Abudher, Munir N.; (1999) Effect of peripheral blood lymphocyte activation on cyclosporine A mediated inhibition of IL-2 production. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Cyclosporine A (CsA) is a potent immunosuppressive drug and to make it efficient, effective concentration of CsA is necessary to produce adequate immunosuppression and minimum side effects. In this study, we have tested the hypothesis that "activated T lymphocytes are less sensitive to CsA". We have compared the inhibitory effect of CsA on IL-2 production of activated human peripheral blood lymphocytes (PBLs) and naive PBLs, as well as before and after haemodialysis. Results: in vitro PHA preactivation of T cells shifted the inhibitory dose response curves to the right and significantly increased the IC50 (concentration causing 50% inhibition of IL-2 production) of CsA, (p < 0.05). In 10 normal subjects the IC50 increased from 50 to 380 ng/ml, in 10 chronic ambulatory peritoneal dialysis (CAPD) patients from 20.5 to 95.5 ng/ml, and in 12 chronic haemodialysis patients from 56 to 283 ng/ml before haemodialysis and from 99 to 721 ng/ml post- haemodialysis. CAPD did not affect the CsA sensitivity of PBLs by comparison with normal volunteers, (CsA IC50 was 20.5 ng/ml vs 50 ng/ml, p > 0.05). In contrast the IC50 was significantly higher after haemodialysis, (99 ng/ml vs 50 ng/ml, p < 0.05). Using CTLL-2 cells as detector of IL-2, the post-haemodialysis IC50 was significantly higher than the pre-haemodialysis IC50, (99 ng/ml vs 56 ng/ml, p < 0.05). Even after in vitro PHA prestimulation of PBLs, the IC50 was much higher post- than pre haemodialysis (721 ng/ml vs 283 ng/ml, p < 0.05). Flow cytometry analysis of intracellular IL-2 showed that CsA reduction of the frequency of IL-2 producing human T cells was significantly less post- than pre-haemodialysis at 100 ng/ml CsA, (36.6% and 48.5% respectively, p < 0.05). Similarly, CsA inhibition of intracellular IL-2 production in T cells was much less post- than pre-haemodialysis at 100 ng/ml CsA, (37.6% and 54.3% respectively, p < 0.05). Measurement of IL-2 concentration in cell culture supernatants by ELISA also showed less CsA inhibition of IL-2 production at 100 ng/ml after haemodialysis by comparison with predialysis, (64.6% and 77.8% respectively, p< 0.05).

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