Biomedical subjects

A G Morris

Publications and source records attributed to A G Morris.

At least 19 recordsLinked to original sources

PubMed1992

Diet and dental caries among later stone age inhabitants of the Cape Province, South Africa.

Stable carbon isotope measurements and incidences of dental caries are presented for three groups of prehistoric human skeletons from different regions of the Cape Province, South Africa. The isotopic analyses of bone collagen demonstrate the importance of marine foods in the diet and vary through time, across space, and according to sex. The incidence of dental caries ranges from 0% among heavily marine-dependent individuals from the south-western Cape coast, to 17.7% among skeletons from an archaeological site on the south coast. The extremely high incidence of caries in a hunter-gatherer population may be related to lack of fluoride in the water.

Dental Caries↗

PubMed1992

The loss of class II MHC antigen expression by ras-transformed murine fibroblasts passaged as tumours correlates with increased tumorigenicity but is not mediated by T cells.

In several murine tumour systems, expression of class II major histocompatibility complex (MHC) antigens by tumour cells, either constitutive or inducible, correlates with reduced tumorigenicity as compared with equivalent class-II-negative cells, and CD4 phenotype T cells together with interferon gamma (which induces the expression of class II) may be involved in the control of the proliferation of class-II-expressing tumours. This implies a potential T-cell-mediated selection pressure against class II expression. To test this possibility, we have repeatedly passaged as tumours in euthymic, syngeneic mice ras-transformed murine fibroblast lines, which are class-II-inducible, to determine whether class-II-non-inducible variants are selected. We examined the expression of both class I and class II antigen in tumour cells re-established in vitro. It was found that the inducibility of class II, but not class I, expression rapidly diminished, correlating with augmented tumorigenicity. However, this loss of class II inducibility occurred in athymic as well as euthymic mice. Therefore, despite the fact that the tumorigenicity of these lines is augmented in euthymic mice depleted of CD4 T cells or interferon gamma, we found no evidence of T-cell-mediated selection against class II expression. The loss of class II expression observed must be due to mechanisms other than immune selection. The possibility that this might result from other soluble factors modulating the response to interferon gamma in vivo is discussed.

Animals↗

PubMed1992

Interferon-gamma receptor expression in chronic hepatitis B virus infection.

It is known that interferon-gamma (IFN gamma) is not effective in inducing a sustained inhibition of HBV replication in patients with chronic HBV infection in contrast to interferon-alpha (IFN alpha). To determine whether this was related to IFN gamma receptor (IFN gamma-R) underexpression, binding characteristics of IFN gamma to peripheral blood lymphocytes were studied in chronic HBV infection using radioiodinated recombinant IFN gamma. Peripheral blood lymphocytes from patients with chronic HBV infection (n = 20), normal healthy controls (n = 12) and patients with non-viral related chronic liver disease expressed a similar number of IFN gamma-R (medians (ranges): 1891 (1581-2515); 1916 (1589-2441); 1893 (1692-2104) sites/cell, respectively, p = N.S.) with a similar dissociation constant (Kd approximately 0.7-2.7 nM). There was no correlation between IFN gamma-R expression and serum transaminase, serum HBsAg and HBV-DNA titres and liver histology. IFN alpha therapy in vivo also did not enhance IFN gamma-R expression (n = 3). There is therefore, no evidence from this data that IFN gamma-R is underexpressed in patients with chronic HBV infection to account for the difference in clinical response to these two forms of therapy.

Adult↗

PubMed1991

Inducibility of class II major histocompatibility complex antigens by interferon gamma is associated with reduced tumorigenicity in C3H mouse fibroblasts transformed by v-Ki-ras.

Paired lines of C3H mouse fibroblasts transformed with murine sarcoma virus (Kirsten strain) were prepared that express high or low levels of class II major histocompatibility complex antigen after treatment with interferon gamma (IFN-gamma). Here, we described a comparison of the tumorigenicity of these lines in euthymic syngeneic and thymus-deficient nu/nu mice and in mice depleted of IFN-gamma. The class II-inducible cells are clearly less tumorigenic than the noninducible cells in syngeneic mice, but of similar tumorigenicity in nu/nu mice and in mice treated with antibodies to deplete IFN-gamma. We propose that in this system, IFN-gamma induction of class II antigens on the tumor cell surface operates to limit tumor growth; ras expression, which inhibits induction of class II antigens, prevents this and so allows tumor growth.

Animals↗

PubMed1991

Interferon-gamma inhibits serotonin release from mouse peritoneal mast cells.

Conditioned medium (CM) from concanavalin A-activated mouse spleen cells inhibits antigen-induced 5-hydroxytryptamine (5-HT) release from mouse peritoneal mast cells when added for 24 or 48 h to cell cultures containing monoclonal IgE sensitizing antibody. We present the following evidence that the spleen cell-derived inhibitory factor is interferon-gamma (IFN-gamma): (a) CM from Con A-activated spleen cells and from Chinese hamster ovary (CHO) cells transfected with the murine (Mu)IFN-gamma gene both produced a graded inhibition of 5-HT release when added to peritoneal cell cultures containing IgE and subsequently challenged with antigen; (b) the relative inhibitory potency of the two preparations corresponded to their relative IFN content as determined by antiviral bioassay; (c) the inhibitory activity of spleen cell CM and of CM from IFN-gamma gene-transfected CHO cells was abolished by treatment with a rat monoclonal MuIFN-gamma-neutralizing antibody, i.e. 5-HT release returned to control levels, and (d) a highly immunopurified preparation of recombinant MuIFN-gamma retained the inhibitory activity, and was active at concentrations as low as 2 U/ml. The inhibitory activity of IFN-gamma appeared to be a direct effect of the cytokine on mast cells, since CM generated for different time periods from unfractionated peritoneal cells treated with purified recombinant MuIFN-gamma contained no inhibitory activity other than IFN-gamma itself, as demonstrated by neutralization of the cytokine with monoclonal antibody. Furthermore, purified recombinant MuIFN-gamma was equally active on mast cells enriched by density centrifugation up to 95% purity as on unfractionated peritoneal cells (1%-2% mast cells). Purified recombinant MuIFN-gamma inhibited 5-HT release induced by a range of different cell activators, namely antigen, anti-IgE, compound 48/80 and calcium ionophore A23187. Hence inhibition is not specific to IgE-dependent activation of mast cells, but seems to be directed more generally at the secretory process of these cells.

Animals↗

PubMed1991

Changes in mandibular condyle morphology related to tooth wear in a prehistoric human population.

The exact relationship between tooth wear and changes in the shape of the articulating surface of the mandibular condyles is unknown. It is assumed that to some degree these changes are in response to the loads on the joint generated during chewing. Excavated skeletal remains from sites of primitive human habitation provide an opportunity to study the masticatory system of human beings in their natural context, with the features of form and function expressed to their full potential. Accurate measurements of the condylar head can also be made on such remains. A collection of skulls from an excavation site known as Oakhurst on the South African coast provided material for this study. Occlusal wear was measured using the scale devised by Molnar; approximal wear was assessed by measuring the size of the wear facet between the first and second molars. The width of the condyles were measured directly, and a method was devised to measure changes in the proportion of medial and lateral articulating facets. An increase in the size of the lateral facet of the condyle was found to be associated with increased tooth wear. It is suggested that the direction of condylar remodelling may give an indication of the reaction at the joint to optimal mastication.

Adult↗

PubMed1991

Identification of a spleen cell-derived factor that inhibits sensitization of murine peritoneal mast cells as interferon-gamma.

We present evidence that a spleen cell-derived factor that inhibits the sensitization of mouse peritoneal mast cells is IFN gamma. Conditioned medium (CM) from Con A-activated mouse spleen cells and recombinant MuIFN gamma both inhibited antigen-induced 5-HT release from peritoneal mast cells when added at the sensitization stage, but were without effect on presensitized cells. Both preparations were active at dilutions corresponding to similar levels of IFN activity (1-10 units/ml). The inhibitory activity of CM was blocked by a rat monoclonal MuIFN gamma-neutralizing antibody, thus confirming that IFN gamma was the active molecule.

Animals↗

PubMed1991

Interferon-alpha receptor expression and regulation in chronic hepatitis B virus infection.

Interferon-alpha elicits antiviral and immunoregulatory activities by binding to specific receptors on the cell surface. In this study, binding characteristics of interferon-alpha to peripheral blood mononuclear cells in patients with chronic hepatitis B virus infection were studied using radioiodinated recombinant interferon-alpha 2b to determine interferon-alpha receptor numbers and dissociation constants. A single class of interferon-alpha receptor was demonstrated on peripheral blood mononuclear cells and mononuclear subsets. Peripheral blood mononuclear cells from patients with chronic hepatitis B virus infection (n = 20) and controls (n = 16) expressed a similar number of interferon-alpha receptors (484 +/- 175 vs. 511 +/- 168 sites/cell respectively, p = NS) with a similar dissociation constant (dissociation constant approximately 0.2 to 0.7 nmol/L). Expression of interferon-alpha receptors was similar in monocyte-enriched and lymphocyte-enriched fractions in both groups. Similar changes were observed in patients receiving alpha-interferon therapy. There was no correlation between interferon-alpha receptors expression and serum transaminase, serum HBsAg, serum HBV DNA, liver histological findings or the response to interferon-alpha therapy. After incubation of lymphocytes in vitro with interferon-alpha 2b (10 to 1,000 U/ml), interferon-alpha receptors number dropped by 42% to 80%, but this was associated with an increase in binding affinity (dissociation constant approximately 0.05 to 0.15 nmol/L) in both patients and controls. There was significant delay in the initial phase of receptor recovery in the patients with chronic hepatitis B virus infection compared with normal controls (days 1 and 2, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1991

Reduced stimulation of helper T cells by Ki-ras transformed cells.

A number of viral genes and cellular oncogenes inhibit major histocompatibility complex (MHC) antigen expression at the cell surface. In the case of inhibition of class I MHC antigens by viral genes this results in a reduced recognition by antigen-specific cytotoxic T cells. The activated Ki-ras cellular oncogene carried by the Ki-murine sarcoma virus (Ki-MuSV) in contrast inhibits class II MHC (or Ia) antigen expression on transformed cells. We have studied how transformation with Ki-ras affects recognition by alloreactive helper T cells. We found that the Ki-ras inhibition of class II MHC antigen expression led to greatly reduced stimulation of alloreactive T cells to proliferate and to secrete interferon-gamma (IFN-gamma). These findings support our hypothesis that the ability of an oncogene to reduce class II MHC antigen expression is crucial to its ability to produce tumour cells.

Animals↗

PubMed1991

Hepatic interferon-alpha gene transcripts and products in liver specimens from acute and chronic hepatitis B virus infection.

In this study we have examined the localization of interferon-alpha in liver tissue from acute and chronic hepatitis B virus carriers to establish whether the defect in interferon-alpha production reported in chronic hepatitis B virus infection is at a pretranscriptional or posttranscriptional level using in situ hybridization and immunohistochemical techniques. Interferon-alpha messenger RNA transcripts and the immunoreactive protein were abundant in liver tissue and in particular in hepatocytes from patients with acute hepatitis B virus infection who subsequently recovered. In contrast interferon-alpha polypeptide was present in a significantly lower number of sinusoidal cells, mononuclear cells and hepatocytes in chronic hepatitis B virus carriers. Although a high proportion of patients with chronic hepatitis B virus infection had cells that expressed interferon-alpha messenger RNA transcripts, the number of such cells was significantly less than in acute hepatitis B virus infection, indicating that the defect in the hepatic interferon-alpha synthesis is at the level of gene activation. Furthermore, using double immunohistochemical staining, the number of hepatocytes containing HBcAg correlated inversely with the proportion of neighboring sinusoidal cells expressing interferon-alpha. These data support previous observations that interferon-alpha production is reduced in chronic hepatitis B virus infection and are consistent with the view that this cytokine is important in the clearance of the virus.

Acute Disease↗

PubMed1990

Major histocompatibility complex antigens in v-Ki-ras transformed cells: the different antigens are expressed and induced by interferons independently of one another and of the anti-viral state.

A series of cell lines, which differed in their expression of class I (H-2K) or II (I-A) major histocompatibility complex (MHC) antigens, was derived from a line of C3H/He (H-2k) mouse embryo fibroblasts transformed by the v-Ki-ras oncogene. These were prepared by fluorescence-activated cell sorting of cells stained for these antigens either without interferon (IFN) treatment or after induction of antigen expression by either IFN-alpha beta or IFN-gamma, selecting for low or high staining. Cells selected for low (undetectable) constitutive H-2Kk expression were still strongly inducible by either IFN; cells selected for high constitutive expression were induced by IFN to express still higher levels. In all cell lines induction of H-2Kk with one IFN type was paralleled by induction with the other. Expression of H-2Kk appeared largely independent of H-2Dk; in lines which were selected for low H-2Kk expression (constitutive or induced), H-2Dk expression was not much reduced, and lines selected for high H-2Kk expression showed only modest augmentation of H-2Dk. Varying inducibility of I-Ak by IFN-gamma was not closely paralleled by H-2K inducibility by either IFN-alpha beta or -gamma, with again only weak correlation of high and low expression of H2-Kk and I-Ak. On the other hand, expression of I-Ak seemed to be correlated with I-Ek. None of these variable effects could be attributed to differing sensitivity to IFN-alpha beta or -gamma since all the lines showed about the same sensitivity to the anti-viral effects of IFN.

Animals↗

PubMed1989

A probable case of prehistoric kidney stone disease from the northern Cape Province, South Africa.

During the excavation of isolated graves along the north shore of the Orange River in the Cape Province of South Africa, a skeleton was uncovered that showed two large calcareous deposits near the lumbar region of the vertebral column. The individual was an adult female of about 55 years of age at the time of death. The calcified residue did not in any way resemble the external or internal anatomical form of a kidney, but X-ray powder diffraction analysis and scanning electron microscopy identified the material as apatite (Ca10(PO4)6 (OH)2), a common constituent of human urinary calculi. It is postulated that the bilateral calcification was the result of a chronic renal disorder. Although it is rarely possible to identify the cause of death from skeletal remains alone, the disorder as seen in this specimen would appear to have been very severe and may well have been the ultimate cause of death.

Apatites↗

PubMed1989

Interaction of v-Ki-ras oncogene and interferon-gamma in the control of histocompatibility antigen expression in mouse fibroblasts.

C3H10T1/2 fibroblasts when transformed with Kirsten murine sarcoma virus lose the ability to be induced to express class II major histocompatibility complex antigens when induced with interferon-gamma (IFN-gamma). Sublines were derived from transformed lines by cell sorting after treatment with IFN-gamma, sorting for low or high expression of H-2Ak. These sublines remained stably noninducible or inducible for class II antigen for several passages after sorting. In all other respects tested, viz, sensitivity to IFN-gamma for the generation of an antiviral state or the induction of class I antigen, content of ras gene products, the sorted sublines were very similar. We conclude that ras oncogene expression in these cells can influence the induction of class II antigen but that because ras expression in the sorted lines is similar the effect of ras expression is indirect and presumably involves interaction with other cellular factors.

Animals↗

PubMed1989

Instability of expression of major histocompatibility antigens in fibroblasts expressing activated ras oncogene: constitutive and interferon-gamma induced class I and class II antigens in a series of clonal isolates of murine fibroblasts transformed by v-Ki-ras.

We have examined the expression of major histocompatibility complex (MHC) antigens, constitutive or induced with interferon gamma (IFN-gamma), in a line of C3H mouse embryo fibroblasts (C3H 201) transformed with a helper-virus-free preparation of the Kirsten strain of murine sarcoma virus. C3H 201 cells expressed some class I antigen (H-2Kk) in the absence of added interferon, unlike the parental C3H 10T1/2 cells from which they were derived. However, this declined with (in vitro) passage level after transformation. Treatment with IFN-gamma induced very high expression of H-2Kk at all passage levels. There was no constitutive expression of class II antigen (I-Ak); however, this could be induced by IFN-gamma. Inducibility of I-Ak was found also to be related to the number of passages after transformation; at early passage levels after transformation more I-Ak was induced than after the cells had been allowed to grow for several passages, until at high passage levels little or no I-Ak was induced. This was not due to the presence of a subpopulation of untransformed cells since when the cells were cloned shortly after infection all the resulting clones were transformed. In addition, IFN-gamma at any passage level induced clearly less I-Ak than was found in C3H 10T1/2 cells, in which I-Ak inducibility was high and stable. Twenty-one clones were derived from C3H 201 cells at early passage (less than 8) either from soft agar or from liquid culture. These clones showed a wide variation in MHC antigen phenotype. Many expressed H-2Kk in the absence of IFN-gamma, and all were strongly inducible for H-2Kk. None showed I-Ak in the absence of IFN-gamma. All but two expressed I-Ak after IFN-gamma treatment but, with four exceptions, clearly less than the untransformed line. Four clones derived at late passage (40) resembled the late passage line. The expression of the ras oncogene and tumorigenicity was studied in representative clones; there was no obvious correlation with MHC phenotype, nor with the method of cloning. We conclude from these studies that the expression of MHC antigens by fibroblasts expressing the v-Ki-ras oncogene, either with or without exposure to interferon gamma, is unstable, varying with the number of cell generations from transformation and from clone to clone.

Animals↗

PubMed1989

Assessment of the functional activity of antigen-bearing dendritic cells isolated from the lymph nodes of contact-sensitized mice.

The immunostimulatory properties of dendritic cells (DC) which rapidly accumulate within the draining lymph nodes of mice topically exposed to contact allergens have been assessed as a function of their ability to initiate proliferative responses by sensitized lymph node cells (LNC) in vitro. A proportion of such DC bear antigen which is in a highly immunogenic form. Thus, at low stimulator:responder ratios, DC-enriched populations prepared from the draining nodes of mice exposed to the skin-sensitizing fluorochrome fluorescein isothiocyanate (FITC) induced significant proliferative responses by FITC-primed responder lymphocytes. Under the same experimental conditions, unfractionated or DC-enriched LNC isolated from naive mice and coated with at least equivalent amounts of FITC in vitro were without effect. The influence of DC populations on lymphocyte proliferation was largely, but not wholly, antigen-specific in nature. Dendritic cell fractions isolated 18 h following topical exposure to high concentrations of FITC or oxazolone induced a marked proliferative response by lymphocytes sensitized to the homologous chemical and a significantly less vigorous response by lymphocytes primed to unrelated haptens. In contrast DC isolated from the nodes of mice sensitized with 2,4-dinitrochlorobenzene (DNCB) caused proliferation only of DNCB-primed lymphocytes. The relative potential of DC populations prepared from FITC- and oxazolone-primed mice to induce antigen-specific and non-specific stimulation was dependent upon both the concentration of chemical used for sensitization and the period of exposure.

Animals↗

PubMed1989

Interactions of interferons in the induction of histocompatibility antigens in mouse fibroblasts and glial cells.

The interactive effects of interferons (IFN) in the induction of class II major histocompatibility complex (MHC) antigens in a murine fibroblast line and murine glial cells (primary astrocytes and an oligodendroglioma line) were examined. It was found that IFN-alpha and -beta were additive with IFN-gamma in the induction of class I antigens but that both IFN-alpha and -beta down-regulated the induction of class II antigens by IFN-gamma. This was most clear cut when the IFN-alpha or -beta was present in large excess in terms of anti-viral activity. Recombinant IFN-alpha 2 was found weakly to induce class II antigens, unlike natural IFN-alpha. The results imply that IFN-alpha and -beta may be important in the control of class II antigen expression in vivo although not by themselves inducing class II antigens.

Animals↗

PubMed1989

Regulation of IFN-gamma-induced host cell MHC antigen expression by Kirsten MSV and MLV. I. Effects on class I antigen expression.

We have reported previously that the Kirsten murine sarcoma virus (Ki-MSV) that carries the v-Ki-ras oncogene prevents C3H10T 1/2 fibroblasts from being able to respond to interferon-gamma (IFN-gamma) with the expression of the class II major histocompatibility complex (MHC) antigen, H-2A. In this report we investigate further as to whether MSV or its parent virus Kirsten murine leukaemia virus (Ki-MLV) is able to reduce host class I MHC antigen expression. The results demonstrate that class I expression is diminished in MSV-infected cells over a time-course of 7 days after exposure to IFN-gamma and over a range of IFN-gamma concentrations. The optimal concentration of IFN-gamma for maximal class I expression remained unchanged. Cells infected with Ki-MLV, which failed to abolish the induction by IFN-gamma of class II antigens, also expressed lower levels of class I antigens, similar to those for cells infected with Ki-MSV, after exposure to IFN-gamma. It is likely therefore that the inhibition of class I induction is due to genetic material shared between the viruses, principally in the long terminal repeats (LTR), and hence that the mechanism of action is distinct from that responsible for the abolition of class II induction by Ki-MSV alone. Since class I antigens are required for CD8+ T cells (mainly cytotoxic T cells) to recognize (foreign) antigen this reduction in class I expression might lead to reduced visibility of infected cells to T cells and thus might contribute to the tumorigenicity of Ki-MSV-infected cells.

Animals↗

PubMed1989

Regulation of IFN-gamma-induced host cell MHC antigen expression by Kirsten MSV and MLV. II. Effects on class II antigen expression.

We have reported previously that the Kirsten murine sarcoma virus (Ki-MSV), which carries the v-Ki-ras oncogene, prevents the induction of the class II MHC antigen H-2A and reduces the induction of class I MHC antigens by interferon-gamma (IFN-gamma) on C3H10T 1/2 fibroblasts. It is here shown that the abolition by the virus of H-2A expression extends also to class II antigen H-2E and that this is maintained for at least 7 days after IFN treatment. In addition no concentration of IFN-gamma tested, including supra-optimal concentrations for class I antigen expression, induced class II antigens on MSV-infected cells. Thus MSV inhibits the induction by IFN-gamma of class II MHC antigens by a mechanism other than via a change in kinetics of response to, or in the sensitivity of the cells to, IFN. The possibility that transformation by MSV could result in the (selective) outgrowth of cells unresponsive to IFN was refuted by the observation that clones of C3H10T 1/2, when infected with Ki-MSV, expressed no or dramatically reduced levels of H-2A or H-2E. One C3H10T 1/2 clone chosen for high class II expression, when transformed with Ki-MSV, did express low levels of class II antigens at optimal concentrations of IFN-gamma, suggesting that the degree of the reduction of class II expression varies with the cells that are infected. Comparison with mechanisms whereby other viruses inhibit MHC antigen display revealed an interesting possibility: IFN response sequences (IRS) identified in the virus genomes might act in trans to (down) regulate MHC antigen expression. This could be an important mechanism determining the tumourigenicity of, and immune evasion by, Ki-MSV and other viruses.

Animals↗