Pharmacodynamic assays of the immunosuppressive action of cyclosporine therapy in transplant recipients

Pharmacodynamics is the study of the effects of a drug on the body, in contradistinction to pharmacokinetics, which refers to the absorption, distribution, metabolism, and elimination of the agent. The pharmacodynamic effect of cyclosporine A (CsA) of greatest interest to transplant physicians is its therapeutic immunosuppressive action. Pharmacodynamic studies aim to establish in vivo, or preferably in vitro, parameters to estimate the efficacy of the therapeutic action of CsA. Ideally, pharmacodynamic assays would assess the content and avidity of critical tissue receptors mediating the immunosuppressive effects. Since these receptors have not yet been elucidated, present investigations must rely upon in vitro immunologic assays to assess the pharmacodynamics of the CsA effect. Since CsA inhibitis lymphokine production, the drug interferes with amplification of the immune response. Since there is neither protein stores nor constitutive synthesis of lymhokines, their production is exquisitely sensitive to inhibitors. In the studies presented herein, interleukin-2 (IL-2), which serves as an important signal to both T and B cell pathways, was used as a prototype to dissect the effect of CsA. In addition, effects of CsA were assessed on gamma-interferon (γ-IFN) production, which represent an important activation signal for macrophages to produce interleukin-1 (IL-1), the second signal accompanying the first signal antigen to stimulate T cell activation. The studies presented herein examined the in vitro generation of IL-2 and γ-IFN by lymphocytes from renal allograft recipients as a pharmacodynamics tool to assess the immunologic impact of in vivo therapy with CsA.