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Biomedical subjects

D A Rowley

Publications and source records attributed to D A Rowley.

At least 19 recordsLinked to original sources
PubMed1992

Stroma is critical for preventing or permitting immunological destruction of antigenic cancer cells.

Inoculated immunogenic cancer cells after initial growth are potentially rejected by specific host immunity; however, the outcome of the interaction between host and inoculated cancer cells is a function of multiple factors including the route of inoculation, the number of cells, the density of antigens on the injected cancer cells, and the state of the immune system of the host. In the present study, we have examined a different kind of variable: the stroma that inoculated tumor cells initially reside in. The impetus to examine this factor arises from observations that cancer cells from several lines inoculated as fragments of solid tumors often grow progressively, whereas the same number or more than 10-fold larger numbers of identical type cells injected as a suspension are rejected, even though fragments or suspended cells are both tumorigenic at the same doses in nude mice. In the present studies, we found that: (a) indeed, cancer cells inoculated as fragments were more tumorigenic than cancer cells in suspension; (b) the tumorigenicity of suspended cancer cells was increased by injection of the cells into polyurethane sponge implants; (c) cancer cells were more tumorigenic embedded in syngeneic stroma than in transgenic antigenic stroma expressing the K216 major histocompatibility complex class I antigen; and (d) antigenic, bone marrow-derived, stromal components (presumably passenger leukocytes) were sufficient to cause rejection of immunogenic but antigenically unrelated cancer.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Portable infrared pupillometry using Pupilscan: relation to somatic and autonomic nerve function in diabetes mellitus.

The relationship between dynamic pupillary function and peripheral nerve function was studied in 85 randomly-selected diabetic patients and 67 age-matched normals using a portable infrared pupillometer (Pupilscan Version 5). Seven measurements were chosen to represent different components of the pupillary constriction-redilatation curve after a standardized light stimulus. Constriction latency was significantly prolonged in diabetic patients (p = 0.05), as was time to 63% redilatation (p = 0.001). Thermal thresholds at the feet weakly correlated with relative reflex amplitude (warm: r = -0.22, p = 0.05; cool: r = -0.23, p = 0.05), but vibration perception thresholds were more strongly associated with constriction and redilatation velocity (r = -0.42, p = 0.001; r = -0.28, p = 0.03). Among the cardiovascular autonomic function tests, only respiratory R-R variation correlated with constriction velocity (r = 0.47, p < 0.001), and Valsalva ratio with redilatation velocity (r = 0.25, p = 0.04), but postural systolic blood pressure change was also correlated with reflex amplitude and latency time (r = -0.42, p < 0.001; r = 0.41, p = 0.001). There were no significant associations with three measures of sweating function in the feet. Pupil measurements were abnormal in 4-11% of diabetic patients, while other neurological tests were abnormal in 8-35%, consistent with the length-dependence of diabetic neuropathy. Median coefficients of variation were 2.0-7.2% in diabetic patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Quantitative measures of sympathetic skin response in diabetes: relation to sudomotor and neurological function.

The sympathetic skin response (SSR) at the foot to a deep inspiration was measured in 68 randomly selected diabetic patients and 46 age matched normal subjects and compared with other quantitative measures of neurological and sudomotor function. SSR was obtained in all but three diabetic patients. The upper limit of normal for the onset latency was 2202 ms and the lower limit for the amplitude of the first wave 92 microV. Ten diabetic patients had measurable but prolonged latencies, and 11 had measurable but low amplitudes. There were no significant associations between latency, height, and age, but in insulin dependent patients there was a significant diminution of response amplitude with increasing duration of diabetes. Latency was weakly associated with Marstock thermal thresholds, respiratory RR variation, and common peroneal nerve conduction velocity. SSR amplitude was associated with the density of pilocarpine activatable sweatspots in the same region of the foot. Patients with abnormal latencies were significantly older and had reduced thermal sensation than those with normal latencies. Median coefficients of variation for repeat testing in diabetic patients were 9% for latency and 13% for amplitude. The test is objective and reproducible, but latency measurements reflect conduction in a long multineuronal pathway and are not purely a measure of peripheral C fibre function; amplitude measurements reflect the density of spontaneously activable sweat glands and are therefore a valid measure of peripheral sympathetic activity, though they depend more on temperature than do latencies (mean change over the range 32-34 degrees C; 8.5% degrees C for amplitude, -2.5%/degrees C for latency).

Adult↗
PubMed1991

Changes in cholinergic sweat gland activation in diabetic neuropathy identified by computerised sweatspot analysis.

Peripheral small-fibre denervation has been reported to result in decreased activation of eccrine sweat glands to muscarinic cholinergic agents. Using computerised image-analysis of pilocarpine-activated sweatspot prints of a 4 cm2 area of the dorsum of the foot in 79 randomly selected diabetic patients we have identified a group of neuropathic patients (18%) with decreased sweatspot activation (less than 20/cm2), and a smaller group (6%) of younger patients with less marked neuropathy who had increased activation (greater than 132/cm2), probably resulting from denervation supersensitivity. The associations between sweatspot density and other conventional tests of peripheral nerve function were weak. The prevalence of abnormal sweatspot density, 24%, was similar to that of other tests, except thermal thresholds at the feet (35-37%), which were not correlated with sweatspot activation, suggesting that diabetic neuropathy has differing effects on afferent and efferent small fibres. The method is rapid and reproducible (median coefficient of variation 14%) and its ability to identify patients with increased, as well as decreased, peripheral nerve function may be of value in the characterisation and longitudinal follow-up of small-fibre abnormalities in diabetes.

Adult↗
PubMed1991

Cytokines and cancer: experimental systems.

The transfer of certain cytokine genes into cancer cells can provide very powerful suppression of tumor growth in the absence of any toxic side effects. Some of these cytokines, such as interleukin-4, granulocyte colony-stimulating factor and tumor necrosis factor, can mediate powerful immune suppression even in T-cell-deficient animals and appear to be effective for poorly or non-antigenic tumors. However, approaches must be found to induce or deliver cytokines locally at the tumor site.

Animals↗
PubMed1991

Assessment of basal and stimulated sweating in diabetes using a direct-reading computerized sudorometer.

Abnormalities of eccrine sweating are thought to be common in diabetes. We describe a ventilated-capsule sudorometer for the continuous measurement of basal and stimulated sweat secretion. It is sensitive (detecting as little as 200 ng water vapour), precise, and stable. Since it measures dewpoint rather than relative humidity, it can be calibrated to read sweat volumes directly and independently of ambient temperature and humidity. Preliminary studies using this technique show that basal skin water loss is significantly diminished in patients with established diabetic neuropathy (0.91 +/- 0.18 g (+/- SD) cm-2 h-1) compared with normal subjects (1.21 +/- 0.39 g cm-2 h-1; p = 0.04) and non-neuropathic diabetic subjects (1.32 +/- 0.48 g cm-2 h-1; p = 0.04), and that local sweating induced by iontophoresis of 10 g l-1 acetylcholine is significantly reduced in diabetic subjects up to 5 min of recording (0.95 +/- 0.43 vs 1.26 +/- 0.40 mg; p = 0.02). In neuropathic subjects both low- and high-amplitude responses are seen, the latter probably representing denervation supersensitivity. Further studies with sensitive sudorometry should enable the mechanisms of these abnormal responses to be established.

Acetylcholine↗
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↗