1979). We havc proposed thc modcl of T-ccll activation dcpictcd in Fig. l (Wagner et al .. l 980c). ..... These findings suggest that thc Jack of IL-1 in the preceding ...
Cyclosporin A Proceedings of an International Conference on Cyclosporin A Cambridge. September 1981
Editor
D. J. G. WHITE Cambnäge
1982
ELSEVIER BIOMEDICAL PRESS AMSTERDAM ·NEW YORK · OXFORD
CHAPTER 22
Studies on the rnechanisrn of action of Cyc1osporin A in the murine and human
T-cell response in vitro DONALD BUNJES. CONNY HAROT. WERNER SOLBACH. KAI DELISCH.
MARTIN RÖLLINGHOFF and HERMANN WAGNER /nsrirur für :\leJi':inischc .\.fikrnh ioloric drr Johannes Cutenher~·Universirär. Obere Zahlhacher Srrassc 6 7. D-6500 .11.fain:, FR.G.
CHAPTER 22
Studies on the rnechanism of action of Cyclosporin A in the murine and human T-cell response in vitro DONALD BUNJES. CONNY HARDT. WERNER SOLBACH. KAI DELISCH. MARTIN RÖLLINGHOFF and HERMANN WAGNER Institut .(ur Medi=inischc Mikrohiolo1:ie der Johannes GutenherJ:-Universität, Obere Zahihacher S1rassc 6 7. D-6500 Main=. f : R.C.
1. In troduc tion Although the potency of Cyclosporin A (CyA) as an immunosuppressive agent has been amply documented both in experimental and in clinical studies the mechanism of action of the drug has not been clearly defined (Bore! et al., 1977; Borel. 1981; Calne et al., 1981 ). There is agreement that Cy A inhibits an early stage of T-cell activation and that B cells are hardly affected at all (White et al., 1979; Wiesinger and Bore!. 1979). In addition recent studies have suggestcd a selective inhibiting effect on Thelper cells (Hess and Tutschka, 1980: Leapman et al.. 1981: Wiesinger and Bore!. 1979). We havc proposed thc modcl of T-ccll activation dcpictcd in Fig. l (Wagner et al .. l 980c). The essential features of this model are as follows: the activation of both the helper cell ancJ thc CTL-P requircs two signals. Antigen as signal J renders thc appropriate T cell clones susceptible to the mitoge.nic action of signal 2 which in the case ofthe T-helper ccll is the macrophage product lnterleuk.in 1 (IL-1) andin the case of the CTL-P the T-helper cell product Interleukin 2 (IL-2). In addition. circumstantial evidence suggests that the release of. IL-1 from macrophages is controlled by a T cell which we have termed the T-inducer cell. To our knowledge only Larsson, Palacios et al. and we ourselves have so far attempted to analyse the effects of CyA in terms of this model (Bunjes et al.. 1981; Larsson. 1980; Palacios, 1981 ). Larsson and Palacios concluded that Cy A renders cells resistant to the effects of the interleukins by preventing the functional expression of the
Abbreviations: Con A. Concanavalin A: PHA, phytohaemaggJutinin A; LPS, lipopolysaccharidc (E. coli strain 028 : B 11); PM A. Phorbolc rnyristic acctatc: TNP, trinitrophcnol: DMSO. dimcthylsulphoxidc: CyA, Cyclosporin A: FCS. fetal ca!f scrum; crMM, alpha-mcthylmannosidt.: : PBMNC, pcritoncal blood mononudcar cclls: C'TL-P, cytotoxic T lymphocytc prccursor(s): CTL, cytotoxic T lymphocytc(s) : AMLR. autologous miwd lymphocyte rcaction: MLR. mixed lymphocytc rcaction : JL-1, lnkrlcukin l: IL-2, lntcrlcukin 2.
