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Biomedical subjects

M R Alderson

Publications and source records attributed to M R Alderson.

At least 19 recordsLinked to original sources
PubMed1992

Regulation of human monocyte cell-surface and soluble CD23 (Fc epsilon RII) by granulocyte-macrophage colony-stimulating factor and IL-3.

We have investigated the regulation of expression of cell-surface and soluble CD23 (sCD23) by purified human peripheral blood monocytes and in cultures of human whole blood. IL-3, IL-4, and GM-CSF were found to markedly enhance the expression of CD23 on the surface of elutriated monocytes and to increase levels of sCD23 in monocyte-culture supernatants. The induction of CD23 expression by monocytes was confirmed at the mRNA level by Northern blot analysis. The ability of GM-CSF, IL-3, or IL-4 to induce cell-surface CD23 on monocytes was inhibited by specific neutralizing antibodies to the corresponding cytokine. IL-3 and GM-CSF induced maximal surface CD23 expression on monocytes by 24 to 48 h, followed by a slight decline at 72 and 96 h. In contrast, IL-4 induced a progressive increase in monocyte CD23 expression that reached a maximum at approximately 72 h. IL-4, GM-CSF, and IFN-gamma increased both surface and soluble CD23 expression by the monocytic cell line U937, whereas IL-3 had no effect. The plasma from fresh human whole blood or nonstimulated whole blood cultured for 24 to 48 h contained detectable sCD23, and addition of IL-3, IL-4, or GM-CSF to these cultures resulted in increased levels of this molecule. Two-color flow cytometry revealed that IL-3, but not GM-CSF, also enhanced CD23 expression by B cells enriched from PBMC, although the effect of IL-3 was weak in comparison with that of IL-4. These findings may have important implications for the in vivo therapeutic use of these cytokines.

Antigens, Differentiation, B-Lymphocyte↗
PubMed1991

Induction of macrophage inflammatory protein-1 beta gene expression in human monocytes by lipopolysaccharide and IL-7.

HuMIP-1 beta is a member of a gene family of inflammatory cytokines whose expression is induced by proinflammatory and mitogenic stimuli. The gene was rapidly induced in human peripheral blood monocytes by either LPS or IL-7. However, IL-7 was unable to induce HuMIP-1 beta mRNA in peripheral blood T cells. The induction of HuMIP-1 beta mRNA in monocytes by IL-7 or LPS was inhibited by IL-4. The 5'-regulatory region of the HuMIP-1 beta gene was cloned and sequenced. An analysis of this sequence revealed three consensus-binding sites for the nuclear factor PU.1 and three potential glucocorticoid response elements. However, the HuMIP-1 beta gene appears to be unresponsive to dexamethasone. Also present in the 5'-regulatory region was a LPS-responsive element located within 455 bp 5' to the start of transcription.

Base Sequence↗
PubMed1991

Interleukin 7 induces cytokine secretion and tumoricidal activity by human peripheral blood monocytes.

Peripheral blood monocytes can be induced by stimuli such as bacterial lipopolysaccharide (LPS) to secrete an array of cytokines. We have studied the effects of interleukin 7 (IL-7) on human peripheral blood mononuclear cells (PBMC) and found that IL-7 is a relatively potent inducer of IL-6 secretion IL-6 protein levels were determined either by the B9 hybridoma growth factor assay or by enzyme-linked immunosorbent assay, and mRNA for IL-6 was analyzed by Northern hybridization. Detailed examination revealed that, among PBMC, monocytes, rather than lymphocytes, were secreting IL-6 in response to IL-7. In contrast to the low concentrations of IL-7 required to stimulate T cell growth and differentiation (as low as 0.1 ng/ml), relatively high concentrations of IL-7 were necessary to induce IL-6 secretion by monocytes (at least 10 ng/ml). An optimal concentration of IL-7 (100 ng/ml) induced monocytes to secrete 10-fold more IL-6 than an optimal concentration of IL-1 beta (10 ng/ml), and almost as much as LPS. However, significantly more IL-7 than IL-1 beta was required to induce detectable levels of IL-6. The kinetics of IL-6 secretion by monocytes were identical in response to IL-7, IL-1 beta, or LPS, with IL-6 protein detectable in culture supernatants as early as 2 h after the initiation of culture. IL-4 was found to markedly inhibit the ability of IL-7 or LPS to induce IL-6 mRNA and IL-6 secretion. In addition to promoting IL-6 production, IL-7 induced the secretion of immunoreactive IL-1 alpha, IL-1 beta, and tumor necrosis factor alpha (TNF-alpha) by monocytes. IL-7 also induced monocyte/macrophage tumoricidal activity against a human melanoma cell target, an activity that may be related to the secretion of IL-1 alpha, IL-1 beta, and TNF-alpha. Finally, we used a whole blood culture system as a bridge to in vivo analysis to demonstrate that IL-7 induces cytokine secretion in the absence of culture medium, fetal calf serum, and adherence to plastic. Our data suggest that IL-7, in addition to regulating lymphocyte growth and differentiation, has potent effects on cells of the monocytic lineage. Thus, IL-7 may be an important mediator in inflammation and in the macrophage immune response to tumors.

Cell Survival↗
PubMed1990

Interleukin 7 enhances cytolytic T lymphocyte generation and induces lymphokine-activated killer cells from human peripheral blood.

The effects of purified recombinant interleukin 7 (IL-7) on the generation of cytolytic T lymphocytes (CTL) in mixed lymphocyte culture (MLC) and on the induction of lymphokine-activated killer (LAK) cells in autologous cultures of human peripheral blood mononuclear cells were investigated. IL-7 was found to induce the generation of both CTL and LAK cells in bulk cultures. The appearance of peak CTL activity in MLC established with exogenous IL-7 was delayed in comparison with replicate cultures containing exogenous IL-2, but both cytokines stimulated quantitatively similar levels of antigen-specific lytic activity. An IL-2-neutralizing antiserum inhibited substantially, but not completely, the effect of IL-7 on CTL generation, implying the existence of both an indirect component of IL-7 activity via IL-2 utilization, as well as an IL-2-independent component. Cell surface phenotypic analysis of IL-2- or IL-7-generated CTL effector cells revealed that CD8+ cells were responsible for the vast majority of lytic activity. Limiting dilution analysis (LDA) revealed that essentially identical frequencies of CTL precursors (CTL-P) were capable of clonal expansion and/or differentiation in the presence of exogenous IL-2, IL-4, or IL-7, supporting the concept that all three of these cytokines are capable of exerting a major influence on T cell growth and differentiation. Approximately half of the CTL-P that responded in IL-7-supplemented LDA cultures did so in an IL-2-independent manner. IL-7 stimulated the development of LAK cells in autologous bulk cultures, but only weakly in comparison with IL-2. In contrast to its effects on CTL generation, the induction of LAK cells by IL-7 was virtually independent of IL-2. LAK cells induced by IL-7, like those induced by IL-2, were phenotypically heterogeneous and included CD8+, CD56+, and gamma/delta+ cells. Limiting dilution analysis indicated that IL-2 stimulated fivefold more LAK-P than IL-7 and 220-fold more than IL-4. Collectively, these data suggest that IL-7 has potent regulatory effects on human cytolytic cell populations and, either alone or in combination with other cytokines, could be important for the in vitro expansion of cells for adoptive immunotherapy.

Antigens, CD↗
PubMed1989

Recombinant human interleukin 6 (B cell stimulatory factor 2) enhances immunoglobulin secretion by single murine hapten-specific B cells in the absence of cell division.

We have assessed the role of recombinant human IL-6 (r-hu-IL-6) in promotion of early activation, proliferation, and immunoglobulin (Ig) secretion amongst single hapten-specific murine splenic B cells in vitro. It was found that r-hu-IL-6 acting alone was able to induce early B cell activation in a proportion of B cells, as measured by a significant increase in cell diameter within 24 h. An enhanced effect was seen in the concomitant presence of a 'T-independent' antigen. None of the B cells activated by r-hu-IL-6 appeared to divide, as the frequencies of proliferating clones induced by either medium alone or antigen alone were virtually identical whether r-hu-IL-6 was present or absent. However, assay of the culture supernatants for the presence of Ig by ELISA revealed that r-hu-IL-6 effected a significant 2-fold increase in the frequency of B cells secreting Ig. Thus, the prime effect of r-hu-IL-6 appears to be to recruit more precursor B cells into Ig secretion, rather than to promote proliferation or to enhance the amount of Ig secreted by pre-committed but non-cycling B cells. Delayed addition experiments showed that r-hu-IL-6 enhanced Ig secretion late in the activation pathway. Kinetics studies demonstrated detectable Ig secretion as early as day 2, and when taken with its apparent ability to induce early activation, these findings suggest that IL-6 is not exclusively a late-acting interleukin. Studies with size fractionated hapten-specific B cells showed the larger B cells to be preferentially responsive to r-hu-IL-6.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Recombinant T cell replacing factor (interleukin 5) acts with antigen to promote the growth and differentiation of single hapten-specific B lymphocytes.

The role of murine recombinant T cell replacing factor (rTRF) (interleukin 5) in the early activation, proliferation, and antibody-forming cell (AFC) clone formation of single fluorescein (FLU)-specific B cells was examined in vitro. FLU-specific B cells were selected by their adherence to FLU-gelatin and then cultured in 10-microliters wells with or without rTRF in the presence or absence of the T-independent antigen FLU-polymerized flagellin (FLU-POL). rTRF acting alone was unable to induce early B cell activation as assessed by significant cell enlargement after 24 hr in culture. When acting in the presence of FLU-POL, however, a greater number of B cells were induced to enlarge than with FLU-POL alone. When FLU-specific B cells were cultured in the presence of FLU-POL, the addition of rTRF markedly increased the frequencies of both proliferating clones and AFC clones above that induced by FLU-POL alone. Furthermore, in the presence of FLU-POL, the activity of rTRF was comparable to that seen with the mixture of B cell growth and differentiation factors contained within the supernatant from concanavalin A-stimulated EL4 cells. However, rTRF exerted little activity when acting alone in contrast to the medium conditioned by concanavalin A-stimulated EL4 cells which showed some activity in the absence of FLU-POL. rTRF acting with FLU-POL also promoted AFC clone development among single B cells stimulated in the presence of 3T3 fibroblast filler cells. Thus rTRF can be added to the list of B cell active factors (including recombinant murine interleukin 1 and recombinant human interleukin 2) that act in the concomitant presence of antigen to induce both growth and differentiation among single hapten-specific murine splenic B cells. This stands in contrast to the activity seen with interleukin 4 (formerly termed B cell stimulatory factor 1) which acts to promote early activation and proliferation but not IgM secretion.

Animals↗
PubMed1987

Effects of antigens and lymphokines on early activation of single hapten-specific B lymphocytes.

An assay was developed to monitor early activation of single fluorescein-specific B cells obtained from the spleens of nonimmunized adult mice by prefractionation on hapten gelatin. Early activation was assessed as a significant increase in the diameter of individual B cells after 24 hr in vitro. Significant enlargement of the single B cells was induced within 24 hr by either T-independent antigens acting alone or a crude source of B cell growth and differentiation factors (EL-BGDF-pik) acting alone. In contrast, T-dependent antigens acting alone were ineffective. When selected T-independent antigens and EL-BGDF-pik acted together, a greater number of B cells were induced to enlarge. B cell stimulatory factor 1 (BSF 1) behaved in a similar manner as EL-BGDF-pik, inducing early B cell enlargement both in the absence and more so in the presence of antigen. Both EL-BGDF-pik and BSF 1 enhanced the survival of single hapten-specific B cells during the 24-hr period. Interleukin 1 was unable to cause B cell enlargement when acting alone, although it was able to augment B cell enlargement induced by antigen. Interleukin 2 did not induce cell enlargement in either the presence or absence of antigen. Activation was demonstrated among cells of all sizes, regardless of the stimulus, although a greater response was demonstrated amongst the larger cell population. The addition of 3T3 filler cells enhanced early B cell activation and cell survival during the 24-hr period. The 24-hr B cell enlargement assay as applied to isolated single cells provides an unequivocal approach to the analysis of early B cell activation, adding a further parameter for the dissection of the precise roles of antigen and the various factors in the B cell differentiation pathway.

Animals↗
PubMed1987

Single cell studies on the role of B-cell stimulatory factor 1 in B-cell activation.

The role of the T-cell-derived lymphokine B-cell stimulatory factor 1 (BSF-1) in the early activation, proliferation, and antibody-forming cell (AFC) clone formation of single fluorescein-specific B lymphocytes isolated from normal mouse spleens by hapten-gelatin adherence has been studied in vitro. BSF-1 acting alone induced early B-cell activation, as assessed by a significant increase in cell diameter of single B cells cultured for 24 hr. A small but significant number of these B cells formed proliferating clones, some of which secreted antibody. When acting with the specific antigen fluorescein-polymerized flagellin, BSF-1 augmented early cell enlargement and markedly enhanced proliferation, but it did not increase the frequency of AFC clones stimulated by fluorescein-polymerized flagellin alone. The further addition of recombinant murine interleukin 1 (IL-1) marginally enhanced proliferation caused by antigen plus BSF-1. No synergy was observed between BSF-1 and IL-1 for antibody formation. In the presence of fibroblast filler cells, BSF-1 substantially inhibited AFC clone development achieved by antigen plus IL-1. BSF-1 was also found to be inhibitory to AFC clone development stimulated by specific antigen acting with either recombinant human interleukin 2 (IL-2) or with IL-2 plus IL-1, both in the presence or absence of filler cells. The results suggest that BSF-1 plays a complex role in the regulation of the B-cell activation pathway by enhancing early activation and antigen-specific proliferation as well as inhibiting the effects of other B-cell factors on antibody formation. BSF-1 is the only cytokine so far tested in the single B-cell system that acts with antigen to promote proliferation without concomitant antibody production.

Animals↗
PubMed1987

T-independent activation of single B cells: an orderly analysis of overlapping stages in the activation pathway.

This review has three chief purposes. It describes a microculture system in which single, hapten-specific B lymphocytes can be microscopically observed, cultured and assayed for antibody production in isolation and thus are the unequivocal target of ligands present in the culture fluid. It defines the respective roles of antigens and cytokines acting singly or in combination in the four discernible phases of the immunoproliferative cascade, namely activation, clonal expansion, IgM antibody secretion and isotype switching. It then argues that this precise stepwise analysis can yield useful information concerning important immunological situations, such as experimentally induced immunological tolerance or the effects of constitutive expression of the c-myc oncogene. Evidence is presented that initial activation of the resting B cell in "T-independent" triggering can be achieved either by attachment of a molecule that has B-cell stimulatory properties, such as FLU-LPS or FLU-polymerized flagellin (FLU-POL) or by the lymphokine interleukin 4 (IL-4). IL-4 + FLU-POL is somewhat more effective than either agent alone. IL-4 alone or, better, FLU-POL + IL-4 can stimulate clonal proliferation of the B cell, but FLU-POL alone does not achieve this. Moreover, IL-4 or FLU-POL + IL-4 lead to very little antibody formation. None of IL-1, IL-2 or IL-5 acting alone causes either activation or proliferation. IgM antibody formation is stimulated most strongly by FLU-POL + IL-5, somewhat less strongly by FLU-POL + IL-1 + IL-2 and rather weakly with antigen plus only one of the latter cytokines. The cloning efficiency in the single cell system, and the median clone size can be markedly enhanced by the addition of small numbers of fibroblast or other filler cells to the cultures. While filler cell-free clones do not progress to the stage of isotype switching, filler cell-supported ones can do so in up to 30% of cases. The only cloned lymphokine which has so far been found to promote such switching is IL-4, and the fact that it is at least as powerful as a T-cell supernatant may mean that it is the only agent active in this particular system. However, the detailed pattern of secreted isotypes is different from that seen when MHC-restricted, carrier-specific T cells act on hapten-specific B cells. Hapten-specific B cells from animals rendered neonatally tolerant to FLU-HGG exhibit anergy in the single cell system.(ABSTRACT TRUNCATED AT 400 WORDS)

Antibody-Producing Cells↗
PubMed1986

The effect of ultraviolet radiation on humoral immune responses to T-dependent antigens.

Multiple exposures to broadband ultraviolet (uv) radiation resulted in alterations in the ability of BALB/c mice to produce antibodies to the T-dependent antigens ovalbumin and sheep erythrocytes following intraperitoneal, intradermal, and intravenous inoculation. A number of differences were observed in the influence of uv radiation on the specific cells producing antibody, as opposed to pure serological analyses. While both enhancement and reduction of the humoral response occurred, the experiments have suggested that the alterations in antibody responses following uv irradiation appear to be dependent on the nature of the antigen, the route of antigen administration, and the sometimes transient nature of the responses. The intradermal route of antigen inoculation was under the greatest influence of uv radiation.

Animals↗
PubMed1986

Relationship of passive smoking to risk of lung cancer and other smoking-associated diseases.

In the latter part of a large hospital case-control study of the relationship of type of cigarette smoked to risk of various smoking-associated diseases, patients answered questions on the smoking habits of their first spouse and on the extent of passive smoke exposure at home, at work, during travel and during leisure. In an extension of this study an attempt was made to obtain smoking habit data directly from the spouses of all lifelong non-smoking lung cancer cases and of two lifelong non-smoking matched controls for each case. The attempt was made regardless of whether the patients had answered passive smoking questions in hospital or not. Amongst lifelong non-smokers, passive smoking was not associated with any significant increase in risk of lung cancer, chronic bronchitis, ischaemic heart disease or stroke in any analysis. Limitations of past studies on passive smoking are discussed and the need for further research underlined. From all the available evidence, it appears that any effect of passive smoke on risk of any of the major diseases that have been associated with active smoking is at most small, and may not exist at all.

Adult↗
PubMed1986

The occupational risks of alcoholism.

The occupations of 6,596 psychiatric admissions with alcoholism were analyzed and their admission rates compared with occupational death rates due to cirrhosis of the liver. Two thirds of occupations with high admission rates had correspondingly high cirrhosis death rates but a dozen occupations had low admission rates and high liver cirrhosis death rates, suggesting a degree of heavy drinking which is not treated. Low-risk occupations are identified and their characteristics discussed.

Adolescent↗
PubMed1985

Risks of lung cancer, chronic bronchitis, ischaemic heart disease, and stroke in relation to type of cigarette smoked.

In a case control study of over 12 000 inpatients aged 35-74, risk of lung cancer, chronic bronchitis, and, particularly in those aged 35-54, ischaemic heart disease was positively associated with the number of manufactured cigarettes smoked daily and was negatively associated with long term giving up. Risk of stroke was not clearly related to smoking. Among manufactured cigarette smokers, lung cancer risk tended to be lowest in those who had always smoked filter cigarettes. This pattern was, however, evident only in men who additionally smoked pipes, cigars or handrolled cigarettes and in women, not being seen in men who smoked only manufactured cigarettes. Risk of lung cancer was not clearly related to time of switch to filter cigarettes. A markedly lower risk of chronic bronchitis was seen in men, but not women, who smoked filter rather than plain cigarettes. Heart disease risk did not vary by type of cigarette smoked 10 years before admission, but, compared with those who had never smoked filter cigarettes, those who had ever smoked filter cigarettes had a higher risk in men and a lower risk in younger women. Compared with the general population, markedly more controls were ex-smokers, suggesting incipient disease, whether or not smoking related, may alter smoking habits, thus affecting the interpretability of the findings. Control smokers were also relatively much more likely to report smoking plain cigarettes than expected. This comparison, not made in other studies relating risk to type of cigarette smoked, indicates that great care must be taken in verifying validity of reported smoking habits. While our findings are compatible with other evidence that risk of lung cancer and chronic bronchitis is probably reduced by switching from plain to filter cigarettes, they underline the difficulties in obtaining valid evidence from epidemiological studies.

Adult↗
PubMed1984

Death certification in cancer of the breast.

The cause of death entered on the death certificates of 193 patients originally diagnosed as having cancer of the breast was compared with information obtained from clinical records, cancer registry records, and necropsy findings to determine the accuracy of death certification and the proportion of patients who, though dying from another cause, still had overt signs of cancer of the breast. It was found that the overall error in certifying cause of death as breast cancer was small, being an underestimate of about 4%. About a third of patients with breast cancer dying from other causes had overt signs of breast cancer at the time of death.

Aged↗
PubMed1984

Pilot study of revised stillbirth and neonatal death certificates.

Draft revised stillbirth and early infant death certificates were sent with a short questionnaire to certifying doctors for 206 stillbirths and 198 neonatal deaths for which death certificates had been received in the Office of Population Censuses and Surveys over a three week period in 1982. The new certificates complied with the recommendations of the World Health Organisation and asked for details of the cause of death, including separate sections for maternal and fetal conditions. Replies were received for 163 stillbirths and 151 neonatal deaths. Questionnaires were examined clerically and answers and comments analysed. Draft certificates were processed by computer to examine any differences between the causes of death given on the new forms and information given on the original certificates. This testing suggested that revised certificates are acceptable. Extension of the early infant death certificate to cover all neonatal deaths does not seem to create problems and should provide information on the association between maternal conditions and deaths occurring in the second to fourth weeks of life. If the full potential of the new certificates is to be realised, attention needs to be given to the detailed layout of the forms and clearer notes of guidance. Certifiers need to be encouraged to give appropriate details of any obstetric problems.

Attitude of Health Personnel↗