Cyclosporin is a lipophilic cyclic polypeptide which produces calcium-dependent, specific, reversible inhibition of transcription of interleukin-2 and several other cytokines, most notably in T helper lymphocytes. This reduces the production of a range of cytokines, inhibiting the activation and/or maturation of various cell types, including those involved in cell-mediated immunity. Thus, cyclosporin has immunosuppressive properties, and has a proven place as first line therapy in the prophylaxis and treatment of transplant rejection. Cyclosporin has also been evaluated in a large range of disorders where immunoregulatory dysfunction is a suspected or proven aetiological factor, and this is the focus of the present review. In patients with severe disease refractory to standard treatment, oral cyclosporin is an effective therapy in acute ocular Behcet's syndrome, endogenous uveitis, psoriasis, atopic dermatitis, rheumatoid arthritis, active Crohn's disease and nephrotic syndrome. Concomitant low dose corticosteroid therapy may improve response rates in some disorders. The drug can be considered as a first line therapy in patients with moderate or severe aplastic anaemia who are ineligible for bone marrow transplantation, with the additional benefit of reducing platelet alloantibody titres. It may also be of considerable therapeutic benefit in patients with primary biliary cirrhosis, particularly those with less advanced disease. Limited evidence suggests cyclosporin is effective in patients with intractable pyoderma gangrenosum, polymyositis/dermatomyositis or severe, corticosteroid-dependent asthma. Indeed, the steroid-sparing effect of cyclosporin is a significant advantage in a number of indications. Furthermore, the drug has shown some efficacy in a wide range of other, generally uncommon disorders in which controlled clinical trials are lacking and/or are unlikely to be performed. Cyclosporin does not appear to be effective in patients with allergic contact dermatitis, multiple sclerosis or amyotrophic lateral sclerosis. It is only temporarily effective in patients with type I (insulin-dependent) diabetes mellitus and should not be used in this indication. To avoid relapse after control of active disease, patients should receive cyclosporin maintenance therapy at the lowest effective dosage. However, maintenance therapy appears to be of no benefit in patients with Crohn's disease and cyclosporin should be discontinued in these patients once active disease is controlled. Hypertrichosis, gingival hyperplasia, and neurological and gastrointestinal effects are the most common adverse events in cyclosporin recipients, but are usually mild to moderate and resolve on dosage reduction. Changes in laboratory variables indicating renal dysfunction are relatively common, although serious irreversible damage is rare.(ABSTRACT TRUNCATED AT 400 WORDS)

/pdf/cyclosporin-a-review-of-its-pharmacodynamic-and-2wjzyh5l5a.pdf

Cyclosporin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in immunoregulatory disorders.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/ajt.14381

The American Society of Transplantation Consensus Conference on the Use of Hepatitis C Viremic Donors in Solid Organ Transplantation

In this report we have approached two questions relating to the mechanism of action of cyclosporin A (CsA). First, we address whether the major cytosolic protein for CsA, cyclophilin, is directly involved in mediating the immunosuppressive activity of this drug, and, in particular, whether inhibition of this protein's peptidyl-prolyl cis-trans isomerase (PPIase) activity results in inhibition of murine T cell activation. Second, we ask whether the nephrotoxicity observed with CsA is related to inhibition of PPIase-dependent pathways in cells other than lymphocytes. Using a series of 61 cyclosporin analogues, we generally found a good correlation between cyclophilin binding and immunosuppressive activity for the majority of analogues analyzed. However, a number of compounds of distinct structural classes were found that could interact with cyclophilin but were much less immunosuppressive than expected. The inability of these analogues to inhibit lymphocyte activation could not be explained by their failure to enter the cell and bind to cyclophilin under the conditions used in the cellular assays. Surprisingly, a nonimmunosuppressive analogue, MeAla-6, which bound well to cyclophilin and was active as a PPIase inhibitor, did not induce renal pathology in vivo. Furthermore, another analogue, MeBm2t, which was immunosuppressive in vitro, possessed little or no activity as a PPIase inhibitor. These findings pose serious questions concerning a direct role of cyclosporin in mediating CsA's immunosuppressive and nephrotoxic activities. In addition, they raise doubts about whether PPIase has a direct function in lymphocyte signal transduction.

https://rupress.org/jem/article-pdf/173/3/619/1101377/619.pdf

Is cyclophilin involved in the immunosuppressive and nephrotoxic mechanism of action of cyclosporin A

Cyclosporin therapy is associated with several forms of nephrotoxicity, the most significant of which are reversible impairment of glomerular filtration and irreversible interstitial fibrosis. Impaired glomerular filtration is due to both reduction in Kf, the glomerular capillary ultrafiltration coefficient, and to reduction in renal blood flow. The mechanisms responsible for the low Kf are not well defined, but heightened mesangial cell contractility may contribute. Reduced renal blood flow with chronic cyclosporin therapy arises from both endothelial damage and altered eicosanoid metabolism, in particular increased thromboxane synthesis. Renal interstitial fibrosis, which develops in some patients after approximately 6-12 months of cyclosporin therapy, poses a major limitation to the chronic use of the drug. Two mechanisms likely contribute to cyclosporin-associated interstitial fibrosis. First, endothelial injury and vasoconstriction produce renal ischemia, which in turn is associated with enhanced synthesis of extracellular matrix proteins. Second, cyclosporin likely influences the accumulation of matrix proteins in the renal interstitium through nonhemodynamic mechanisms, as suggested by altered matrix accumulation in non-renal tissues. This effect of cyclosporin may be direct or indirect, via mediators including cytokines, peptide growth factors, and thromboxane. The molecular mechanisms of cyclosporin action on immunologic and mesenchymal cells are active areas of investigation. Intracellular targets of cyclosporin include mitochondrial respiration, cellular calcium signaling, protein kinase C, protein synthesis, and peptidyl-prolyl isomerases. However, the significance of these intracellular effects for cyclosporin nephrotoxicity remains to be demonstrated.

/pdf/cellular-and-molecular-mechanisms-of-cyclosporin-2884e434zb.pdf

Cellular and molecular mechanisms of cyclosporin nephrotoxicity.

Renal Vascular and Thrombotic Effects of Cyclosporine

Cyclosporine appears to have abrogated age as a contraindication to kidney transplantation in the elderly, although it is unclear whether this is true for other types of solid organ transplantation. We performed a retrospective analysis of liver transplant recipients who were 60 years of age and older (n = 23) versus recipients of primary transplants who were 18 to 59 years of age (n = 84). Indications in recipients over 60 included alcoholism (6), postnecrotic cirrhosis (6), cancer (4), primary biliary cirrhosis (3), sclerosing cholangitis (2), and one patient with polycystic liver disease. There were no important differences in the initial transplant hospitalization or the incidence of infection and rejection between the two groups. No patient in the over-60 population required retransplantation. Actuarial patient survival is 83% at 2 years for recipients 60 years of age and above compared to 76% patient survival in adult recipients who are under the age of 60. Liver transplant recipients over the age of 60 years have excellent patient and graft survival and the same postoperative morbidity as recipients who are under 60 years of age. Therefore, advanced age does not appear to be a contraindication to orthotopic liver transplantation.

Orthotopic liver transplantation in patients 60 years of age and older.

The survival benefit of transplanting hepatitis C (HCV)-positive donor kidneys into HCV-positive recipients remains uncertain. The purpose of this study was to assess the effect of HCV-status of the donor (D) kidney on the long-term outcomes in kidney transplant recipients (R). We evaluated 2169 consecutive recipients of deceased-donor kidney transplants performed between 1991 and 2007. The following HCV cohorts were identified: D-/R- (n = 1897), D-/R+ (n = 59), D+/R- (n = 118), and D+/R+ (n = 95). Patients were followed for a mean of 6.02 (standard deviation = 4.26) yr. In a mulitvariable Cox-proportional hazards model, D+/R+ cohort had significantly lower patient survival (adjusted-hazard ratio [HR] 2.1, 95% CI [1.4-2.9]) with respect to the reference D-/R- group, whereas mortality was not increased in D-/R+ group. The rate of graft loss was increased in both D+/R+ and D-/R+ but was comparable with each other (adjusted-HR 1.8, 95% CI [1.4-2.5]) vs. adjusted-HR 2.0, 95% CI [1.4-2.8], respectively). D-/R+ cohort experienced significantly higher rate of rejection (adjusted-HR 1.7, 95% CI [1.2-2.5]) and chronic allograft nephropathy (adjusted-HR 2.1, 95% CI [1.2-3.7]). Neither donor nor recipient HCV-status impacted the risk of recurrent or de novo GN. Transplanting HCV-positive kidneys as opposed to HCV-negative kidneys into HCV-positive recipients provided similar graft survival but compromised patient survival in the long term.

The impact of hepatitis C virus donor and recipient status on long‐term kidney transplant outcomes: University of Wisconsin experience

The effects of cyclosporine (CsA) on prostacyclin (PGI2) release by cultured human umbilical vein endothelial cells were investigated. PGI2 production was measured by radioimmunoassay of its stable metabolite 6-Keto-PGF1 alpha. CsA induced a time and concentration-dependent reduction in unstimulated (basal) and Ca++ ionophore (A23187)-stimulated release of PGI2. A 16-hr incubation with CsA reduced A23187 PGI2 release by 64% (P less than 0.05); CsA at concentrations of 1.0, 10.0, and 100.0 micrograms/ml reduced A23187 PGI2 release by 67%, 80%, and 90%, respectively (P less than 0.05). This suppression was reversed within 24 hr after withdrawal of CsA. Arachidonic acid-stimulated PGI2 release was also decreased in CsA-treated cells, indicating an inhibitory effect distal to phospholipase A2. 3H-deoxyglucose release, an indicator of cell injury, was not increased by CsA, thus excluding nonspecific cell damage as a mechanism of the observed suppressive effect. This inhibition of PGI2 release from endothelial cells by CsA may explain the increased renal vascular resistance and renal microvascular thrombosis seen on occasion with CsA administration.

Cyclosporine suppression of endothelial prostacyclin generation. A possible mechanism for nephrotoxicity.

Peripheral neuroepithelioma is a rare and controversial neoplasm that may occur at any age. Fifteen of the 38 previously reported cases have involved children from birth to 17 years of age. The authors observed the course of a 3-month-old girl who presented with an enlarging mass in the left arm and manifested hepatic metastases at the time of diagnosis. The urinary level of vanillylmandelic acid (VMA) was moderately elevated. The primary lesion was excised and metastatic foci showed response to a regimen of vincristine, cyclophosphamide, Adriamycin (doxorubicin), and cisplatin. However, tumor recurred in the brain and liver and the child died 14 months after diagnosis. At autopsy, there was no involvement of adrenal glands or sympathetic ganglia and the liver contained numerous involuted lesions as well as active metastases. It is suggested that this is a unique neoplasm, derived from neural crest but distinct from neuroblastoma, which can be characterized by peripheral origin, a histologic pattern of confluent pseudorosettes, and aggressive clinical behavior.

Peripheral neuroepithelioma in childhood

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Orthotopic liver transplantation in patients 60 years of age and older.

The impact of hepatitis C virus donor and recipient status on long‐term kidney transplant outcomes: University of Wisconsin experience

Cyclosporine suppression of endothelial prostacyclin generation. A possible mechanism for nephrotoxicity.

Peripheral neuroepithelioma in childhood