MODULATION OF IN-VITRO AND IN-VIVO T-CELL RESPONSES BY TRANSFERRIN-GALLIUM AND GALLIUM NITRATE

Gallium is a group IIIa metal that has efficacy in the therapy of mali gnant disorders such as lymphoma and urothelial tract tumors. Preclini cal studies also indicate a role for gallium in autoimmune disorders, suggesting that gallium is able to modulate T-cell immune reactivity, The purpose of this study was to examine the in vitro and in vivo immu no-modulatory action ef gallium on T-cell function. Since gallium bind s to transferrin in vivo, in vitro studies evaluated the effect of tra nsferrin-gallium (Tf-Ga) on human T cells. Tf-Ga inhibited the mitogen -induced proliferative response of peripheral blood mononuclear cells (PBMC) in a dose-dependent fashion. Alloantigen-induced proliferation was also potently suppressed when evaluated in a mixed lymphocyte cult ure assay. Tf-Ga affected a significant reduction in the density of IL -2 receptors on activated T cells and a slight reduction in the number of CD3(+)/CD25(+) T cells in PHA-stimulated cultures, Neither secreti on of interleukin-2 (IL-2) nor the induction of IL-2-stimulated lympho kine-activated killer activity, however, was inhibited by if-Ga, Tf-Ga produced significant upregulation of the transferrin receptor (CD71) in T cells as determined by flow cytometric analysis and northern blot assay, but did not affect the percentage of CD3(+)/CD71(+) T cells af ter mitogen stimulation, To assess the in vivo effects of gallium on a lloreactive T cells, we evaluated the immunosuppressive effect of gall ium in a murine model of graft-versus-host disease (GVHD). Administrat ion of gallium significantly prolonged survival in mice undergoing sev ere GVHD, suggesting that gallium can ameliorate GVH reactivity, Colle ctively, these data demonstrate that, at clinically achievable concent rations, if-Ga potently inhibits T-cell activation and that this immun osuppressive property of gallium may be of adjunctive therapeutic valu e in the management of disorders characterized by the presence of auto reactive or alloreactive T-cell populations. (C) 1996 by The American Society of Hematology.