DIFFERENTIAL-EFFECTS OF GALLIUM NITRATE ON T-LYMPHOCYTE AND ENDOTHELIAL-CELL ACTIVATION

The immunosuppressive agents used clinically to prevent allograft reje ction exert their effects by interfering with antigen-dependent T cell activation, endothelial cell function, or both. Gallium nitrate (GN) is immunosuppressive both in vitro and in vivo, and has potential for clinical use in transplant recipients. Therefore, we analyzed the infl uence of GN on gonadal vein endothelial cell (GVEC) and T cell activat ion. GVEC were stimulated with IFN gamma or TNF alpha in the presence or absence of GN, and tested for changes in levels of MHC class I, MHC class II, vascular cell adhesion molecule-1, and intercellular adhesi on molecule-1 expression. GN did not interfere with the baseline or cy tokine enhanced expression of these molecules. Rather, it increased th e expression of intercellular adhesion molecule-1 on GVEC, and this ef fect was further augmented in the presence of IFN gamma. In contrast, GN inhibited T cell proliferation stimulated by allogeneic GVEC or all ogeneic monocytes in a dose-dependent manner. In transwell experiments , GN blocked the induction of MHC class II expression on isolated GVEC caused by alloactivated T cells, but not by recombinant IFN gamma. Th is suggests that GN can interfere indirectly with inflammatory respons es of endothelial cells by interfering with local T cell activation an d lymphokine production. Once lymphokines are produced, GN does not in terfere with their effects on endothelial cells. GN is thought to act through transferrin receptors, but GVEC, unlike T cells, do not increa se their expression of transferrin receptors, after stimulation with c ytokines. This may explain their relative lack of sensitivity to GN. I n general, GN appears to stimulate endothelial cells but suppress T ce lls. This paradoxic effect suggests that therapy with GN may enhance T cell-independent inflammatory responses, such as cellular infiltratio n and repair of tissue damage, while suppressing T cell dependent resp onses, such as T cell-mediated tissue destruction and allograft reject ion.