Immunosuppressive Doses Of Cyclosporine Research Articles

Anti-Rejection Drug Treatment Increases Basal Cell Carcinoma Burden in Ptch1+/- Mice

The development of extensive and severe non-melanoma skin cancer is an extremely common complication of organ transplantation and is assumed to be caused by long-term treatment with anti-rejection drugs (ARD). Despite this florid clinical problem, ARD treatments have been reported to affect experimental murine skin carcinogenesis only weakly. We report here that treatment of cesium-137-irradiated Ptch1+/- mice with immunosuppressive doses of cyclosporine A plus prednisolone for 4-1/2 mo increased basal cell carcinoma burden by 2.5-fold. Thus, these mice provide a good model for study of the effects of long-term administration of ARD on at least one type of non-melanoma skin cancer.

Cyclosporine-induced folliculodystrophy

We describe a 34-year-old kidney transplant patient who developed a distinct cutaneous side-effect to cyclosporine manifested as an infiltrated appearance to the skin with abundant flesh-colored, follicular papules predominantly affecting the ears, nose, and surrounding areas of the face, but also the trunk and extremities. The clinical and histologic findings in this case closely match those presented in 2 previous case reports, in which immunosuppressive doses of cyclosporine appeared to be causative. We present a detailed report of the clinical and histologic findings that are unique to these 3 cases and we introduce a theory, based on the recent in vitro studies involving cyclosporine, to help explain the pathogenic events induced by cyclosporine in these patients. We propose the term “cyclosporine induced folliculodystrophy” or CIF as an appropriate name for this distinct clinicohistopathologic entity. Finally, we set forth 3 clinical and 4 histopathologic criteria upon which the diagnosis of CIF can be made.

Effect of immunosuppressive doses of cyclosporine on pancreatic beta cell function in pigs.

To evaluate whether immunosuppressive doses of cyclosporine (CsA) have an adverse effect on the liver, kidney, and pancreatic beta cells of pigs. 8 juvenile 8-week-old Landrace X Large White crossbred pigs. CsA (100 to 140 mg/kg) was administered orally to euglycemic pigs to reach whole blood trough concentrations of approximately 1500 ng/mL. To determine pancreatic beta cell function, plasma C-peptide and insulin concentrations were measured in response to i.v. administration of glucose, glucagon, arginine, and oral administration of glucose. Effects on liver and kidney were determined by monitoring serum measurements of liver function and serum creatinine concentrations, respectively. Plasma concentrations of C-peptide were significantly lower in euglycemic CsA-treated pigs, compared with control pigs, following i.v. administration of glucose, glucagon, arginine, and oral administration of glucose. Furthermore, the glucose clearance rate was decreased in euglycemic CsA-treated pigs, compared with control pigs. Serum creatinine concentrations and 4 of 7 serum measurements of liver function were not adversely affected by CsA administration. Serum concentrations of bilirubin and albumin were significantly increased, and serum alanine aminotransferase activity was significantly decreased in CsA-treated pigs, compared with control pigs. Histologic evaluation of liver and kidney sections revealed no pathologic findings in CsA-treated or control pigs. In our study, immunosuppressive doses of CsA caused an impairment of porcine pancreatic beta cell function, but did not have toxic effects on the kidney. However, on the basis of changes in serum bilirubin and albumin concentrations and alanine aminotransferase activity, subclinical toxic effects on the liver did occur when immunosuppressive doses of CsA were administered.

Anthropometric Parameters and the Igf-I-Igfbp3 Aiis Pre and Post Heart Transplantation. 34

Since May 1990, in the Italian Hospital 30 transplantation procedures (TX)[28 orthotopic heart transplantations (HTX) & 2 lungs and heart transplantations (HLTX)] have been performed in 28 children with a 65% overall survival at 6 years. Anthropometric parameters & the IGF-I-IGFBP3 axis were evaluated in 29 patients (19 females), 16 in a waiting list for HTX(n=6) or HLTX (n=10), ages ranging from 1.9 to 20.7 years (median 7.4) (10 Tanner I) & 13 transplanted patients, HTX (n=11), LHTX (n=2), ages ranging from 2.4 to 16.6 years (median 11) (B Tanner I), treated with immunosuppressive doses of cyclosporine, azathioprine & aethylprednisone. Pre & post TX sean weight/height ratio (W/H) was -9.1±10.7 vs-5.9±8.8% (p=NS), body mass index (BMI) 15.9±2.5 vs 16.4±2.4 kg/s2 (p=NS), SDS of height -0.84±1.1 vs-0.51±0.9DS (p=NS). The SDS of height was significantly below normal in the preTX group only (p<0.05,Wilcoxon test). We found:Table: [Illegible Text] p<0.001 pre vs post TX(Mann-Whitney test); [Illegible Text] p<0.05 vs normal (Wilcoxon test). There was correlation between: IGF-1 & IGFBP3 preTX r=0.80, posTX r=0.80; years post TX & IGFBP3 r=0.74; IGFBP3 & both W/H & BMI r=0.55 y 0.53 only in the preTX group (Spearman rank correlation). Conclusions: Patients in the preTX group presented low mean height SDS with normal mean values of IGFBP3, IGF-I & IGF-I/IGFBP3 molar ratio. PosTX we found an improvement in height & an increase of 0.9 SD in IGF-I mean value and of 1.85 SD in IGFBP3 mean value with preservation of molar ratio. The significantly elevated IGFBP3 mean level (compared to normal and preTX values) could be related to favorable changes in the somatotrophic axis and/or to the concomitant immunosuppressive therapy.

Absence of Acute Nephrotoxicity with Low Doses of Cyclosporin: Experimental Study in the Rat

No study has, to our knowledge, evaluated the acute effects of low immunosuppressive doses of cyclosporin (CsA) on renal function. To establish whether a relationship exists between the dosage of CsA and the onset of nephrotoxicity, 28 rats were studied by renal clearances before (control) and after i.v. administration of different doses of CsA: 3 mg/kg b.w. (group 1); 7 mg/kg b.w. (group 2); 11 mg/kg b.w. (group 3); 15 mg/kg b.w. (group 4). No change in renal function was observed between control and the post-CsA period in groups 1 and 2. GFR (inulin clearance) was decreased vs the control period in group 3 and group 4 (-22% and -37%, respectively, P less than 0.001); the difference between these two groups was statistically significant (P less than 0.01). Effective renal plasma flow (PAH clearance) was similarly decreased in groups 3 and 4 vs their control periods (-21% and -28%, respectively, P less than 0.001) due to the increase of total renal vascular resistance (+41% and +42%, respectively, P less than 0.001). Filtration fraction was significantly decreased by CsA in group 4 (P less than 0.01 vs the control period). PAH renal extraction, urinary volume, and sodium and potassium excretion were similar in all groups before and after CsA. PRA and ADH were significantly increased only in group 4 (P less than 0.01) vs the baseline values. A high and significant relationship was detected between CsA dosage and the decrease of GFR (r = 0.81, P less than 0.001) and RPF (r = 0.612, P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of host defenses on the hepatic colonization of B16F10 melanoma cells.

To investigate the significance of host immunity in metastasis we have simultaneously evaluated metastatic development and the tumoricidal action of host defenses in an experimental system for liver metastasis which involves the intrasplenic injection of B16F10 melanoma cells in syngeneic mice. In addition, three experimental groups were treated with immunosuppressive doses of cyclosporin A (CsA) during the following periods of the malignant process: 1st-5th days, 1st-12th days and 7th-12th days. Analysis of cytolytic effects of macrophages, NK cells and T-lymphocytes on tumor cells reveals a decay in antitumor immunity from the 7th day to the 12th day and a marked resistance of B16F10 melanoma cells derived from hepatic metastases to T-lymphocytes and NK cells. The 1st-5th day CsA treatment of tumor-bearing mice produced a reduction in both T-lymphocyte and macrophage reactions against tumor cells and a significant increase in the 7th day micrometastasis incidence in the liver. Once micrometastases have been established the CsA-treatment suppression on the 5th day allows the tumor growth rate in these mice to become the same as in controls. However, the 7th-12th day CsA treatment produces a clear inhibitory effect on focal metastatic development which may correspond to the in vitro antiproliferative effect of CsA, detected on cultured B16F10 melanoma cells.

Effects of cyclosporine on the immune system of the mouse. II. Cyclosporine inhibits the effector function of primary T helper cells, but not helper cell priming.

This paper describes various effects of cyclosporine on T helper (TH) cells for antibody production in the mouse. Immunosuppressive doses of cyclosporine abolish the help provided by virgin (primary) TH cells, but allow the priming of normal (and under certain conditions supranormal) numbers of TH cells as assayed by adoptive transfer experiments. The helper function of primed (secondary) TH cells is normally resistant to cyclosporine. However, if T cells are exposed to cyclosporine during priming their helper function remains totally cyclosporine-sensitive as long as the drug therapy is continued. The mechanisms involved in these selective effects are unknown, but the results indicate that in vivo cyclosporine can dissociate effector function (primary help) from TH cell proliferation (priming).