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Biomedical subjects

D A Rowley

Publications and source records attributed to D A Rowley.

At least 37 records · Page 2Linked to original sources
PubMed1990

Major histocompatibility complex class I and unique antigen expression by murine tumors that escaped from CD8+ T-cell-dependent surveillance.

The rejection of murine UV-induced skin cancers by normal mice is a striking example of powerful immune surveillance of the normal host against malignant cells. In this study, we show that UV-induced regressor tumors regularly grew progressively and killed mice that were depleted of CD8+ T-cells. Depletion of CD4+ T-cells had no effect, suggesting that CD8+ but not CD4+ T-cells were required for this immune surveillance. To determine whether change in major histocompatibility complex (MHC) class I expression was a frequent event that caused low immunogenicity of tumors or facilitated escape from immune destruction, recently isolated murine tumors of varying degrees of immunogenicity, including highly immunogenic UV-induced regressor, less immunogenic UV-induced progressor, and poorly immunogenic spontaneous progressor tumors, were compared. There was no correlation between the ability of a tumor to grow progressively in a normal immunocompetent host and the level of constitutive class I expression or the level of expression induced in vitro by gamma interferon. (Only 1 of more than 20 progressor tumors analyzed showed complete loss of a MHC class I molecule.) Some progressor variants showed loss of a unique tumor-specific cytotoxic T-lymphocyte-defined antigen, consistent with earlier evidence of antigen loss providing a mechanism for tumor escape. However, most of the host-selected progressor variants retained both MHC class I antigens and the unique tumor antigens that we could detect with cytotoxic T-lymphocyte clones, suggesting that mechanisms other than loss of MHC class I or of the unique target antigen may be involved in escape of some tumors from a highly effective CD8-dependent host surveillance.

Animals↗
PubMed1990

The liver of MRL/lpr mice contains defective accessory cells and a population of immunosuppressive lymphocytes.

Immunoregulatory abnormalities in the MRL/lpr mouse strain include activation of macrophages and hepatic natural killer cells, spontaneous production of tumor necrosis factor, defective oral tolerance, and impaired production of interleukin-2. Because the liver is the major organ responsible for the clearance, degradation, and presentation of foreign antigens from the gastrointestinal tract, we have investigated antigen presentation activity of hepatic nonparenchymal cells (NPC) from MRL/lpr, MRL/++, and C3H/HeN female mice in the primary immune response as measured by stimulation of allogeneic one-way mixed lymphocyte response (MLR), and allogeneic cell-mediated lympholysis (CML). Whereas adherent NPC from C3H/HeN, MRL/++, and young MRL/lpr mice were effective stimulators, NPC from MRL/lpr mice older than 9 weeks were defective stimulators of both MLR and CML responses. This abnormality was not observed in splenic accessory cells from these mice. Moreover, a population of hepatic NPC from older MRL/lpr mice are immunosuppressive: mixing of MRL/lpr NPC with splenic stimulators from MRL/++ mice profoundly inhibited primary allogeneic CML responses. The inhibitory hepatic nonparenchymal cell population was nonadherent, radioresistant and was removed by pretreatment with antibodies to either asialoAGM-1 or Lyt-2 plus complement. This inhibition was not observed with the addition of MRL/++ NPC or supernates from cultured MRL/lpr NPC. These findings suggest a selective organ-specific and age-dependent impairment of antigen presentation and the presence of an immunosuppressive lymphocyte population in the liver of MRL/lpr mice which may contribute to the autoimmune process.

Age Factors↗
PubMed1990

A highly immunogenic tumor transfected with a murine transforming growth factor type beta 1 cDNA escapes immune surveillance.

A highly immunogenic C3H-derived UV-induced tumor was cotransfected with a murine transforming growth factor type beta 1 (TGF-beta 1) cDNA and a neomycin-resistance gene. Stable clones were isolated and used in vitro and in vivo to determine the effects of endogenously produced TGF-beta on cytolytic T-lymphocyte (CTL) responses. Tumor cells producing TGF-beta, though retaining expression for class I major histocompatibility complex molecules and the tumor-specific antigen, did not stimulate primary CTL responses in vitro and were not effective in vivo for directly stimulating primary CTL or in priming for CTL responses. Furthermore, TGF-beta-producing tumors grew progressively in transiently immunosuppressed mice without losing the tumor antigen; thus, TGF-beta produced by tumors may promote escape from immune surveillance.

Animals↗
PubMed1989

Powerful immunosuppression mediated by interleukin 2-activated, nonantigen-specific, or H-2-restricted THY-1+ CD8+ cells.

Normal spleen cells cultured in high or low concentrations of interleukin (IL) 2 for 3 days contain Thy-1+ CD4- CD8+ cells that powerfully suppress primary but not ongoing or active lymphocyte responses. The precursors of these cells are Thy-1+ AGM-1- and are absent or present in greatly diminished numbers in athymic and scid mice. Suppression is neither antigen nor H-2 restricted and apparently results from reversible inactivation of resting lymphocytes. Comparable Thy-1+ CD8+ suppressor cells were also recovered from normal spleen cells cultured for 3 days with anti-CD3 antibody without added IL-2, indicating that these cells can be activated during the course of immune responses. Such cells may prevent local recruitment/activation of lymphocytes specific for new epitopes that may be expressed sequentially by proliferating tumor cells or infectious organisms.

Animals↗
PubMed1989

Highly immunogenic regressor tumor cells can prevent development of postsurgical tumor immunity.

Highly immunogenic malignant cells form small tumors that spontaneously regress after initial growth because the tumor induces specific immunity. However, variants may arise during the initial tumor growth that lose antigens, grow progressively, often become the predominant tumor population, and eventually kill the host. These progressively growing variants usually have not lost all tumor antigens and remain susceptible to rejection by T cells specific for antigens present on the parental tumor and retained by the progressively growing variants. Thus, it would seem logical for therapy to actively immunize with the parental highly immunogenic tumor (or sublines made similarly immunogenic by tumor heterogenization) after maximal surgical removal of the growing tumor. However, the present findings suggest that such a strategy may be ineffective and have adverse effects: the parental highly immunogenic tumor cells, either remaining or reintroduced, may perpetuate unresponsiveness to both the parental and the variant tumor. These findings suggest that unless tumor-induced suppression is first abrogated, immunization with highly immunogenic tumor cells may be counterproductive because this maneuver may maintain preexisting immune suppression and prevent development of postsurgical tumor immunity.

Animals↗
PubMed1989

A comparison of murine hepatic accessory cells and splenic dendritic cells.

Accessory cells are required for proliferation and antibody synthesis of B lymphocytes and proliferation of T lymphocytes in primary immune responses in vitro. The obligatory cells derived from the spleen are referred to as dendritic cells. Accessory cells were isolated from normal adult livers which were functionally interchangeable with splenic DC. Both hepatic accessory cells (AC) and splenic DC adhere firmly to plastic culture dishes or wells within 2 hr; but hepatic AC, unlike splenic DC, do not detach during 22 hr additional incubation. Hepatic AC, unlike splenic DC, are not lysed or inactivated by monoclonal antibody 33D1 and C'. Hepatic AC and splenic DC are similarly sensitive to irradiation in vivo and insensitive to irradiation in vitro. Hepatic AC are separated with cells which are predominantly phagocytic and FcR+ and contain nonspecific esterase. Both hepatic AC and splenic DC are suppressed or eliminated by activation of NK cells in vivo, a phenomenon prevented by prior elimination of NK cells.

Animals↗
PubMed1986

Immunoregulation by natural killer cells.

Polyinosinic-polycytidilic acid (poly (I:C], a synthetic analog of viral double-stranded RNA (dsRNA), activates natural killer (NK) cells and inhibits induction or promotes termination of the primary IgM response in vivo. Suppression of responses was reproduced in vivo by interferons (IFN) which activate NK cells and in vitro by cells enriched for NK cells. The likelihood that NK cells may be involved in the normal regulation of IgM responses is supported by the following observations: immunization itself induces NK activity at times appropriate to account for termination, NK cells activated by immunization suppress in vitro, mice with high NK activity induced by immunization with one antigen have reduced responses to immunization with a second antigen, and mice with induced loss of NK activity fail to down-regulate IgM antibody responses normally.

Animals↗
PubMed1986

Thy-1+ and Thy-1- natural killer cells. Only Thy-1- natural killer cells suppress dendritic cells.

Cells enriched for NK activity (poly I:C induced, x-ray resistant, and nonadherent), include two phenotypically and functionally different populations. Both populations of NK cells are AGM1+, Ly-1.1-, Ly-2.1-, Ia-, and have the morphology of large granular lymphocytes. One population, however, is Thy-1+ while the second population is Thy-1-. Thy-1+ NK cells lyse YAC-1 and P815 target cells; Thy-1- NK cells lyse YAC-1 but not P815 target cells. The FACS was used to obtain homogeneous populations of Thy-1+ and Thy-1- NK cells, which retain high cytotoxicity. While Thy-1- NK cells suppress the antibody response in vitro by suppressing or eliminating DC, Thy-1+ NK cells do not suppress antibody responses in vitro.

Animals↗
PubMed1985

Multiple cancers. Tumor burden permits the outgrowth of other cancers.

We demonstrate that tumor-bearing hosts permit the outgrowth of "potentially malignant" cells that are located at a different site. These second cancers continued to grow and kill their hosts even though they retain the "premalignant" phenotype, even after removal of the original malignancy. The potentially malignant cells used in these experiments were ultraviolet light- or methylcholanthrene-induced regressor tumor cells that are rejected regularly by normal mice at any testable dose, and only form progressive tumors in immunosuppressed individuals. The immunological rejection of these highly immunogenic, potentially malignant cells was suppressed by Thy-1+, Ly-2-, nonadherent, radio-sensitive suppressor cells in the tumor-bearing mice. These suppressor cells were absent in nude tumor-bearing mice. Unlike helper and cytolytic T cell-mediated responses, which are exquisitely tumor specific, the suppression caused by a progressively growing tumor was crossreactive among many syngeneic, independently derived tumors induced by different carcinogens. However, T cell-mediated immune responses to alloantigens, allogeneic tumors, certain syngeneic tumors, and humoral responses to xenogeneic red blood cells were normal in these mice. The immune suppression in the tumor-bearing animals closely simulated that induced by ultraviolet light irradiation, and both types of suppression might therefore share common mechanisms. Our findings may contribute to understanding the growth, development, and possible control of multicentric malignancies and add a precaution to the potential use of strongly immunogenic tumor variants for active immunotherapy in hosts bearing less immunogenic tumors.

Animals↗
PubMed1985

Dendritic cells that have interacted with antigen are targets for natural killer cells.

Natural killer (NK) cells (poly I:C induced, x-ray resistant, nonadherent, Thy-1-, Ly-1.1-, Ly-2.1-, anti-asialo GM1-positive, and cytotoxic for YAC-1) suppressed T lymphocyte proliferation in mixed lymphocyte reaction (MLR) and autologous MLR cultures. Dendritic cells (DC) were required for proliferation of lymphocytes in both responses. The question whether lymphocytes or DC were the targets for NK cells was resolved by taking advantage of the fact that NK cells, but not DC, lose activity after 24 h in culture. Three findings indicate that DC, not lymphocytes, are targets for NK cells. First, responses suppressed by NK cells were fully restored by adding small numbers of DC to cultures 24 h after NK cells had been added. Second, DC incubated alone with NK cells and antigen for 24 h did not stimulate proliferation of lymphocytes. Third, lymphocytes incubated alone with NK cells for 24 h proliferated normally when DC were added. Additional experiments showed that DC became targets only after interaction with antigen. Thus, we suggest that NK cells may regulate lymphocyte proliferation by monitoring antigen presentation by DC.

Animals↗
PubMed1985

Copper and iron complexes catalytic for oxygen radical reactions in sweat from human athletes.

Sweat collected from 'explosive' and 'endurance' athletes immediately after exercise contains low molecular mass complexes of copper detectable by their ability to bind to o-phenanthroline. Concentrations of these copper complexes are much greater in arm sweat than in trunk sweat. The iron content of arm sweat, as determined by the ferrozine method, is also greater than that of trunk sweat. However, much of the iron in trunk sweat exists in a low molecular mass form that can bind to the antibiotic bleomycin, whereas the iron in arm sweat does not exist in this form. The metal complexes in human sweat are capable of stimulating the peroxidation of membrane lipids in the presence of ascorbic acid. The physiological significance of the presence of iron and copper complexes in sweat is discussed.

Anemia↗
PubMed1985

Low-molecular-weight iron complexes and oxygen radical reactions in idiopathic haemochromatosis.

The sera of patients with idiopathic haemochromatosis and iron-overload have been found to contain low-molecular-weight iron complexes detectable in the 'bleomycin assay'. These complexes stimulate both the peroxidation of membrane lipids and the formation of the highly reactive and damaging hydroxyl radical. The iron chelator desferrioxamine interferes with these reactions. We suggest that oxygen radical reactions stimulated by iron salts are important in the pathology of idiopathic haemochromatosis.

Bleomycin↗
PubMed1983

DNA damage by superoxide-generating systems in relation to the mechanism of action of the anti-tumour antibiotic adriamycin.

A mixture of NADPH and ferredoxin reductase is a convenient way of reducing adriamycin in vitro. Under aerobic conditions the adriamycin semiquinone reacts rapidly with O2 and superoxide radical is produced. Superoxide generated either by adriamycin:ferredoxin reductase or by hypoxanthine:xanthine oxidase can promote the formation of hydroxyl radicals in the presence of soluble iron chelates. Hydroxyl radicals produced by a hypoxanthine:xanthine oxidase system in the presence of an iron chelate cause extensive fragmentation in double-stranded DNA. Protection is offered by catalase, superoxide dismutase or desferrioxamine. Addition of double-stranded DNA to a mixture of adriamycin, ferredoxin reductase, NADPH and iron chelate inhibits formation of both superoxide and hydroxyl radicals. This is not due to direct inhibition of ferredoxin reductase and single-stranded DNA has a much weaker inhibitory effect. It is concluded that adriamycin intercalated into DNA cannot be reduced.

Chemical Phenomena↗
PubMed1983

Homeostasis of the antibody response: immunoregulation by NK cells.

When injected into mice, the synthetic double-stranded polynucleotide poly(inosinic) X poly(cytidylic) acid induces high natural killer (NK) cell activity within 4 to 12 hours. Induction of NK activity in mice immunized 2 or 3 days previously, or the addition of NK cells to cultures immunized in vitro 2 or 3 days previously, promotes early termination of the ongoing primary immunoglobulin M antibody response. A target for NK cells is a population of accessory cells that has interacted with antigen and is necessary for sustaining the antibody response. The inference is strong that NK cells induced normally by immunization also terminate the usual antibody response in vivo by elimination of antigen-exposed accessory cells.

Animals↗
PubMed1983

Superoxide-dependent and ascorbate-dependent formation of hydroxyl radicals in the presence of copper salts: a physiologically significant reaction?

Copper (Cu2+) ions at physiological concentrations can promote the formation of hydroxyl radical (OH) or a species of equivalent reactivity. The reaction requires H2O2 and a reducing agent. Reduction of Cu2+ can be achieved by superoxide ion generated by a mixture of hypoxanthine and xanthine oxidase or added directly as its potassium salt. Reduction of Cu2+ can also be achieved by ascorbic acid. Hence both O2- -dependent and ascorbate-dependent formation of OH from H2O2 in the presence of Cu2+ can be observed. Only the former reaction is significantly inhibited by superoxide dismutase. The binding of Cu2+ to histidine or albumin at physiological concentrations decreases the formation of OH radicals in free solution in the presence of either ascorbate or an (O2- -generating system. It is suggested that OH is still formed but reacts immediately with the binding molecule.

Ascorbic Acid↗