Disease relevance of cyclosporine

• Hepatitis B virus (HBV) DNA-transfected hepatoma cells were incubated with the immunosuppressive agents prednisolone, azathioprine, and cyclosporin A (CsA) and the antiviral agents ganciclovir and foscarnet to investigate the effects of these compounds on HBV replication [1].
• Syngeneic graft-vs-host disease (SGVHD) develops following lethal irradiation, reconstitution with syngeneic bone marrow, and treatment with a 21-day course of the immunosuppressive agent cyclosporin A (CsA) [2].
• Following cessation of CsA, this inducible disease is characterized by weight loss, diarrhea, and development of inflammation in the colon and liver [2].
• In contrast, IFN-alpha/beta production by Newcastle disease virus-infected spleen cells, bone marrow cells, or L cells was not inhibited by the addition of CsA (1 microgram/ml) [3].
• Decreases in transplant function may be attributable to a variety of conditions, including prerenal and postrenal failure, cyclosporin A (CsA) toxicity, polyoma nephritis, recurrent glomerulonephritis, and rejection [4].

High impact information on cyclosporine

• A tricyclic variant (TCsA) of the immunosuppressant cyclosporin A (CsA), which inhibits the proliferation of T lymphocytes by forming a cyclophilin-CsA-calcineurin complex, was designed with the known three-dimensional structure of a cyclophilin-CsA complex [5].
• CD16 (Fc gamma RIIIA)-induced expression of cytokine mRNA in NK cells occurs via a CsA-sensitive and Ca(2+)-dependent mechanism [6].
• This occurs with fast kinetics after stimulation, via a CsA-sensitive and Ca(2+)-dependent mechanism that does not require de novo protein synthesis [6].
• TNF-alpha gene transcription is also highly inducible, CsA-sensitive, and protein synthesis-independent in B cells stimulated through their surface immunoglobulin receptors [7].
• The ability of analogues of CsA and FK506 to block calcineurin phosphatase activity correlates completely with their ability to inhibit induction of TNF-alpha mRNA, induction of a TNF-alpha promoter reporter plasmid in transiently transfected T cells, and induction of the kappa 3 binding factor in an electrophoretic mobility shift assay [7].

Chemical compound and disease context of cyclosporine

• All patients initially responded to prednisolone at 60 mg/m2/day, and subsequent frequent relapses were treated sequentially with oral cyclophosphamide 168 mg/kg over 8-12 weeks (n = 10), CYA (n = 10), intravenous mustine or a second course of cyclophosphamide (n = 7) and then TAC (n = 10) [8].
• For CYA and TAC treatment periods, the median NS relapse rate was two and one relapses per year, respectively, and cumulative steroid dosage was 73.9 and 105.2 mg/kg/day, respectively (P = 0.54) [8].
• We found no significant differences in C2 levels between patients with rejection and CyA toxicity [9].
• Chymase-positive mast cells may play a role in formation of gingival overgrowth, especially in patients receiving cyclosporin A (CsA) medication with no concomitant nifedipine [10].
• Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporin A (CyA) and methotrexate (18 patients) or CyA and methylprednisolone (5 patients) [11].

Biological context of cyclosporine

• The immunosuppressive complexes cyclophilin A-cyclosporin A (CsA) and FKBP12-FK506 inhibit calcineurin, a heterodimeric Ca(2+)-calmodulin-dependent protein phosphatase that regulates signal transduction [12].
• Three mutations that confer dominant CsA resistance are single amino acid substitutions (T350K, T350R, Y377F) in the calcineurin A catalytic subunit CMP1 [12].
• In TMC-treated rats that received a heterotopic cardiac allograft, the graft survived more than 160 days, comparable to graft survival in allografted rats treated with CsA [13].
• T-cell receptor (TCR)-mediated apoptosis in immature thymocytes and T-cell hybridomas is calcium dependent and can be inhibited by cyclosporin A (CsA) [14].
• In addition, Nur77 promoter deletion analysis revealed two RSRF (related to serum-responsive factor) binding sites, which can confer calcium and CsA sensitivity on a heterologous promoter [14].

Anatomical context of cyclosporine

• SAC-, PMA plus SAC-, and PMA plus anti-mu-stimulated, but not PMA-stimulated, increases in TNF mRNA accumulations in tonsillar B cells were inhibited by CsA [15].
• Furthermore, it is not inhibited by cyclosporin A (CsA), in contrast to NK cell cytotoxicity against the K562 target cell line which is augmented by interferon, inhibited by CsA, and not affected by MVF [16].
• The effect of CsA on IFN production by alloantigen-stimulated bone marrow and spleen cells was investigated [3].
• On the contrary, RAP diminished the autonomous proliferation of hybridoma cells, whereas FK-506 and CsA had little effect [17].
• Ceramide replaced TNF in killing L929 fibroblasts, an effect also prevented by CyA plus ArA [18].

Associations of cyclosporine with other chemical compounds

• To test this, cyclosporin-A (CyA), a T-lymphocyte function inhibitor known to suppress CSA production in PWM-SCM, was added to marrow cultures in the presence of 2 mM Li [19].
• The MPT was demonstrated independently of its effect on viability as the CyA-sensitive loss of rhodamine 123 fluorescence from cells preloaded with the dye [18].
• From these results, the synergistic effect of FTY720 combined with CsA on prolongation of allograft survival is presumably based on the respective inhibitions of T cell infiltration and cytokine production in grafts [20].
• In such a system, as well as in normal T cells stimulated with high ionomycin concentrations, FK-506 and CsA enhanced proliferation, indicating that they both abrogate negative signals associated with T cell activation [17].
• Cyclosporin A (CsA) completely blocked the activation-induced death of T cell hybridomas, but actually enhanced the killing caused by Dex [21].

Gene context of cyclosporine

• Double mutant calcineurin A subunits (Y377F, W388C CMP1 and Y419F, W430C CMP2) confer resistance to CsA, to FK506 and to CsA plus FK506 [12].
• The immunosuppressant and cytotoxic effects of CsA are thought to result from formation of a toxic complex between cyclophilin and CsA rather than from inhibition of cyclophilin function [22].
• Here, TNF-alpha gene transcription is shown also to be highly and rapidly induced in human B cells after stimulation via the CD40 and interleukin 4 pathways, which similarly is inhibited by CsA and a panel of CsA or FK506 analogues that block calcineurin phosphatase activity [23].
• Similarly, murine mdr3 expression confers resistance to the immunosuppressants cyclosporin A (CsA) and FK506 in a CsA-FK506-sensitive vph6 mutant yeast strain [24].
• SDZ PSC 833, a non-immunosuppressive analogue of cyclosporin A (CsA), is another potent MDR-reversing drug [25].

Analytical, diagnostic and therapeutic context of cyclosporine

• CONCLUSIONS: Alloimmune injury induces the expression of PDGF ligands, especially of PDGF-AA, in the graft vasculature and sufficient immunosuppression with CsA suppresses the expression of PDGF and inhibits the development of CAV [26].
• Beginning on the day of bone marrow transplantation, groups of control and CsA-treated animals were treated with mAb against either CD4 or CD8 for 21 days [2].
• CsA is cytoprotective in many cellular and animal models, but protection may result from either inhibition of the MPT through an interaction with CYP D or inhibition of calcineurin-mediated dephosphorylation of BAD through an interaction with CYP A [27].
• When PSC concentrations obtained by the TDx CsA assay were divided by 0.17, we found agreement between the TDx CsA assay and the HPLC PSC assay for samples from nine patients [28].
• Using CsA affinity chromatography, only one cyclophilin with a molecular mass of about 17.8 kDa was separated [29].

References