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Biomedical subjects

R Kiessling

Publications and source records attributed to R Kiessling.

At least 127 records · Page 7Linked to original sources
PubMed1983

Human natural killer cells can inhibit clonogenic growth of fresh leukemic cells.

The effect of allogenic human natural killer (NK) cells on fresh leukemic cells from three patients was investigated. The low levels of leukemic target cell lysis in the conventional 51Cr-release assay contrasted with a pronounced inhibitory effect on the colony growth of the clonogeneic leukemic target cells (L-CFC). The ability of allogeneic lymphocytes to inhibit L-CFC increased if they were pretreated with interferon (IFN), which also increased their NK activity, monitored in parallel cytotoxicity assay, against K562. Furthermore, cell separation procedures, based on differences in density among nonadherent lymphocytes, revealed that only NK cell containing fractions were inhibitory. We have also compared the susceptibility to NK-mediated L-CFC inhibition of IFN pretreated leukemic target cells with that of nontreated target cells. As in the case of NK lysis in general, this pretreatment of target cells abolished the presumably NK-mediated L-CFC inhibition. In conclusion, these data provide the first indication that NK cells can inhibit the in vitro growth of fresh clonogenic leukemia cells from patients with nonlymphocytic leukemia. The identity of NK cells as effector is strongly suggested by Percoll separation and responsiveness to interferon; the final proof awaits more sophisticated purification of these cells.

Clone Cells↗
PubMed1983

Genetic control of in vitro NK-activity and in vivo resistance to tumors.

Natural Killer (NK) cells are lymphocyte like cells which lack conventional B- and T-cell characteristics, and have the ability to rapidly kill certain tumor cells in vitro. Analysis of the genetic control of NK-activity in mice have provided several models to test the in vivo role of NK-cells in defence against neoplasia. Studies of certain F1-hybrid and backcross combinations have revealed a correlation between H-2 linked in vivo resistance and in vitro NK-activity against semisyngeneic transplantable tumors. The beige (bg) mutation in C57B1 mice causes a partial impairment of NK-activity, and can therefore serve to evaluate whether NK-cells can contribute to resistance against syngeneic tumors in the normal intact host. We have recently studied natural resistance against the ascitic lines of one chemically and two virally induced syngeneic leukemias in C57B1.bg/bg mice and their phenotypically normal heterozygous littermates. S.c. threshold inocula of all three leukemia lines grew faster and caused death earlier in bg/bg than in +/bg mice, and two of the lines were rejected completely at a significantly higher frequency in +/bg control animals. The +/bg mice also eliminated 125I-IdUrd-labelled leukemia cells at a faster rate than bg/bg mice, as measured by pulmonary, hepatic and splenic radioactivity retained 14-30 h after i.v. injection. The bg mutation was also possible to study in T-cell free mice, by combining it with the nu mutation on a C57B1 background. The NK-activity of such beige-nude mice was found to be partially impaired compared to nude (non-beige) or wild type animals, but higher than that of beige (non-nude) mice. Our results suggest that NK-cells may be responsible for elimination of small numbers of tumor cells in the intact syngeneic host. The further use of beige and beige-nude mice in studies of transplanted and primary, autochthonous tumors will be discussed.

Animals↗
PubMed1982

Thymus independence of hybrid resistance against a panel of T-cell lymphomas of H-2b origin.

Adult thymectomy, followed by whole-body irradiation and reconstitution with fetal liver, was performed to study the T-cell dependence of F1 hybrid resistance to a panel of lymphomas of H-2b origin. Previously, the pattern of hybrid resistance against the same lymphomas was found to correlate with the pattern of NK-activity in a spectrum of F1 hybrids (Kiessling et al., 1975). We now show that hybrid resistance against three lymphomas of C57BL/6 origin, P-52-127-166, RBL-5 and EL-4 and against YLD, of C57L origin, is expressed in the absence of thymus. In another series of experiments, the effectors responsible for hybrid resistance to the transplanted lymphoma EL-4 were studied by reconstituting thymectomized and non-thymectomized C57BL mice with syngeneic bone marrow from NK-deficient beige mutant or wild-type C57BL donors. While the recipients of beige bone marrow had a clearly reduced tumor resistance, thymectomy did not decrease resistance further. This study supports the hypothesis that resistance to these lymphomas in F1 hybrids as well as in syngeneic mice is mainly mediated by natural killer cells.

Animals↗
PubMed1982

NK-patterned binding expressed by non-NK mouse leukocytes.

Previous studies demonstrated that NK-cell-enriched spleen cells bind to sensitive but not to resistant mouse lymphoma targets, measured by a single-cell target binding assay. In the present report we further analyzed this "NK-patterned" binding using effector cells with high, low or no NK activity. In agreement with previous results, nylon-wool-passed spleen cells as well as a cloned cytotoxic cell line with NK activity bound tumor targets largely according to their NK sensitivity; NK-sensitive tumors had a higher frequency of binders than the more resistant ones. The correlation coefficient relating the percentage target binding cells (TBC) for each tumor with the ability of the same tumor to inhibit lysis in cold target competition assays was consistently higher than that relating percentage TBC with direct NK lysis. A non-lytic variant of the cloned cytotoxic cell line had a binding pattern identical to that of the lytic line, demonstrating that "NK-patterned" binding occurred in the absence of lysis. Thymocytes, which are totally devoid of NK activity, also bound preferentially NK-sensitive targets, and their binding was decreased after trypsin treatment or in the presence of EDTA. Peritoneal macrophages also showed "NK-patterned" binding, thus demonstrating that this was not restricted to cells in the T-cell lineage. Variants from a mouse lymphoma selected for decreased NK sensitivity bound a lower frequency of NK-active (nylon-wool-passed spleen cells) and inactive cells (thymocytes, peritoneal macrophages). This study therefore showed that the membrane property conferring NK-binding selectivity exists on several types of non-NK leukocytes.

Animals↗
PubMed1982

Hybrid resistance against a natural killer (NK) cell-resistant lymphoma (YWA) is mediated by a T cell-dependent mechanism.

Rejection of the Moloney virus-induced YAC lymphoma of strain A origin by semisynegeneic F1 hybrids has previously been shown to correlate with the levels of natural killer (NK) cell activity in the same F1 hybrids against this target cell line in vitro. In the present study, YAC and another Moloney virus-induced lymphoma,, YWA, derived from the A congenic A.SW strain, were tested for F1 hybrid resistance after s.c. inoculation of small numbers of cells into syngeneic and semisyngeneic F1 mice. While YAC cells invariably grew progressively once they formed a palpable tumor, regression of YWA tumors was frequently observed in both susceptible and resistant genotypes. The hybrid resistance pattern for YAC and YWA differed in one important respect: outcross of the syngeneic host to the A-congenic A.BY strain introduced a strong H-2b-associated resistance factor against YWA, but not against YAC. Compared to YAC, which is highly NK-sensitive and rapidly eliminated from mice with high NK activity, YWA was insensitive to NK-mediated lysis in vitro and [125I] UdR-labelled YWA cells were not eliminated more efficiently from the highly resistant (A.SW X A.BY) F1 then from the parental strain in short-term (4-18h) in vivo rejection assays. It was therefore concluded that the H-2b-associated resistance against YWA was independent of NK cells or other rapidly acting effector mechanisms. Moreover, thymectomy, followed by irradiation and fetal liver reconstitution, completely abolished the resistance against YWA but left the resistance against YAC virtually intact. These data suggest that two lymphomas induced by the same agent can be rejected by different effectors. The NK-resistant YWA lymphoma is rejected by a T-dependent mechanism, while the resistance against the inoculation of the highly NK-sensitive YAC line is T-independent and, in all probability, mediated by NK cells.

Animals↗
PubMed1982

Decreased sensitivity of immunoselected and NK-selected YAC lymphoma sublines to hybrid resistance in vivo.

Two sublines of the Moloney lymphoma YAC, selected by alternating in vitro exposure to anti-MCSA + complement and in vivo passage in preimmunized hosts, had a decreased or undetectable expression of MCSA. These 'immunoselected' sublines were compared with the original YAC line with regard to their ability to grow in a panel of semisyngeneic F1 hybrids. Natural hybrid resistance to YAC, previously found to be mediated by NK cells, affected the immunoselected sublines to a much smaller extent. This was further corroborated by the fact that the same sublines showed a decreased sensitivity to the in vitro lysis by NK cells from the same hybrid genotypes. Another set of YAC variants were produced by repeated in vitro exposure to NK cells and intermittent passage in highly NK-active F1 hosts. These 'NK-selected' sublines showed a permanently decreased sensitivity to NK lysis after 8-10 selections. When compared for in vivo growth with the parental YAC-1 tissue culture line in a spectrum of relatively resistant F1 hybrids, they had an increased frequency of takes. This is in line with recent findings which show a relationship between the target site for natural antibodies and anti-MCSA on the one hand, and between the natural antibody-binding site and the NK target site on the other.

Animals↗
PubMed1982

Inhibition of in vitro granulopoiesis by autologous allogeneic human NK cells.

This study demonstrates the ability of human NK cells to inhibit in vitro granulopoiesis of autologous and allogeneic BM cells. NK lytic activity and GM-CFC inhibition was present among nonstimulated lymphocytes from healthy donors and could be increased by treatment of PBL with IFN. Both the cytotoxic NK cells and the GM-CFC inhibitory cells could be enriched for among nonadherent, low-density cells. High-density cells were not cytotoxic, only inhibitory to a small extent, and could become neither cytotoxic nor more inhibitory after IFN treatment. In contrast, low-density cells showed an increased cytotoxic and GM-CFC inhibitory capacity after IFN treatment. The NK mediated GM-CFC inhibition was dependent on cell contact with BM cells, increased with longer preincubation times, and was most efficient against 7-day GM-CFC as compared with 14 day GM-CFC progenitors. In conclusion, these data provide new information about the human NK cell as a potent inhibitor of in vitro granulopoiesis and also as a possible regulator of hematopoiesis in vivo.

Binding, Competitive↗
PubMed1981

Correlation of glycosphingolipids and sialic acid in YAC-1 lymphoma variants with their sensitivity to natural killer-cell-mediated lysis.

Sialoglycoconjugates and glycosphingolipids were quantitated in a series of variants derived from the YAC-1 lymphoma, known to be highly sensitive to natural killer (NK)-cell-mediated lysis. The variants, which had widely diverging sensitivities to NK cells, were obtained by a number of methods, including selection in the presence of NK cells, antibody to H-2, or antibody to the murine leukemia-virus-induced antigen, and by fusion of sensitive cells with an NK-resistant cell line, A9HT. The sensitivities of these cells to NK-cell-mediated lysis did not correlate with their sensitivities to anti-H-2a cytotoxic T cells. While no correlation could be made between the NK-sensitivity of these variants and their total cellular sialic acid, a statistically significant inverse correlation was observed between the levels of percentage neuraminidase releasable surface sialic acid of total labelled sialyl components and sensitivity to NK cells. This correlation with cell surface sialic acid was observed with either endogenous or lymphocytic choriomeningitis virus-induced activated NK cells as effectors. Neuraminidase treatment of insensitive target cells caused a moderate increase in sensitivity but failed to render the resistant targets as sensitive as YAC-1. Analysis of glycosphingolipids among the variants revealed a strong positive correlation between the total cell neutral glycolipid with chromatographic migration of asialo-GM2 and sensitivity to endogenous or activated NK-cell-mediated lysis. Significant correlations were not found with any other neutral glycolipids. However, ganglioside homologues with chromatographic mobility of GM1, GD1a, GD1b, And GT also showed a positive correlation with both endogenous and activated NK-cell-mediated lysis. The ratio of asialo-GM2 to GM2 had a highly significant positive correlation with sensitivity. These correlative results suggest that asialo-GM2 and certain gangliosides could be involved in binding or lytic events in NK cell:target cell interactions, and that high levels of sialic acid and sialylation on the surface may inhibit and/or modify such interactions. Further studies with these YAC variants should be useful for examining the biochemical bases of target cell-effector cell interactions in the NK-system.

Animals↗
PubMed1980

In vitro NK-activity and in vivo resistance to leukemia: studies of beige, beige//nude and wild-type hosts on C57BL background.

The bg mutation in C57BL mice causes a partial impairment of NK activity, and has therefore been proposed as a model to evaluate the in vivo function of NK cells. In the present report, we studied natural resistance against the ascitic lines of one chemically and two virally induced syngeneic leukemias in C57BL bg/bg mice and their phenotypically normal heterozygous +/bg littermates. S.c. threshold inocula of all three leukemia lines grew faster and caused death earlier in bg/bg than in +/bg mice, and two of the lines were rejected completely at a significantly higher frequency in +/bg control animals. The +/bg mice also eliminated [125I]-IdUrd-labelled leukemia cells at a faster rate than bg/bg mice, as measured by pulmonary, hepatic and splenic radioactivity retained 18-30 h after i.v. injection. Direct splenic killing of 51Cr-labelled leukemia cells was also studied in vitro, and was found to be severely depressed in bg/bg compared to +/bg. This natural killer activity was independent of adherent cells and showed a rapid, but transient, increase after inoculation of the tumor cell doses used in the transplantation tests. It was also possible to study the bg mutation in T-cell-free mice, by combining it with the nu mutation on a C57BL background. The NK activity of such beige-nude mice was found to be partially impaired compared to nude (non-beige) or wild-type animals, but higher than that of beige (non-nude) mice. Our results suggest that NK cells may be responsible for elimination of small numbers of tumor cells in the intact syngeneic host. The further use of beige and beige-nude mice in studies of transplanted and primary tumors is discussed.

Animals↗