigate a panel of chemicals including 2,3,7,8-tetrachlorodibenzo-p-dioxin, polybrominated biphenyls, diethylstilbestrol, benzo(a)pyrene and indomethacin. All were immunotoxic, some to pleuripotent hemopoetic stem cells and other to granulocyte-macrophage progenitors, and at concentrations below those causing other toxic manifestations. This shows that these bone marrow clonal assays, and hopefully future one for erythroid, B- and T-lymphocytes, and megakaryocytes, will provide the specificity and sensitivity necessary to delineate the myelotoxicity of a broad spectrum of environmental chemicals.

Animals↗
PubMed1982

Methods and approaches for assessing immunotoxicity: an overview.

The goals of the National Toxicology Program as they relate to immunological evaluation in toxicity assessment are discussed. The advantages of immune function assays for defining cellular injury as subtoxic levels following exposure to general or immunocyte specific chemical toxicants are proposed. A comprehensive screening panel of immune function and host resistance assays is presented in the context of an NIEHS approach for immunotoxicity assessment and methods selection. A second panel for defining the mechanism underlying immunological injury was also described. Studies utilizing these methods and approaches are described in companion papers by our group.

Drug Evaluation, Preclinical↗
PubMed1982

Cell-mediated immunity and its application in toxicology.

A variety of in vivo and more recently in vitro assays have been described to assess cell mediated immunity (CMI). Two methods routinely employed in our laboratory to assess CMI following exposure to chemicals in rodents include delayed hypersensitivity and in vitro lymphoproliferation. Preliminary studies indicate that depressed delayed hypersensitivity responses, as performed by a radiometric assay, correlates with altered susceptibility to infectious agents and tumor cell challenge following exposure to immunotoxic chemicals. Furthermore, suppression of T-cell lymphoproliferative responses to at least 50% below control values correlated with depressed delayed hypersensitivity responses and altered host susceptibility. On the other hand, when suppression of T-cell lymphoproliferative responses are within 50% of control values, delayed hypersensitivity and host susceptibility parameters are not affected. Assuming adequate technical expertise and accurate data interpretation, CMI assays of these types can provide a valuable data base for toxicology studies and immunotoxicity assessment.

Animals↗
PubMed1982

Application of tumor, bacterial and parasite susceptibility assays to study immune alterations induced by environmental chemicals.

Model systems to study the effects of chemicals of environmental concern on bacterial and parasitic diseases as well as the immunosurveillance and destruction of transplantable tumor cells were described and evaluated. Studies were conducted in female B6C3F1 mice following adult or pre/postnatal exposure to several prototype chemicals. The prototype chemicals employed included the synthetic estrogen diethylstilbestrol (DES), the polycyclic aromatic hydrocarbon benzo(a)pyrene (B[a]P), and the carcinogenesis promoting agent 12-0-tetradecanoyl-phorbol-13-0-acetate (TPA). The host resistance models employed depend primarily on functional thymus-dependent immunity, although humoral immunity is suggested to have a role in the parasite model as well. These models include: subcutaneous challenge with a dose of PYB6 tumor cell causing a 10-20% incidence (TD(10-20)) of tumor; intravenous challenge with B16 melanoma cells; challenge with a dose of Listeria monocytogenes causing a 10-20% incidence of mortality (LD(10-20)); challenge with a dose of E. coli lipopolysaccharide endotoxin causing a 10-20% incidence of lethality (LD(10-20)); and challenge with larvae of Trichinella spiralis for parasite expulsion kinetic studies. Increased mortality was observed following Listeria monocytogenes challenge in DES-exposed mice. B(a)P and TPA exposure did not alter host resistance to this organism. The increased mortality observed following DES was associated with a significant increase in the number of viable Listeria in the spleens and livers at 4 days, a time when T-cell immunity is thought to be expressed, but bacterial counts were similar to control mice at day 1, a time when MPhi are thought to exert their greatest effect. These data suggest that the increased Listeria susceptibility found following DES exposure may result from a T-cell defect, although the intracellular killing capacity of DES-treated Mvarphi's has not been well examined. Tumor susceptibility studies following challenge with 5 x 10(3) viable syngeneic PYB6 tumor cells revealed that nontreated adult B6C3F1 mice resisted tumor formation, with only a 10-20% incidence of tumor formation. In contrast, mice exposed to DES or TPA as adults had a tumor frequency of from 70-100% following TPA and up to 90% following DES exposure. In all cases the tumors were progressive and resulted in death. B(a)P did not alter the frequency of tumor incidence from controls in this model. Preliminary data, using the B16 melanoma intravenous challenge model and (125)IUdR to quantitate tumor mass revealed this model was sensitive to non-specifically activated macrophage kill. DES treated mice with activated macrophages did not demonstrate increased tumor mass, while mice exposed to TPA or the potent immunosuppressive agent cyclophosphamide had a significantly increased tumor mass in their lungs. Expulsion of Trichinella spiralis adults from the gut also apparently required functional T-cells and possibly some element of humoral immunity. Mice exposed to DES and B(a)P exhibited increased numbers of adult worms in the gut at day 14. Sensitivity to gram-negative endotoxin (LPS) was apparently increased following exposure to DES or B(a)P. These data suggest that the detoxification of LPS is related to an intact Mvarphi population. The data presented here demonstrate the sensitivity of the host resistance assay panel proposed for detecting immune alteration. Alteration of T-cell function appeared to correlate with increased susceptibility to bacterial and tumor cell challenge.

Animals↗
PubMed1982

Peritoneal macrophage alterations caused by naturally occurring mouse hepatitis virus.

During routine harvest of murine resident peritoneal cells for macrophage function assays the authors recently noted that mice showed a 3-4-fold spontaneous increase in number of peritoneal cells within 1 week of being placed in one of their animal rooms. While the mice appeared clinically normal, the collected macrophages had highly convoluted membranes, showed enhanced spontaneous tumor cell killing, and showed increased erythrophagocytosis. Histopathologic findings included mild peritonitis and occasional foci of individual hepatocyte necrosis. The results of routine murine serologic studies and bacterial cultures of the peritoneal cavity were negative. Immunosuppressed mice placed in this room showed severe hepatic necrosis within 4 days, and ultrastructural particles characteristic of corona virus could be demonstrated in the necrotic foci. Mouse hepatitis virus (MHV) was isolated from these livers. Untreated mice showed positive MHV titers, as detected by the enzyme-linked immunoabsorbent assay (ELISA) after 21 days in the room. This episode demonstrates that MHV have profound effects on macrophage parameters while causing few clinical signs or histopathologic alterations. Secondly, the complement fixation assay for MHV as included in routine viral screens appears relatively insensitive for detecting outbreaks of MHV.

Animals↗
PubMed1982

Procedures available to examine the immunotoxicity of chemicals and drugs.

The discipline of immunology should provide toxicology with sensitive models to assess toxicity as well as provide better safety assessment. More information on correlations between immune function and host resistance changes and a more standardized panel of methods for immunotoxicity screening will add further credence to the already impressive immunotoxicology data base. Research efforts are needed to evaluate newer in vitro methods with microsome activation systems to screen chemicals for immunotoxicity, to evaluate chemicals for induction of hypersensitization or allergy, and to better determine whether there are chemical structure activity relationships for chemically induced immunotoxicity. The studies described here represent preliminary examples of these approaches.

Animals↗
PubMed1982

Immune functions in methyl and ethyl carbamate treated mice.

Female B6C3F1 hybrid mice (5-7 weeks of age) were given methyl or ethyl carbamate over a 2 week period and subsequently examined for alterations in various immunological parameters. Exposure to methyl carbamate, a non-carcinogen, did not cause any alterations in the parameters examined. In contrast, exposure to the multipotential carcinogen, ethyl carbamate (urethan) at tumourigenic dosages caused severe myelotoxicity at all dosage levels. Related to the myelotoxicity was a marked depression of natural killer cell activity. Other parameters including susceptibility to tumour cell challenge, humoral immunity, cellular immunity and macrophage function were less affected. These studies indicate that non-toxic, but carcinogenic dosages of urethan, have profound but selective effects on the immune system which can be related to alterations in bone marrow functions.

Animals↗
PubMed1982

Effect of indomethacin on the bone marrow and immune system of the mouse.

Bone marrow cellularity, hematopoietic progenitor cells and immune alterations were evaluated in mice following short term adult exposures to non-ulcerogenic levels of indomethacin. Body and organ weights showed no significant changes with the exception of the spleen where a dose dependent weight increase was noted. Bone marrow cellularity and pleuripotent hemopoietic stem cells (CFU-S) were unaltered while granulocyte-macrophage progenitors (CFU-GM) and splenic erythropoiesis were increased. Indomethacin exposure caused increased macrophage function as evidenced by enhanced phagocytosis. Lymphoproliferative response of splenocytes to T-cell mitogens was depressed while B-cell mitogenic response was not affected. These results indicate that indomethacin affects selective components of the immune and hemopoietic cells at dose levels that cause no other significant pathological alterations.

Animals↗
PubMed1980

Examination of bone marrow, immunologic parameters and host susceptibility following pre- and postnatal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).

The effects of pre/postnatal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on various immunological, bone marrow and host susceptibility assays were examined in B6C3F1 hybrid mice. Exposure was accomplished by maternal dosing on Day 14 of gestation and again on Days 1, 7, and 14 following birth, employing dosages of 0, 1.0, 5.0 or 15.0 micrograms/kg body weight. The 15.0 micrograms/kg dosage was lethal to 70% of the offspring with the remainder of that dosage group revealing overt toxicity. Bone marrow toxicity occurred in both the 15.0 and 5.0 micrograms/kg dosage groups as evidenced by bone marrow hypocellularity and depressed colony formation of macrophage-granulocyte progenitor cells and pleuripotent stem cells. Evidence was presented that depression of lymphoproliferative responses following mitogen stimulation in TCDD-immunosuppressed mice was due to a functional defect of lymphocyte activation rather than suppressor cell activity. Administration of either Listeria monocytogenes or syngeneic PYB6 tumor cells in mice exposed to relatively low levels of TCDD during pre- and postnatal development increased their susceptibility to either bacterial or tumor challenge.

Animals↗