In vitro immunosuppressive properties of spergualins to murine T cell response.

Abstract

Deoxyspergualin has strong immunosuppressive activity in animals. However, it shows less in vitro immunosuppressive activity at the therapeutic concentration used for in vivo administration. Recently, we reported that there are sometechnical problems with in vitro experiments. In this report, the effects of spergualins were examined under in vitro conditions which excluded these problems, and compared with cyclosporine A (CYA). Spergualins have suppressive effects on mixed lymphocyte response (MLR)and cytotoxic T lymphocyte induction. Furthermore, interleukin-2 (IL-2) induced proliferation of concanavalin A blasts and CTLL-2were inhibited at low concentration. However, spergualins have little effect in the early stage of MLR or the mitogenresponse. These results suggest that spergualins act on the proliferation and differentiation of T cells which respond to growth factors, such as IL-2. Deoxyspergualin(DSG, NKT-01), an analog of spergualin15, has antitumor activity2) and immunosuppressive activity35. As reported previously, DSG acts to prolong allogeneic4~8) and xenogeneic graft9) survival in various experimental transplantation models and shows therapeutic effect on various autoimmune disease models10). Wehave been investigating the mode of action of DSGon immunosuppressive activity, but it shows little in vitro activity at the therapeutic concentration used for in vivo administration. Recently we reported that there are some technical problems with in vitro experiments, that is, stability of DSGin culture medium115 and oxidation by amine oxidase in fetal calf serum (FCS)12). In this report, the in vitro effect of spergualins was examined using a stable analogue, deoxymethylspergualin (MeDSG), and a culture mediumwhich has practically no amine oxidase activity. The immunosuppressive effect of spergualins on murine lymphocytes were demonstrated in vitro and the immunosuppressive properties were compared with cyclosporine A (CYA).

Effect of 15-Deoxyspergualin on Lupus Nephropathy in New Zealand Black/White F1 Mice

“…1). However, no decrease in in vitro IL-2 production was observed in the treated animals, in accordance with other reports [9][10][11]. In contrast, the IL-2 levels in animals treated with lower doses of DSP such as 0.6 and 1.5 mg/kg was significantly higher than the control level ( fig.…”

LF 15-0195 Inhibits the Development of Rat Central Nervous System Autoimmunity by Inducing Long-Lasting Tolerance in Autoreactive CD4 T Cells

“…Concerning the activation of autoreactive lymphocytes, the beneficial effect of LF 15-0195 may be due to a direct effect of this drug on T cell activation or to an indirect effect by interfering with APC functions. It has been shown that DSG inhibits the T cell proliferation induced by T cell mitogens or alloantigens (34,35) and the generation of secondary CTLs (36). Furthermore, DSG inhibits Agspecific T cell proliferation at the level of the Ag-presenting monocytes by interfering with the capacity of these cells to process and present Ags (37).…”

Tacrolimus Pretreatment Attenuates Preexisting Xenospecific Immunity and Abrogates Hyperacute Rejection in a Presensitized Hamster to Rat Liver Transplant Model1

“…The ability of an immunosuppressant to prevent donor species presensitization and coincidentally induce short-term species specific tolerance was first described with deoxyspergualin (9) and ascribed at the time to a direct B cell inhibition. However, it is now recognized that the manifold actions of DSG include potent T-cell suppression (38,39).…”