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Biomedical subjects

A W Thomson

Publications and source records attributed to A W Thomson.

At least 19 recordsLinked to original sources
PubMed1992

The effects of cyclosporin A on non-T cell components of the immune system.

Cyclosporin A (CsA) is a potent inhibitor of cytokine (IL-2-IL-6, IFN gamma) production by CD4+ T lymphocytes stimulated via the T cell antigen receptor pathway. This action results in indirect inhibitory effects on the growth and differentiation of B lymphocytes (IL-4 and IL-6). Using experimental models, it has also been shown that the functional activities of mononuclear phagocytes (IFN-gamma) and other antigen-presenting cells, production of mast cells (IL-3) and eosinophils (IL-5) and the activity of natural killer (NK) cells may be inhibited indirectly by CsA. In addition, however, CsA blocks B cell responses to Ca(2+)-dependent signals (e.g., anti-IgM) downstream of phosphatidyl inositol diphosphate hydrolysis; Ca(2+)-independent responses (e.g., to LPS or IL-4) are largely unaffected. In general terms, the functions of macrophages are unchanged or reduced in the presence of CsA. These include phagocytic activity in vitro and in vivo, chemotactic migration, superoxide and H2O2 production, protein (including monokine) secretion and MHC gene product expression. Antigen presentation (e.g., by epidermal Langerhans cells) may be affected, especially at high drug concentrations. There is recent evidence that CsA inhibits mediator (histamine and prostaglandin) release from human mast cells and that mucosal mast cell numbers may be diminished in CsA-treated animals exhibiting graft-versus-host disease or helminth infections.

Animals↗
PubMed1992

Immunomodulatory agents in the laboratory and clinic.

This paper reviews naturally occurring and synthetic compounds that either enhance immune defences or lower both natural and acquired immunity. Immunomodulatory agents used both for laboratory study and clinically for the management of immunologically based diseases are considered.

Acute-Phase Reaction↗
PubMed1992

The effects of rapamycin on humoral immunity in vivo. Suppression of primary responses but not of ongoing alloantibody synthesis or memory responses.

The effect of rapamycin on primary and secondary alloantibody responses to major histocompatibility complex class I antigens was investigated in inbred rat strains. Primary anti-MHC class I alloantibody responses, detected by indirect hemagglutination and complement-dependent cytotoxicity assays, were abrogated in high-responder WAG (RT1u) recipients of DA (RT1a) blood transfusions, given on days 0 and 7 of a 14-day course of rapamycin (3 mg/kg/day). Antibody class studies showed that both IgM and IgG responses were equally effectively inhibited. Moreover, when these animals were rechallenged with DA transfusions, 28 days after drug withdrawal, they exhibited donor-specific humoral unresponsiveness. Similar results were observed in cyclosporine-treated rats. In preimmunized high-responder LEW (RT1(1)) rats with high titer anti-DA class I alloantibodies, a 35-day course of rapamycin (3 mg/kg/day) had no significant suppressive effect on serum alloantibody levels when compared with untreated preimmunized control animals. WAG rats were immunized by DA transfusions and serum antibody levels then allowed to decay over 16 weeks. The animals were then challenged with a further DA transfusion given on the second day of a 14-day course of rapamycin (3 mg/kg/day). Alloantibody responses to the challenge transfusion in this group were not, however, significantly suppressed when compared with a non-drug-treated control group. The results of this study indicate that rapamycin is a potent inhibitor of primary alloantibody synthesis in high-responder rat strains, but does not significantly suppress alloantibody synthesis in animals with established humoral reactivity. These results may be of relevance if rapamycin is to be used in clinical renal transplantation, because in man similar antibodies mediate hyperacute rejection, and when they develop after transplantation are associated with very high rates of rejection.

Animals↗
PubMed1992

Interphotoreceptor retinoid binding protein induced experimental autoimmune uveitis: an immunophenotypic analysis using alkaline phosphatase anti-alkaline phosphatase staining, dual immunofluorescence and confocal microscopy.

Using a Lewis rat model of IRBP induced EAU, we have examined the progress of leucocytes infiltrating the uveitic eye. APAAP and dual immunofluorescence were used to show that ED7 and 8 (CD11b/CD18) positive monocytes, W3/25 and OX8 (CD4 and CD8) lymphocytes were prominent in the initial inflammatory exudate around the retinal vessels and in the choroid. ED1 positive monocytes were also observed in the choroid. As disease progressed, these cells moved into the inner retina, vitreous and ROS. ED8 positive cells were the first to appear in the ROS. This was followed by the later appearance of ED2 tissue macrophages in the vitreous and ED3 inflammatory macrophages in the vitreous and ROS.

Alkaline Phosphatase↗
PubMed1991

FK 506: an immunosuppressant for the 1990s?

The novel macrolide immunosuppressant FK 506 is a powerful and selective anti-T-cell agent which has a similar mode of action to that of cyclosporin. Clinical studies of FK 506 in liver allograft recipients indicate a lower risk/benefit ratio than with cyclosporin, and wider evaluation of FK 506 in transplant recipients is now under way in multicentre, prospective, controlled trials in both Europe and North America.

Animals↗
PubMed1991

The immunosuppressive macrolides FK-506 and rapamycin.

Cyclosporin (CsA) and FK-506 are structurally distinct fungal metabolites, which exert powerful inhibitory effects on CD4+ T (helper) cell activation and on the secretion of interleukin-2 (IL-2) and other cytokines, including various cell growth factors and interferon-gamma. Both drugs also inhibit IL-2 receptor expression on T cells. Consequently, when administered from the time of transplant surgery, both CsA and FK-506 inhibit the generation and proliferation of cytotoxic T cells which would otherwise mediate allograft rejection; T-cell dependent antibody responses are also inhibited by both drugs. CsA and FK-506 however, differ markedly in immunosuppressive potency. FK-506 is at least 100 times as potent as CsA in inhibiting human mixed lymphocyte reactions in vitro, whilst the ID50 of FK-506 for inhibition of allograft survival in animals is approximately one tenth that of CsA. FK-506 and CsA, both of which are highly lipophilic molecules, bind to distinct cytosolic proteins, each of which is a peptidyl-prolyl isomerase and the activities of which may play critical roles in signal transduction within activated T cells. The precise molecular mechanism by which these drugs selectively inhibit cytokine gene expression at a pretranscriptional level is not understood but a transcription activator has been implicated as the target. Compared with CsA, the inhibitory action of FK-506 appears more difficult to reverse, e.g., in response to pre-formed IL-2. Both drugs are however, ineffective in inhibiting directly the cytotoxic activity of cytotoxic T cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

The effect of rapamycin on renal function in the rat: a comparative study with cyclosporine.

Male adult Sprague-Dawley rats were treated for 14 days with either rapamycin (RAP, 1.5 mg/kg/d i.p.) in carboxymethylcellulose (RAP/CMC) or polyethyleneglycol (RAP/PEG), cyclosporine (CsA, 15 mg/kg/d by gavage) or with the appropriate drug vehicles. Biochemical indices of renal function and integrity were determined throughout the experimental period, at the end of which the rats were killed and kidneys examined histologically. All animals gained weight at a similar rate to untreated animals except those treated with RAP; RAP/PEG animals were lighter on day 14 compared with day 0 values, whilst RAP/CMC animals were lighter only in comparison with CMC-only controls on day 14. Significant increases in urinary flow rate (UFR) were found in each drug treatment group. RAP/CMC, RAP/PEG and CsA caused mild renal functional impairment, but only with CsA was there a significant reduction in 51Cr-EDTA clearance. Significant enzymuria, resulting from drug but not vehicle administration, was observed only in the CsA-treatment group. Increased plasma and urinary glucose levels, elevated in all drug-treatment groups, were related to increased UFR. Kidneys of RAP-treated rats appeared normal, whereas mild, focal, acute tubular necrosis was evident in all CsA-tested animals. Pancreases of all drug-treated animals were histologically normal.

Acetylglucosaminidase↗
PubMed1991

Immunomodulation: suppression, enhancement and autoimmunity.

Recent reports highlight new approaches to immunointervention (suppression or enhancement) based on the known roles of lymphocyte populations, cytokines and their receptors, and adhesion molecules in immune responses. Considerable interest over the past year has focused on immunophilins (cyclophilin and the FK506-binding protein) which appear to play key roles in signal transduction within activated T cells and provide a molecular basis for new advances in immunosuppressive drug therapy.

Animals↗
PubMed1991

The larvicidal activity of cyclosporin A against Schistosoma mansoni in mice.

Treatment of BALB/c or MF1 mice with cyclosporin A (CsA) around the time of infection with Schistosoma mansoni conferred almost complete protection. The migration kinetics of L-[75Se]selenomethionine-labelled infective cercariae were investigated by compressed tissue autoradiography. Similar levels of skin penetration were achieved by cercariae in control and drug-treated individuals. CsA arrested 87-94% of the worms in the skin and ultimately all of these died in this site. Few worms (7-14%) migrated from the skin to the lungs and none completed migration to the liver. Nevertheless, the autoradiograms revealed a limited degree of lateral cutaneous migration by the worms present in the skins of CsA-treated mice. Results of perfusion recovery experiments carried out during the course of infection reinforced the tracking data.

Animals↗
PubMed1991

Effects of cyclosporin A on growth and polyamine metabolism of MOLT-4 T-lymphoblastic leukaemia cells.

We have examined the effects of Cyclosporin A (CsA) on growth and polyamine metabolism of MOLT-4, human T lymphoblastic leukaemia cells to ascertain the role of the polyamine biosynthetic pathway in the antitumour action of CsA. We observed that CsA had a dose-dependent inhibitory effect on growth of the cells in vitro, decreasing protein content, cell number and the rate of incorporation of 3H-thymidine into the cells. However, CsA treatment had no significant effect on intracellular polyamine levels in the cells. Contrary to previous reports, simultaneous addition of the diamine, putrescine, with CsA did not block or lessen the growth inhibitory effects of CsA. On the other hand, ornithine decarboxylase activity, the rate limiting enzyme of polyamine biosynthesis which converts ornithine to putrescine, was decreased by CsA treatment. This decrease appeared to be reversible and contrasts with the inhibition by alpha-difluoromethyl-ornithine, which is irreversible and can be overcome by addition of putrescine. This suppression of ornithine decarboxylase by CsA is more likely to occur by indirect effects on translation and/or transcription rather than a direct effect on the enzyme. It may be a contributory factor in the overall antiproliferative effects of CsA but is more likely to be a response to these growth inhibitory effects rather than a direct effect of the drug.

Cell Division↗