Differential effects of gallium nitrate on t lymphocyte and endothelial cell activation

Emina H. Huang, Dawn M. Gabler, Mary E. Krecic, Nicholas Gerber, Ronald M. Ferguson, Charles G. Orosz

Research output: Contribution to journalArticlepeer-review

Abstract

The immunosuppressive agents used clinically to prevent allograft rejection 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 inñuence of GN on gonadal vein endothelial cell (GVEC) and T cell activation. GVEC were stimulated with IFNγ or TNFα 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 adhesion molecule-1 expression. GN did not interfere with the baseline or cytokine-enhanced expression of these molecules. Rather, it increased the expression of intercellular adhesion molecule-1 on GVEC, and this effect was further augmented in the presence of IFNγ. In contrast, GN inhibited T cell proliferation stimulated by allogeneic GVEC or allogeneic monocytes in a dose-depend-ent 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 IFNγ. This suggests that GN can interfere indirectly with inflammatory responses of endothelial cells by interfering with local T cell activation and lymphokine production. Once lymphokines are produced, GN does not interfere with their effects on endothelial cells. GN is thought to act through transferrin receptors, but GVEC, unlike T cells, do not increase their expression of transferrin receptors, after stimulation with cytokines. This may explain their relative lack of sensitivity to GN. In general, GN appears to stimulate endothelial cells but suppress T cells. This paradoxic effect suggests that therapy with GN may enhance T cell-independent inflammatory responses, such as cellular infiltration and repair of tissue damage, while suppressing T cell-dependent responses, such as T cell-mediated tissue destruction and allograft rejection.

Original languageEnglish (US)
Pages (from-to)1216-1222
Number of pages7
JournalTransplantation
Volume58
Issue number12
DOIs
StatePublished - Dec 15 1994
Externally publishedYes

ASJC Scopus subject areas

  • Transplantation

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