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Biomedical subjects

O Stutman

Publications and source records attributed to O Stutman.

At least 73 records · Page 4Linked to original sources
PubMed1981

Normal levels of natural cytotoxic cells against solid tumours in NK-deficient beige mice.

Natural cell-mediated cytotoxicity (NCMC) capable of in vitro lysis of various lymphoid and non-lymphoid tumours has been described in mice and other species, including man. NCMC has been proposed as a first level of defence against tumour growth in vivo, one which does not need the priming of the conventional immunological response. The effector cells of NCMC seem to belong to a special category of lymphoid cells, being neither classical T or B cells nor macrophages; natural killer (NK) cells have been proposed as the prototype effector cell, although some heterogeneity among effector cells seems to exist, depending on the target cells used for testing. Two main subgroups of NCMC effector cells have been defined: NK cells directed against lymphoma targets and natural cytotoxic (NC) cells directed against solid non-lymphoid tumours. We describe here another distinction between the two systems: while NK activity is low in mice homozygous for the beige (bg) gene NC activity in spleen cell preparations from these animals is comparable with that observed in the appropriate controls (bg/+ and +/+ littermates). The bg syndrome of mice affects lysosome, melanosome and enzymatic functions and is a homologue of the Chediak--Higashi syndrome of man. Defective NK activity in blood lymphocytes has also been reported in patients with Chediak--Higashi syndrome. We also show that several mouse strains which have low NK activity, have normal or high levels of NC functions, expanding our previous observation that NC and NK cells are under distinct genetic control.

Animals↗
PubMed1981

Interleukin 2, production in the syngeneic mixed lymphocyte reaction.

In the syngeneic mixed lymphocyte reaction, Ly 1 cells proliferate following stimulation with Ia-positive macrophage-like cells. The proliferation is accompanied by the release of interleukin 2 into the medium. Both the proliferation and interleukin 2 production are dependent on the expression of Ia antigenic determinants, as the addition of haplotype-specific anti-Ia antisera to the cultures inhibits both parameters.

Animals↗
PubMed1981

Decline, in aging mice, of the anti-2,4,6-trinitrophenyl (TNP) cytotoxic T cell response attributable to loss of Lyt-2-, interleukin 2-producing helper cell function.

The in vitro generation of cytotoxic T lymphocytes (CTL) specific for 2,4,6-trinitrophenyl (TNP)-modified syngeneic spleen cells is found to be almost invariably depressed in apparently healthy 18-month-old mice of the long-lived (BALB/c x C57BL/6)F1 hybrid strain. Studies of CTL production from Lyt-2+ thymus cells have suggested that pre-killer cells may require, for maturation into effectors, the presence of a soluble helper factor, interleukin 2 (IL2), produced by Lyt-2- cells which are themselves devoid of pre-CTL activity. We have therefore developed a petri-dish adherence technique for separating spleen cells into Lyt-2+ and Lyt-2- populations in order to test for helper and pre-killer activity independently. Pre-CTL function is measured by stimulating Lyt-2+ cells in the presence of exogenous IL2. Helper cell activity is tested by adding Lyt-2- cells to "indicator" populations of Lyt-2+ pre-CTL. Estimation of IL2 levels in medium conditioned by unfractionated, TNP-self-stimulated splenocytes provides a second measurement of helper cell function. Mice 18 months of age, when compared to 4 month-old controls, are found to retain nearly all of their pre-CTL activity, but to have lost sufficient helper cell activity to account for the decline in unseparated spleen cell cultures. Older mice also produce lower IL2 levels.

Aging↗
PubMed1981

Cellular immunity during pregnancy. II. Response to T and B cell mitogens.

Immune reactivity of primiparous pregnant C57Bl/6J mice was investigated using in vitro assays of mitogen reactivity. The response to the T cell mitogens phytohemagglutinin (PHA) and concanavalin A of cells from the paraaortic (PA) lymph nodes, which drain the uterus, was decreased in pregnant animals. Reactivity to lipopolysaccharide, a B cell mitogen, was normal. The decreased PHA response was seen with PA cells from mice bearing syngeneic or allogeneic (to DBA/2J) fetuses. It was not due to a change in sensitivity to PHA dose or to active suppression (as demonstrated by mixing experiments). Phytohemagglutinin reactivity of cells from inguinal nodes of pregnant mice showed a more variable depression of response in comparison to that seen with cells from the draining PA nodes. The response of axillary and brachial node cells was similar to virgin values. Statistical analysis revealed no differences in the average number of PA lymphocytes or fetuses per mouse between mice bearing syngeneic or allogeneic fetuses. This parallels the similarities found between syngeneic and allogeneic matings in in vitro functional assays. This study demonstrates that pregnant mice (syngeneic or allogeneic) show only a decrease in T proliferative capacity localized to the area of the uterus, while such responses in the rest of the body are left essentially intact.

Animals↗
PubMed1981

Natural cytotoxic cells against solid tumors in mice. III. A comparison of effector cell antigenic phenotype and target cell recognition structures with those of NK cells.

Antisera directed to antigens present on natural killer (NK) cells such as Qa-2,3, Qa-5, NK-1.2, Ly 11.2, and Asialo GM 1 failed to eliminate natural cytotoxic (NC) cell activity from murine spleen cells, suggesting a heterogeneity of effector populations involved in natural cell-mediated cytotoxicity (NCMC). Cross-cold target inhibition studies demonstrated that certain similar recognition structures are present both on NK and NC susceptible tumor target cells.

Animals↗
PubMed1981

Natural cytotoxic cells against solid tumors in mice: a comparison with natural killer cells.

From the comparison of the similarities and differences between lymphoid cells from normal mice capable of killing targets in vitro, derived from solid tumors (termed natural cytotoxic or NC cells), and those cells capable of killing target cells in suspension, mostly derived from lymphoid tumors (natural killer or NK cells), it is apparent that natural cell-mediated cytotoxicity (CMC) is mediated by a family of effector cells of still undefined lineage (i.e., neither T, B, nor macrophages) of which NC and NK cells may be examples. Natural CMC has unique properties not shared by conventional specific immune CMC and, although the structures in the target cells recognized by NC-NK cells are still undefined, they appear to be related to simple sugars of the membrane. Since the properties of both NC and NK cells appear to correlate well with in vivo resistance or susceptibility to tumors as well as with early responses to some infectious agents, it is probable that natural CMC may represent an early defense mechanism of physiological importance.

Animals↗
PubMed1980

Host age and H-2 tolerance in chimeric mice: mixed lymphocyte reactivity, cell-mediated lympholysis and responses to hapten-modified self.

In order to further our understanding of the reasons for the increased susceptibility of aged animals to autoimmunity, neoplasms and infectious diseases, experiments were performed to determine the ability of an aged environment to induce and support tolerance to major histocompatibility complex (MHC) determinants as well as to support the development of a specific immune response to modified self-determinants. The degree and mechanisms of tolerance to host and donor histocompatibility antigens were studied in bone marrow chimeras of the type (C57B1/6 X CBA)F1 leads to (C57B1/6 X DBA/2)F1 (BCF1 and BDF1, respectively). BCF1 bone marrow donors were 6 weeks old and BDF1 hosts were 18 months old at the time of chimerization. Four to ten months later, chimeras were found to fully tolerant to all three parental haplotyes and competent to respond to fourth-party strains as assessed in both mixed lymphocyte reactions and cell-mediated lympholysis. Tolerance to parental haplotypes could not be attributed to active suppression of reactivity. The aged host environment proved incapable of supporting the development of anti-modified self-reactivity as attested by the fact that neither the senescent BDF1 mice nor the BCF1 leads to BDF1 chimeras established in aged hosts could respond to trinitrophenol-modified autologous parental cells. In contrast, young BDF1 mice and BCF 1 leads to BDF1 chimeras established in young adult hosts were competent to respond to trinitrophenol-modified autologous and parental cells in an MHC restricted fashion. The significance of these results to the susceptibility of aged animals to intracellular parasitic infections and neoplasia is discussed.

Aging↗
PubMed1980

Natural cytotoxic cells against solid tumors in mice: blocking of cytotoxicity by D-mannose.

Natural cytotoxic (NC) and natural killer (NK) cells have been defined by their ability to lyse certain solid or lymphoid tumor targets in vitro, without prior sensitization. Our present studies describe an attempt to characterize the structures involved in the effector-target recognition leading to tumor cell lysis. Addition of the monosaccharide D-mannose to the NC cell assay significantly blocked cytotoxicity of the fibrosarcoma Meth A target by the effector cells at 50 mM and lower concentrations. D-Galactose showed blocking activity in one of five experiments, only at 50 mM. L-Fucose, D-glucose, and N-acetyl-D-glucosamine did not affect NC cell cytotoxicity at similar concentrations. All of the sugars tested inhibited NK cell lysis of the lymphoma YAC-I target. None of the sugars affected killing of the appropriate target by allosensitized cytotoxic T lymphocytes. The blocking of NC-mediated cytotoxicity was not due to a direct toxic action of the sugars on the effector cells. These findings suggest that, in the NC system, recognition involves lectin-like structures with a specificity for D-mannose (or D-galactose, or both), whereas, in the NK system, such lectin-like structures are less restricted. Such structures appear not to be involved in the specific cytotoxicity mediated by T cells.

Animals↗
PubMed1980

Cellular immunity during pregnancy. I. Proliferative and cytotoxic reactivity of paraaortic lymph nodes.

The possibility of changes in immune reactivity during pregnancy was studied by measuring cellular immunity in vitro of the paraaortic (PA) lymph nodes, which drain the uterus in pregnant mice. The proliferation of PA lymph node cells from primiparous pregnant C57Bl/6J mice, in mixed lymphocyte cultures (MLC) against alloantigens, was lower in magnitude, but had the same kinetics, as the response of virgins. This was observed in syngeneic and allogeneic (to DBA/2J) pregnancies, and using the paternal as well as third party allogeneic stimulators. The response was depressed by day 8 of gestation and returned to normal two days after delivery. The decrease was not due to an active suppressor mechanism, as assayed by mixing experiments. Irradiation (1500R) of the lymphocytes from pregnant mice, prior to mixing with cells from virgins, did not reveal the presence of a radioresistant suppressor cell. In contrast to the MLC results, no differences were found between lymphocytes from pregnant and virgin mice in their ability to develop MLC-generated cell-mediated lympholysis (CML) against alloantigens, as measured in a chromium release assay. The PA lymph node cells from pregnant animals bearing allogeneic fetuses also did not show evidence of in vivo sensitization to the paternal alloantigens. Therefore, the local nodes draining the uterus from primiparous pregnant animals bearing syngeneic or allogeneic fetuses show a nonspecific decrease of MLC proliferation while retaining the capacity to generate normal CML activity.

Animals↗
PubMed1980

Allogeneic radiation chimeras respond to TNP-modified donor and host targets.

Tolerance to major histocompatibility antigens as well as the ability to mount a cytotoxic response to hapten-modified cells of bone marrow donor and host origin was studied in allogeneic radiation chimeras. Lethally irradiated (C57BL/6 X DBA/2)F1 hosts reconstituted with anti-Thy 1.2 + C-treated bone marrow from (C57BL/6 X CBA)F1 mice showed tolerance to the MHC antigens of the three parental strains as measured by MLC and CML assay. The chimeras responded normally to unrelated allogeneic cells. Chimeric animals generated a cytotoxic response to hapten-modified cells of both donor (CBA) and host (DBA/2) haplotypes, as well as to C57BL/6, demonstrating that tolerance to the hapten-presenting host haplotype is sufficient to allow a cytotoxic antihapten response, and that processing through a semiallogeneic host environment does not affect the ability to generate a response to hapten in conjunction with self-determinants. Chimeras failed to mount a cytotoxic response to hapten presented on nontolerated allogeneic spleen cells.

Animals↗
PubMed1979

Ontogeny of culture-generated suppressor cells.

Culture of murine lymphoid cells without added antigen results in the generation of cells which suppress a variety of in vitro immune responses, such as the mixed lymphocyte response (MLR) and the generation of alloreactive cytotoxic T cells (CTL). The ontogeny of this phenomenon was studied. Cells which suppressed the MLR after preculture were isolated from spleens and hematopoietic livers of fetal and young (less than 1 wk old) mice. On the other hand, the generation of alloreactive CTL could be suppressed only by precultured spleen cells taken from 1-w-old or older mice. The parallel between the development of the suppressor functions and the maturation of the responses they regulate, suggests a possible biological significance of the effect.

Animals↗
PubMed1979

Cellular and humoral requirements for T-cell development.

T-cells develop as a consequence of intrathymic and postthymic events, in which hemopoietic progenitors are differentiated into precursors and effector cells. We are proposing that such process includes three integrated steps: (1) T-cell differentiation; (2) selection of the T-cell repertoire and (3) specialization into functional subsets of T-cells. Although there is evidence of specific and nonspecific humoral factors (i.e. thymic extracts, etc.) affecting T-cell differentiation, it is also proposed that the most critical component in this integrated process is the consequence of direct cell to cell interactions between precursor and inducer cells. Thus, the three processes are the consequence of the appropriate or condordant matching of precursor-inducer populations, both at intra- and extrathymic sites. It is also proposed that MHC determinants are critical in permitting the appropriate matching. The model can thus account for nonfunctional differentiation when the appropraite matching is not available and with intrathymic selection by excess cell production favoring the appropriate matching.

Cell Communication↗
PubMed1979

Spontaneous tumors in nude mice: effect of the viable yellow gene.

The incidence and type of spontaneous tumors in athymic nude (nu/nu) mice (partially inbred in CBA/H background) which were also carrying the viable yellow gene (Avy, derived from C57BL/6JAvy mice), were comparable to those observed in the phenotypically normal nu/+ and +/+ control crosses carrying the Avy gene. The Avy gene increases the incidence of spontaneous and induced tumors in most mouse strains. These results would argue against the thymus dependency of the putative immunological surveillance mechanisms.

Animals↗