Research Articles
Pharmacodynamic Interaction of Recombinant Human Interleukin-10 and Prednisolone Using in vitro Whole Blood Lymphocyte Proliferation

https://doi.org/10.1002/jps.3000Get rights and content

Abstract

Prednisolone, a commonly used synthetic corticosteroid, and IL-10, a cytokine under investigation for strong antiinflammatory properties, are being contemplated as a potential joint therapeutic regimen in immune disorders. Their pharmacodynamic interactions were examined in blood from healthy adult male and female volunteers using an in vitro phytohemagglutinin (PHA)-stimulated whole—blood lymphocyte proliferation technique. Isobolograms along with parametric competitive and noncompetitive interaction models were used to determine the nature and intensity of interactions. Single drug effects show prednisolone more efficacious in inhibiting lymphocyte proliferation with an IC50 of 3.3 ng/mL and Imax value of 1, signifying complete suppression. Analogous parameters for IL-10 were 16.2 ng/mL for IC50 and 0.89 for Imax. There were no significant differences in the single drug immunosuppressive effects among genders. Their joint effects showed additive interaction based on isobolographic analysis. Parametric analysis using the competitive interaction model described their interaction as slightly synergistic, while the noncompetitive interaction modeling indicate a small degree of antagonism. Also, the joint effects in females tend to be more antagonistic than males. Concomitant use of prednisolone and IL-10 should thus reflect the net additive responses to concentrations of each agent. © 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:1334–1342, 2002

Section snippets

INTRODUCTION

Current strategy for immunosuppressive therapy involves use of combination regimens of therapeutic agents.1,2 Such combinations offer possible advantages of synergistic/additive effectiveness as well as reduction of drug-specific side effects due to reduced individual doses. Corticosteroids have been an established part of immunosuppressant drug therapy. Synergistic interactions have been observed between double drug combinations of cyclosporine, prednisolone, and sirolimus,3 justifying their

Subjects

Healthy male (n = 4) and female (n = 4, not taking birth control pills) drug-free volunteers of ages between 25 and 40 years were recruited for study. Blood was drawn at 9 AM on the day of the experiment.

Reagents

Recombinant human interleukin-10 was obtained as gift from Schering-Plough Research Institute (Kenilworth, NJ). Pred and PHA were purchased from Sigma Chemical Co. (St. Louis, MO). Serial dilutions of the drugs were made in complete media [RPMI 1640 supplemented with 2 mM L-glutamine, 20 mM HEPES,

RESULTS

Single drug sigmoidal Imax inhibition curves for IL-10 and prednisolone are presented in Figure 1. Prednisolone was more efficacious (Imax = 1.00) than IL-10, which did not completely suppress lymphocyte proliferation (Imax = 0.89 ± 0.07). However, both drugs showed appreciable inhibitory activity on lymphocyte proliferation with mean IC50 values of 16.7 and 15.7 ng/mL (IL-10) and 4.43 and 2.16 ng/mL (prednisolone) for the male and female subjects. The single-drug as well as the interaction

DISCUSSION

No significant gender-related differences were observed in the single-dose effects of IL-10 and prednisolone, although there were reports of gender-related differences for other glucocorticoids.22 The lack of significant differences, also observed by Ferron et al.,3 may be ascribed to the small study size and the time of blood collection. For female subjects, the period of blood collection was limited to within 5 days following the end of their menstrual bleeding period when gonodal steroid

Acknowledgements

This work was supported by the National Institute of General Medical Sciences, NIH, grant number GM 24211.

REFERENCES (25)

  • K. Taga et al.

    IL-10 inhibits human T cell proliferation and IL-2 production

    J Immunol

    (1992)
  • S. Gillis et al.

    Glucocorticoid-induced inhibition of T cell growth factor production I. The effect on mitogen-induced lymphocyte proliferation

    J Immunol

    (1979)
  • Cited by (0)

    View full text