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- Johansson Borg, Anette
(författare)
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Effects and mechanisms of actions of cyclosporin, FK506 and 15-deoxyspergualin
- 1995
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Immunosuppressive drugs can be used to deal with unwanted or inappropriate immune reactions, such as the rejection of a transplanted organ. However, treatment with these drugs are often associated with serious adverse effects, and therefore less toxic immunosuppressants are desired. The aims of the present study were to evaluate the immunologic effects of cyclosporin-sulphate, FK506 and 15-deoxy-spergualin (DSG). CsA-sulphate, a previously unidentified CsA metabolite, is present in high concentration in the bile and plasma of transplanted patients. In vitro and in vivo studies showed that this metabolite has limited immunosuppressive effects. It is likely that the mother compound is responsible for both the immunosuppressive and adverse effects associated with treatment. FK506 is structurally completely distinct from CsA, but was found to have identical immunosuppressive effects in vitro, although at l0-l00 times lower concentrations. Based on studies of combinations of the two drugs, the effects CsA and FK506 are stipulated to be additive. The similar and additive effects of the drugs indicate that they share a common mechanism of action. The prevailing theory is that the drugs first bind to their respective immunophilin. The drug-immunophilin complexes inhibit the calcineurin-mediated dephosphorylation and thus the translocation to the nucleus of the cytoplasmic component of the transcription factor NF-AT. DSG have immunosuppressive properties that are distinct from CsA and FK506, but its mechanism of action remains elusive. In a safety-study, where DSG was given in combination with methyl-prednisolone as treatment of acute graft rejection in kidney transplant recipients, the effects of DSG on blood mononuclear cells were studied. DSG decreased the number of leukocytes, and results indicated that DSG may affect B-cells and perhaps also CD4+ cells. Our in vitro studies confirmed an effect of DSG on the development of cytotoxic T cells. DSG also suppressed the proliterative responses to S. aureus and PHA, if added within 24 hours after stimulation. These effects could be explained by a DSG-dependent reduced Il-6 production. However, addition of recombinant Il-6 only partly restored the development of cytotoxic T-cells, and thus, additional Il-6 independent steps should be DSG-sensitive in the differentiation of CTL. In the transplantation of fetal porcine islet cells, reactivity against the graft is likely to have been induced via the indirect activation pathway of immune recognition. CsA was found to be less efficient in inhibiting the cytotoxicity induced by xenogeneic porcine Iymphocytes via the indirect as compared to the direct pathway. In contrast, DSG inhibited the induction of cytotoxicity equally, irrespective of activation pathway. Although DSG did not suppress antibody production to pig PBL in mice completely, it was more efficient than CsA. DSG may act by modulating the activities of the heat shock proteins Hsc70 and Hsp90. This thesis adds to the knowledge of the effects and mechanisms of action of cyclosporin, FK506 and DSG, knowledge that may be valuable for the optimal treatment of transplant recipients, and in the further development of immuno-suppressive drugs.
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- Johansson, L, et al.
(författare)
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Effects of red clover silage and ageing time on sensory characteristics and cooking losses of loin (M. longissimus dorsi) from Hampshire crosses with and without the RN− allele
- 1999
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Ingår i: Food Quality and Preference. - : Elsevier. - 0950-3293 .- 1873-6343. ; 10:4-5, s. 299-303
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Tidskriftsartikel (refereegranskat)abstract
- The study concerns the effects of red clover silage (silage) and ageing time on sensory characteristics and cooking loss of loin from Hampshire crosses with and without the RN− allele. Half of each litter received conventional feed and the other half conventional feed with admixed red clover silage. Loins were aged at 4°C (4 and 8 days), prepared at 150° to 68°C and sensory evaluated by descriptive analyses. RN− carriers had loins of higher meat taste intensity and a more acidulous taste than non-carriers. Meat taste intensity and tenderness increased as ageing time increased while acidulous taste decreased. Loins, aged 4 days, from conventionally fed pigs were juicier than those of silage-fed pigs. RN− carriers had a greater total cooking loss than non-carriers
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- Risedal, Anette, et al.
(författare)
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Infarct volume and functional outcome after pre- and postoperative administration of metyrapone, a steroid synthesis inhibitor, in focal brain ischemia in the rat
- 1999
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Ingår i: European Journal of Neurology. - : Wiley. - 1351-5101 .- 1468-1331. ; 6:4, s. 481-486
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Tidskriftsartikel (refereegranskat)abstract
- High blood levels of glucocorticoids are associated with increased mortality, confusion and poor functional outcome in stroke patients. It has been proposed that inhibition of glucocorticoids in acute stroke might be beneficial, but experimental data are conflicting and no long-term follow-up study has been reported. We have studied whether pre- or postoperative administration of metyrapone, a steroid synthesis inhibitor, can influence long-term outcome after ligation of the right middle cerebral artery (MCA) distal to the striatal branches in hypertensive rats. Metyrapone (200 mg/kg) was administered either 30 min before or 1, 12 and 24 h after MCA occlusion. Limb placements and ability to traverse a rotating pole were evaluated pre- and postoperatively. Infarct size, histology and GFAP immunoreactivity were evaluated on 5 microm coronal sections from brains perfused in situ 4 weeks after the ischemic event. Pretreatment did not influence outcome, whereas postoperative administration of metyrapone significantly increased infarct volume (P < 0.05). Post-treated rats performed significantly worse than vehicle-treated rats on the rotating pole 3 weeks after the operation (P < 0.05). Our results do not support the hypothesis that inhibition of glucocorticoid synthesis improves outcome after cerebral ischemia.
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